1. 疾病概述与流行病学特征
1.1 定义与临床表型
华氏巨球蛋白血症（Waldenström Macroglobulinemia, WM）是一种罕见的B细胞非霍奇金淋巴瘤，其核心特征为骨髓中淋巴浆细胞样淋巴瘤细胞的浸润，并伴有血清中单克隆免疫球蛋白M（IgM）的异常增高123。世界卫生组织（WHO）将其归类为淋巴浆细胞淋巴瘤（Lymphoplasmacytic Lymphoma, LPL）的一种临床病理学实体14。WM的诊断标准通常包括骨髓中克隆性淋巴浆细胞≥10%的浸润，以及血清中存在IgM单克隆蛋白23。
WM的临床表现具有多样性，主要由肿瘤细胞浸润和异常增高的IgM单克隆蛋白引起1。典型的临床症状和体征包括：
- 贫血：这是最常见的表现之一，85%的患者在诊断时即出现贫血，导致疲劳和乏力56。贫血通常是由于骨髓被淋巴浆细胞浸润所致7。
- 高黏滞血症：由高水平的IgM单克隆蛋白引起，可能导致一系列症状，如视力模糊或丧失、头晕、头痛、出血倾向和神经系统症状17。高达20%的WM患者可能出现高黏滞血症综合征1。
- 肝脾肿大和淋巴结病：部分患者可能出现肝脏、脾脏或淋巴结的肿大，但淋巴结病通常不常见1267。
- 神经病变：约22%的患者可能出现周围神经病变8，其中一些与IgM单克隆蛋白的自身抗体活性有关，例如抗髓鞘相关糖蛋白（MAG）抗体介导的神经病变910。
- 冷球蛋白血症：部分患者可能出现冷球蛋白血症，表现为对寒冷的敏感，导致雷诺现象、紫癜、关节痛和神经病变等811。
- 其他异质性表现：还可能包括Bing-Neel综合征（中枢神经系统受累）1、淀粉样变性、慢性冷凝集素病和Schnitzler综合征等IgM相关疾病1112。这些并发症的出现可能与IgM单克隆蛋白的特定生物学特性及其与机体组织相互作用有关1112。WM患者的临床病程变异较大，有些患者可能长期无症状，而另一些则可能出现严重的并发症并需要立即治疗23。
1.2 流行病学分布
华氏巨球蛋白血症（WM）是一种罕见的恶性肿瘤，其全球发病率较低。WM是一种罕见的非霍奇金淋巴瘤亚型，其特征是骨髓中存在淋巴浆细胞淋巴瘤（LPL）并伴有血清中的单克隆免疫球蛋白M（IgM）13。由于其罕见性，WM在许多国家被归类为罕见病，这使得对其流行病学特征的系统研究相对较少，但在过去的二十年里，随着国际华氏巨球蛋白研讨会（IWWM）的推动，相关研究已显著增加 13。
发病率：
WM的发病率因地理区域和种族而异。亚洲地区的发病率通常低于西方国家。例如，根据日本血液学会2016年的登记数据，WM和LPL病例在日本占17,957例成熟淋巴样恶性肿瘤的1.97%，年发病率为每百万人中2.8例 14。尽管存在地区差异，但总体而言，WM是一种全球范围内发病率较低的疾病。
好发人群与年龄：
WM主要影响老年人，患者通常伴有MYD88 L265P突变，该突变在90%以上的病例中可见 15。随着全球人口老龄化的加剧，预计WM的诊断数量可能会有所增加。在诊断时，绝大多数患者的年龄超过50岁，这表明年龄是WM发病的一个重要风险因素。
性别差异：
关于WM的性别差异，男性发病率略高于女性。尽管某些疾病如冠心病在女性绝经后发病率显著增加，且心血管疾病的流行病学存在性别差异 1617，但WM的性别差异不如其他恶性肿瘤或慢性疾病显著。这种轻微的男性倾向在多种恶性血液肿瘤中均有观察到。
疾病负担与研究趋势：
WM作为一种不可治愈的疾病，患者的中位预期寿命为10至12年 15。这意味着即使发病率不高，其所带来的疾病负担对个体和医疗系统而言仍然是显著的。在过去的几十年中，WM领域的研究取得了显著进展，特别是在分子病理机制的理解（如MYD88 L265P突变）以及新型靶向治疗的开发方面。这些研究不仅提升了诊断的精准性，也为患者带来了更多有效的治疗选择，改善了预后和生活质量。未来研究将继续聚焦于更深入地理解疾病生物学、开发更个体化的治疗策略以及更好地管理疾病相关并发症。
2. 分子病理机制与关键驱动因素
2.1 核心基因突变与信号通路
华氏巨球蛋白血症（WM）的分子发病机制研究已取得显著进展，其中最重要的发现是MYD88和CXCR4基因的体细胞突变，它们是WM肿瘤细胞增殖和存活的关键驱动因素。这些突变通过激活特定的信号通路，促进WM细胞的异常生长并影响治疗反应。
2.1.1 MYD88 L265P突变
MYD88（髓样分化原代反应基因88）是Toll样受体（TLRs）和白细胞介素-1受体（IL-1Rs）信号通路中的一个关键接头蛋白，在先天免疫反应和炎症中发挥核心作用18。在WM患者中，MYD88基因的L265P点突变发生率极高，超过90%的患者携带此突变25151920。这种突变是WM的标志性遗传改变，也是IgM型意义未明单克隆丙种球蛋白病（IgM MGUS）向WM进展的重要分子事件之一。
MYD88 L265P突变是一个功能获得性突变，它通过促进Myddosome（由MYD88、IRAK4和IRAK1组成的信号复合体）的形成，导致组成型激活21。MYD88 L265P突变激活的下游信号通路主要包括：
- BTK（布鲁顿酪氨酸激酶）通路：MYD88 L265P通过激活BTK，进而驱动WM细胞的生存和增殖。BTK是B细胞受体信号通路中的关键组分，其持续激活促进了WM细胞的生长19。BTK抑制剂如伊布替尼（Ibrutinib）在治疗MYD88突变型WM患者中显示出显著疗效，尤其是在CXCR4野生型患者中5。
- NF-κB（核因子-κB）通路：MYD88 L265P突变是NF-κB信号通路持续激活的主要原因之一20222324。NF-κB是一个转录因子家族，在细胞增殖、凋亡抑制和炎症反应中发挥关键作用。组成型激活的NF-κB信号促进WM细胞的存活和抵抗凋亡。研究表明，靶向NF-κB通路的药物，如蛋白酶体抑制剂，在WM治疗中具有活性22。
- JAK-STAT通路：MYD88 L265P突变也被认为能增强JAK-STAT信号通路，该通路在细胞增殖和分化中也扮演重要角色20。
- PI3K/Akt/mTOR通路：有证据表明，MYD88 L265P突变可能通过影响PI3K/Akt/mTOR信号通路促进WM细胞生长和存活，并影响药物抵抗212225。
2.1.2 CXCR4突变
C-X-C趋化因子受体4（CXCR4）在造血干细胞和克隆性B细胞的细胞迁移中起关键作用。在WM患者中，约30%-40%的患者检测到CXCR4基因的突变，其中最常见的是C1013G/CXCR4突变192627。CXCR4突变通常与MYD88 L265P突变共存。
CXCR4突变的功能和影响包括：
- 肿瘤进展和播散：C1013G/CXCR4突变被认为是WM肿瘤进展的驱动突变，并与肿瘤细胞向髓外器官的播散相关，导致疾病进展和预后较差26。
- 药物抵抗：CXCR4突变型WM细胞对多种药物表现出抵抗，包括BTK抑制剂、哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂和磷脂酰肌醇3-激酶（PI3K）抑制剂，但对蛋白酶体抑制剂（如硼替佐米）不表现抵抗26。这表明CXCR4突变通过特定机制影响药物敏感性，提示在CXCR4突变型WM患者中可能需要调整治疗策略。
- 信号通路调控：CXCR4突变通过影响趋化因子CXCL12（也称为SDF-1α）与其受体CXCR4的结合及下游信号传导，促进WM细胞的生长、迁移和存活。
2.1.3 其他基因突变
除了MYD88和CXCR4，WM中还发现其他一些基因突变，尽管发生率较低，但它们也可能在WM的发生发展中发挥作用。例如，大约17%的患者存在ARID1A突变，8%-15%的患者存在CDKN2D突变19。此外，染色体6q缺失在MYD88突变型患者中较为常见，该区域包含调节NFKB、BCL2、BTK和凋亡的基因19。这些基因的突变和染色体异常共同构成了WM复杂的基因组图谱，影响疾病的生物学特性和对治疗的反应。
总而言之，MYD88 L265P和CXCR4突变是WM病理机制的核心驱动因素，它们通过激活BTK、NF-κB等关键信号通路，促进肿瘤细胞的增殖和存活。对这些突变及其下游通路的深入理解，为WM的精准诊断和靶向治疗策略的开发提供了重要的理论基础。
2.2 肿瘤微环境与免疫调控
华氏巨球蛋白血症（WM）肿瘤细胞的增殖和存活不仅受其内在基因突变（如MYD88和CXCR4）的驱动，还受到其所处骨髓微环境（Bone Marrow Microenvironment, BMME）的显著影响。BMME为WM细胞提供了必要的生长支持、信号传导和免疫逃逸机制，使其能够抵抗治疗并持续进展。
2.2.1 骨髓微环境对WM细胞的支持作用
骨髓微环境是一个复杂的生态系统，包含多种细胞类型（如基质细胞、内皮细胞、免疫细胞）和非细胞组分（如细胞外基质、细胞因子）。这些组分共同促进WM细胞的生长和存活 2829。
- 基质细胞和内皮细胞：骨髓基质细胞（BMSCs）通过直接接触和分泌可溶性因子（如细胞因子和趋化因子）为WM细胞提供支持。例如，WM细胞与BMSCs的黏附可以促进WM细胞的增殖和抵抗凋亡 30。此外，缺氧环境也被证明能够促进WM细胞的播散和在新的骨髓生态位中定植，这部分是通过减少WM细胞与骨髓基质之间的黏附来实现的 31。
- 细胞因子与趋化因子：BMME中的多种细胞因子和趋化因子在WM细胞的生长、迁移和存活中发挥关键作用。例如，基质细胞衍生的生长因子1（SDF-1/CXCL12）与其受体CXCR4的相互作用，是WM细胞归巢到骨髓和在骨髓中存活的重要机制 31。肿瘤坏死因子-α (TNF-α) 和粒细胞集落刺激因子 (G-CSF) 等炎症因子能促进髓源性抑制性细胞 (MDSCs) 的扩增，进一步加剧免疫抑制 32。此外，可溶性核因子κB受体激活剂配体（sRANKL）和CC趋化因子配体3（CCL-3）也被发现与WM患者的生存期相关，表明这些因子在疾病生物学和WM细胞与基质细胞相互作用中的重要性 33。
- 免疫细胞：BMME中的免疫细胞（如调节性T细胞、髓源性抑制性细胞）在WM的免疫逃逸中扮演重要角色。
2.2.2 免疫调控与免疫逃逸机制
WM肿瘤微环境表现出明显的免疫抑制特征，这有助于WM细胞逃避免疫监视并持续增殖：
- 调节性T细胞（Tregs）：WM患者的BMME中Treg细胞数量增加，这些Treg细胞表现出独特的WM特异性mRNA特征，并富集了与NF-κB、MAPK和PI3K/AKT信号通路相关的基因。WM细胞，特别是CXCR4C1013G突变的WM细胞，能够显著诱导Treg细胞的增殖和扩张，形成一种Treg介导的免疫抑制微环境 25。
- 髓源性抑制性细胞（MDSCs）：WM患者骨髓中的MDSCs，特别是多形核MDSCs（PMN-MDSCs），显著增加。这些PMN-MDSCs表现出免疫抑制基因特征，并能有效抑制T细胞功能。WM恶性B细胞能够主动招募PMN-MDSCs，并通过释放G-CSF/TNF-α促进其扩增，从而加剧骨髓微环境的免疫抑制 32。
- 免疫检查点分子：WM的BMME中存在多种免疫检查点分子（如PD-1/PD-L1&PD-L2, TIGIT/PVR, CTLA-4等）的表达，这些分子调节着先天性和适应性免疫细胞的功能，导致WM细胞的免疫逃逸 34。针对这些检查点的靶向治疗可能为WM提供新的治疗途径。
- CD40/CD40L轴：CD40/CD40L轴在B细胞和T细胞的相互作用中至关重要。研究发现，在WM细胞与Treg细胞的相互作用中，CD40/CD40L轴是潜在的关键机制。阻断CD40L/CD40轴可以抑制WM细胞的生长，逆转Treg介导的免疫抑制表型 25。
- 肿瘤细胞异质性与免疫抑制：单细胞RNA测序（scRNA-seq）研究揭示了WM恶性细胞的异质性，并发现了共表达T细胞标记基因的新亚群（CD19+CD3+和CD138+CD3+），其中CD19+CD3+恶性细胞可能作为潜在的WM前体细胞。同时，WM中存在前耗竭的CD8+T细胞和NK细胞的功能缺失，提示CD47可能是逆转免疫细胞功能障碍的潜在治疗靶点 35。
2.2.3 表观遗传修饰的潜在干预价值
表观遗传修饰在基因表达调控和WM发病机制中发挥作用，为WM治疗提供了新的靶点：
- BET抑制剂：溴结构域和末端外域蛋白（BET）抑制剂已被证明能够有效抑制WM细胞的生长。研究显示，BET抑制剂（如JQ1和I-BET-762）与BCL2抑制剂（如维奈克拉）或组蛋白去乙酰化酶（HDAC）抑制剂（如Panobinostat）联合使用时，能产生显著的协同效应，进一步增强对WM细胞的杀伤作用 36。这提示BET抑制剂可能成为WM治疗的重要组成部分，尤其是在联合治疗中。
- 其他表观遗传靶点：除了BET蛋白，组蛋白去乙酰化酶（HDACs）、DNA甲基转移酶（DNMTs）等表观遗传调节因子也可能在WM的发生发展中发挥作用。靶向这些表观遗传机制的药物有望克服WM细胞的耐药性并提高治疗效果。
综上所述，骨髓微环境通过多种机制支持WM细胞的生长和免疫逃逸，包括基质细胞的直接支持、细胞因子和趋化因子的作用、Treg和MDSCs介导的免疫抑制以及免疫检查点分子的参与。同时，表观遗传修饰也为WM的治疗提供了新的干预靶点。深入理解这些机制将有助于开发更有效的靶向治疗和联合治疗策略，改善WM患者的预后。
3. 诊断标准与鉴别诊断
3.1 诊断体系与实验室检测
华氏巨球蛋白血症（WM）的诊断是一个综合性的过程，需要结合临床表现、实验室检测结果以及骨髓活检病理学分析。国际华氏巨球蛋白血症研讨会（IWWM）发布了一系列共识，指导WM的诊断和治疗。最新IWWM-11共识重申并更新了诊断标准，尤其强调了分子标志物在诊断和风险分层中的重要性 37。
3.1.1 诊断标准
WM的诊断主要依赖于以下两个核心标准：
- 骨髓淋巴浆细胞浸润：骨髓穿刺活检和组织学检查显示骨髓中存在≥10%的淋巴浆细胞样细胞（小淋巴细胞、浆细胞样细胞和浆细胞）浸润，这些细胞表现出克隆性增殖。
- IgM单克隆蛋白：血清免疫固定电泳检测到任何水平的IgM单克隆蛋白。
IWWM-11共识强调，不能随意设定IgM水平或骨髓浸润的任意阈值来区分WM和IgM型意义未明单克隆丙种球蛋白病（IgM MGUS），而应根据整体临床和病理学特征进行判断 37。这意味着，即使IgM水平较低或骨髓浸润未达到10%，如果临床表现高度提示WM，也应进行更深入的评估。
3.1.2 实验室检测
WM的实验室检测涵盖血常规、血生化、IgM定量、免疫固定电泳、骨髓形态学、免疫组化以及分子遗传学检测。
血常规与血生化：贫血是WM的常见表现，因此血常规中的血红蛋白水平降低是常见发现。肝肾功能、乳酸脱氢酶（LDH）等指标的异常可能提示器官受累或疾病活动。
IgM定量与免疫固定电泳：定量检测血清IgM水平，并结合免疫固定电泳确认单克隆IgM的存在，这是诊断WM的标志性特征。
骨髓活检与形态学：骨髓穿刺和活检是诊断WM的关键步骤。在WM中，骨髓通常被小淋巴细胞、浆细胞样细胞和浆细胞组成的淋巴浆细胞浸润，这些细胞呈现克隆性增殖。免疫组化染色可进一步确认淋巴浆细胞的表型，例如CD20、CD79a、CD138阳性等。
分子标志物检测：MYD88和CXCR4突变是WM中最常见的体细胞突变，对诊断、预后评估和治疗选择具有重要临床意义 38。IWWM-11共识建议，在开始治疗的患者以及基于临床问题进行骨髓采样时，应进行分子研究 39。
MYD88突变：MYD88 L265P突变在WM患者中的发生率高达90%-97% 38，是WM的诊断性分子标志物。MYD88 L265P突变可通过多种技术检测：
- 等位基因特异性PCR (AS-PCR)：AS-PCR具有较高的灵敏度，即使在低肿瘤负荷的样本中也能检测到MYD88突变 40。一项研究显示，AS-PCR在未分选样本中检测MYD88突变的灵敏度达到98.5% 40。
- 数字PCR (ddPCR)：ddPCR被认为是检测MYD88突变的高灵敏度方法，尤其适用于低肿瘤负荷或循环肿瘤DNA（ctDNA）的检测 4142。ddPCR的检测限可低至0.4%的变异等位基因频率（VAF）42。
- 下一代测序 (NGS)：NGS能够同时检测多个基因突变，提供更全面的基因组信息。尽管早期研究认为常规NGS在检测MYD88 L265P突变方面可能灵敏度不足，但通过优化覆盖度和特定的评估参数，NGS也可以成为一种敏感可靠的检测方法，在低至0.5% VAF时与ddPCR具有可比性 42。
- 临床意义：MYD88 L265P突变状态对BTK抑制剂的疗效预测具有重要指导作用。MYD88突变型患者通常对BTK抑制剂反应良好 38。
CXCR4突变：CXCR4突变在WM患者中的发生率约为30%-40% 38。主要突变类型包括无义突变和移码突变 38。CXCR4突变通常与MYD88 L265P突变共存 43。
其他分子标志物：IWWM-11共识还建议检测6q和17p染色体异常以及TP53基因状态，特别是对于即将接受治疗的患者 39。这些分子标志物共同构成了WM的分子诊断图谱，有助于更精确地评估疾病特征和预测治疗反应。
3.1.3 检测样本要求
分子检测通常使用整骨髓样本进行，但对于CXCR4和TP53基因的测序以及6q和17p染色体的荧光原位杂交（FISH）检测，建议使用CD19+富集的骨髓样本，以提高检测的准确性 39。对于低肿瘤负荷的患者，高灵敏度的方法如ddPCR和AS-PCR在未分选样本中检测MYD88突变具有优势 4045。
通过这些全面的诊断方法和分子标志物检测，可以对WM进行准确诊断，并为后续的个体化治疗方案制定提供关键依据。
3.2 与相关疾病的鉴别
华氏巨球蛋白血症（WM）的诊断，特别是与IgM单克隆丙种球蛋白病相关疾病的鉴别诊断，至关重要。这些疾病包括IgM型意义未明单克隆丙种球蛋白病（IgM MGUS）、多发性骨髓瘤（MM）和慢性淋巴细胞白血病（CLL），它们在临床表现、IgM水平、骨髓形态学和分子突变谱上存在相似性与差异性。准确的鉴别诊断对于选择恰当的治疗策略和评估患者预后具有决定性意义 46。
3.2.1 IgM型意义未明单克隆丙种球蛋白病（IgM MGUS）
IgM MGUS被认为是WM的潜在前体状态 4748。其主要鉴别要点如下：
- IgM水平：IgM MGUS患者的血清IgM单克隆蛋白水平通常低于WM，但并非绝对。有研究指出，IgM MGUS与WM之间的区别并非依赖于IgM水平或骨髓浸润的任意阈值 46。
- 骨髓形态：IgM MGUS患者骨髓中淋巴浆细胞浸润程度较低。浸润模式常表现为斑片状间质浸润，而WM常表现为小梁旁和间质浸润相结合的模式 49。骨髓活检对鉴别IgM MGUS和WM至关重要，因为它可以识别显著的淋巴浸润 49。
- 分子突变谱：尽管MYD88 L265P突变是WM的标志性特征，但在25%的IgM MGUS病例中也可发现此突变 1949。这表明MYD88 L265P突变可能是疾病进展的早期事件。然而，CXCR4突变在IgM MGUS中不常见。
- 临床表现：IgM MGUS患者通常无症状，无终末器官损伤，而WM患者常因骨髓浸润和IgM单克隆蛋白引起症状（如贫血、高黏滞血症等）。有研究指出，IgM MGUS患者在5年、10年和15年时的累积进展风险分别为10%、18%和24% 50。
3.2.2 多发性骨髓瘤（Multiple Myeloma, MM）
MM是另一种浆细胞恶性肿瘤，但与WM在多个方面存在显著差异：
- IgM水平：经典的MM多表现为IgG或IgA型单克隆蛋白。虽然存在IgM型MM，其特点是染色体易位t(11;14)(q13;q32)的高发生率，而这在WM中从未观察到 51。
- 骨髓形态：MM的骨髓浸润主要为浆细胞。根据国际骨髓瘤工作组（IMWG）的诊断标准，骨髓中克隆性浆细胞比例≥60%是MM的诊断标准之一，即使没有CRAB特征 52。而WM的骨髓浸润则由淋巴细胞、浆细胞和浆细胞样细胞组成，呈现淋巴浆细胞样分化。
- 免疫表型：MM细胞通常表达CD38、CD138，不表达或低表达CD20，而WM细胞通常表达CD20、CD79a和表面IgM 46。
- 分子突变谱：MYD88 L265P突变是WM的特征性突变，但在MM中不常见。MM有其独特的细胞遗传学异常，如IGH易位（如t(11;14)、t(4;14)等）和染色体缺失（如del(17p)）。
- 临床表现：MM患者常伴有CRAB特征（高钙血症、肾功能不全、贫血、骨病变），而WM患者主要表现为贫血、高黏滞血症和器官肿大。影像学检查如PET/CT在MM诊断中具有重要价值，可评估骨骼受累及髓外病灶 53。
3.2.3 慢性淋巴细胞白血病（Chronic Lymphocytic Leukemia, CLL）
CLL是一种CD5+ B细胞淋巴增殖性疾病，尽管其与WM都起源于B细胞，但两者在临床和分子水平上存在明显区别 47。
- IgM水平：CLL患者通常不伴有显著的IgM单克隆丙种球蛋白血症，如果出现单克隆蛋白，通常为IgM型，但水平较低，且可能不是疾病的主要特征。
- 骨髓形态：CLL骨髓浸润主要为成熟小淋巴细胞，形态单一。淋巴细胞浸润常呈弥漫性或结节性。
- 免疫表型：CLL细胞具有典型的免疫表型，表达CD5、CD19、CD20（弱表达）、CD23，且表面Ig轻链呈弱表达 54。WM细胞则表达CD20、CD22、CD79a和表面IgM，通常不表达CD5和CD23。
- 分子突变谱：CLL具有独特的遗传学异常，如del(13q)、del(11q)、del(17p)和trisomy 12等，其中del(17p)和del(11q)与不良预后相关 5556。MYD88 L265P突变在CLL中不常见。
- 临床表现：CLL患者常表现为外周血淋巴细胞增多、淋巴结肿大和脾大。早期CLL患者可能长期无症状 55。
综上所述，WM与其他IgM单克隆丙种球蛋白相关疾病的鉴别诊断需要综合评估患者的临床症状、血清IgM水平、骨髓活检病理学特征（包括形态学和免疫组化）以及分子遗传学特征（特别是MYD88和CXCR4突变状态）。这种多维度分析是确保准确诊断和优化治疗方案的关键。下表总结了这些疾病的主要鉴别要点。
| 特征 | 华氏巨球蛋白血症 (WM) | IgM型意义未明单克隆丙种球蛋白病 (IgM MGUS) | 多发性骨髓瘤 (MM) | 慢性淋巴细胞白血病 (CLL) |
|---|---|---|---|---|
| IgM单克隆蛋白 | 任何水平，常较高，引起高黏滞血症 | 任何水平，通常较低 | 存在IgM型MM，但较少见 51 | 通常无显著单克隆蛋白，偶有低水平IgM |
| 骨髓浸润 | ≥10%淋巴浆细胞浸润，小梁旁和间质混合模式 49 | 淋巴浆细胞浸润程度较低，斑片状间质模式 49 | 克隆性浆细胞比例≥60%或伴疾病定义事件 52 | 小淋巴细胞弥漫性或结节性浸润 |
| 特征性免疫表型 | CD20+, CD79a+, sIgM+, CD5-/+, CD22-/+, CD23-/+ | 类似WM，但浸润细胞较少 | CD38+, CD138+, CD20-, cIg+, CD5-, CD23- | CD5+, CD19+, CD20(弱), CD23+, sIg(弱) 54 |
| 核心基因突变 | MYD88 L265P (90-97%), CXCR4 (30-40%) 19 | 约25% MYD88 L265P 49，CXCR4不常见 | 缺乏MYD88 L265P，常见IGH易位，del(17p) 57 | 缺乏MYD88 L265P，常见del(13q), del(11q), trisomy 12 56 |
| 典型临床表现 | 贫血、高黏滞血症、肝脾肿大、神经病变 | 无症状，无器官损伤 | CRAB特征 (高钙、肾功能不全、贫血、骨病变) 52 | 淋巴结肿大、脾大、外周血淋巴细胞增多 55 |
| 疾病进展风险 | 已是恶性疾病 | 5年、10年和15年累积进展风险分别为10%、18%和24% 50 | 恶性疾病 | 恶性疾病 |
4. 分层治疗策略与药物选择
4.1 一线治疗方案对比
华氏巨球蛋白血症（WM）的治疗选择日益丰富，包括化疗免疫治疗和靶向治疗，特别是布鲁顿酪氨酸激酶（BTK）抑制剂。治疗方案的选择需要综合考虑患者的临床特征、疾病风险分层、共病情况以及分子基因突变状态。对于所有符合治疗指征的WM患者，无论是初治还是复发/难治，都应个体化地选择最佳治疗方案 58。
4.1.1 化疗免疫治疗：苯达莫司汀+利妥昔单抗
化疗免疫治疗曾是WM的一线标准治疗方案，其中苯达莫司汀（Bendamustine, B）联合利妥昔单抗（Rituximab, R）是最常用的组合之一。利妥昔单抗作为抗CD20单克隆抗体，能有效清除表达CD20的WM细胞。苯达莫司汀则是一种烷化剂，具有独特的双重作用机制，能有效杀伤肿瘤细胞。
- 疗效与特点：B+R方案在初治WM患者中显示出良好的疗效，尤其是在快速减低肿瘤负荷、缓解症状方面表现突出。该方案通常能达到较高的总缓解率（ORR）和较长的无进展生存期（PFS）。IWWM-10共识将B+R方案推荐为症状性WM患者的一线治疗选择之一 58。
- 局限性与不良反应：B+R方案的不良反应主要包括骨髓抑制（中性粒细胞减少、血小板减少）、感染风险增加以及胃肠道反应。此外，利妥昔单抗可能导致IgM水平在治疗初期短暂升高，引发“IgM反跳”现象，可能加重高黏滞血症，因此对于高IgM水平且伴有高黏滞血症风险的患者，可能需要先进行血浆置换或单独使用化疗药物，或考虑BTK抑制剂单药治疗。
4.1.2 BTK抑制剂：伊布替尼与泽布替尼
BTK抑制剂代表了WM治疗的重大突破，尤其适用于存在MYD88 L265P突变的患者，该突变是BTK信号通路激活的关键驱动因素 59。伊布替尼（Ibrutinib）是首个获批用于WM的BTK抑制剂，而泽布替尼（Zanubrutinib）作为第二代BTK抑制剂，在选择性和安全性方面有所改进。
- 伊布替尼（Ibrutinib）：
- iNNOVATE研究：这项III期临床试验比较了伊布替尼联合利妥昔单抗（IR）与安慰剂联合利妥昔单抗（PR）在初治和复发/难治WM患者中的疗效。结果显示，IR组的疾病缓解率显著高于PR组，并且无进展生存期（PFS）也更长。在长达5年的随访中，IR方案在改善疾病和延长无进展生存期方面优于利妥昔单抗单药治疗，且副作用可控并随时间推移逐渐减轻。IR方案因此被确立为WM的标准治疗方案之一 60。
- MYD88/CXCR4突变状态的影响：伊布替尼在MYD88突变且CXCR4野生型（MYD88MUT/CXCR4WT）的WM患者中效果最佳，能达到更高的缓解率和更快的反应时间 3859。然而，对于CXCR4突变型患者，伊布替尼的反应率较低且反应延迟 59。特别是CXCR4无义突变（CXCR4NS）与伊布替尼治疗后的不良PFS相关 3861。
- 泽布替尼（Zanubrutinib）：
- ASPEN研究：这是一项头对头比较泽布替尼和伊布替尼在WM患者中疗效和安全性的III期临床试验。结果显示，泽布替尼在MYD88突变型WM患者中表现出与伊布替尼相当的疗效，但在安全性方面具有显著优势，特别是心脏毒性（如房颤）和出血风险低于伊布替尼 62。
- MYD88/CXCR4突变状态的影响：ASPEN研究的生物标志物分析显示，在CXCR4突变型患者中，泽布替尼与伊布替尼相比具有更好的主要缓解率（MRR）和无进展生存期（PFS）趋势 61。对于MYD88野生型（MYD88WT）WM患者，泽布替尼单药治疗也能诱导高质量缓解，约27%的MYD88WT患者达到非常好的部分缓解（VGPR），并且18个月PFS和OS率分别为68%和88% 63。
- TP53突变的影响：ASPEN研究还发现，对于TP53突变型WM患者，泽布替尼治疗组的VGPR和CR率（34.6% vs 13.6%）显著高于伊布替尼组，MRR和PFS也呈现改善趋势 3861。这表明泽布替尼可能对预后较差的TP53突变患者提供更好的治疗选择。
- BTK抑制剂的整体优势：BTK抑制剂通常耐受性良好，方便口服给药，能显著改善患者生活质量 60。它们被推荐作为WM的一线治疗选择，特别是在初治患者中，与化疗免疫治疗相比，可能提供更优的风险-效益比 3。
4.1.3 MYD88/CXCR4突变状态对方案选择的指导作用
分子突变状态已成为WM个体化治疗的关键因素：
- MYD88 L265P突变型患者：这类患者通常对BTK抑制剂反应良好。如果同时为CXCR4野生型，则BTK抑制剂是首选，且疗效最佳。如果存在CXCR4突变，BTK抑制剂仍然有效，但可能反应较慢或缓解深度较浅，泽布替尼可能优于伊布替尼 3861。
- MYD88野生型（MYD88WT）患者：这类患者对BTK抑制剂的反应通常不如MYD88突变型患者，但泽布替尼在MYD88WT WM患者中仍显示出有意义的临床活性和高质量的缓解 63。对于MYD88WT患者，化疗免疫治疗（如B+R方案）或蛋白酶体抑制剂（如硼替佐米）可能仍然是重要的治疗选择 64。
总结
一线治疗方案的选择应综合考虑患者的MYD88和CXCR4突变状态、年龄、共病情况以及对特定药物不良反应的耐受性。对于MYD88突变型WM患者，BTK抑制剂（尤其是泽布替尼）因其良好的疗效和安全性，正逐渐成为优选。对于特定亚群，如MYD88WT或CXCR4突变型，化疗免疫治疗或新型BTK抑制剂的优势可能更为突出。治疗方案的选择需要与患者充分沟通，权衡利弊，制定个体化的治疗策略。
| 治疗方案 | 适应症 | 主要特点 | 疗效（MYD88MUT/CXCR4WT） | 疗效（MYD88MUT/CXCR4MUT） | 疗效（MYD88WT） | 主要不良反应 |
|---|---|---|---|---|---|---|
| 苯达莫司汀+利妥昔单抗 | 初治或复发/难治WM，症状性患者 | 快速减低肿瘤负荷，缓解症状。 | 良好 | 良好 | 良好 | 骨髓抑制、感染、胃肠道反应、IgM反跳（利妥昔单抗） |
| 伊布替尼 | 初治或复发/难治WM，主要适用于MYD88突变型患者 | 口服方便，长期有效，但对CXCR4突变患者疗效受影响。 | 最佳缓解率和更快的反应时间 59 | 反应率较低，反应延迟 59，PFS较差 61 | 疗效有限，对伊布替尼单药治疗反应较差 63 | 房颤、出血、高血压、腹泻和肌肉骨骼疼痛等不良事件风险可能因BTKi类型而异 38 |
| 泽布替尼 | 初治或复发/难治WM，尤其适用于MYD88突变型患者 | 第二代BTK抑制剂，安全性更好，心脏毒性风险较低。 | 与伊布替尼相当，甚至更优的安全性 62 | 更优的主要缓解率和PFS趋势 61，对TP53突变亦有益 61 | 有效，能诱导高质量缓解，VGPR率27% 63 | 腹泻、恶心/呕吐、中性粒细胞减少、疲劳。与伊布替尼相比，腹泻和恶心/呕吐等具有临床意义的差异，长期体力功能和疲劳也有改善 6566 |
4.2 复发/难治性WM的新兴疗法
对于华氏巨球蛋白血症（WM）患者而言，尽管一线治疗方案能够有效缓解疾病，但部分患者会经历疾病复发或对现有疗法产生耐药性，此时需要探索新的治疗策略。针对复发/难治性WM（R/R WM），新的药物和联合治疗方案正在不断涌现，特别是非共价BTK抑制剂、BCL-2抑制剂以及旨在克服耐药机制的靶向干预。
4.2.1 非共价BTK抑制剂
第一代共价BTK抑制剂（如伊布替尼、泽布替尼）的出现显著改善了WM患者的预后，但部分患者会因BTK C481S突变或其他耐药机制而对共价BTK抑制剂产生耐药性 67。非共价BTK抑制剂的开发正是为了克服这一挑战。
- Pirtobrutinib：Pirtobrutinib是一种高度选择性的非共价（可逆）BTK抑制剂。它在既往接受过共价BTK抑制剂治疗的R/R WM患者中显示出活性 3。Pirtobrutinib的出现为共价BTK抑制剂耐药的患者提供了新的治疗选择。临床前和临床研究表明，Pirtobrutinib对携带BTK C481S突变的WM细胞仍然有效，因为其结合方式不依赖于C481半胱氨酸位点，从而绕过了共价BTK抑制剂的耐药机制。
4.2.2 BCL-2抑制剂
BCL-2蛋白家族在WM细胞的生存中扮演关键角色，其过表达赋予了细胞抗凋亡能力。维奈克拉（Venetoclax）作为一种有效的BCL-2拮抗剂，通过选择性抑制BCL-2蛋白，恢复细胞的凋亡程序，在多种血液恶性肿瘤中显示出活性。
- 维奈克拉（Venetoclax）：一项多中心、前瞻性II期研究评估了维奈克拉在R/R WM患者中的疗效和安全性。该研究入组了32名患者，其中16名曾接受BTK抑制剂治疗。结果显示，维奈克拉在R/R WM患者中表现出高度活性，总缓解率（ORR）达到84%，主要缓解率（MRR）为81% 68。中位无进展生存期（PFS）达到30个月。值得注意的是，MYD88突变状态（所有患者均为MYD88突变型）或CXCR4突变状态（17名患者携带CXCR4突变）并未影响治疗反应或PFS 68。最常见的≥3级治疗相关不良事件是中性粒细胞减少（45%），包括一例发热性中性粒细胞减少 68。这些结果表明，维奈克拉在既往接受过治疗的WM患者中，包括那些曾接受BTK抑制剂治疗的患者中，是安全且高效的 68。
4.2.3 联合治疗方案
为了提高疗效和克服耐药性，多种联合治疗方案正在探索中，包括BTK抑制剂与其他靶向药物的组合。
- BTK抑制剂 + PI3K抑制剂：PI3K/Akt/mTOR信号通路在B细胞恶性肿瘤中发挥关键作用，其激活可促进细胞增殖和存活 67。因此，BTK抑制剂与PI3K抑制剂的联合应用有望产生协同抗肿瘤效应。这种联合策略在其他B细胞淋巴瘤中已显示出潜力，且可能克服BTK抑制剂的一些耐药机制 67。
- BTK抑制剂 + BCL-2抑制剂：伊布替尼和维奈克拉的联合治疗作为症状性初治WM患者的一线疗法进行过研究。在症状性、初治、MYD88突变型WM患者中，伊布替尼联合维奈克拉达到了较高的VGPR率（42%），并在治疗结束后显示出持久的缓解 69。然而，该联合方案与高于预期的室性心律失常发生率相关，导致研究提前终止 69。这提示我们在探索联合治疗时需密切关注药物毒性，并进行严格的风险效益评估。
- BTK抑制剂 + CXCR4拮抗剂：CXCR4突变在约30%-40%的WM患者中存在，并与对BTK抑制剂的反应延迟和耐药相关 387071。CXCR4拮抗剂（如普乐沙福Plerixafor）能够阻断CXCR4与其配体CXCL12的相互作用，从而可能增强BTK抑制剂的疗效，尤其是在CXCR4突变型WM患者中。研究表明，CXCR4拮抗剂与分子靶向药物联合使用，可以协同增强抗增殖/促凋亡作用 71。这种联合策略旨在克服CXCR4突变介导的BTK抑制剂耐药，通过改变肿瘤微环境中的趋化因子信号传导，促进WM细胞对BTK抑制剂的敏感性。
4.2.4 针对耐药机制的靶向干预
理解WM对治疗的耐药机制是开发新疗法的关键。除了BTK C481S突变导致的共价BTK抑制剂耐药外，CXCR4突变也是一个重要的耐药因素 38。
- CXCR4突变：CXCR4突变，特别是无义突变和移码突变，可导致BTK抑制剂反应的延迟或不完全缓解 38。对于CXCR4突变的患者，除了考虑CXCR4拮抗剂的联合应用外，泽布替尼可能比伊布替尼在疗效上更具优势 38。在选择治疗方案时，应考虑CXCR4突变状态，以优化治疗效果。
总而言之，R/R WM的治疗格局正在发生深刻变化。非共价BTK抑制剂如Pirtobrutinib为共价BTK抑制剂耐药的患者提供了重要选择。维奈克拉作为BCL-2抑制剂，在R/R WM中显示出显著疗效，且其活性不受CXCR4突变状态的影响。此外，BTK抑制剂与其他靶向药物的联合治疗，以及针对CXCR4突变等特定耐药机制的靶向干预，预示着未来WM治疗的更大突破。未来的研究将继续致力于更深入地理解这些耐药机制，并开发出更精准、更有效的个体化治疗策略。
4.3 特殊人群管理
华氏巨球蛋白血症（WM）患者群体具有高度异质性，尤其在老年患者、合并症患者以及存在特殊并发症（如Bing-Neel综合征）的患者中，其治疗策略需高度个体化，以平衡疗效与药物毒性，并关注患者的生活质量。
4.3.1 老年患者管理
WM主要影响老年人群，中位发病年龄较大。老年患者常伴有多种合并症和生理功能下降，这使得治疗选择更为复杂。
- 风险评估：在选择治疗方案前，应对老年患者进行全面的体能和合并症评估。这包括Charlson合并症指数、综合老年学评估（CGA）等，以识别高危患者，避免过度治疗或不足治疗。
- 药物选择：
- BTK抑制剂：BTK抑制剂（如伊布替尼、泽布替尼）因其口服方便、无需住院、且通常耐受性良好，在老年患者中具有吸引力。泽布替尼在ASPEN研究中与伊布替尼相比，在腹泻、恶心/呕吐以及长期体力功能和疲劳方面，对健康相关生活质量的改善更为显著，这对于老年患者的整体生活质量尤为重要 66。
- 化疗免疫治疗：对于体能状况较好的老年患者，苯达莫司汀联合利妥昔单抗（BR）仍可作为有效的一线选择，但需密切监测骨髓抑制及感染风险。
- 剂量调整与支持治疗：根据患者的肾功能、肝功能和整体耐受性，可能需要进行药物剂量调整。此外，积极的支持治疗，如预防性使用集落刺激因子、抗感染治疗等，对老年患者至关重要。
4.3.2 合并症患者管理（特别是心血管疾病）
WM患者常伴有心血管疾病、糖尿病、慢性肾病等合并症，这些疾病可能影响药物选择和毒性管理。
- 心血管疾病：心血管毒性是WM治疗中需要特别关注的问题，尤其是BTK抑制剂。
- 伊布替尼：伊布替尼已被证实与房颤和高血压等心血管不良事件风险增加相关 7273。一项研究显示，伊布替尼治疗的患者中，房颤发生率可达10% 74，甚至在长期随访中可能达到20% 75。对于有既往心血管疾病或心血管风险因素的患者，伊布替尼的使用需谨慎。
- 泽布替尼：与伊布替尼相比，泽布替尼在ASPEN研究中展现出在健康相关生活质量方面具有更佳的改善，尤其在腹泻和恶心/呕吐症状以及长期体力功能和疲劳方面，提示其可能具有更优的耐受性，对于有心血管疾病史或高危风险的患者，泽布替尼可能是一个值得考虑的选择 66。
- 管理策略：对于使用BTK抑制剂的患者，应定期监测血压、心率和心电图。若出现房颤或其他心律失常，可能需要暂停或减量BTK抑制剂，并转诊至心内科进行评估和治疗。在治疗前充分评估患者的心血管风险，并与心血管专家协作管理至关重要 76。
4.3.3 中枢神经系统受累（Bing-Neel综合征, BNS）患者管理
Bing-Neel综合征（BNS）是WM的一种罕见但严重的并发症，表现为WM淋巴浆细胞浸润脑膜和/或中枢神经系统（CNS） 77。BNS患者可能出现各种神经系统症状，如头痛、视力障碍、认知功能障碍、局部神经功能缺损等 7879。
- 诊断挑战：BNS的临床表现多样且非特异性，诊断常有延迟，可能导致永久性神经损伤 79。诊断主要依靠脑脊液（CSF）检查（包括克隆性淋巴浆细胞检测、MYD88 L265P突变分析）和中枢神经系统影像学（如增强MRI） 7780。
- 治疗策略：BNS的治疗目标是清除CNS中的WM细胞，缓解神经系统症状。由于许多化疗药物难以有效穿透血脑屏障，因此需要选择具有良好CNS渗透性的药物。
- BTK抑制剂：伊布替尼已被证实能有效穿透血脑屏障，并在BNS患者中显示出显著疗效。多项研究表明，伊布替尼单药治疗BNS患者的总缓解率高，可达85%的患者症状改善或缓解，83%的影像学异常改善或缓解 8182。伊布替尼作为BNS的一线或二线治疗均取得了良好的效果，特别是对于MYD88突变阳性的BNS患者 788083。
- 鞘内化疗与全身化疗：鞘内注射甲氨蝶呤、阿糖胞苷和地塞米松可用于BNS的初始治疗，但通常需联合全身性治疗 78。对于适合的患者，高剂量甲氨蝶呤联合利妥昔单抗、阿糖胞苷等化疗药物也可考虑 7881。
- 个性化治疗：BNS的治疗应根据患者的神经系统症状、病变范围、MYD88突变状态以及既往WM治疗史进行个体化选择。
4.3.4 生活质量（QOL）的平衡
无论何种治疗方案，都应关注患者的生活质量。WM患者常报告存在癌症复发的恐惧、焦虑和抑郁症状，这些都会影响其健康相关生活质量（HRQOL） 8485。
- 药物选择对QOL的影响：不同药物的副作用谱不同，直接影响患者的QOL。例如，泽布替尼在ASPEN研究中显示出更低的腹泻和恶心/呕吐发生率，并改善了长期体力功能和疲劳，可能带来更好的QOL 66。
- 支持性护理：除了肿瘤治疗外，疼痛管理、营养支持、心理咨询等支持性护理对改善患者QOL至关重要。
- 患者教育与共同决策：与患者充分沟通治疗方案的利弊、潜在副作用及其管理，让患者参与治疗决策过程，有助于提高患者依从性和QOL。
综上所述，WM特殊人群的治疗管理需充分考虑其独特的临床特征和个体需求，在确保疗效的同时，最大程度地降低药物毒性，并持续关注和改善患者的生活质量。
5. 并发症处理与支持治疗
5.1 高黏滞血症与急性事件管理
高黏滞血症综合征（Hyperviscosity Syndrome, HVS）是华氏巨球蛋白血症（WM）最常见的、可危及生命的并发症之一 8687。它主要由血清中高浓度的单克隆IgM蛋白导致血液黏度显著增加引起，这些异常IgM蛋白体积大，增加了血液的摩擦阻力，尤其影响微循环系统 86。HVS是一种肿瘤急症，需要及时诊断和干预 87。
5.1.1 临床表现
HVS的临床表现多种多样，主要累及眼睛、神经系统和出血倾向：
- 眼部症状：是最常见的表现之一，包括视力模糊、复视、黑矇、视网膜病变等 86。眼底镜检查常可见特征性的视网膜静脉充盈、扭曲（呈“香肠样”改变）、出血和渗出 8687。未经治疗的严重HVS可导致视力丧失。
- 神经系统症状：可表现为头痛、眩晕、耳鸣、听力下降、共济失调、意识模糊、嗜睡，甚至昏迷和中风 868889。这些症状是由于大脑血液灌注不足或微血栓形成所致。听力丧失是WM的一种不常见但可能存在的症状，其病因可能与高黏滞血症和血栓形成有关 89。
- 出血倾向：表现为皮肤黏膜出血，如鼻出血（尤其是双侧鼻出血）、牙龈出血、瘀斑等 8687。这是因为高黏滞度影响了血小板功能和凝血级联反应。
- 其他症状：还可能包括疲劳、虚弱、呼吸困难和心力衰竭等。
5.1.3 诊断依据
HVS的诊断主要基于临床症状、血清IgM水平和血液黏度测定：
- 临床症状：出现上述典型眼部、神经系统或出血症状应高度怀疑HVS 87。
- IgM水平：通常血清IgM水平显著升高，是引起HVS的主要原因 86。
- 血清黏度测定：通过奥斯特瓦尔德黏度计（Ostwald tube）测定血清相对黏度是诊断HVS的金标准 86。当相对黏度升高时，常出现HVS症状。
5.1.3 急性事件管理：血浆置换
血浆置换（Plasma Exchange, PLEX）是HVS最有效、最迅速的紧急处理措施，能够快速降低血清IgM水平和血液黏度，从而缓解症状 869091。
- 适应症：出现任何HVS症状（如视力模糊、神经系统症状、严重出血）均应立即启动血浆置换 9092。即使在诊断WM之前，当患者出现HVS症状时，血浆置换也应作为紧急救治手段。
- 操作流程：
- 效果：血浆置换能够迅速改善HVS症状，防止不可逆的器官损伤（如永久性视力丧失或神经功能缺损） 8692。它通过物理方式清除IgM，而非杀伤肿瘤细胞，因此其效果是暂时的。
5.1.4 与后续抗瘤治疗的衔接
血浆置换仅是HVS的紧急对症治疗，其作用是暂时的。为了从根本上控制疾病并预防HVS复发，必须在血浆置换后尽快启动特异性的抗WM治疗 8790。
- 抗瘤治疗的重要性：一旦患者症状稳定，血清黏度得到控制，应立即开始针对WM的系统性治疗，如化疗免疫治疗（苯达莫司汀+利妥昔单抗）或BTK抑制剂等 90。
- 方案选择：抗瘤治疗方案的选择应依据WM的诊断和分期、MYD88/CXCR4突变状态、患者的体能状态和合并症等因素进行个体化决策。
- 利妥昔单抗使用注意事项：需要注意的是，利妥昔单抗可能导致治疗初期IgM水平短暂升高（IgM反跳），这可能会加重HVS。因此，对于IgM水平极高且伴有HVS风险的患者，建议在开始利妥昔单抗治疗前先进行血浆置换，或考虑在利妥昔单抗给药的同时预防性进行血浆置换，或在开始化疗后再给予利妥昔单抗，以避免或减轻IgM反跳的风险 90。
通过迅速而有效的血浆置换来管理HVS，并及时衔接针对WM的抗瘤治疗，是确保患者安全、改善预后的关键。
5.2 相关器官损伤的干预
华氏巨球蛋白血症（WM）除了导致高黏滞血症外，其产生的IgM单克隆蛋白还可能直接或间接损伤多个器官系统，引发一系列并发症，其中神经病变和冷球蛋白血症是临床上较为常见的两种。
5.2.1 WM相关神经病变
WM患者可能发生外周神经病变 93，其机制复杂，常与IgM单克隆蛋白的自身抗体活性有关。最常见的类型是脱髓鞘性神经病变，尤其是抗髓鞘相关糖蛋白（MAG）抗体阳性者。另一种罕见但临床意义重大的类型是CANOMAD综合征。
- CANOMAD综合征：CANOMAD（Chronic Ataxic Neuropathy with Ophthalmoplegia, IgM paraprotein, Cold Agglutinins, and Anti-disialyl antibodies）是一种罕见的、临床显著的神经系统并发症，其特征为慢性共济失调性神经病变、眼肌麻痹、IgM单克隆蛋白、冷凝集素以及抗双唾液酸苷抗体 94。
- 发病机制：CANOMAD的发生与IgM单克隆蛋白作为自身抗体，靶向神经组织中的双唾液酸苷（disialosyl epitopes）抗原有关 94。这些IgM抗体直接攻击神经细胞膜或髓鞘，导致神经功能障碍。尸检研究显示，患者可出现严重的背柱萎缩和背根神经节病变，以及克隆性B淋巴细胞在神经内膜、神经周围和软脑膜内的浸润 95。病毒感染，特别是丙型肝炎病毒（HCV），可能通过诱导淋巴增殖，与冷球蛋白血症相关 1096。
- 临床表现：主要表现为感觉性共济失调、感觉异常、感觉减退、运动无力、眼肌麻痹和延髓症状 94。患者通常有进行性加重的慢性病程。45%的患者可能存在中度至重度残疾 94。约34%的CANOMAD患者伴有冷凝集素 94。
- 诊断：确诊依赖于血清中IgM单克隆蛋白和抗双唾液酸苷抗体的检测，以及神经电生理检查显示的脱髓鞘或轴索损伤模式 94。在CANOMAD患者中，约20%合并WM 94。
- 治疗效果及序贯策略：针对CANOMAD的治疗主要集中于清除产生自身抗体的B细胞克隆以及减轻炎症反应。
- 利妥昔单抗：作为抗CD20单克隆抗体，利妥昔单抗通过清除B细胞来减少IgM单克隆蛋白的产生，对CANOMAD表现出显著疗效。法国一项多中心回顾性研究显示，利妥昔单抗治疗方案（基于利妥昔单抗的治疗）在CANOMAD患者中取得了52%的部分或更好临床反应率 94。
- 静脉免疫球蛋白（IVIg）：IVIg是一种快速起效的免疫调节剂，可以通过中和自身抗体、抑制炎症反应等机制改善神经症状。研究表明，IVIg在CANOMAD的一线治疗中表现出53%的部分或更好临床反应率，应作为CANOMAD的一线标准治疗 94。
- 其他治疗：糖皮质激素和免疫抑制剂效果不佳 94。对于合并WM的CANOMAD患者，WM的系统性治疗，如BTK抑制剂或化疗，也可能有助于改善神经病变。
5.2.2 冷球蛋白血症
冷球蛋白血症是一种由冷球蛋白（在低于体温时可逆性沉淀的免疫球蛋白）引起的多系统疾病。在WM中，最常见的是I型冷球蛋白血症，由单克隆IgM引起。
- 发病机制：WM产生的单克隆IgM蛋白在低温下发生可逆性沉淀，形成冷球蛋白，沉积在小血管壁，导致血管炎、血栓形成和器官损伤 9798。丙型肝炎病毒（HCV）感染是混合型（II/III型）冷球蛋白血症的主要病因之一，其诱导的淋巴增殖也可能与WM伴冷球蛋白血症相关 9699。
- 临床表现：I型冷球蛋白血症的临床表现多样，包括雷诺现象、紫癜、关节痛、皮肤溃疡、肾脏损害（如急性肾衰竭、膜性肾小球肾炎）和神经病变 9798。肾脏受累可能表现为肾小球毛细血管内增殖和血管内PAS染色阳性无定形物质沉积 9798。
- 治疗效果及序贯策略：治疗旨在减少冷球蛋白的产生并控制炎症。
5.2.3 其他器官损伤
除了神经病变和冷球蛋白血症，WM还可能导致其他器官损伤：
- 肾脏损害：肾脏受累在WM中不常见，但可以发生，包括IgM相关的肾小球病变（如膜增生性肾小球肾炎）和轻链淀粉样变性（AL淀粉样变）。AL淀粉样变性患者中约10%合并WM，这会影响患者的治疗选择 100。对于有心脏受累的AL淀粉样变性患者，自体干细胞移植在心脏移植后可能改善长期预后 101。
- 肺部浸润：WM细胞可浸润肺部，导致呼吸困难、咳嗽等症状。
- 骨骼受累：尽管不如多发性骨髓瘤常见，但WM患者也可能出现骨骼病变，通常表现为溶骨性病变或骨质疏松。
WM相关器官损伤的干预策略是多方面的，需要根据具体的并发症类型、严重程度和患者的整体状况进行个体化选择。通过靶向WM肿瘤本身和对症治疗相结合，可以有效减轻并发症，改善患者的生活质量。
6. 预后评估与长期监测
6.1 预后评分系统与分子标志物
华氏巨球蛋白血症（WM）的预后评估对于指导治疗选择和预测患者生存至关重要。虽然WM是一种惰性淋巴瘤，但其临床病程具有异质性，一些患者可能长期无症状，而另一些则可能表现出侵袭性进展。因此，开发和应用有效的预后工具对于个体化治疗决策具有重要意义。
6.1.1 国际预后评分系统（IPSSWM）
国际预后评分系统（International Prognostic Scoring System for Waldenström's Macroglobulinemia, IPSSWM）是目前WM领域最广泛应用的预后工具。该系统于2009年由国际WM工作组（IWWM）建立，通过结合多个临床和实验室参数对患者进行风险分层 102。
IPSSWM主要基于以下独立的预后因素 102：
- 年龄。
- 血红蛋白水平。
- 血清β2-微球蛋白水平。
- 血清白蛋白水平。
参考文献[1]中提到，一项基于年龄、血红蛋白和白蛋白的预后指数能够识别出具有不同治疗需求的患者群体，并且Cox多变量分析显示年龄、血红蛋白水平和血清白蛋白水平可以预测生存期。在有β2-微球蛋白数据的亚组中，β2-微球蛋白是主要的预后决定因素。
IPSSWM在多个WM患者队列中得到了验证，并被证实能够有效区分不同生存结局的患者群体 103104。然而，IPSSWM也有其局限性：它主要基于传统的临床和实验室指标，未纳入近年来发现的重要的分子遗传学信息。
6.1.2 分子标志物在WM预后分层中的作用
随着对WM分子病理机制理解的深入，MYD88和CXCR4突变等分子标志物被发现对WM的预后具有显著影响，并能为IPSSWM提供补充信息，构建更全面的预后模型。
MYD88突变状态：
- MYD88 L265P突变：该突变在WM患者中发生率较高。一项研究显示，在西方队列中MYD88突变率较高，而在中国队列中，MYD88突变率为87.8% 40。MYD88 L265P突变阳性患者的预后可能受多种因素影响。参考文献[7]指出MYD88突变状态有助于治疗决策，尤其是在考虑BTK抑制剂治疗时。参考文献[8]在BTKi治疗组中，MYD88野生型被认为是独立的不良预后因素，这意味着MYD88突变型的预后优于野生型。
- MYD88野生型（MYD88WT）：MYD88WT的WM患者通常预后较差，对BTK抑制剂的反应率较低 105。对于这部分患者，传统的化疗免疫治疗（如苯达莫司汀+利妥昔单抗）可能仍然是重要的选择 105。
CXCR4突变状态：
染色体异常：
- 6q缺失（del6q）：del6q是WM中最常见的细胞遗传学异常，发生率约在27%-50%之间 106107108109110。研究表明，del6q与WM患者的不良预后特征相关 107108。有研究指出del6q与更短的PFS和OS显著相关 106107，尤其是在无症状WM患者中，del6q与更短的进展为有症状疾病的时间相关，且一旦需要治疗，6q缺失患者的PFS更短 107。然而，也有研究认为del6q对总体生存没有显著影响 109110，这可能与研究队列、随访时间及治疗方案的差异有关。
- 17p缺失（del17p）和TP53突变：del17p和TP53突变在WM中相对较少见，但它们的出现通常预示着极差的预后 106。TP53异常（包括del17p和TP53突变）与更短的PFS和OS显著相关 106。
- 复杂核型（CK）：CK与较差的预后相关 106。高度复杂核型（high-CK）患者的PFS和OS更短 106。
其他分子标志物：
6.1.3 构建多维度预后模型
当前的IPSSWM未纳入分子遗传学信息，因此其预测能力有待提升。整合MYD88、CXCR4突变状态以及细胞遗传学异常（如6q缺失、TP53异常、复杂核型）等分子标志物，有助于构建更全面的多维度预后模型 106。这种结合临床参数和分子特征的综合性模型，可以更精确地识别高危患者，指导治疗方案的选择，尤其是在BTK抑制剂时代，MYD88和CXCR4突变状态对治疗反应具有决定性影响 40。
未来的研究方向应包括：
- 前瞻性验证：在大型前瞻性临床试验中进一步验证整合分子标志物的新型预后模型的准确性和可靠性。
- MRD监测：微小残留病（MRD）检测可能成为重要的预后指标，指导治疗决策和长期监测。
- 新型生物标志物：探索新的循环生物标志物（如ctDNA）在预后评估中的应用。
通过将传统的临床预后因素与先进的分子标志物相结合，可以为WM患者提供更精准的预后评估，实现真正的个体化治疗。
表1：WM预后因素总结
| 类别 | 预后因素 | 影响 | 临床意义 | 资料来源 |
|---|---|---|---|---|
| IPSSWM | 年龄 | 较差 | 指导风险分层，但未纳入分子信息 | 102 |
| Hb < 11.5 g/dL | 较差 | 102 | ||
| 血清β2-微球蛋白 > 正常上限 | 较差 | 显著预测不良OS 104 | 102104 | |
| 白蛋白 < 正常下限 | 较差 | 102 | ||
| 分子标志物 | MYD88 L265P突变 | MYD88野生型在BTKi组中为独立不良预后因素 | BTK抑制剂治疗的预测标志物，整合IPSSWM可提高预测能力 40 | 40105 |
| CXCR4突变 | 较差，与BTK抑制剂反应延迟/耐药相关 | 指导BTK抑制剂选择，可能需联合治疗 40106 | 40106 | |
| 6q缺失（del6q） | 较差，与PFS和OS缩短相关 | 提示不良预后，需密切监测 106107 | 106107108 | |
| TP53突变/17p缺失 | 极差，与PFS和OS显著缩短相关 | 提示高危疾病，可能需更激进或新型治疗 106 | 106 | |
| 复杂核型（CK）/高度复杂核型（high-CK） | 较差，与PFS和OS缩短相关 | 提示高危疾病 106 | 106 | |
| 三体4 (tri4) | 较差，与OS缩短相关 | 106 | ||
| SPI1突变 | 较差，与OS缩短相关 | 106 |
6.2 治疗反应评估与随访策略
华氏巨球蛋白血症（WM）治疗效果的评估和长期监测对于指导患者管理至关重要。随着治疗手段的进步，疾病缓解的深度和持久性日益成为关注焦点。国际华氏巨球蛋白研讨会（IWWM）定期更新共识，以适应新的诊断和治疗进展，提供标准化的反应评估和随访建议。
6.2.1 IWWM-11简化反应标准
在IWWM-11共识中，专家组对WM的治疗反应评估标准进行了更新和简化，旨在使其更适用于日常临床实践和新兴疗法的评估。这些简化标准主要关注血清IgM水平 37。
- 完全缓解（Complete Remission, CR）：需满足以下所有条件：
- 血清IgM单克隆蛋白消失（免疫固定电泳阴性）。
- 骨髓活检显示淋巴浆细胞浸润<10%且无克隆性证据。
- 影像学检查（如淋巴结、脾脏）无活动性疾病证据。
- 无疾病相关症状和体征。
- 非常好的部分缓解（Very Good Partial Remission, VGPR）：需满足以下所有条件：
- 血清IgM水平较基线下降≥90%。
- 骨髓活检显示淋巴浆细胞浸润<10%且无克隆性证据。
- 部分缓解（Partial Remission, PR）：需满足以下所有条件：
- 血清IgM水平较基线下降≥50%。
- 骨髓活检显示淋巴浆细胞浸润<25%。
- 轻微缓解（Minor Response, MR）：需满足以下所有条件：
- 血清IgM水平较基线下降≥25%但<50%。
- 疾病稳定（Stable Disease, SD）：未达到MR或以上缓解，且未达到疾病进展标准。
- 疾病进展（Progressive Disease, PD）：以下任一条件：
- 血清IgM水平较最低点升高≥25%或出现新发IgM。
- 出现新的WM相关症状或已有症状恶化。
- 骨髓浸润或淋巴结/脾脏肿大增加。
- 出现新的髓外病变。
IWWM-11共识特别指出，可以使用仅基于血清IgM的“简化”反应评估来确定部分缓解和非常好的部分缓解，这对于多项评估新型药物的临床试验很有价值 37。
6.2.2 微小残留病（Minimal Residual Disease, MRD）检测的潜在价值
MRD是指通过高度敏感的检测方法，在形态学缓解后仍能检测到的少量肿瘤细胞。在WM中，MRD检测主要通过检测MYD88 L265P突变来评估。
- 检测方法：
- 等位基因特异性定量PCR (ASqPCR)：长期以来是WM中MYD88 L265P MRD检测的主要方法，其灵敏度较高。
- 液滴数字PCR (ddPCR)：相对于ASqPCR，ddPCR具有更高的灵敏度，可达到5.00×10^-5的检测限 111。ddPCR能够更灵敏地检测低浸润样本中的突变，特别适用于WM患者的常规筛查和MRD监测 112。
- 下一代测序 (NGS)：随着测序技术的进步，NGS也逐渐应用于WM的MRD检测，它能够提供更全面的基因组信息，并有可能检测到多个突变。
- 循环肿瘤DNA (ctDNA)：通过ddPCR检测血浆ctDNA中的MYD88 L265P突变，已显示出与骨髓检测结果良好的相关性，为WM提供了一种有吸引力的、创伤性更小的MRD监测方法 111。
- 临床意义：WM中MRD的检测对于评估治疗深度、预测疾病复发和指导治疗策略具有潜在价值。虽然WM的MRD尚未像多发性骨髓瘤或慢性淋巴细胞白血病那样被广泛纳入临床决策指南，但多项研究表明，达到MRD阴性与更长的无进展生存期和总生存期相关。未来，MRD可能成为WM治疗后评估的重要生物标志物，帮助识别需要强化治疗或维持治疗的患者。
6.2.3 长期随访中疾病进展、二次肿瘤监测的具体方案
WM患者的长期随访是疾病管理的重要组成部分，旨在早期发现疾病进展、监测治疗相关并发症和二次肿瘤的发生。
疾病进展监测：
- 定期临床评估：定期进行体格检查，评估是否有新的WM相关症状（如疲劳、淋巴结肿大、肝脾肿大、神经系统症状）或原有症状恶化。
- 实验室检查：
- 血常规和生化：定期监测血红蛋白、血小板、白细胞计数、肝肾功能等，以评估骨髓抑制、器官功能及治疗相关毒性。
- 血清IgM定量和免疫固定电泳：这是监测疾病负荷和评估治疗反应的核心指标。IgM水平的持续升高往往预示着疾病进展。
- 分子标志物：对于接受靶向治疗的患者，定期检测骨髓或外周血中的MYD88和CXCR4突变负荷可能有助于预测疾病进展或耐药的出现。
- 影像学检查：根据临床指征，可进行CT、PET-CT或MRI等影像学检查，以评估淋巴结、脾脏或髓外病变的进展情况。
- 骨髓活检：如果出现血液学异常或IgM水平持续升高，提示疾病进展，应考虑再次进行骨髓活检以确认淋巴浆细胞浸润程度和特征。
二次肿瘤监测：WM患者发生二次恶性肿瘤的风险高于普通人群 113114。这可能与遗传易感性、免疫功能障碍或治疗相关因素有关。
- 风险：一项分析SEER数据库的研究显示，WM患者发生二次肿瘤的总风险比普通人群高53%，绝对超额风险为102.69/10000人年 113。另一项SEER数据库分析也指出，WM患者发生二次肿瘤的风险比普通人群高49% 114。
- 类型：WM患者二次肿瘤的风险增加主要包括实体瘤（如肺癌、泌尿道肿瘤、甲状腺癌、黑色素瘤）和血液系统恶性肿瘤（如侵袭性淋巴瘤和急性白血病） 113114。
- 监测方案：
- 常规癌症筛查：根据年龄和性别，建议WM患者进行常规的癌症筛查，如乳腺X线摄影、结肠镜检查、前列腺特异性抗原（PSA）检测等。
- 皮肤检查：定期进行皮肤自我检查和皮肤科医生检查，以筛查黑色素瘤和其他皮肤癌。
- 肺癌筛查：对于有吸烟史或高风险因素的患者，可考虑低剂量CT进行肺癌筛查。
- 血液学监测：密切关注血常规变化，如持续性贫血加重、血细胞减少等，可能提示继发性骨髓增生异常综合征（MDS）或急性髓系白血病（AML）。
- 风险因素：既往化疗、免疫抑制剂的使用以及免疫功能障碍可能增加二次肿瘤的风险，因此在制定随访计划时应考虑这些因素。
通过实施标准化的反应评估和全面的长期监测策略，可以及时识别疾病进展和并发症，从而调整治疗方案，改善WM患者的长期预后和生活质量。
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参考文献
1Lymphoplasmacytic lymphoma-Waldenstrom's macroglobulinemia.PubMed
Umberto Vitolo, Andrés J M Ferreri, Silvia Montoto
Crit Rev Oncol Hematol. 2008 Aug;67(2):172-85. doi: 10.1016/j.critrevonc.2008.03.008. Epub 2008 May 21.
The presence of IgM paraproteinemia in low-grade lymphomas is usually considered a clinical syndrome known as Waldenstrom's macroglobulinemia (WM). In the WHO classification, WM is associated to lymphoplasmacytic lymphoma (LPL); it is a clinicopathologic entity characterized by a monoclonal expansion of predominantly small B-lymphocytes with variable plasmacytoid differentiation. LPL constitutes less than 5% of all NHL and it is associated with hepatitis C virus infection in 26% of cases. Cells of LPL/WM are B cells positive for monocytic Ig light chains, IgM, pan-B-cell markers, and negative for CD3 and CD103. The t(9;14)(p13;q32) is present in 50% of LPL, and determines PAX-5 over-expression. 6q21 deletion is observed in 42% of cases. LPL occurs in older adults. Clinical presentation usually consists of disseminated disease, but extranodal involvement and leukemic phase are rare. Most WM patients have symptoms attributable to tumour infiltration and/or monoclonal protein. In fact, a monoclonal serum paraprotein of IgM type and hyperviscosity symptoms may occur in more than 20% of cases (WM). Hyperviscosity syndrome is usually manifested by bleeding, blurring or loss of vision, dizziness, headache, and neurologic symptoms. Malignant infiltration of the CNS (Bing-Neel syndrome) is uncommon. LPL/WM is an indolent malignancy that is not usually curable with conventional treatments. The median survival of patients with LPL or WM is 50-60 months, transformation to large cell lymphoma may occur. Stage definition is irrelevant in WM considering that initiation of therapy is decided on the bases of prognostic factors and the development of disease-related symptoms and signs. The main adverse prognostic factors are older age, B symptoms, anemia, low albumin serum levels, raised SGOT, and high beta 2-microglobulin values. Several therapeutic alternatives for newly diagnosed or relapsed LPL/WM are available; however, the best location for every strategy is a matter of investigation. Several new drugs are being assessed in prospective trials. As a significant progress in this field, response criteria and therapeutic recommendations were updated during the Third International Workshop on WM (7-10 October 2004, Paris, France).
2Waldenström macroglobulinemia: 2023 update on diagnosis, risk stratification, and management.PubMed
Morie A Gertz
Am J Hematol. 2023 Feb;98(2):348-358. doi: 10.1002/ajh.26796. Epub 2023 Jan 1.
DISEASE OVERVIEW: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. DIAGNOSIS: Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in most IgM MGUS patients. MYD88 is not required for the diagnosis. RISK STRATIFICATION: Age, hemoglobin level, platelet count, β microglobulin, LDH, and monoclonal IgM concentrations are characteristics that are predictive of outcomes. RISK-ADAPTED THERAPY: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or a BTK inhibitor. The preferred Mayo Clinic induction is either rituximab and bendamustine (without rituximab maintenance) or zanubrutinib. MANAGEMENT OF REFRACTORY DISEASE: Bortezomib, cyclophosphamide, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, bendamustine, and venetoclax have all been shown to have activity in relapsed WM. Given WM's natural history, the reduction of therapy toxicity is an important part of treatment selection.
3Waldenström Macroglobulinemia: 2025 Update on Diagnosis, Risk Stratification, and Management.PubMed
Morie A Gertz
Am J Hematol. 2025 Jun;100(6):1061-1073. doi: 10.1002/ajh.27666. Epub 2025 Mar 17.
DISEASE OVERVIEW: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. DIAGNOSIS: The presence of IgM monoclonal protein associated with ≥ 10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in most IgM MGUS patients. MYD88 is not required for the diagnosis. RISK STRATIFICATION: Age, albumin, hemoglobin level, platelet count, β microglobulin, Lactate dehydrogenase (LDH), and monoclonal IgM concentrations are characteristics that are predictive of outcomes. RISK-ADAPTED THERAPY: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to combination regimens. Recommended first-line therapy can be chemoimmunotherapy or a covalent Bruton tyrosine kinase inhibitor. The preferred Mayo Clinic induction is either rituximab and bendamustine (without rituximab maintenance) or zanubrutinib. MANAGEMENT OF REFRACTORY DISEASE: Bortezomib, cyclophosphamide, fludarabine, thalidomide, everolimus, pirtobrutinib, carfilzomib, lenalidomide, bendamustine, and venetoclax have all been shown to have activity in relapsed WM. Given WM's natural history, the reduction of therapy toxicity is an important part of treatment selection. Most patients succumb to causes unrelated to macroglobulinemia.
4Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia.PubMed
Roger G Owen, Steven P Treon, Ayad Al-Katib, et al.
Semin Oncol. 2003 Apr;30(2):110-5. doi: 10.1053/sonc.2003.50082.
This presentation represents consensus recommendations for the clinicopathological definition of Waldenstrom's macroglobulinemia (WM), which were prepared in conjunction with the Second International Workshop held in Athens, Greece during September 2002. WM is an uncommon lymphoproliferative disorder characterized primarily by bone marrow infiltration and IgM monoclonal gammopathy. It should be considered a distinct clinicopathological entity rather than a clinical syndrome secondary to IgM secretion. The underlying pathological diagnosis in WM is lymphoplasmacytic lymphoma as defined by the World Health Organization (WHO) and Revised European-American Lymphoma (REAL) classification criteria. The concentration of monoclonal IgM can vary widely in WM and it is not possible to define a concentration that reliably distinguishes WM from monoclonal gammopathy of undetermined significance (MGUS) and other lymphoproliferative disorders. A diagnosis of WM can therefore be made irrespective of IgM concentration if there is evidence on a bone marrow trephine biopsy of bone marrow infiltration by lymphoplasmacytic lymphoma with predominantly an intertrabecular pattern, supported by appropriate immunophenotypic studies. Simple criteria to distinguish patients with symptomatic WM who require therapy from those with asymptomatic WM and MGUS were also proposed. Patients with clinical features attributable to IgM monoclonal gammopathy but no overt evidence of lymphoma are considered to constitute a distinct clinical group and the term "IgM-related disorders" is proposed.
5Waldenström macroglobulinemia.PubMed
K Baďurová, J Gregorová, M Vlachová, et al.
Klin Onkol. 2021 Fall;34(6):428-433. doi: 10.48095/ccko2021428.
BACKGROUND: Waldenström macroglobulinemia (WM) is a hematological malignancy; it is a monoclonal gammopathy, a disease characterized by presence of a monoclonal immunoglobulin in serum and/or urine. The median age at dia-gnosis is 71 years. WM is not an aggres-sive disease and patients with this dia-gnosis can live for several years. Infiltration of the bone marrow with lymphoplasmacytoid cells causes anemia, leading to various problems, mainly fatigue. Hepatomegaly, splenomegaly and lymphadenopathy can also occur. Hyperviscosity syndrome can appear and is caused by excessive production of immunoglobulin M. A mutation in MYD88 gene is detected in almost every WM patient, and in almost one third of them, a mutation in CXCR4 gene is detected. The detection of MYD88 mutation is important for a correct therapeutic strategy, since a Brutons tyrosine kinase inhibitor, ibrutinib, is most effective in patients with mutated MYD88 and wt CXCR4. The therapy is started when first symptoms occur. PURPOSE: The aim of this study is to summarize current knowledge about this disease, its dia-g-nostics, molecular basis and treatment.
6Waldenström's macroglobulinemia: clinical course and prognostic factors in 60 patients. Experience from a single hematology unit.PubMed
M C Kyrtsonis, T P Vassilakopoulos, M K Angelopoulou, et al.
Ann Hematol. 2001 Dec;80(12):722-7. doi: 10.1007/s00277-001-0385-8. Epub 2001 Oct 30.
Waldenström's macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by the presence in patients' serum of an IgM monoclonal component. We report on our experience with 60 WM patients, focusing on their clinical findings, response to treatment, and the possible identification of prognostic factors. Of these patients, 70% presented with fatigue, and lymphadenopathy was observed in 22%, splenomegaly in 18%, hepatomegaly in 13%, and extranodal site of involvement in 6%. Bleeding tendency was seen in 17%, infections in 17%, hyperviscosity syndrome in 12%, and cardiac failure in 25% of the patients. The median of IgM levels was 30 g/l with hypoalbuminemia in 20% of cases, hypogammaglobulinemia in 27%, polyclonal hypergammaglobulinemia in 15%, kappa light-chain restriction in 78%, and Bence-Jones proteinuria in 54%. Anemia was frequent (85%), followed by leukocytosis (18%), lymphocytosis (12%), leukopenia (10%), and thrombocytopenia (10%). Cryoglobulinemia and autoimmune hemolytic anemia were encountered in 5%. In all cases but two, bone marrow was involved. Of 50 patients initially treated with intermittent oral chlorambucil, 46 (92%) responded. Median overall survival was 108 months. Factors associated with adverse prognosis were age > or =65 years (p=0.06), presence of lymphadenopathy (p=0.06), bone marrow infiltration > or =50% (p=0.007), international prognostic index (IPI) > or =3 (p=0.0001), and Morel's scoring system (p=0.04). Concluding, we found in this series of WM patients that chlorambucil is an effective treatment and that the parameters of age, lymphadenopathy, percentage of bone marrow infiltration, IPI, and Morel's scoring system carry prognostic significance.
7Simple headache revealed a rare lymphoma: Waldenstrom macroglobulinemia with unique markers: a case report and review of the literature.PubMed
Ahmed K Awad, Merihan A Elbadawy, Maty Boury, et al.
J Egypt Natl Canc Inst. 2022 Mar 7;34(1):10. doi: 10.1186/s43046-022-00107-6.
BACKGROUND: Waldenstrom macroglobulinemia (WM) is a rare lymphoma with an incidence rate of 3 per million people per year, with approximately 1000 to 1500 new cases diagnosed each year in the USA. It is primarily seen in Caucasian males with a median age of 70 years old. Patients are most often asymptomatic, but WM can manifest itself with constitutional symptoms such as lethargy, bleeding, organomegaly, and neurological or fundoscopic abnormalities. WM is characterized by immunoglobulin M (IgM) monoclonal gammopathy, lymphocytic infiltration of bone marrow, and normocytic anemia due to bone marrow replacement. CASE PRESENTATION: Our patient is a Hispanic 67-year-old female that presents with one month of intermittent band-like bilateral headache accompanied by dizziness, light-headedness, nausea, and blurred vision. A thorough diagnostic workup was performed, including serum protein electrophoresis (SPEP) with serum immunofixation (SIFE) showing an M spike and IgM kappa. Bone marrow biopsy was significant for lymphoplasmacytic infiltration with nodular B cells (CD19+, CD20+, CD22+). Computerized Tomography (CT) imaging showed splenomegaly in the patient. Treatment was provided for hyperviscosity syndrome with plasmapheresis twice. The patient reported improvement of her symptoms and was then scheduled for chemotherapy. Throughout 7 months, our patient received multiple cycles of bortezomib, dexamethasone, and rituximab. While her symptoms improved her psychiatric status got progressively worse. CONCLUSION: It is important not to neglect symptoms such as a headache, which may seem small, but could serve as a clue in the diagnosis of Waldenstrom's macroglobulinemia.
8Clinical and clonal characteristics of monoclonal immunoglobulin M-associated type I cryoglobulinaemia.PubMed
Jahanzaib Khwaja, Josephine M I Vos, Tessa E Pluimers, et al.
Br J Haematol. 2024 Jan;204(1):177-185. doi: 10.1111/bjh.19112. Epub 2023 Sep 19.
Monoclonal immunoglobulin M-associated type I cryoglobulinaemia is poorly characterised. We screened 534 patients with monoclonal IgM disorders over a 9-year period and identified 134 patients with IgM type I cryoglobulins. Of these, 76% had Waldenström macroglobulinaemia (WM), 5% had other non-Hodgkin lymphoma (NHL) and 19% had IgM monoclonal gammopathy of undetermined significance (MGUS). Clinically relevant IgM-associated disorders (including cold agglutinin disease [CAD], anti-MAG antibodies, amyloidosis and Schnitzler syndrome) coexisted in 31%, more frequently in MGUS versus WM/NHL (72% vs. 22%/29%, p < 0.001). The majority of those with cryoglobulins and coexistent CAD/syndrome had the molecular characteristics of a CAD clone (wild-type MYD88 in 80%). A half of all patients had active manifestations at cryoglobulin detection: vasomotor (22%), cutaneous (16%), peripheral neuropathy (22%) and hyperviscosity (9%). 16/134 required treatment for cryoglobulin-related symptoms alone at a median of 38 days (range: 6-239) from cryoglobulin detection. At a median follow-up of 3 years (range: 0-10), 3-year cryoglobulinaemia-treatment-free survival was 77% (95% CI: 68%-84%). Age was the only predictor of overall survival. Predictors of cryoglobulinaemia-related treatment/death were hyperviscosity (HR: 73.01; 95% CI: 15.62-341.36, p < 0.0001) and cutaneous involvement (HR: 2.95; 95% CI: 1.13-7.71, p = 0.028). Type I IgM cryoglobulinaemia is more prevalent than previously described in IgM gammopathy and should be actively sought.
9Paraproteinemic neuropathies.PubMed
A Vital
Brain Pathol. 2001 Oct;11(4):399-407. doi: 10.1111/j.1750-3639.2001.tb00407.x.
The occurrence of a peripheral neuropathy (PN) in association with a monoclonal gammopathy is quite common and suggests that monoclonal proteins may play a pathogenetic role in peripheral nervous system damage. In fact, paraproteinemic PN constitute an heterogeneous group of disorders related to various pathogenetic factors, and the histopathologic features in peripheral nerve biopsies differ from one condition to another. In several well defined disorders, the responsibility of the monoclonal component in the development of the PN has been evidenced. This is the case for most of the PN associated with an IgM monoclonal gammopathy, either a monoclonal gammopathy of undetermined significance (MGUS) or Waldenstrom's macroglobulinemia. The responsibility of the monoclonal protein in the occurrence of amyloid neuropathy related to multiple myeloma is also recognized. However, most IgG or IgA MGUS, as well as the monoclonal component in POEMS syndrome, have an uncertain causal relationship with the neuropathy. PN associated with monoclonal cryoglobulin (type 1) are occasional and differ from those associated with mixed cryoglobulins (types 2 or 3).
10Paraproteinemic neuropathies.PubMed
Jebin M Chacko, Warren D Spinner
J Clin Neuromuscul Dis. 2006 Jun;7(4):185-97. doi: 10.1097/01.cnd.0000211403.02069.9f.
Paraproteinemic neuropathies comprise a diverse group of disorders that includes monoclonal gammopathy of undetermined significance, primary amyloidosis, multiple myeloma, cryoglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) syndrome, and Waldenstrom macroglobulinemia. Various factors including hepatitis C virus, vascular endothelial growth factor, and an array of cytokines are implicated in the pathogenesis of these conditions. More recently, a variety of novel antibody specificities, and vasculitis, have also been described as contributory factors in the development of these neuropathies. Therapeutic approaches for paraproteinemic neuropathies have included administration of cytotoxic agents, steroids, interferon-alpha, intravenous immunoglobulin, radiation, bone marrow transplantation, and more recently, drugs such as rituximab and bevacizumab. In this article, we review some of the well-known features of these diseases, and highlight some of the more recent findings from the vast literature for these diseases.
11Pathogenesis and morbidity of autoantibody syndromes in Waldenstrom's macroglobulinemia.PubMed
Marvin J Stone
Clin Lymphoma Myeloma Leuk. 2011 Feb;11(1):157-9. doi: 10.3816/CLML.2011.n.037.
A number of autoantibody syndromes have been identified that are mediated by monoclonal macroglobulins. Chronic cold agglutinin disease (CAD), mixed cryoglobulinemia (MC), and various polyneuropathies produce symptoms and signs such as cold sensitivity and sensorimotor neuropathies that bring the patients to attention ("the patients tell you"). Many of these patients would be classified as having monoclonal gammopathy of undetermined significance (MGUS) were it not for the consequences of antigen-antibody interaction. Other patients with autoantibody syndromes have overt Waldenström's macroglobulinemia (WM). These individuals present at an earlier stage than WM patients who do not have evident antibody activity. Thus the presence of autoreactive antibodies influences clinical presentation and natural history of the disorder. The frequency of monoclonal IgMs with functional antibody activity is unknown. The principal problem is detection. New methods have been described which may more precisely identify the antigens reacting with M-proteins. Some "autoimmune" disorders may represent cross-reactions to exogenous antigens. Elucidation of antigens reacting with monoclonal IgM proteins may provide important insights into the pathogenesis of WM.
12IgM monoclonal gammopathies of clinical significance: diagnosis and management.PubMed
Jahanzaib Khwaja, Shirley D'Sa, Monique C Minnema, et al.
Haematologica. 2022 Sep 1;107(9):2037-2050. doi: 10.3324/haematol.2022.280953.
IgM monoclonal gammopathy of undetermined significance is a pre-malignant condition for Waldenström macroglobulinemia and other B-cell malignancies, defined by asymptomatic circulating IgM monoclonal protein below 30 g/L with a lymphoplasmacytic bone marrow infiltration of less than 10%. A significant proportion, however, develop unique immunological and biochemical manifestations related to the monoclonal protein itself in the absence of overt malignancy and are termed IgM-related disorders or, more recently, monoclonal gammopathy of clinical significance. The indication for treatment in affected patients is dictated by the pathological characteristics of the circulating IgM rather than the tumor itself. The clinical workup and treatment options vary widely and differ from those for Waldenström macroglobulinemia. The aim of this review is to alert clinicians to IgM monoclonal gammopathy of clinical significance and to provide practical guidance on when to screen for these phenotypes. We discuss clinical characteristics, the underlying clonal profile, diagnostic workup and treatment considerations for five important subtypes: cold agglutinin disease, type I and II cryoglobulinemia, IgM-associated peripheral neuropathy, Schnitzler syndrome and IgM-associated AL amyloidosis. The inhibition of the pathogenic effects of the IgM has led to great success in cold agglutinin disease and Schnitzler syndrome, whereas the other treatments are centered on eradicating the underlying clone. Treatment approaches in cryoglobulinemia and IgM-associated peripheral neuropathy are the least well developed. A multidisciplinary approach is required, particularly for IgM-related neuropathies and Schnitzler syndrome. Future work exploring novel, clone-directed agents and pathogenic IgM-directed therapies is welcomed.
13The epidemiology of Waldenström macroglobulinemia.PubMed
Mary L McMaster
Semin Hematol. 2023 Mar;60(2):65-72. doi: 10.1053/j.seminhematol.2023.03.008. Epub 2023 Mar 31.
Waldenström macroglobulinemia (WM) is a rare subtype of non-Hodgkin lymphoma characterized by the presence of lymphoplasmacytic lymphoma (LPL) in the bone marrow accompanied by a monoclonal immunoglobulin type M (IgM) in the serum. WM was first described only 80 years ago and became reportable in the US as a malignancy in 1988. Very little systematic research was conducted prior to 2000 to characterize incidence, clinical characteristics, risk factors or diagnostic and prognostic criteria, and there were essentially no WM-specific clinical interventional trials. Since the inaugural meeting of the International Workshop in Waldenström's Macroglobulinemia (IWWM) in 2000, WM has become the focus of a steadily increasing and productive body of research, engaging a growing number of investigators throughout the world. This introductory overview provides summary of the current understanding of the epidemiology of WM/LPL as a backdrop for a series of consensus panel recommendations arising from research presented at the 11th IWWM.
14[Waldenström macroglobulinemia: Japanese perception].PubMed
Naohiro Sekiguchi
Rinsho Ketsueki. 2019;60(8):988-997. doi: 10.11406/rinketsu.60.988.
Waldenström macroglobulinemia (WM) is a rare low-grade B-cell lymphoma. This report focuses on WM in Japan. Regarding epidemiology, per the 2016 registry data by the Japanese Society of Hematology, WM and lymphoplasmacytic lymphoma (LPL) cases were 229 and 125, respectively (1.97% of 17,957 mature lymphoid malignancies), with the annual incidence of WM/LPL in Japan 2.8 per million. In addition, 6q deletion (6q del) is the leading aberration and one of the poor prognostic factors in WM. Our findings suggested that the serum IgM level was higher in WM with 6q del compared with those without, and the B-cell receptor signaling pathway and IL-21 receptor expression were activated in WM with 6q del. Hence, these findings might be attributed to the aggressiveness of the WM with 6q del. Regarding treatment, recent studies investigating the epidemiological treatment pattern for WM have reported rituximab (R) monotherapy and alkylating regimen (±R) as the leading initial treatment. Nevertheless, ideal treatment algorithm in Japan warrants further investigation.
15Waldenström Macroglobulinemia - A State-of-the-Art Review: Part 1: Epidemiology, Pathogenesis, Clinicopathologic Characteristics, Differential Diagnosis, Risk Stratification, and Clinical Problems.PubMed
Michele Bibas, Shayna Sarosiek, Jorge J Castillo
Mediterr J Hematol Infect Dis. 2024 Jul 1;16(1):e2024061. doi: 10.4084/MJHID.2024.061. eCollection 2024.
Waldenström macroglobulinemia (WM) is an infrequent variant of lymphoma, classified as a B-cell malignancy identified by the presence of IgM paraprotein, infiltration of clonal, small lymphoplasmacytic B cells in the bone marrow, and the MYD88 L265P mutation, which is observed in over 90% of cases. The direct invasion of the malignant cells into tissues like lymph nodes and spleen, along with the immune response related to IgM, can also lead to various health complications, such as cytopenias, hyperviscosity, peripheral neuropathy, amyloidosis, and Bing-Neel syndrome. Chemoimmunotherapy has historically been considered the preferred treatment for WM, wherein the combination of rituximab and nucleoside analogs, alkylating drugs, or proteasome inhibitors has exhibited notable efficacy in inhibiting tumor growth. Recent studies have provided evidence that Bruton Tyrosine Kinase inhibitors (BTKI), either used independently or in conjunction with other drugs, have been shown to be effective and safe in the treatment of WM. The disease is considered to be non-curable, with a median life expectancy of 10 to 12 years.
16Cardiovascular Risk Factors: Does Sex Matter?PubMed
Gretchen L Wells
Curr Vasc Pharmacol. 2016;14(5):452-457. doi: 10.2174/1570161114666160722113116.
Coronary heart disease (CHD) is the leading cause of death for women worldwide, most of which is believed to be preventable. Numerous risk factors for CHD are well described, and understanding these risk factors is the first step to reducing the burden of CHD. There are clear differences in risk factors between women and men. The incidence of myocardial infarction is much lower among women under the age of 50 years compared with men, but after menopause, the incidence in women dramatically increases to approach that of men. For this reason, estrogen is postulated to be cardioprotective but results of recent randomized clinical trials challenge this hypothesis. The significance of cardiovascular risk factors appears to vary between women and men, the reasons for which remain elusive but could include the interaction of these risk factors with hormones. Confounding this observation is that most early studies of cardiovascular risk factors enrolled primarily men. This review will focus solely on the differences in cardiovascular risk factors in women and men including the current role of hormone therapy in CHD prevention, sex differences in established CHD risk factors and emerging risk factors for CHD in women.
17Sex Differences in Epidemiology of Cardiac and Vascular Disease.PubMed
Tatiana Kuznetsova
Adv Exp Med Biol. 2018;1065:61-70. doi: 10.1007/978-3-319-77932-4_4.
In spite of a remarkable decline in death rates from cardiovascular disease (CVD) observed over the last decades, CVD still remains the leading cause of mortality in both men and women worldwide. Overall the age-adjusted CVD mortality and morbidity rates are highest in men than in women. However, the risk of CVD in women should not be underestimated given that approximately one of two women in developed countries will die of mostly preventable heart diseases or stroke. Although men and women share the same cardiovascular risk factors, there are substantial sex differences in the first manifestation and clinical presentation of CVD. In this part of the chapter, we will discuss the recent epidemiological data on sex discrepancies in the prevalence and burden of different CVDs.
18A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4.PubMed
Laia Alsina, Elisabeth Israelsson, Matthew C Altman, et al.
Nat Immunol. 2014 Dec;15(12):1134-42. doi: 10.1038/ni.3028. Epub 2014 Oct 26.
Loss of function of the kinase IRAK4 or the adaptor MyD88 in humans interrupts a pathway critical for pathogen sensing and ignition of inflammation. However, patients with loss-of-function mutations in the genes encoding these factors are, unexpectedly, susceptible to only a limited range of pathogens. We employed a systems approach to investigate transcriptome responses following in vitro exposure of patients' blood to agonists of Toll-like receptors (TLRs) and receptors for interleukin 1 (IL-1Rs) and to whole pathogens. Responses to purified agonists were globally abolished, but variable residual responses were present following exposure to whole pathogens. Further delineation of the latter responses identified a narrow repertoire of transcriptional programs affected by loss of MyD88 function or IRAK4 function. Our work introduces the use of a systems approach for the global assessment of innate immune responses and the characterization of human primary immunodeficiencies.
19Genomic Landscape of Waldenström Macroglobulinemia and Its Impact on Treatment Strategies.PubMed
Steven P Treon, Lian Xu, Maria Luisa Guerrera, et al.
J Clin Oncol. 2020 Apr 10;38(11):1198-1208. doi: 10.1200/JCO.19.02314. Epub 2020 Feb 21.
Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM), including (95%-97%), (30%-40%), (17%), and (8%-15%). Deletions involving chromosome 6q are common in patients with mutated and include genes that modulate NFKB, BCL2, Bruton tyrosine kinase (BTK), and apoptosis. Patients with wild-type WM show an increased risk of transformation and death and exhibit many mutations found in diffuse large B-cell lymphoma. The discovery of and mutations in WM has facilitated rational drug development, including the development of BTK and CXCR4 inhibitors. Responses to many agents commonly used to treat WM, including the BTK inhibitor ibrutinib, are affected by and/or mutation status. The mutation status of both and can be used for a precision-guided treatment approach to WM.
20MYD88 L265P mutation in Waldenstrom macroglobulinemia.PubMed
Stéphanie Poulain, Christophe Roumier, Audrey Decambron, et al.
Blood. 2013 May 30;121(22):4504-11. doi: 10.1182/blood-2012-06-436329. Epub 2013 Mar 26.
Mutation of the MYD88 gene has recently been identified in activated B-cell-like diffuse cell lymphoma and enhanced Janus kinase/signal transducer and activator of transcription (JAK-STAT) and nuclear factor κB (NF-κB) signaling pathways. A whole exome-sequencing study of Waldenstrom macroglobulinemia (WM) suggested a high frequency of MYD88 L265P mutation in WM. The genetic background is not fully deciphered in WM, although the role of NF-κB and JAK-STAT has been demonstrated. We analyzed MYD88 mutation in exon 5 and characterized the clinical significance of this genetic alteration in 67 WM patients. Clinical features; immunophenotypic markers; and conventional cytogenetic, fluorescence in situ hybridization, and single nucleotide polymorphism array data were analyzed. MYD88 L265P mutation was acquired in 79% of patients. Overall, we have identified alteration of the MYD88 locus in 91% of WM patients, including 12% with gain on chromosome 3 at the 3p22 locus that included the MYD88 gene. Patients with absence of MYD88 mutation were WM characterized with a female predominance, a splenomegaly, gain of chromosome 3, and CD27 expression. Importantly, inhibition of MYD88 signaling induced cytotoxicity and inhibited cell growth of cell lines issued from patients with WM. In conclusion, these results confirm a high frequency of MYD88 L265P mutation in WM. The discovery of MYD88 L265P mutation may contribute to a better understanding of the physiopathogeny of WM.
21Targeting Myddosome Signaling in Waldenström's Macroglobulinemia with the Interleukin-1 Receptor-Associated Kinase 1/4 Inhibitor R191.PubMed
Haiwen Ni, Fazal Shirazi, Veerabhadran Baladandayuthapani, et al.
Clin Cancer Res. 2018 Dec 15;24(24):6408-6420. doi: 10.1158/1078-0432.CCR-17-3265. Epub 2018 Aug 20.
PURPOSE: Waldenström's macroglobulinemia is an incurable lymphoproliferative disorder driven by an L265P mutation in the myeloid differentiation primary response gene 88 (), which activates downstream NF-κB signaling through the Myddosome. As this pathway depends in part on activity of interleukin-1 receptor-associated kinases (IRAKs)-1 and -4, we sought to evaluate the potential of the IRAK1/4 inhibitor R191 in preclinical models. EXPERIMENTAL DESIGN: Patient-derived cell lines and primary samples were used in both and experiments to model Waldenström's macroglobulinemia and its response to IRAK1/4 inhibitors. RESULTS: R191 induced a dose- and time-dependent reduction in viability of BCWM.1 and MWCL-1 Waldenström's cell lines, and suppressed activation of IRAK1/4. This was associated with cell-cycle arrest at G-G, reduced levels of cyclin-dependent kinases 4 and 6, and induction of apoptosis in cell lines and primary patient samples. Further downstream, R191 exposure led to reduced activation of NF-κB, and of protein kinase B/Akt/mammalian target of rapamycin signaling, whereas expression of a constitutively active Akt mutant induced R191 resistance. Gene expression profiling and gene set enrichment analysis revealed a signature consistent with inhibition of c-Myc and activation of the endoplasmic reticulum stress response. In both subcutaneous and systemic murine models of Waldenström's, R191 showed antitumor activity. Finally, the activity of R191 was enhanced when it was combined with novel chemotherapeutics such as bortezomib, afuresertib, and ibrutinib. CONCLUSIONS: Taken together, these data support the translation of R191 as an approach to target IRAK1/4 to the clinic for patients with Waldenström's macroglobulinemia.
22Targeting NF-kappaB in Waldenstrom macroglobulinemia.PubMed
Xavier Leleu, Jérôme Eeckhoute, Xiaoying Jia, et al.
Blood. 2008 May 15;111(10):5068-77. doi: 10.1182/blood-2007-09-115170. Epub 2008 Mar 11.
The nuclear factor-kappaB (NF-kappaB) path-way has been implicated in tumor B-cell survival, growth, and resistance to therapy. Because tumor cells overcome single-agent antitumor activity, we hypothesized that combination of agents that target differentially NF-kappaB pathway will induce significant cytotoxicity. Therapeutic agents that target proteasome and Akt pathways should induce significant activity in B-cell malignancies as both pathways impact NF-kappaB activity. We demonstrated that perifosine and bortezomib both targeted NF-kappaB through its recruitment to the promoter of its target gene IkappaB using chromatin immunoprecipitation assay. This combination led to synergistic cytotoxicity in Waldenstrom macroglobulinemia (WM) cells that was mediated through a combined reduction of the PI3K/Akt and ERK signaling pathways, found to be critical for survival of WM cells. Moreover, a combination of these drugs with the CD20 monoclonal antibody rituximab further increased their cytotoxic activity. Thus, effective WM therapy may require combination regimens targeting the NF-kappaB pathway.
23Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom's macroglobulinemia.PubMed
Esteban Braggio, Jonathan J Keats, Xavier Leleu, et al.
Cancer Res. 2009 Apr 15;69(8):3579-88. doi: 10.1158/0008-5472.CAN-08-3701. Epub 2009 Apr 7.
Waldenström's macroglobulinemia (WM) is a distinct clinicobiological entity defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in bone marrow (BM) and IgM paraprotein production. Cytogenetic analyses were historically limited by difficulty in obtaining tumor metaphases, and the genetic basis of the disease remains poorly defined. Here, we performed a comprehensive analysis in 42 WM patients by using a high-resolution, array-based comparative genomic hybridization approach to unravel the genetic mechanisms associated with WM pathogenesis. Overall, 83% of cases have chromosomal abnormalities, with a median of three abnormalities per patient. Gain of 6p was the second most common abnormality (17%), and its presence was always concomitant with 6q loss. A minimal deleted region, including MIRN15A and MIRN16-1, was delineated on 13q14 in 10% of patients. Of interest, we reported biallelic deletions and/or inactivating mutations with uniparental disomy in tumor necrosis factor (TNF) receptor-associated factor 3 and TNFalpha-induced protein 3, two negative regulators of the nuclear factor-kappaB (NF-kappaB) signaling pathway. Furthermore, we confirmed the association between TRAF3 inactivation and increased transcriptional activity of NF-kappaB target genes. Mutational activation of the NF-kappaB pathway, which is normally activated by ligand receptor interactions within the BM microenvironment, highlights its biological importance, and suggests a therapeutic role for inhibitors of NF-kappaB pathway activation in the treatment of WM.
24Expression of the prosurvival kinase HCK requires PAX5 and mutated MYD88 signaling in MYD88-driven B-cell lymphomas.PubMed
Xia Liu, Jiaji G Chen, Manit Munshi, et al.
Blood Adv. 2020 Jan 14;4(1):141-153. doi: 10.1182/bloodadvances.2019000947.
Hematopoietic cell kinase (HCK) is an SRC family member that is aberrantly upregulated in B-cell neoplasms dependent on MYD88-activating mutations and supports their growth and survival. We showed herein that activation of Toll-like receptor (TLR) signaling in MYD88 wild-type B cells also triggered HCK expression, denoting on path regulatory function for HCK by MYD88. To clarify the signaling cascades responsible for aberrant HCK expression in MYD88-mutated B-cell lymphomas, we performed promoter-binding transcription factor (TF) profiling, PROMO weighted TF consensus binding motif analysis, and chromatin immunoprecipitation studies. We identified PAX5, and the mutated MYD88 downstream signaling mediators STAT3, NF-κB, and AP-1, as important drivers of HCK transcription. Knockdown of PAX5, a crucial regulatory factor required for B-cell commitment and identity, abrogated HCK transcription in MYD88-mutated lymphoma cells. Among AP-1 complex components, JunB showed greatest relevance to TLR/MYD88 signaling and HCK transcription regulation. In MYD88-mutated Waldenström macroglobulinemia and activated B-cell-diffuse large B-cell lymphoma cells, knockdown of MYD88 reduced phosphorylation of JunB but not c-Jun, and knockdown of JunB reduced HCK protein levels. Deletion of STAT3, NF-κB, and AP-1 binding sites reduced corresponding TFs binding and HCK promoter activity. Moreover, inhibitors to STAT3, NF-κB, and AP-1 reduced HCK promoter activity and messenger RNA levels, particularly in combination, in MYD88-mutated lymphoma cells. The findings provide new insights into the transcriptional regulation of HCK prosurvival signaling by mutated MYD88, and the importance of JunB as a downstream mediator of the MYD88-directed signaling apparatus.
25Targeting the immune microenvironment in Waldenström macroglobulinemia via halting the CD40/CD40-ligand axis.PubMed
Antonio Sacco, Vanessa Desantis, Jon Celay, et al.
Blood. 2023 May 25;141(21):2615-2628. doi: 10.1182/blood.2022019240.
Recent investigations have improved our understanding of the molecular aberrations supporting Waldenström macroglobulinemia (WM) biology; however, whether the immune microenvironment contributes to WM pathogenesis remains unanswered. First, we showed how a transgenic murine model of human-like lymphoplasmacytic lymphoma/WM exhibits an increased number of regulatory T cells (Tregs) relative to control mice. These findings were translated into the WM clinical setting, in which the transcriptomic profiling of Tregs derived from patients with WM unveiled a peculiar WM-devoted messenger RNA signature, with significant enrichment for genes related to nuclear factor κB-mediated tumor necrosis factor α signaling, MAPK, and PI3K/AKT, which was paralleled by a different Treg functional phenotype. We demonstrated significantly higher Treg induction, expansion, and proliferation triggered by WM cells, compared with their normal cellular counterpart; with a more profound effect within the context of CXCR4C1013G-mutated WM cells. By investigating the B-cell-to-T-cell cross talk at single-cell level, we identified the CD40/CD40-ligand as a potentially relevant axis that supports WM cell-Tregs interaction. Our findings demonstrate the existence of a Treg-mediated immunosuppressive phenotype in WM, which can be therapeutically reversed by blocking the CD40L/CD40 axis to inhibit WM cell growth.
26C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma.PubMed
Aldo M Roccaro, Antonio Sacco, Cristina Jimenez, et al.
Blood. 2014 Jun 26;123(26):4120-31. doi: 10.1182/blood-2014-03-564583. Epub 2014 Apr 7.
The C-X-C chemokine receptor type 4 (CXCR4) plays a crucial role in modulating cell trafficking in hematopoietic stem cells and clonal B cells. We screened 418 patients with B-cell lymphoproliferative disorders and described the presence of the C1013G/CXCR4 warts, hypogammaglobulinemia, infections, and myelokathexis-associated mutation in 28.2% (37/131) of patients with lymphoplasmacytic lymphoma (Waldenström macroglobulinemia [WM]), being either absent or present in only 7% of other B-cell lymphomas. In vivo functional characterization demonstrates its activating role in WM cells, as demonstrated by significant tumor proliferation and dissemination to extramedullary organs, leading to disease progression and decreased survival. The use of a monoclonal antibody anti-CXCR4 led to significant tumor reduction in a C1013G/CXCR4 WM model, whereas drug resistance was observed in mutated WM cells exposed to Bruton's tyrosine kinase, mammalian target of rapamycin, and phosphatidylinositol 3-kinase inhibitors, but not proteasome inhibitors. These findings demonstrate that C1013G/CXCR4 is an activating mutation in WM and support its role as a critical regulator of WM molecular pathogenesis and as an important therapeutic target.
27Current approach to Waldenström macroglobulinemia.PubMed
Prashant Kapoor, S Vincent Rajkumar
Blood Rev. 2023 Nov;62:101129. doi: 10.1016/j.blre.2023.101129. Epub 2023 Aug 26.
Waldenström macroglobulinemia (WM) is a unique CD20+, B-cell non-Hodgkin lymphoma, characterized by lymphoplasmacytic infiltration of the bone marrow and circulating monoclonal immunoglobulin M. The clinical manifestations and outcomes of patients are highly variable. High-level evidence supports integration of monoclonal anti-CD20 antibody, rituximab, to the chemotherapy backbone to treat WM. However, its contemporary management has become more nuanced, with deeper understanding of the pathophysiology and incorporation of Bruton's tyrosine kinase (BTK) inhibitors to the treatment paradigm. Prior knowledge of the patients' MYD88 and CXCR4 mutation status may aid in the treatment decision-making. Currently, the two frequently utilized approaches include fixed-duration chemoimmunotherapy and BTK inhibitor-based continuous treatment until progression. Randomized trials comparing these two vastly divergent approaches are lacking. Recent studies demonstrating efficacy of B cell lymphoma-2 (BCL2) inhibitors and non-covalent BTK inhibitors in patients, previously exposed to a covalent BTK inhibitor, are a testament to the rapidly expanding options against WM.
28The Bone Marrow Microenvironment in Waldenström Macroglobulinemia.PubMed
Shahrzad Jalali, Stephen M Ansell
Hematol Oncol Clin North Am. 2018 Oct;32(5):777-786. doi: 10.1016/j.hoc.2018.05.005. Epub 2018 Jul 25.
Waldenström macroglobulinemia (WM) is an indolent B-cell lymphoma defined predominantly by infiltration of lymphoplasmacytic cells into the bone marrow (BM) and increased production of monoclonal immunoglobulin M (IgM) by lymphoplasmacytic cells, and the secretion of IgM is enhanced by cytokines in the bone marrow microenvironment. This article highlights the available data regarding the interaction of WM cells with both the cellular and noncellular compartments of the BM microenvironment and discusses how the BM promotes malignant cell growth and increases IgM production in this disease.
29Bone marrow microenvironment in Waldenstrom's Macroglobulinemia.PubMed
Shahrzad Jalali, Stephen M Ansell
Best Pract Res Clin Haematol. 2016 Jun;29(2):148-155. doi: 10.1016/j.beha.2016.08.016. Epub 2016 Sep 4.
Waldenstrom Macroglobulinemia (WM) is a low-grade B-cell lymphoma defined firstly by infiltration of lymphoplasmacytic cells into the bone marrow (BM), the milieu where the cells acquire signals that promote malignant growth and proliferation. A second characteristic associated with WM is the increased synthesis of monoclonal immunoglobulin M (IgM) by lymphoplasmacytic cells, which is secreted in the serum and often results in hyperviscosity. Advanced genomic tools have improved our understanding of the genetic events that contribute to malignant transformation in WM, but the role of BM microenvironment is also emerging as having an essential role in WM disease progression. Therefore, delineation of malignant WM cell growth in the context of its microenvironment would benefit the design of more efficient therapeutic strategies. Here, we highlight available data regarding the interaction of the WM cells with the cellular and non-cellular compartments of the BM and discuss how BM provides a permissive environment for WM cell growth and proliferation.
30Eph-B2/ephrin-B2 interaction plays a major role in the adhesion and proliferation of Waldenstrom's macroglobulinemia.PubMed
Feda Azab, Abdel Kareem Azab, Patricia Maiso, et al.
Clin Cancer Res. 2012 Jan 1;18(1):91-104. doi: 10.1158/1078-0432.CCR-11-0111. Epub 2011 Oct 18.
PURPOSE: The ephrin receptors (Eph) are found in a wide range of cancers and correlate with metastasis. In this study, we characterized the role of Eph-B2 receptor in the interaction of Waldenstrom's macroglobulinemia (WM) cells with the bone marrow microenvironment. EXPERIMENTAL DESIGN: We screened the activity of different receptor tyrosine kinases in WM patients and found that Eph-B2 was overexpressed compared with control. Also, we tested the expression of ephrin-B2 ligand on endothelial cells and bone marrow stromal cells (BMSC) isolated from WM patients. We then tested the role of Eph-B2/Ephrin-B2 interaction in the adhesion of WM cells to endothelial cells and BMSCs; the cell signaling induced by the coculture in both the WM cells and the endothelial cells; WM cell proliferation, apoptosis, and cell cycle in vitro and tumor progression in vivo; and in angiogenesis. RESULTS: Eph-B2 receptor was found to be activated in WM patients compared with control, with a 5-fold increase in CD19(+) WM cells, and activated cell adhesion signaling, including focal adhesion kinase, Src, P130, paxillin, and cofilin, but decreased WM cell chemotaxis. Ephrin-B2 ligand was highly expressed on endothelial cells and BMSCs isolated from WM patients and on human umbilical vein endothelial cells and induced signaling in the endothelial cells promoting adhesion and angiogenesis. Blocking of ephrin-B2 or Eph-B2 inhibited adhesion, cytoskeletal signaling, proliferation, and cell cycle in WM cells, which was induced by coculture with endothelial cells and decreased WM tumor progression in vivo. CONCLUSION: Ephrin-B2/Eph-B2 axis regulates adhesion, proliferation, cell cycle, and tumor progression in vivo through the interaction of WM with the cells in the bone marrow microenvironment.
31Hypoxia promotes dissemination and colonization in new bone marrow niches in Waldenström macroglobulinemia.PubMed
Barbara Muz, Pilar de la Puente, Feda Azab, et al.
Mol Cancer Res. 2015 Feb;13(2):263-72. doi: 10.1158/1541-7786.MCR-14-0150. Epub 2014 Sep 17.
UNLABELLED: Waldenström macroglobulinemia, a rare and indolent type of non-Hodgkin lymphoma, is characterized by widespread lymphoplasmacytic B cells in the bone marrow. Previous studies have shown that hypoxic conditions play a key role in the dissemination of other hematologic malignancies. In this study, the effect of hypoxia was tested on the progression and spread of Waldenström macroglobulinemia. Interestingly, tumor progression correlated with hypoxia levels in Waldenström macroglobulinemia cells and other cells in the bone marrow and correlated with the number of circulating tumor cells in vivo. Mechanistic studies demonstrated that hypoxia decreased cell progression and cell cycle, did not induce apoptosis, and reduced the adhesion between Waldenström macroglobulinemia cells and bone marrow stroma, through downregulation of E-cadherin expression, thus explaining increased egress of Waldenström macroglobulinemia cells to the circulation. Moreover, hypoxia increased the extravasation and homing of Waldenström macroglobulinemia cells to new bone marrow niches in vivo, by increased CXCR4/SDF-1-mediated chemotaxis and maintaining the VLA4-mediated adhesion. Re-oxygenation of hypoxic Waldenström macroglobulinemia cells enhanced the rate of proliferation and cell cycle progression and restored intercellular adhesion between Waldenström macroglobulinemia cells and bone marrow stroma. This study suggests that targeting hypoxic response is a novel strategy to prevent dissemination of Waldenström macroglobulinemia. IMPLICATIONS: This study provides a better understanding of the biology of dissemination of Waldenström macroglobulinemia and opens new windows for investigation of new therapeutic targets in Waldenström macroglobulinemia based on tumor hypoxia mechanisms.
32Expanded tumor-associated polymorphonuclear myeloid-derived suppressor cells in Waldenstrom macroglobulinemia display immune suppressive activity.PubMed
Vaishali Bhardwaj, Zhi-Zhang Yang, Shahrzad Jalali, et al.
Blood Cancer J. 2024 Dec 18;14(1):217. doi: 10.1038/s41408-024-01173-w.
The role of the bone marrow (BM) microenvironment in regulating the antitumor immune response in Waldenstrom macroglobulinemia (WM) remains poorly understood. Here we transcriptionally and phenotypically profiled non-malignant (CD19 CD138) BM cells from WM patients with a focus on myeloid derived suppressive cells (MDSCs) to provide a deeper understanding of their role in WM. We found that HLA-DRCD11bCD33 MDSCs were significantly increased in WM patients as compared to normal controls, with an expansion of predominantly polymorphonuclear (PMN)-MDSCs. Single-cell immunogenomic profiling of WM MDSCs identified an immune-suppressive gene signature with upregulated inflammatory pathways associated with interferon and tumor necrosis factor (TNF) signaling. Gene signatures associated with an inflammatory and immune suppressive environment were predominately expressed in PMN-MDSCs. In vitro, WM PMN-MDSCs demonstrated robust T-cell suppression and their viability and expansion was notably enhanced by granulocyte colony stimulating factor (G-CSF) and TNFα. Furthermore, BM malignant B-cells attracted PMN-MDSCs to a greater degree than monocytic MDSCs. Collectively, these data suggest that malignant WM B cells actively recruit PMN-MDSCs which promote an immunosuppressive BM microenvironment through a direct T cell inhibition, while release of G-CSF/TNFα in the microenvironment further promotes PMN-MDSC expansion and in turn immune suppression. Targeting PMN-MDSCs may therefore represent a potential therapeutic strategy in patients with WM.
33Circulating Soluble Receptor Activator of Nuclear Factor Kappa B Ligand and C-C Motif Ligand 3 Correlate With Survival in Patients With Waldenström Macroglobulinemia.PubMed
Evangelos Eleutherakis-Papaiakovou, Efstathios Kastritis, Maria Gavriatopoulou, et al.
Clin Lymphoma Myeloma Leuk. 2018 Jun;18(6):431-437. doi: 10.1016/j.clml.2018.03.010. Epub 2018 Mar 31.
BACKGROUND: Serum receptor activator of nuclear factor κB ligand (sRANKL) and chemokine (C-C) motif ligand 3 (CCL-3) have been reported to be elevated in Waldenström macroglobulinemia (WM) patients. However, there are no published data regarding the prognostic value of these molecules in WM regarding progression-free and overall survival. METHODS: To evaluate the effect of these markers of bone remodeling on survival parameters, we prospectively evaluated serum cytokines and biological markers in 55 patients with symptomatic WM before they received any kind of treatment. Serum levels of CCL-3 and bone remodeling markers were also evaluated in asymptomatic WM and IgM monoclonal gammopathy of undetermined significance. Furthermore, we assessed bone marrow biopsy samples from newly diagnosed WM patients for CCL-3 and RANKL expression. RESULTS: High circulating sRANKL values predicted shorter median overall survival (46 months vs. not reached, P = .025). High serum levels of CCL-3 predicted shorter median progression-free survival (27 months vs. not reached, P = .048). At bone marrow biopsy evaluation, the whole number of the neoplastic cells revealed strong cytoplasmic positivity for CCL-3, while the neoplastic clone did not express RANKL. CONCLUSION: We conclude that WM cells produce CCL-3 and possibly enhance the production of RANKL in the bone microenvironment. The correlation of sRANKL and CCL-3 with survival reveals the importance of these cytokines in disease biology and highlights the significance of the interactions between WM and stromal cells for the development of WM. Finally, these findings provide the rationale for the use of anti-RANKL and anti-CCL-3 drugs in animal models of WM before their clinical evaluation.
34Dysfunctions of innate and adaptive immune tumor microenvironment in Waldenström macroglobulinemia.PubMed
Danka Cholujova, Gabor Beke, Zachary R Hunter, et al.
Int J Cancer. 2023 May 1;152(9):1947-1963. doi: 10.1002/ijc.34405. Epub 2022 Dec 30.
Waldenström macroglobulinemia (WM) is a rare subtype of non-Hodgkin lymphoma characterized by malignant lymphoplasmacytic cells in the bone marrow (BM). To dissect the pathophysiology of WM, we evaluated clonal cells by mapping of B cell lymphomagenesis with adaptive and innate immune tumor microenvironment (TME) in the BM of WM patients using mass cytometry (CyTOF). In-depth immunophenotypic profiling of WM cells exhibited profound expansion of clonal cells in both unswitched and switched memory B cells and also plasma cells with aberrant expression variations. WM B lymphomagenesis was associated with reduction of most B cell precursors assessed with the same clonally restricted light chain and phenotypic changes. The immune TME was infiltrated by mature monocytes, neutrophils and adaptive T cells, preferentially subsets of effector T helper, effector CTL and effector memory CTL cells that were associated with superior overall survival (OS), in contrast to progenitors of T cells and myeloid/monocytic lineage subsets that were suppressed in WM cohort. Moreover, decrease in immature B and NKT cells was related to worse OS in WM patients. Innate and adaptive immune subsets of WM TME were modulated by immune checkpoints, including PD-1/PD-L1&PD-L2, TIGIT/PVR, CD137/CD137-L, CTLA-4, BTLA and KIR expression. The response of ibrutinib treatment to the reduction of clonal memory B cell was associated with high levels of immature B cells and effector memory CTL cells. Our study demonstrates that CyTOF technology is a powerful approach for characterizing the pathophysiology of WM at various stages, predicting patient risk and monitoring the effectiveness of treatment strategies.
35Single-cell profiles reveal tumor cell heterogeneity and immunosuppressive microenvironment in Waldenström macroglobulinemia.PubMed
Hao Sun, Teng Fang, Tingyu Wang, et al.
J Transl Med. 2022 Dec 9;20(1):576. doi: 10.1186/s12967-022-03798-6.
BACKGROUND: Waldenström macroglobulinemia (WM) is a rare and incurable indolent B-cell malignancy. The molecular pathogenesis and the role of immunosuppressive microenvironment in WM development are still incompletely understood. METHODS: The multicellular ecosystem in bone marrow (BM) of WM were delineated by single-cell RNA-sequencing (scRNA-seq) and investigated the underlying molecular characteristics. RESULTS: Our data uncovered the heterogeneity of malignant cells in WM, and investigated the kinetic co-evolution of WM and immune cells, which played pivotal roles in disease development and progression. Two novel subpopulations of malignant cells, CD19CD3 and CD138CD3, co-expressing T-cell marker genes were identified at single-cell resolution. Pseudotime-ordered analysis elucidated that CD19CD3 malignant cells presented at an early stage of WM-B cell differentiation. Colony formation assay further identified that CD19CD3 malignant cells acted as potential WM precursors. Based on the findings of T cell marker aberrant expressed on WM tumor cells, we speculate the long-time activation of tumor antigen-induced immunosuppressive microenvironment that is involved in the pathogenesis of WM. Therefore, our study further investigated the possible molecular mechanism of immune cell dysfunction. A precursor exhausted CD8-T cells and functional deletion of NK cells were identified in WM, and CD47 would be a potential therapeutic target to reverse the dysfunction of immune cells. CONCLUSIONS: Our study facilitates further understanding of the biological heterogeneity of tumor cells and immunosuppressive microenvironment in WM. These data may have implications for the development of novel immunotherapies, such as targeting pre-exhausted CD8-T cells in WM.
36Epigenetic targeting of Waldenström macroglobulinemia cells with BET inhibitors synergizes with BCL2 or histone deacetylase inhibition.PubMed
Stephan J Matissek, Weiguo Han, Mona Karbalivand, et al.
Epigenomics. 2021 Jan;13(2):129-144. doi: 10.2217/epi-2020-0189. Epub 2020 Dec 24.
Waldenström macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by overproduction of monoclonal IgM. To date, there are no therapies that provide a cure for WM patients, and therefore, it is important to explore new therapies. Little is known about the efficiency of epigenetic targeting in WM. WM cells were treated with BET inhibitors (JQ1 and I-BET-762) and venetoclax, panobinostat or ibrutinib. BET inhibition reduces growth of WM cells, with little effect on survival. This finding was enhanced by combination therapy, with panobinostat (LBH589) showing the highest synergy. Our studies identify BET inhibitors as effective therapy for WM, and these inhibitors can be enhanced in combination with BCL2 or histone deacetylase inhibition.
37Report of consensus Panel 4 from the 11th International Workshop on Waldenstrom's macroglobulinemia on diagnostic and response criteria.PubMed
Steven P Treon, Alessandra Tedeschi, Jesus San-Miguel, et al.
Semin Hematol. 2023 Mar;60(2):97-106. doi: 10.1053/j.seminhematol.2023.03.009. Epub 2023 Apr 20.
Consensus Panel 4 (CP4) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) was tasked with reviewing the current criteria for diagnosis and response assessment. Since the initial consensus reports of the 2nd International Workshop, there have been updates in the understanding of the mutational landscape of IgM related diseases, including the discovery and prevalence of MYD88 and CXCR4 mutations; an improved recognition of disease related morbidities attributed to monoclonal IgM and tumor infiltration; and a better understanding of response assessment based on multiple, prospective trials that have evaluated diverse agents in Waldenstrom's macroglobulinemia. The key recommendations from IWWM-11 CP4 included: (1) reaffirmation of IWWM-2 consensus panel recommendations that arbitrary values for laboratory parameters such as minimal IgM level or bone marrow infiltration should not be used to distinguish Waldenstrom's macroglobulinemia from IgM MGUS; (2) delineation of IgM MGUS into 2 subclasses including a subtype characterized by clonal plasma cells and MYD88 wild-type, and the other by presence of monotypic or monoclonal B cells which may carry the MYD88 mutation; and (3) recognition of "simplified" response assessments that use serum IgM only for determining partial and very good partial responses (simplified IWWM-6/new IWWM-11 response criteria). Guidance on response determination for suspected IgM flare and IgM rebound related to treatment, as well as extramedullary disease assessment was also updated and included in this report.
38How I use genomics and BTK inhibitors in the treatment of Waldenström macroglobulinemia.PubMed
Steven P Treon, Shayna Sarosiek, Jorge J Castillo
Blood. 2024 Apr 25;143(17):1702-1712. doi: 10.1182/blood.2022017235.
Mutations in MYD88 (95%-97%) and CXCR4 (30%-40%) are common in Waldenström macroglobulinemia (WM). TP53 is altered in 20% to 30% of patients with WM, particularly those previously treated. Mutated MYD88 activates hematopoietic cell kinase that drives Bruton tyrosine kinase (BTK) prosurvival signaling. Both nonsense and frameshift CXCR4 mutations occur in WM. Nonsense variants show greater resistance to BTK inhibitors. Covalent BTK inhibitors (cBTKi) produce major responses in 70% to 80% of patients with WM. MYD88 and CXCR4 mutation status can affect time to major response, depth of response, and/or progression-free survival (PFS) in patients with WM treated with cBTKi. The cBTKi zanubrutinib shows greater response activity and/or improved PFS in patients with WM with wild-type MYD88, mutated CXCR4, or altered TP53. Risks for adverse events, including atrial fibrillation, bleeding diathesis, and neutropenia can differ based on which BTKi is used in WM. Intolerance is also common with cBTKi, and dose reduction or switchover to another cBTKi can be considered. For patients with acquired resistance to cBTKis, newer options include pirtobrutinib or venetoclax. Combinations of BTKis with chemoimmunotherapy, CXCR4, and BCL2 antagonists are discussed. Algorithms for positioning BTKis in treatment naïve or previously treated patients with WM, based on genomics, disease characteristics, and comorbidities, are presented.
39Report of Consensus Panel 3 from the 11th International workshop on Waldenström's Macroglobulinemia: Recommendations for molecular diagnosis in Waldenström's Macroglobulinemia.PubMed
Ramón Garcia-Sanz, Marzia Varettoni, Cristina Jiménez, et al.
Semin Hematol. 2023 Mar;60(2):90-96. doi: 10.1053/j.seminhematol.2023.03.007. Epub 2023 Apr 6.
Apart from the MYD88 mutation, extensive information exists on the molecular mechanisms in Waldenström's Macroglobulinemia and its potential utility in the diagnosis and treatment tailoring. However, no consensus recommendations are yet available. Consensus Panel 3 (CP3) of the 11th International Workshop on Waldenström's Macroglobulinemia (IWWM-11) was tasked with reviewing the current molecular necessities and best way to access the minimum data required for a correct diagnosis and monitoring. Key recommendations from IWWM-11 CP3 included: (1) molecular studies are warranted for patients in whom therapy is going to be started; such studies should also be done in those whose bone marrow (BM) material is sampled based on clinical issues; (2) molecular studies considered essential for these situations are those that clarify the status of 6q and 17p chromosomes, and MYD88, CXCR4, and TP53 genes. These tests in other situations, and/or other tests, are considered optional; (3) independently of the use of more sensitive and/or specific techniques, the minimum requirements are allele specific polymerase chain reaction for MYD88 and CXCR4 using whole BM, and fluorescence in situ hybridization for 6q and 17p and sequencing for CXCR4 and TP53 using CD19+ enriched BM; (4) these requirements refer to all patients; therefore, sample should be sent to specialized centers.
40Determination of MYD88 and CXCR4 Mutations for Clinical Detection and Their Significance in Waldenström Macroglobulinemia.PubMed
Yuting Yan, Ying Yu, Wenjie Xiong, et al.
Clin Cancer Res. 2024 Dec 2;30(23):5483-5493. doi: 10.1158/1078-0432.CCR-23-3939.
PURPOSE: This study aims to explore the incidence and clinical features of MYD88 and CXCR4 mutations in patients with Waldenström macroglobulinemia (WM) and determine the optimal method for routine clinical practice. Additionally, we seek to evaluate the prognostic significance of these features across various therapeutic backgrounds [the cytotoxic group, the rituximab/bortezomib-based group, and the Bruton tyrosine kinase inhibitor (BTKi) group]. EXPERIMENTAL DESIGN: A total of 385 symptomatic patients with WM were analyzed for MYD88 and CXCR4 mutations using Sanger sequencing, next-generation sequencing, allele-specific qPCR (AS-PCR), and/or droplet digital PCR (ddPCR). RESULTS: The overall MYD88 mutation rate was 87.8%, relatively lower than that in the Western cohort. Both AS-PCR and ddPCR demonstrated high sensitivity in unsorted samples, detecting 98.5% and 97.7% of mutations, respectively, including those with low tumor burdens. The total CXCR4 mutation rate was 30.9%, with next-generation sequencing exhibiting the highest sensitivity of 78.0%. CXCR4 mutation was significantly linked to shorter OS only within the BTKi treatment group. The multivariate analysis indicated that MYD88 and CXCR4 mutations were not independent prognostic factors in the non-BTKi group when considering the International Prognostic Scoring System for Waldenström macroglobulinemia (IPSSWM) clinical staging. However, in the BTKi treatment group, these mutations emerged as independent adverse prognostic factors, overshadowing the prognostic significance of the IPSSWM classification (MYD88: HR, 0.229; P = 0.030; CXCR4: HR, 3.349; P = 0.012). CONCLUSIONS: Testing for MYD88 mutations using AS-PCR or ddPCR in unsorted samples is viable for routine clinical practice. Under BTKi treatment, MYD88 and CXCR4 mutations hold greater prognostic importance than IPSSWM staging in WM.
42Diagnostic next-generation sequencing to detect MYD88 L265P in Lymphoplasmacytic lymphoma compared to ddPCR.PubMed
Lauren M Wainman, Guohong Huang, Donald C Green, et al.
Exp Mol Pathol. 2025 Mar;141:104956. doi: 10.1016/j.yexmp.2025.104956. Epub 2025 Feb 15.
Lymphoplasmacytic lymphoma (LPL) is a B-cell lymphoproliferative disorder typically involving the bone marrow with infiltration by small lymphocytes and plasma cells. Studies have identified MYD88 L265P mutation as a diagnostic marker to distinguish LPL from other small B-cell lymphomas. Detection rates for this mutation have varied depending on the analytic methodology, with previous data suggesting that routine next-generation sequencing (NGS) does not demonstrate the required sensitivity to reliably detect MYD88 L265P. NGS has become part of routine clinical testing because it allows detection of variants across multiple genes. To study the utility of NGS in the detection of MYD88 L265P, we performed droplet digital PCR (ddPCR) and routine NGS on a cohort of 34 cases of lymphoid neoplasms (22 LPL, 4 CLL, 1 MCL, 1 MGUS, 2 plasma cell myeloma, and 4 negative bone marrow cases). We utilized manual review and BAMtools to assess MYD88 L265P in NGS cases. Limit of detection for ddPCR was determined to be 0.4 % variant allele frequency (VAF) with 10 ng DNA input. MYD88 L265P VAF detection by NGS and ddPCR was comparable down to 0.5 % VAF (R = 0.968). Setting an appropriate threshold for detection based on ddPCR results resulted in zero NGS false positives. We found that low tumor content did not impact the detection of MYD88 L265P by NGS. This study demonstrates that NGS can be a sensitive and reliable method for detection of MYD88 L265P with adequate coverage and specific assessment parameters.
43Genomic Landscape of CXCR4 Mutations in Waldenström Macroglobulinemia.PubMed
Stéphanie Poulain, Christophe Roumier, Aurélie Venet-Caillault, et al.
Clin Cancer Res. 2016 Mar 15;22(6):1480-8. doi: 10.1158/1078-0432.CCR-15-0646. Epub 2015 Oct 21.
PURPOSE: Whole-genome sequencing has revealed MYD88 L265P and CXCR4 mutations (CXCR4(mut)) as the most prevalent somatic mutations in Waldenström macroglobulinemia. CXCR4 mutation has proved to be of critical importance in Waldenström macroglobulinemia, in part due to its role as a mechanism of resistance to several agents. We have therefore sought to unravel the different aspects of CXCR4 mutations in Waldenström macroglobulinemia. EXPERIMENTAL DESIGN: We have scanned the two coding exons of CXCR4 in Waldenström macroglobulinemia using deep next-generation sequencing and Sanger sequencing in 98 patients with Waldenström macroglobulinemia and correlated with SNP array landscape and mutational spectrum of eight candidate genes involved in TLR, RAS, and BCR pathway in an integrative study. RESULTS: We found all mutations to be heterozygous, somatic, and located in the C-terminal domain of CXCR4 in 25% of the Waldenström macroglobulinemia. CXCR4 mutations led to a truncated receptor protein associated with a higher expression of CXCR4. CXCR4 mutations pertain to the same clone as to MYD88 L265P mutations but were mutually exclusive to CD79A/CD79B mutations (BCR pathway). We identified a genomic signature in CXCR4(mut) Waldenström macroglobulinemia traducing a more complex genome. CXCR4 mutations were also associated with gain of chromosome 4, gain of Xq, and deletion 6q. CONCLUSIONS: Our study panned out new CXCR4 mutations in Waldenström macroglobulinemia and identified a specific signature associated to CXCR4(mut), characterized with complex genomic aberrations among MYD88L265P Waldenström macroglobulinemia. Our results suggest the existence of various genomic subgroups in Waldenström macroglobulinemia.
44Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia.PubMed
Yingjun Wang, Vasantha Lakshmi Gali, Zijun Y Xu-Monette, et al.
Neoplasia. 2021 Apr;23(4):361-374. doi: 10.1016/j.neo.2021.02.002. Epub 2021 Mar 15.
Waldenström macroglobulinemia (WM) is a distinct type of indolent lymphoplasmacytic lymphoma (LPL) with a high frequency of MYD88 mutation. Treatment for WM/LPL is highly variable in clinic and ibrutinib (a Bruton tyrosine kinase inhibitor, BTKi) has become a new treatment option for WM. To investigate the clinical impact of genetic alterations in WM, we assembled a large cohort of 219 WMs and 12 LPLs dividing into two subcohorts: a training cohort, patients sequenced by a same targeted 29-gene next-generation sequencing (NGS) panel, and a validation cohort, patients sequenced by allele specific-PCR or other targeted NGS panels. In both training and validation subcohorts, MYD88 and TP53 mutations showed favorable and adverse prognostic effects, respectively. CXCR4 nonsense/missense mutations (CXCR4), cytogenetic complex karyotypes, and a family history of lymphoma/leukemia in first-degree relatives were associated with significantly worse clinical outcomes only or more in the validation subcohort. We further investigated the efficacy of various treatments and interaction with genetic factors in the entire cohort. Upfront dexamethasone usage was associated with poorer clinical outcomes in patients who received non-proteasome-containing chemotherapy as first-line treatment independent of genetic factors. Maintenance rituximab was associated with better survival. Ibrutinib/BTKi showed potential benefit in relapsed/refractory patients and patients without CXCR4 including those with TP53 mutations. In conclusion, genetic testing for MYD88, TP53, and CXCR4 mutations and cytogenetic analysis provide important information for prognosis prediction and therapy selection. The findings in these study are valuable for improving treatment decisions on therapies available for WM/LPL patients with integration of NGS in clinic.
45Detection of L265P Mutation by Allele-Specific Polymerase Chain Reaction in Atypical Lymphoplasmacytic Lymphoma.PubMed
Ja Young Lee, Ha Young Park
Clin Case Rep. 2025 Oct 10;13(10):e71111. doi: 10.1002/ccr3.71111. eCollection 2025 Oct.
Herein, we report a case of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia that presented with atypical bone marrow morphology and rapid clinical deterioration. Despite inconclusive flow cytometry findings and negative results for L265P mutation via both next-generation and Sanger sequencing, allele-specific polymerase chain reaction ultimately detected the mutation and confirmed the diagnosis. This case emphasizes the role of highly sensitive molecular techniques when evaluating low-tumor-burden or morphologically atypical lymphoid neoplasms.
46New developments in the diagnosis and characterization of Waldenström's macroglobulinemia.PubMed
Ramón García-Sanz, Zachary R Hunter, Stéphanie Poulain, et al.
Expert Rev Hematol. 2023 Jul-Dec;16(11):835-847. doi: 10.1080/17474086.2023.2270779. Epub 2023 Nov 17.
INTRODUCTION: Waldenström's macroglobulinemia (WM) is defined as a lymphoplasmacytic lymphoma (LPL) with immunoglobulin M (IgM) monoclonal gammopathy and morphologic evidence of bone marrow infiltration by LPL. Immunophenotyping and genotyping provide a firm pathological basis for diagnosis and are particularly valuable in differential diagnosis between WM and related diseases. Emerging technologies in mutational analysis present new opportunities, but challenges remain around standardization of methodologies and reporting of mutational data across centers. AREAS COVERED: The review provides an overview of the diagnosis of WM, with a particular focus on the role of immunophenotyping and genotyping. EXPERT OPINION: Demonstration of LPL with a bone marrow biopsy is essential to reach a definitive diagnosis of WM. However, and a typical WM immunophenotypic profile are valuable for the differential diagnosis of WM and related diseases, such as marginal zone lymphoma, multiple myeloma, and chronic lymphocytic leukemia. These methodologies must be utilized across centers and with appropriate standards followed in the evaluation and reporting of sensitivities and specificities. The diagnostic and/or prognostic value of mutations in genes such as and that are currently not routinely evaluated in the diagnosis of WM should be explored.
47Waldenström macroglobulinaemia and IgM monoclonal gammopathy of undetermined significance: emerging understanding of a potential precursor condition.PubMed
Mary L McMaster, Neil Caporaso
Br J Haematol. 2007 Dec;139(5):663-71. doi: 10.1111/j.1365-2141.2007.06845.x.
Previously thought to be best described as a plasma cell disorder, Waldenström macroglobulinaemia (WM) is now understood to be a distinct clinicobiological entity. WM shares B-cell origin and certain other features with both chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM). WM and CLL arise from B-cells at discrete stages in their maturation process, and MM arises from B-cells that have fully differentiated into plasma cells. While MM has a well-known precursor condition, monoclonal gammopathy of undetermined significance (MGUS), CLL and WM may also have associated precursor states, monoclonal B-cell lymphocytosis (MBL) and IgM MGUS, respectively. This review explores the features that link or distinguish these haematolymphoid malignancies, with special attention to emerging data regarding IgM MGUS and its unique relationship to WM, and identifies important gaps in our understanding of the putative precursor conditions, MBL and IgM MGUS.
48Clinical characteristics and factors predicting evolution of asymptomatic IgM monoclonal gammopathies and IgM-related disorders.PubMed
E Morra, C Cesana, C Klersy, et al.
Leukemia. 2004 Sep;18(9):1512-7. doi: 10.1038/sj.leu.2403442.
We evaluated the prognostic features of 384 asymptomatic IgM-monoclonal gammopathies (aIgM-MGs) and 74 IgM-related disorders (IgM-RDs), two clinically distinct groups as proposed by the Second International Workshop on Waldenström's Macroglobulinemia (WM). The cumulative probability of evolution to lymphoid malignancy at 5 and 10 years was 8% (95% CI, 5-13%) and 29% (95% CI, 21-38%), respectively, in aIgM-MGs; it was 9% (95% CI, 4-20%) and 16% (95% CI, 7-31%), respectively, in IgM-RDs (P=0.26). At a median follow-up of 45 months (12-233), 45 aIgM-MGs (11.7%) evolved to symptomatic WM (n=41), non-Hodgkin's lymphoma (NHL) (n=2), IgM multiple myeloma (n=1), and primary amyloidosis (n=1). At a median follow-up of 60 months (13-195), seven IgM-RDs (9.5%) evolved to symptomatic WM (n=6), and B-chronic lymphocytic leukaemia (n=1). At univariate analysis, in aIgM-MGs bone marrow lymphoplasmacytic infiltration, high erythrocyte sedimentation rate (ESR), haemoglobin level, IgM size, and lymphocytosis significantly correlated with evolution probability. At multivariate analysis, the latter two parameters strongly correlated with prognosis, haemoglobin being associated with a trend for a higher progression risk. In IgM-RDs IgM size, neutropenia, lymphocytosis, detectable Bence Jones proteinuria, and high ESR were associated with evolution probability. In conclusion, asymptomatic IgM-MGs and IgM-RDs are distinct clinical entities with similar probability of transformation to lymphoid malignancy.
49Diagnostic value of bone marrow core biopsy patterns in lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia and description of its mutational profiles by targeted NGS.PubMed
Julia Garcia-Reyero, Nerea Martinez Magunacelaya, Sonia Gonzalez de Villambrosia, et al.
J Clin Pathol. 2020 Sep;73(9):571-577. doi: 10.1136/jclinpath-2019-206282. Epub 2020 Jan 24.
AIMS: The aim of this study was to describe the characteristics of the bone marrow infiltration found in a series of clinically defined lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinaemia (WM) and IgM-monoclonal gammopathy of undetermined significance (MGUS) and to perform a targeted next-generation sequencing (NGS) for the identification of additional somatic mutations to p.L265P in LPL/WM. METHODS: We have reviewed a series of 35 bone marrow biopsies from 28 patients with a clinical diagnosis of LPL/WM (24 cases) or MGUS (4 cases). Bone marrow infiltration characteristics by morphology, immunohistochemistry, flow cytometry (FCM), allele-specific real-time PCR for the detection of p.L265P mutation, targeted exonic amplicon-based NGS of 35 lymphoma-related genes and direct sequencing were analysed. RESULTS: Our findings show that bone marrow trephine biopsy evaluation is superior to FCM in the identification of significant lymphoid infiltrates. A combined paratrabecular and interstitial infiltration pattern is the most common feature in LPL/WM while a patchy interstitial pattern characterises IgM-MGUS cases. p.L265P mutation was found by allele-specific-PCR in 92% of the LPL cases (22 out of 24) and 25% of IgM-MGUS cases (1 out of 4 cases). In addition to p.L265P somatic mutations in , , /Blimp1, and were found by NGS and direct sequencing in 4 cases. CONCLUSIONS: In conclusion, bone marrow core biopsy evaluation is critical in the identification of unequivocal bone marrow infiltration by LPL/WM. In addition to p.L265P, somatic mutations in , , /Blimp1, and can appear in a fraction of LPL/WM.
50Long-term follow-up of IgM monoclonal gammopathy of undetermined significance.PubMed
Robert A Kyle, Terry M Therneau, S Vincent Rajkumar, et al.
Blood. 2003 Nov 15;102(10):3759-64. doi: 10.1182/blood-2003-03-0801. Epub 2003 Jul 24.
Little effort has been made to quantitate adverse outcomes of monoclonal gammopathy of undetermined significance (MGUS) of the immunoglobulin M (IgM) class, which progresses to lymphoma or Waldenström macroglobulinemia, whereas IgA and IgG MGUS progress to multiple myeloma, primary amyloidosis (AL), or a related plasma cell disorder. From 1960 to 1994, IgM MGUS was diagnosed in 213 patients in southeastern Minnesota. The end point was progression to lymphoma or a related disorder, as assessed with the Kaplan-Meier method. The 213 patients were followed up for 1567 person-years (median, 6.3 years per patient). Lymphoma developed in 17 patients (relative risk [RR], 14.8), Waldenström macroglobulinemia in 6 (RR, 262), primary amyloidosis in 3 (RR, 16.3), and chronic lymphocytic leukemia in 3 (RR, 5.7). The relative risk of progression was 16-fold higher in the patients with IgM MGUS than in the white population of the Iowa Surveillance, Epidemiology, and End Results Program. Cumulative incidence of progression was 10% at 5 years, 18% at 10 years, and 24% at 15 years. On multivariate analysis, the serum monoclonal protein and serum albumin concentrations at diagnosis were the only risk factors for progression to lymphoma or a related disorder. Risk for progression to lymphoma or a related disorder at 10 years after the diagnosis of MGUS was 14% with an initial monoclonal protein concentration of 0.5 g/dL or less, 26% with 1.5 g/dL, 34% for 2.0 g/dL, and 41% for more than 2.5 g/dL.
51Translocation t(11;14)(q13;q32) is the hallmark of IgM, IgE, and nonsecretory multiple myeloma variants.PubMed
Hervé Avet-Loiseau, Richard Garand, Laurence Lodé, et al.
Blood. 2003 Feb 15;101(4):1570-1. doi: 10.1182/blood-2002-08-2436. Epub 2002 Oct 3.
In an attempt to address the issue of cytogenetic features of multiple myeloma (MM) variants, we have analyzed a series of 8 IgM, 9 IgD, 2 IgE, and 14 nonsecretory (NS) MM cases using fluorescence in situ hybridization. A very high incidence (83%) of t(11;14)(q13;q32) was detected in the IgM (7 of 8), IgE (2 of 2), and NS (11 of 14) MM cases, but not in the IgD cases (2 of 9). Of note, no t(4;14) was observed in this cohort of patients. This increased incidence of t(11;14) was associated with 2 dominant features in these variants, namely, a "lymphoplasmacytic" presentation mainly in IgM MM and a lower secreting capacity in the others, 2 features previously associated with t(11;14). Of major interest, t(11;14) was never observed in Waldenström macroglobulinemia or in IgG/IgA "lymphoplasmacytic" lymphomas. Thus, for unknown reasons, t(11;14) is the hallmark of IgM, IgE, and NS MM, (but not IgD MM), with a 5-fold increase of its incidence compared to that of IgG and IgA MM.
52Updated Diagnostic Criteria and Staging System for Multiple Myeloma.PubMed
S Vincent Rajkumar
Am Soc Clin Oncol Educ Book. 2016;35:e418-23. doi: 10.1200/EDBK_159009.
There has been remarkable progress made in the diagnosis and treatment of multiple myeloma (MM). The median survival of the disease has doubled as a result of several new active drugs. These advances have necessitated a revision of the disease definition and staging of MM. Until recently, MM was defined by the presence of end-organ damage, specifically hypercalcemia, renal failure, anemia, and bone lesions (CRAB features) that can be attributed to the clonal process. In 2014, the International Myeloma Working Group (IMWG) updated the diagnostic criteria for MM to add three specific biomarkers that can be used to diagnose the disease in patients who did not have CRAB features: clonal bone marrow plasma cells greater than or equal to 60%, serum free light chain (FLC) ratio greater than or equal to 100 provided involved FLC level is 100 mg/L or higher, or more than one focal lesion on MRI. In addition, the definition was revised to allow CT and PET-CT to diagnose MM bone disease. These changes enable early diagnosis and allow the initiation of effective therapy to prevent the development of end-organ damage for patients who are at the highest risk. A new staging system has been developed that incorporates high-risk cytogenetic abnormalities in addition to standard laboratory markers of prognosis.
53Role of F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group.PubMed
Michele Cavo, Evangelos Terpos, Cristina Nanni, et al.
Lancet Oncol. 2017 Apr;18(4):e206-e217. doi: 10.1016/S1470-2045(17)30189-4.
The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of fluorodeoxyglucose (F-FDG) PET/CT in patients with multiple myeloma and other plasma cell disorders, including smouldering multiple myeloma and solitary plasmacytoma. F-FDG PET/CT can be considered a valuable tool for the work-up of patients with both newly diagnosed and relapsed or refractory multiple myeloma because it assesses bone damage with relatively high sensitivity and specificity, and detects extramedullary sites of proliferating clonal plasma cells while providing important prognostic information. The use of F-FDG PET/CT is mandatory to confirm a suspected diagnosis of solitary plasmacytoma, provided that whole-body MRI is unable to be performed, and to distinguish between smouldering and active multiple myeloma, if whole-body X-ray (WBXR) is negative and whole-body MRI is unavailable. Based on the ability of F-FDG PET/CT to distinguish between metabolically active and inactive disease, this technique is now the preferred functional imaging modality to evaluate and to monitor the effect of therapy on myeloma-cell metabolism. Changes in FDG avidity can provide an earlier evaluation of response to therapy compared to MRI scans, and can predict outcomes, particularly for patients who are eligible to receive autologous stem-cell transplantation. F-FDG PET/CT can be coupled with sensitive bone marrow-based techniques to detect minimal residual disease (MRD) inside and outside the bone marrow, helping to identify those patients who are defined as having imaging MRD negativity.
54Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry: An European Research Initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) Harmonisation project.PubMed
Andy C Rawstron, Karl-Anton Kreuzer, Asha Soosapilla, et al.
Cytometry B Clin Cytom. 2018 Jan;94(1):121-128. doi: 10.1002/cyto.b.21595. Epub 2018 Jan 17.
The diagnostic criteria for CLL rely on morphology and immunophenotype. Current approaches have limitations affecting reproducibility and there is no consensus on the role of new markers. The aim of this project was to identify reproducible criteria and consensus on markers recommended for the diagnosis of CLL. ERIC/ESCCA members classified 14 of 35 potential markers as "required" or "recommended" for CLL diagnosis, consensus being defined as >75% and >50% agreement, respectively. An approach to validate "required" markers using normal peripheral blood was developed. Responses were received from 150 participants with a diagnostic workload >20 CLL cases per week in 23/150 (15%), 5-20 in 82/150 (55%), and <5 cases per week in 45/150 (30%). The consensus for "required" diagnostic markers included: CD19, CD5, CD20, CD23, Kappa, and Lambda. "Recommended" markers potentially useful for differential diagnosis were: CD43, CD79b, CD81, CD200, CD10, and ROR1. Reproducible criteria for component reagents were assessed retrospectively in 14,643 cases from 13 different centers and showed >97% concordance with current approaches. A pilot study to validate staining quality was completed in 11 centers. Markers considered as "required" for the diagnosis of CLL by the participants in this study (CD19, CD5, CD20, CD23, Kappa, and Lambda) are consistent with current diagnostic criteria and practice. Importantly, a reproducible approach to validate and apply these markers in individual laboratories has been identified. Finally, a consensus "recommended" panel of markers to refine diagnosis in borderline cases (CD43, CD79b, CD81, CD200, CD10, and ROR1) has been defined and will be prospectively evaluated. © 2017 International Clinical Cytometry Society.
55Pathogenesis of chronic lymphocytic leukemia and the development of novel therapeutic strategies.PubMed
Yoshikane Kikushige
J Clin Exp Hematop. 2020 Dec 15;60(4):146-158. doi: 10.3960/jslrt.20036. Epub 2020 Nov 4.
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and is characterized by the clonal expansion of mature CD5 B cells. There have been substantial advances in the field of CLL research in the last decade, including the identification of recurrent mutations, and clarification of clonal architectures, signaling molecules, and the multistep leukemogenic process, providing a comprehensive understanding of CLL pathogenesis. Furthermore, the development of therapeutic approaches, especially that of molecular target therapies against CLL, has markedly improved the standard of care for CLL. This review focuses on the recent insights made in CLL leukemogenesis and the development of novel therapeutic strategies.
56Genomic aberrations and survival in chronic lymphocytic leukemia.PubMed
H Döhner, S Stilgenbauer, A Benner, et al.
N Engl J Med. 2000 Dec 28;343(26):1910-6. doi: 10.1056/NEJM200012283432602.
BACKGROUND: Fluorescence in situ hybridization has improved the detection of genomic aberrations in chronic lymphocytic leukemia. We used this method to identify chromosomal abnormalities in patients with chronic lymphocytic leukemia and assessed their prognostic implications. METHODS: Mononuclear cells from the blood of 325 patients with chronic lymphocytic leukemia were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 6q21, 11q22-23, 13q14, and 17p13; trisomy of bands 3q26, 8q24, and 12q13; and translocations involving band 14q32. Molecular cytogenetic data were correlated with clinical findings. RESULTS: Chromosomal aberrations were detected in 268 of 325 cases (82 percent). The most frequent changes were a deletion in 13q (55 percent), a deletion in 11q (18 percent), trisomy of 12q (16 percent), a deletion in 17p (7 percent), and a deletion in 6q (7 percent). Five categories were defined with a statistical model: 17p deletion, 11q deletion, 12q trisomy, normal karyotype, and 13q deletion as the sole abnormality; the median survival times for patients in these groups were 32, 79, 114, 111, and 133 months, respectively. Patients in the 17p- and 11q-deletion groups had more advanced disease than those in the other three groups. Patients with 17p deletions had the shortest median treatment-free interval (9 months), and those with 13q deletions had the longest (92 months). In multivariate analysis, the presence or absence of a 17p deletion, the presence or absence of an 11q deletion, age, Binet stage, the serum lactate dehydrogenase level, and the white-cell count gave significant prognostic information. CONCLUSIONS: Genomic aberrations in chronic lymphocytic leukemia are important independent predictors of disease progression and survival. These findings have implications for the design of risk-adapted treatment strategies.
57Multiple myeloma: Every year a new standard?PubMed
S Vincent Rajkumar
Hematol Oncol. 2019 Jun;37 Suppl 1(Suppl 1):62-65. doi: 10.1002/hon.2586.
The treatment of myeloma is rapidly evolving. This article reviews the current diagnostic criteria, risk stratification, and approach to treatment of multiple myeloma. Treatment approach for both newly diagnosed and relapsed disease are discussed.
58Consensus treatment recommendations from the tenth International Workshop for Waldenström Macroglobulinaemia.PubMed
Jorge J Castillo, Ranjana H Advani, Andrew R Branagan, et al.
Lancet Haematol. 2020 Nov;7(11):e827-e837. doi: 10.1016/S2352-3026(20)30224-6.
Waldenström macroglobulinaemia is an indolent B-cell lymphoma with clearly defined criteria for diagnosis, initiation of therapy, and response, which was established by consensus panels at previous International Workshops for Waldenström Macroglobulinaemia (IWWM). The treatment options for Waldenström macroglobulinaemia continued to be researched after the publication of the eighth IWWM consensus recommendations in 2016, and at the tenth IWWM in New York, USA (October, 2018) an international consensus panel was formed to update treatment recommendations. Participants were selected as members of the consensus panel based on their expertise on Waldenström macroglobulinaemia. The initial live discussion took place during the tenth IWWM meeting and two separate teleconferences were held in June, 2019, and January, 2020, to refine recommendations. No external or financial support was received for the elaboration of these recommendations. According to these updated consensus recommendations, alkylating drugs (bendamustine, cyclophosphamide) and proteasome inhibitors (bortezomib, carfilzomib, ixazomib), both in combination with rituximab, as well as BTK inhibitors (ibrutinib), alone or in combination with rituximab, are preferred first-line therapy options for symptomatic patients with Waldenström macroglobulinaemia. In previously treated patients with Waldenström macroglobulinaemia who had an initial durable response, reuse of a previous regimen or another primary therapy regimen are acceptable options. Novel BTK inhibitors (acalabrutinib, zanubrutinib, tirabrutinib) and the BCL2 antagonist venetoclax appear safe and active, and represent emerging options for the treatment of Waldenström macroglobulinaemia. The choice of therapy should be guided by the patient's clinical profile, genomic features, and drug availability.
59Genomics, Signaling, and Treatment of Waldenström Macroglobulinemia.PubMed
Zachary R Hunter, Guang Yang, Lian Xu, et al.
J Clin Oncol. 2017 Mar 20;35(9):994-1001. doi: 10.1200/JCO.2016.71.0814. Epub 2017 Feb 13.
Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM). Commonly recurring mutations include MYD88 (95% to 97%), CXCR4 (30% to 40%), ARID1A (17%), and CD79B (8% to 15%). Diagnostic discrimination of WM from overlapping B-cell malignancies is aided by MYD88 mutation status. Transcription is affected by MYD88 and CXCR4 mutations and includes overexpression of genes involved in VDJ recombination, CXCR4 pathway signaling, and BCL2 family members. Among patients with MYD88 mutations, those with CXCR4 mutations show transcriptional silencing of tumor suppressors associated with acquisition of mutated MYD88. Deletions involving chromosome 6q are common and include genes that modulate nuclear factor-κB, BCL2, BTK, apoptosis, differentiation, and ARID1B. Non-chromosome 6q genes are also frequently deleted and include LYN, a regulator of B-cell receptor signaling. MYD88 and CXCR4 mutations affect WM disease presentation and treatment outcome. Patients with wild-type MYD88 show lower bone marrow disease burden and serum immunoglobulin M levels but show an increased risk of death. Patients with CXCR4 mutations have higher bone marrow disease burden, and those with nonsense CXCR4 mutations have higher serum immunoglobulin M levels and incidence of symptomatic hyperviscosity. Mutated MYD88 triggers BTK, IRAK1/IRAK4, and HCK growth and survival signaling, whereas CXCR4 mutations promote AKT and extracellular regulated kinase-1/2 signaling and drug resistance in the presence of its ligand CXCL12. Ibrutinib is active in patients with WM and is affected by MYD88 and CXCR4 mutation status. Patients with mutated MYD88 and wild-type CXCR4 mutation status exhibit best responses to ibrutinib. Lower response rates and delayed responses to ibrutinib are associated with mutated CXCR4 in patients with WM. MYD88 and CXCR4 mutation status may be helpful in treatment selection for symptomatic patients. Novel therapeutic approaches under investigation include therapeutics targeting MYD88, CXCR4, and BCL2 signaling.
60Plain Language Summary of the iNNOVATE study: ibrutinib plus rituximab is well-tolerated and effective in people with Waldenström's macroglobulinemia.PubMed
Christian Buske, Alessandra Tedeschi, Judith Trotman, et al.
Future Oncol. 2023 Feb;19(5):345-353. doi: 10.2217/fon-2022-1015. Epub 2023 Feb 23.
WHAT IS THIS SUMMARY ABOUT?: This article provides a short summary of 5-year results from the iNNOVATE trial. The original paper was published in the in October 2021. People with Waldenström's macroglobulinemia (WM) were randomly divided into two groups of 75 people each. One group received a combination treatment composed of two drugs, ibrutinib plus rituximab, and the other group took placebo ("sugar pill") plus rituximab. Ibrutinib (also known by the brand name Imbruvica) is a drug that reduces cancer cells' ability to multiply and survive. Ibrutinib is an FDA-approved drug for the treatment of WM. Rituximab is a drug that helps the immune system find and kill cancer cells. Participants in the trial were treated and their health monitored for up to 5 years (63 months). WHAT WERE THE RESULTS?: During the 5 years of monitoring, more people who took ibrutinib plus rituximab experienced an improvement in their disease and lived longer without their disease getting worse compared to those who took placebo plus rituximab. Side effects from ibrutinib and rituximab were manageable and generally decreased over time. Participants in both study groups reported improvements in quality of life, but those who took ibrutinib plus rituximab reported significantly greater improvement in their quality of life (as measured by FACT-An score) compared to those who took placebo plus rituximab. WHAT DO THE RESULTS MEAN?: These results show that ibrutinib plus rituximab is better than rituximab alone in people with WM and that ibrutinib plus rituximab is safe and effective in the long term. This information confirms the role of ibrutinib plus rituximab as a standard of care for WM. : NCT02165397 (ClinicalTrials.gov).
61Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenström macroglobulinemia.PubMed
Constantine S Tam, Stephen Opat, Shirley D'Sa, et al.
Blood Adv. 2024 Apr 9;8(7):1639-1650. doi: 10.1182/bloodadvances.2023010906.
The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.
62Zanubrutinib Shows Clinical Benefits in Waldenström Macroglobulinemia.PubMed
Oncologist. 2020 Jul;25 Suppl 1(Suppl 1):S16-S17. doi: 10.1634/theoncologist.2020-0557. Epub 2020 Jun 26.
In the head‐to‐head phase III ASPEN trial, zanubrutinib showed clinically meaningful improvements in safety and tolerability versus ibrutinib, with comparable efficacy, in patients with Waldenström macroglobulinemia.
63Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial.PubMed
Meletios Dimopoulos, Ramon Garcia Sanz, Hui-Peng Lee, et al.
Blood Adv. 2020 Dec 8;4(23):6009-6018. doi: 10.1182/bloodadvances.2020003010.
Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.
64How to Sequence Therapies in Waldenström Macroglobulinemia.PubMed
Shayna Sarosiek, Steven P Treon, Jorge J Castillo
Curr Treat Options Oncol. 2021 Aug 23;22(10):92. doi: 10.1007/s11864-021-00890-9.
There are multiple treatment options in patients with Waldenström macroglobulinemia, including chemotherapy, monoclonal antibodies, proteasome inhibitors, and covalent Bruton tyrosine kinase (BTK) inhibitors. The choice of therapy should take into account the patient's clinical presentation, comorbidities, and preferences. A thorough discussion should take place to outline the administration, safety, and efficacy of the regimens under consideration. The patient's genomic profile can provide insightful information for the treatment selection. In the frontline and relapsed settings, we favor ibrutinib monotherapy over chemoimmunotherapy or proteasome inhibitor-based regimens in patients with MYD88 and without CXCR4 mutations. For patients with MYD88 and CXCR4 mutations or without MYD88 or CXCR4 mutations, chemoimmunotherapy or proteasome inhibitor-based regimens are favored, but efficacy data with ibrutinib in combination with rituximab and with novel covalent BTK inhibitors are emerging. Autologous stem cell transplant should be considered in special cases in the relapsed setting. Participation in clinical trials is positively encouraged in WM patients in frontline and relapsed settings. Agents of interest include the BCL2 antagonist venetoclax, the CXCR4 inhibitor mavorixafor, and the non-covalent BTK inhibitors pirtobrutinib and ARQ-531.
65"Real-Life" Data of Zanubrutinib in Patients with Waldenström Macroglobulinemia: A Multicenter Retrospective Study.PubMed
Gilad Itchaki, Ohad Benjamini, Mor Levi, et al.
Acta Haematol. 2025;148(4):462-467. doi: 10.1159/000542936. Epub 2024 Dec 4.
INTRODUCTION: Waldenström macroglobulinemia (WM) is a rare indolent lymphoma. Zanubrutinib (ZAN), a second-generation BTK inhibitor, has been approved for the treatment of WM in any line of therapy in 2021. Between November 2020 and January 2022, an expanded access program of ZAN opened in Israel for the treatment of patients with relapsed/refractory (R/R)-WM or those ineligible for chemotherapy or ibrutinib in first line. METHODS: This is a multicenter retrospective study aiming to provide real-world data on ZAN in patients with WM in Israel. Demographic and clinical data were collected and coded from electronic files. Response was evaluated by the investigator's assessment. As the program closed, patients transitioned to commercial ZAN. RESULTS: Thirteen patients (12 R/R; 1 treatment-naive) were enrolled across 8 centers in Israel. The median age at ZAN initiation was 71 years (range, 50-85); 6 were males; 10 had high IPSS-WM. R/R patients had a median of 1 (1-4) prior lines of therapy. Other than progressive disease after chemoimmunotherapy, the most common considerations for choosing ZAN were patients' age and/or comorbidities (n = 5), as well as ibrutinib toxicity. The initial ZAN dose was reduced in 4 patients. The median time on ZAN was 19.5 months (2.9-29.5). Of 12 evaluable patients, the ORR was 83% with 3 minor responses, 6 PRs, and 1 VGPR. With a median follow-up of 19.6 months, 7 patients were still on ZAN, 5 progressed, 4 while on ZAN, and 1 after ZAN was stopped due to AE. Eighteen-month PFS and OS were 60.5% and 77%, respectively. Eight (61%) patients had AEs of any grade, and 3 (23%) of grade 3-4; 2 stopped ZAN due to congestive heart failure and extreme fatigue. CONCLUSION: The results of this real-world high-risk population are consistent with prospective studies highlighting the efficacy and safety of ZAN.
66Health-related quality of life in patients with Waldenström macroglobulinemia: results from the ASPEN trial.PubMed
Alessandra Tedeschi, Constantine S Tam, Roger G Owen, et al.
Future Oncol. 2024;20(25):1789-1798. doi: 10.1080/14796694.2024.2355079. Epub 2024 Jul 29.
ASPEN is a randomized, open-label, Phase III study comparing zanubrutinib and ibrutinib in patients with Waldenström macroglobulinemia (WM). Patient-reported outcomes were exploratory end points assessed using the EORTC QLQ-C30 and EQ-5D-5L VAS scores. Overall, 201 patients (102 zanubrutinib; 99 ibrutinib) were enrolled. Clinically meaningful differences were observed in diarrhea and nausea/vomiting in both the intent-to-treat population and in patients attaining very good partial response (VGPR) in earlier cycles of treatment, as well as in long-term physical functioning and fatigue in patients achieving VGPR. Treatment with zanubrutinib was associated with greater improvements in health-related quality of life compared with ibrutinib in patients with WM and mutations. NCT03053440 (ClinicalTrials.gov).
67Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies.PubMed
Laura Ondrisova, Marek Mraz
Front Oncol. 2020 Oct 26;10:591577. doi: 10.3389/fonc.2020.591577.
The approval of BTK and PI3K inhibitors (ibrutinib, idelalisib) represents a revolution in the therapy of B cell malignancies such as chronic lymphocytic leukemia (CLL), mantle-cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), or Waldenström's macroglobulinemia (WM). However, these "BCR inhibitors" function by interfering with B cell pathophysiology in a more complex way than anticipated, and resistance develops through multiple mechanisms. In ibrutinib treated patients, the most commonly described resistance-mechanism is a mutation in itself, which prevents the covalent binding of ibrutinib, or a mutation in which acts to bypass the dependency on BTK at the BCR signalosome. However, additional genetic aberrations leading to resistance are being described (such as mutations in the , , loss of chromosomal region 6q or 8p, a gain of Toll-like receptor (TLR)/MYD88 signaling or gain of 2p chromosomal region). Furthermore, relative resistance to BTK inhibitors can be caused by non-genetic adaptive mechanisms leading to compensatory pro-survival pathway activation. For instance, PI3K/mTOR/Akt, NFkB and MAPK activation, BCL2, MYC, and XPO1 upregulation or PTEN downregulation lead to B cell survival despite BTK inhibition. Resistance could also arise from activating microenvironmental pathways such as chemokine or integrin signaling CXCR4 or VLA4 upregulation, respectively. Defining these compensatory pro-survival mechanisms can help to develop novel therapeutic combinations of BTK inhibitors with other inhibitors (such as BH3-mimetic venetoclax, XPO1 inhibitor selinexor, mTOR, or MEK inhibitors). The mechanisms of resistance to PI3K inhibitors remain relatively unclear, but some studies point to MAPK signaling upregulation both genetic and non-genetic changes, which could be co-targeted therapeutically. Alternatively, drugs mimicking the BTK/PI3K inhibition effect can be used to prevent adhesion and/or malignant B cell migration (chemokine and integrin inhibitors) or to block the pro-proliferative T cell signals in the microenvironment (such as IL4/STAT signaling inhibitors). Here we review the genetic and non-genetic mechanisms of resistance and adaptation to the first generation of BTK and PI3K inhibitors (ibrutinib and idelalisib, respectively), and discuss possible combinatorial therapeutic strategies to overcome resistance or to increase clinical efficacy.
68Venetoclax in Previously Treated Waldenström Macroglobulinemia.PubMed
Jorge J Castillo, John N Allan, Tanya Siddiqi, et al.
J Clin Oncol. 2022 Jan 1;40(1):63-71. doi: 10.1200/JCO.21.01194. Epub 2021 Nov 18.
PURPOSE: BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells in Waldenström macroglobulinemia (WM). Venetoclax is a potent BCL2 antagonist and triggers in vitro apoptosis of WM cells. The activity of venetoclax in WM remains to be clarified. PATIENTS AND METHODS: We performed a multicenter, prospective phase II study of venetoclax in patients with previously treated WM (NCT02677324). Venetoclax was dose-escalated from 200 mg to a maximum dose of 800 mg daily for up to 2 years. RESULTS: Thirty-two patients were evaluable, including 16 previously exposed to Bruton tyrosine kinase inhibitors (BTKis). All patients were -mutated, and 17 carried mutations. The median time to minor and major responses was 1.9 and 5.1 months, respectively. Previous exposure to BTKis was associated with a longer time to response (4.5 1.4 months; < .001). The overall, major, and very good partial response rates were 84%, 81%, and 19%, respectively. The major response rate was lower in those with refractory versus relapsed disease (50% 95%; = .007). The median follow-up time was 33 months, and the median progression-free survival was 30 months. mutations did not affect treatment response or progression-free survival. The only recurring grade ≥ 3 treatment-related adverse event was neutropenia (n = 14; 45%), including one episode of febrile neutropenia. Laboratory tumor lysis without clinical sequelae occurred in one patient. No deaths have occurred. CONCLUSION: Venetoclax is safe and highly active in patients with previously treated WM, including those who previously received BTKis. mutation status did not affect treatment response.
69Ibrutinib and venetoclax as primary therapy in symptomatic, treatment-naïve Waldenström macroglobulinemia.PubMed
Jorge J Castillo, Andrew R Branagan, David Sermer, et al.
Blood. 2024 Feb 15;143(7):582-591. doi: 10.1182/blood.2023022420.
Concurrent Bruton tyrosine kinase and BCL2 inhibition has not yet been investigated in Waldenström macroglobulinemia (WM). We performed an investigator-initiated trial of ibrutinib and venetoclax in symptomatic treatment-naïve patients with MYD88-mutated WM. Patients received ibrutinib 420 mg once daily (cycle 1), followed by a ramp-up of venetoclax to 400 mg daily (cycle 2). The combination was then administered for 22 additional 4-week cycles. The attainment of very good partial response (VGPR) was the primary end point. Forty-five patients were enrolled in this study. The median baseline characteristics were as follows: age 67 years, serum IgM 43 g/L, and hemoglobin 102 g/L. Seventeen patients (38%) carried CXCR4 mutations. Nineteen patients (42%) achieved VGPR. Grade 3 or higher adverse events included neutropenia (38%), mucositis (9%), and tumor lysis syndrome (7%). Atrial fibrillation occurred in 3 (9%), and ventricular arrhythmia in 4 (9%) patients that included 2 grade 5 events. With a median follow-up of 24.4 months, the 24-month progression-free survival (PFS) and overall survival (OS) rates were 76% and 96%, respectively, and were not impacted by CXCR4 mutations. The median time on therapy was 10.2 months, and the median time after the end of therapy (EOT) was 13.3 months. Eleven of the 12 progression events occurred after EOT, and the 12-month PFS rates after EOT were 79%; 93% if VGPR was attained, and 69% for other patients (P = .12). Ibrutinib and venetoclax induced high VGPR rates and durable responses after EOT, although they were associated with a higher-than-expected rate of ventricular arrhythmia in patients with WM, leading to early study treatment termination. This trial was registered at www.clinicaltrials.gov as #NCT04273139.
70Novel Treatment Strategies in the Management of Waldenström Macroglobulinemia.PubMed
Saurabh Zanwar, Jithma Prasad Abeykoon, Prashant Kapoor
Curr Hematol Malig Rep. 2020 Feb;15(1):31-43. doi: 10.1007/s11899-020-00559-4.
PURPOSE OF REVIEW: Recent advances the genomic profiling of patients with Waldenström macroglobulinemia (WM) have led to the identification of novel therapeutic targets in these patients. In this review, we cover the current standard of care and the recently evaluated novel approaches with high potential to be incorporated in the therapeutic armamentarium against WM. RECENT FINDINGS: The MYD88 mutation is the most common genomic abnormality in WM, and is encountered in 80-95% of patients, making it an important target for drug development. The success of the first-generation Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has generated tremendous interest in the study of more selective and potent BTK inhibitors. Additionally, the identification of CXCR4 mutations in up to approximately 40% of patients with WM has fueled research regarding their implication on systemic therapy in WM. In a rapidly advancing field of targeted therapies, the treatment options for patients with WM are expanding as researchers continue to uncover and harness the survival pathways active in this hematologic malignancy.
71Chemokine receptor CXCR4: An important player affecting the molecular-targeted drugs commonly used in hematological malignancies.PubMed
Liangliang Li, Ye Chai, ChongYang Wu, et al.
Expert Rev Hematol. 2020 Dec;13(12):1387-1396. doi: 10.1080/17474086.2020.1839885. Epub 2020 Nov 10.
INTRODUCTION: A variety of molecular-targeted drugs have been widely used in hematological malignancies and have shown great advances. Nevertheless, as the use of drugs in clinical practice increases, the problem of relapse or of the disease being refractory to treatment is becoming apparent. This problem is closely related to the C-X-C chemokine receptor 4 (CXCR4). AREAS COVERED: This review focuses mainly on the effect of CXCR4 on molecular-targeted drug resistance in hematological malignancies as well as the clinical efficacy of CXCR4 antagonists combined with molecular-targeted drugs. Relevant literatures published between 2006 and 2020 were searched using PubMed/Medline for this review. EXPERT OPINION: Monoclonal antibodies and non-antibody molecular-targeted drugs provide new therapeutic approaches for B-lineage malignancies and leukemia, but the clinical activity of these drugs is affected by CXCR4. In general, high CXCR4 expression or mutation inhibits the effects of molecular-targeted drugs, but there are exceptions, and in studies of proteasome inhibitors bortezomib (Bz) in multiple myeloma (MM), low CXCR4 expression or loss of CXCR4 was associated with Bz resistance (BzR) and poor treatment outcomes. Given that CXCR4 is a critical mediator of molecular-targeted drug resistance, numerous studies have combined molecular-targeted drugs with CXCR4 antagonists, which synergistically enhance the anti-proliferative/pro-apoptotic effect of molecular-targeted drugs.
73Rates and Risk of Atrial Arrhythmias in Patients Treated With Ibrutinib Compared With Cytotoxic Chemotherapy.PubMed
Michael G Fradley, Matthew Gliksman, Josephine Emole, et al.
Am J Cardiol. 2019 Aug 15;124(4):539-544. doi: 10.1016/j.amjcard.2019.05.029. Epub 2019 May 25.
There is increasing evidence that rates of atrial arrhythmias (AA), specifically atrial fibrillation and flutter are elevated in patients treated with the tyrosine kinase inhibitor, ibrutinib; however, the exact risk of ibrutinib-associated AA is not definitively established. We conducted a retrospective study of 137 patients diagnosed with B-cell malignancies treated with ibrutinib compared with 106 patients treated with chemotherapy for the same cancers in order to quantify the rates and risk of AA in a "real-world" sample of cancer patients. Fisher's exact test was used to evaluate for any statistically significant differences between groups. Logistic regression was used to generate odds ratios, adjusting for potential confounders. Incidence of AA was 14% (n = 17) in ibrutinib-treated patients compared with 3% (n = 3) in patients treated with chemotherapy (p = 0.009). Ibrutinib-treated patients were significantly older (mean age 67 vs 63 years, p = 0.003); however, there were no other significant differences in baseline characteristics. Ibrutinib use, age, hypertension, and previous use of ACE inhibitors, angiotensin receptor blocker use, β blocker use, and aspirin use were independently associated with incident arrhythmias. In multivariable analysis, patients treated with ibrutinib were associated with a 5-fold increased risk of developing AA (odds ratio = 5.18, 95% confidence interval 1.42 to 18.89). In conclusion, the rates and risk of AA are higher in patients treated with ibrutinib compared with chemotherapy, and this study provides strong evidence that ibrutinib itself is an independent risk factor for the development of incident AA.
74Ibrutinib Monotherapy in Symptomatic, Treatment-Naïve Patients With Waldenström Macroglobulinemia.PubMed
Steven P Treon, Joshua Gustine, Kirsten Meid, et al.
J Clin Oncol. 2018 Sep 20;36(27):2755-2761. doi: 10.1200/JCO.2018.78.6426. Epub 2018 Jul 25.
Purpose Ibrutinib is active in previously treated Waldenström macroglobulinemia (WM). MYD88 mutations ( MYD88) and CXCR4 mutations ( CXCR4) affect ibrutinib response. We report on a prospective study of ibrutinib monotherapy in symptomatic, untreated patients with WM, and the effect of CXCR4 status on outcome. Patients and Methods Symptomatic, treatment-naïve patients with WM were eligible. Ibrutinib (420 mg) was administered daily until progression or unacceptable toxicity. All tumors were genotyped for MYD88 and CXCR4. Results A total of 30 patients with WM received ibrutinib. All carried MYD88, and 14 (47%) carried a CXCR4. After ibrutinib treatment, median serum IgM levels declined from 4,370 to 1,513 mg/dL, bone marrow involvement declined from 65% to 20%, and hemoglobin level rose from 10.3 to 13.9 g/dL ( P < .001 for all comparisons). Overall (minor or more than minor) and major (partial or greater than partial) responses for all patients were 100% and 83%, respectively. Rates of major (94% v 71%) and very good partial (31 v 7%) responses were higher and time to major responses more rapid (1.8 v 7.3 months; P = 0.01) in patients with wild-type CXCR4 versus those with CXCR4, respectively. With a median follow-up of 14.6 months, disease in two patients (both with CXCR4) progressed. The 18-month, estimated progression-free survival is 92% (95% CI, 73% to 98%). All patients are alive. Grade 2/3 treatment-related toxicities in > 5% of patients included arthralgia (7%), bruising (7%), neutropenia (7%), upper respiratory tract infection (7%), urinary tract infection (7%), atrial fibrillation (10%), and hypertension (13%). There were no grade 4 or unexpected toxicities. Conclusion Ibrutinib is highly active, produces durable responses, and is safe as primary therapy in patients with symptomatic WM. CXCR4 status affects responses to ibrutinib.
75Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia.PubMed
Jorge J Castillo, Kirsten Meid, Joshua N Gustine, et al.
Leukemia. 2022 Feb;36(2):532-539. doi: 10.1038/s41375-021-01417-9. Epub 2021 Sep 16.
Herein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without CXCR4 mutations (14% vs. 44%; p = 0.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated CXCR4 at 1.7 months (p = 0.07) and 7.3 months (p = 0.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without CXCR4 mutations (59% vs. 92%; p = 0.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4 mutations impacted VGPR attainment, time to major response, and 4-year PFS rate.
76Report of consensus panel 2 from the 11th international workshop on Waldenström's macroglobulinemia on the management of relapsed or refractory WM patients.PubMed
S D'Sa, J V Matous, R Advani, et al.
Semin Hematol. 2023 Mar;60(2):80-89. doi: 10.1053/j.seminhematol.2023.03.003. Epub 2023 Mar 27.
The consensus panel 2 (CP2) of the 11th International Workshop on Waldenström's macroglobulinemia (IWWM-11) has reviewed and incorporated current data to update the recommendations for treatment approaches in patients with relapsed or refractory WM (RRWM). The key recommendations from IWWM-11 CP2 include: (1) Chemoimmunotherapy (CIT) and/or a covalent Bruton tyrosine kinase (cBTKi) strategies are important options; their use should reflect the prior upfront strategy and are subject to their availability. (2) In selecting treatment, biological age, co-morbidities and fitness are important; nature of relapse, disease phenotype and WM-related complications, patient preferences and hematopoietic reserve are also critical factors while the composition of the BM disease and mutational status (MYD88, CXCR4, TP53) should also be noted. (3) The trigger for initiating treatment in RRWM should utilize knowledge of patients' prior disease characteristics to avoid unnecessary delays. (4) Risk factors for cBTKi related toxicities (cardiovascular dysfunction, bleeding risk and concurrent medication) should be addressed when choosing cBTKi. Mutational status (MYD88, CXCR4) may influence the cBTKi efficacy, and the role of TP53 disruptions requires further study) in the event of cBTKi failure dose intensity could be up titrated subject to toxicities. Options after BTKi failure include CIT with a non-cross-reactive regimen to one previously used CIT, addition of anti-CD20 antibody to BTKi, switching to a newer cBTKi or non-covalent BTKi, proteasome inhibitors, BCL-2 inhibitors, and new anti-CD20 combinations are additional options. Clinical trial participation should be encouraged for all patients with RRWM.
77Bing-Neel Syndrome: Update on the Diagnosis and Treatment.PubMed
Abdelrahman Nanah, Samer Al Hadidi
Clin Lymphoma Myeloma Leuk. 2022 Mar;22(3):e213-e219. doi: 10.1016/j.clml.2021.09.014. Epub 2021 Sep 24.
Bing-Neel syndrome (BNS) is a rare syndrome that occurs in patients with Waldenstrom macroglobulinemia and is characterized by lymphoplasmacytic infiltration into the leptomeningeal tissue and/or the central nervous system. It represents an extramedullary manifestation which may translate into various neurological symptoms. Accurate diagnosis of BNS can be established via histologic sampling and cerebrospinal fluid examination with molecular analysis of some genetic markers including immunoglobulin heavy locus rearrangements and MYD88 L265P mutation. The use of Bruton tyrosine kinase inhibitors such as ibrutinib resulted in promising outcomes. In this review, we discuss the pathophysiology, clinical manifestations, diagnostic characteristics, and an overview of the current treatment modalities of BNS.
78Bing-Neel Syndrome: Real-Life Experience in Personalized Diagnostic Approach and Treatment.PubMed
Dimitrios Kotsos, Sofia Chatzileontiadou, Athanasia Apsemidou, et al.
Front Oncol. 2022 Jun 29;12:891052. doi: 10.3389/fonc.2022.891052. eCollection 2022.
The involvement of the central nervous system (CNS) in Waldenström's Macroglobulinemia (WM) is a rare extramedullary manifestation of the disease known as Bing-Neel syndrome (BNS). To expand our understanding of this disease manifestation, we conducted a retrospective analysis of the incidence of BNS in 86 consecutive patients with WM [70% male, median age 65 years (range 33-86)] seen in our center during a 30-year period. Six patients (7%) from this group were diagnosed with BNS. The median period of time between WM diagnosis and BNS diagnosis was 6.8 years (range 2.3-15). They demonstrated a range of neurological deficits, including transient expressive aphasia, impaired vision, resting hand tremor, foot drop, and headache. Between the onset of symptoms and the diagnosis of BNS, the median time interval was 12.5 months (range 1-30). The diagnosis was made not on the basis of neurological symptoms or radiological evidence, but on the basis of the presence of WM cells in cerebrospinal fluid (CSF). Intrathecal chemotherapy with methotrexate, cytarabine, and dexamethasone (IT MTX, ARA-C, DEX) was used as front-line treatment, followed by intensive immunochemotherapy with rituximab, high-dose MTX, and ARA-C (R-Hi MTX/ARA-C) in three patients who were fit enough to receive this type of cytotoxic regimen, and rituximab plus bendamustine (R-Benda) in two patients who simultaneously required treatment for WM. Ibrutinib was administered to five patients (three as consolidation and two for initial treatment). All patients responded to front-line treatment, with four (67%) achieving partial response (PR) and two (33%) achieving complete response (CR). This study provides insight into the clinical presentation, diagnostic and treatment options, as well as the outcome of patients who have BNS.
79Evaluation and Management of Bing-Neel Syndrome.PubMed
Sarah J Schep, Josephine M I Vos, Monique C Minnema
Hematol Oncol Clin North Am. 2023 Aug;37(4):777-786. doi: 10.1016/j.hoc.2023.04.008. Epub 2023 May 29.
Bing-Neel syndrome is a rare manifestation of Waldenström macroglobulinemia (WM), which is caused by infiltration of the malignant lymphoplasmacytic cells in the central nervous system. Patients can present with a diverse range of neurologic symptoms, and differentiation with other comorbidities seen in WM, such as immunoglobulin M-related polyneuropathy, can be challenging. Both the rarity of this disorder and the heterogeneity of the clinical presentation often cause a significant diagnostic delay with the risk of permanent neurologic damage. This review summarizes current knowledge regarding diagnosis, treatment and prognosis of Bing-Neel syndrome.
80Bing-Neel Syndrome: Illustrative Cases and Comprehensive Review of the Literature.PubMed
Marzia Varettoni, Irene Defrancesco, Luca Diamanti, et al.
Mediterr J Hematol Infect Dis. 2017 Oct 18;9(1):e2017061. doi: 10.4084/MJHID.2017.061. eCollection 2017.
The Bing-Neel syndrome is a rare neurological complication of Waldenström's Macroglobulinemia which results from a direct involvement of central nervous system by malignant lymphoplasmacytic cells. The clinical suspicion of Bing-Neel syndrome may be overlooked because neurologic symptoms are heterogeneous, nonspecific and sometimes underhand. A definitive diagnosis of Bing-Neel syndrome can be confidently made using brain and spinal cord magnetic resonance imaging as well as histopathology and/or cerebrospinal fluid analysis to confirm the neoplastic infiltration of central nervous system. The detection in the cerebrospinal fluid of patients with Bing-Neel syndrome of the MYD88 (L265P) somatic mutation, which is highly recurrent in Waldenström's Macroglobulinemia, proved useful for the diagnosis and monitoring of central nervous system involvement. Despite recommendations recently published, there is still no clear consensus on treatment of Bing-Neel syndrome, which includes systemic immunochemotherapy, intrathecal chemotherapy and brain irradiation as possible options. Ibrutinib, a Bruton kinase inhibitor approved for Waldenström's Macroglobulinemia, has been recently added to the therapeutic armamentarium of Bing-Neel syndrome due to its ability to pass the blood-brain barrier. However, prospective clinical trials are eagerly awaited with the aim to define the optimal treatment strategy. Here we describe four illustrative cases of Bing-Neel syndrome diagnosed and treated at our Institution and review the literature on this topic.
81How we manage Bing-Neel syndrome.PubMed
Jorge J Castillo, Steven P Treon
Br J Haematol. 2019 Nov;187(3):277-285. doi: 10.1111/bjh.16167. Epub 2019 Aug 20.
Bing-Neel syndrome (BNS) is an uncommon presentation of Waldenström macroglobulinaemia (WM), seen during the course of the disease in about 1% of patients. BNS occurs when WM cells gain access to the central nervous system (CNS) causing neurological deficits. The diagnosis of BNS is suggested by the presence of radiological abnormalities, such as leptomeningeal enhancement on magnetic resonance imaging and confirmed by the presence of clonal lymphoplasmacytic cells and MYD88 L265P in the cerebrospinal fluid. The treatment of BNS requires agents with good penetration into the CNS, such as fludarabine, methotrexate and cytarabine. The novel Bruton Tyrosine Kinase inhibitor ibrutinib has shown CNS-penetrating properties, and recent data suggest a therapeutic role in BNS. In this review, we will discuss the clinical and pathological features, diagnostic criteria, treatment options and outcomes of patients with BNS.
82Ibrutinib for the treatment of Bing-Neel syndrome: a multicenter study.PubMed
Jorge J Castillo, Gilad Itchaki, Jonas Paludo, et al.
Blood. 2019 Jan 24;133(4):299-305. doi: 10.1182/blood-2018-10-879593. Epub 2018 Dec 6.
The treatment of patients with Bing-Neel syndrome (BNS) is not standardized. We included patients with Waldenström macroglobulinemia (WM) and a radiologic and/or cytologic diagnosis of BNS treated with ibrutinib monotherapy. Response assessment was based on criteria for BNS from the 8th International Workshop for WM. Survival from BNS diagnosis (BNS survival), survival from ibrutinib initiation to last follow-up or death (ibrutinib survival), and time from ibrutinib initiation to ibrutinib discontinuation for toxicity, progression, or death (event-free survival [EFS]) were estimated. Twenty-eight patients were included in our study. The median age at BNS diagnosis was 65 years. Ibrutinib was the first line of treatment for BNS in 39% of patients. Ibrutinib was administered orally at a dose of 560 and 420 mg once daily in 46% and 54% of patients, respectively; symptomatic and radiologic improvements were seen in 85% and 60% of patients within 3 months of therapy. At best response, 85% of patients had improvement or resolution of BNS symptoms, 83% had improvement or resolution of radiologic abnormalities, and 47% had cleared the disease in the cerebrospinal fluid. The 2-year EFS rate with ibrutinib was 80% (95% confidence interval [CI], 58%-91%), the 2-year ibrutinib survival rate was 81% (95% CI, 49%-94%), and the 5-year BNS survival rate was 86% (95% CI, 63%-95%). Ibrutinib therapy is effective in patients with BNS and should be considered as a treatment option in these patients.
83Bing-Neel syndrome: A case reports.PubMed
Sinan Demircioğlu, Pembe Oltulu, Ganime D Emlik, et al.
J Oncol Pharm Pract. 2021 Oct;27(7):1758-1761. doi: 10.1177/1078155220983426. Epub 2020 Dec 26.
INTRODUCTION: Bing-Neel syndrome (BNS) is a rare complication of of Waldenström macroglobulinemia (WM) identified by involvement of central nervous system (CNS) lymphoplasmacytic cells. CASE REPORT: We present a patient who was diagnosed with Bing-Neel syndrome four years after the diagnosis of Waldenström macroglobulinemia. MANAGEMENT & OUTCOME: The patient was admitted with neurological symptoms. There were lesions associated with WM involvement on brain imaging. The diagnosis was made by brain biopsy. High dose methotrexate treatment was given. DISCUSSION: CNS infiltrating agents such as fludarabine, methotrexate and cytarabine are often used in BNS treatment. Ibrutinib, which is a new bruton tyrosine kinase inhibitor, has recently started to be used in BNS treatment, as it has been shown to be effective and penetrate the CNS.
85Quality of life and fear of cancer recurrence in patients and survivors of non-Hodgkin lymphoma.PubMed
Susan Ellis, Rhonda F Brown, Einar B Thorsteinsson, et al.
Psychol Health Med. 2022 Sep;27(8):1649-1660. doi: 10.1080/13548506.2021.1913756. Epub 2021 Apr 30.
Non-Hodgkin lymphoma (NHL) is a common haematological cancer that is comprised of approximately 30 subtypes, of which Waldenström Macroglobulinemia (WM) is a rare incurable form. It is typically managed using a watch-and-wait strategy that can contribute to illness uncertainty which may result in fear of cancer recurrence (FCR) and poor health-related quality of life (QOL). However, few studies have examined the correlates of FCR and QOL in NHL patients, including WM patients. One-hundred males and 92 females with a mean age of 62.7 years who were an average of 6.8 years from diagnosis completed the online questionnaire which asked about demographics, medical history, QOL, FCR, stress, anxiety and depression. Few NHL patients reported significant stress or affective distress, most had moderate-high QOL and 41% experienced recent FCR, relative to published cut-off scores. Poorer QOL was related to depression symptoms, FCR, higher illness burden (i.e. comorbidity) and fewer personal resources (i.e. unemployed), whereas FCR was related to shorter time since diagnosis and more depressive symptoms. Results suggest that FCR and depressive symptoms may adversely impact QOL, whereas a recent cancer diagnosis and depression-related pessimism may contribute to FCR.
86Waldenström's macroglobulinemia: hyperviscosity syndrome and cryoglobulinemia.PubMed
Marvin J Stone
Clin Lymphoma Myeloma. 2009 Mar;9(1):97-9. doi: 10.3816/CLM.2009.n.026.
Hyperviscosity syndrome (HVS) is a common manifestation of Waldenström's macroglobulinemia (WM). Patients with HVS have skin and mucosal bleeding, retinopathy with visual disturbances, and a variety of neurologic disorders. HVS can be diagnosed from physical examination by identifying the characteristic retinal venous engorgement ("sausaging") on funduscopic inspection. HVS can be accurately monitored with an Ostwald tube and reversed by plasmapheresis. Cryoglobulins precipitate or gel at temperatures < 37 degrees C and dissolve on re-warming. They may be composed of single or multiple components. Most cryoglobulins are mixed monoclonal IgMpolyclonal IgG immune complexes and many are associated with hepatitis C viral infection. Monoclonal macroglobulin autoreactive antibodies are included among the "IgM-related" disorders that influence the clinical presentation and natural history of WM.
87Hyperviscosity Syndrome: An Oncologic Emergency.PubMed
Tareg Bey, Aiham Qdaisat
Emerg Med Clin North Am. 2025 Aug;43(3):445-452. doi: 10.1016/j.emc.2025.03.001. Epub 2025 Apr 17.
Hyperviscosity syndrome (HVS) is considered an oncologic emergency. In this review, we describe the pathophysiology, clinical presentation, diagnosis, and treatment of this life-threatening condition. The most common etiology of HVS is hypergammaglobulinemia, such as Waldenström macroglobulinemia. Other causes include bone marrow hyperproliferative states, autoimmune diseases, and human immunodeficiency virus infection. The presence of mucosal and specifically bilateral nasal bleeding, along with neurologic and ophthalmologic symptoms, should raise suspicion for HVS, but the condition can affect principally all organ systems. Fundoscopic examination is important when evaluating patients with HVS. The mainstays of treatment of HVS are supportive care, plasmapheresis, and chemotherapy.
88A rare neurological complication of Waldenstrom's Macroglobulinemia.PubMed
Gabriel Torrealba-Acosta, Rajan Gadhia, Thabele Leslie-Mazwi
J Clin Neurosci. 2018 Feb;48:143-146. doi: 10.1016/j.jocn.2017.10.081. Epub 2017 Nov 4.
Bilateral and simultaneous facial nerve palsy (FNP) is a rare clinical condition occurring in 0.3-2.0% of facial palsy cases and is typically a manifestation of an underlying systemic disease. We here describe a case of a 67-year-old Hispanic man with a known history of Waldenstrom's Macroglobulinemia (WM) who presented to the clinic with a sub-acute onset of bilateral facial weakness. No alternate etiology for the facial weakness was identified after a thorough diagnostic approach. WM is a rare hematological condition due to low-grade B cell lymphoma, where lymphoplasmacytoid cells infiltrate different tissues and secrete monoclonal IgM. Peripheral neuropathy develops in 15-30% of the cases, being usually a chronic, progressive, symmetric, predominantly distal polyneuropathy. Facial nerve impairment is unusual; however, it could be caused by anoxic damage as a result of an increased blood viscosity from IgM monoclonal gammopathy, direct nerve infiltration of tumorous cells and an antibody (anti-MAG) mediated demyelinating process. Treatment is directed to the established mechanism for neural injury. This report highlights a rare condition (WM) with a rare complication (bilateral facial nerve palsy) and illustrates the broad differential comprised by this presenting complaint.
89Waldenstrom's macroglobulinemia and sensorineural hearing loss.PubMed
M J Syms, M E Arcila, M R Holtel
Am J Otolaryngol. 2001 Sep-Oct;22(5):349-53. doi: 10.1053/ajot.2001.26494.
Waldenstrom's macroglobulinemia, (WM) first described in 1944, is an uncommon disease caused by the abnormal production of immunoglobulin M monoclonal macroglobulin. Presenting signs and symptoms most frequently include fatigue or generalized weakness; tendency to bleed from mucosal surfaces; characteristic retinal lesions, including dilated and tortuous retinal veins, retinal hemorrhages, and exudates; lymphadenopathy; hepatosplenomegaly; sensory motor peripheral neuropathy; worsening normochromic anemia; increased sedimentation rate; and extremely high serum viscosity. Hearing loss is an unusual presenting symptom of WM; only 6 cases are reported in literature. The etiology of hearing loss is unclear; however, hyperviscosity and thrombus formations are the most likely causes. We present a patient diagnosed with WM whose initial presenting symptoms were hearing loss and progressive sensory peripheral neuropathy with subsequent development of lymphadenopathy and hyperviscosity syndrome. Treatment with Fludarabine lead to improvement of her hearing and neurological deficits, as well as resolution of her other hyperviscosity-related symptoms.
90Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016.PubMed
Prashant Kapoor, Stephen M Ansell, Rafael Fonseca, et al.
JAMA Oncol. 2017 Sep 1;3(9):1257-1265. doi: 10.1001/jamaoncol.2016.5763.
IMPORTANCE: Waldenström macroglobulinemia (WM), an IgM-associated lymphoplasmacytic lymphoma, has witnessed several practice-altering advances in recent years. With availability of a wider array of therapies, the management strategies have become increasingly complex. Our multidisciplinary team appraised studies published or presented up to December 2015 to provide consensus recommendations for a risk-adapted approach to WM, using a grading system. OBSERVATIONS: Waldenström macroglobulinemia remains a rare, incurable cancer, with a heterogeneous disease course. The major classes of effective agents in WM include monoclonal antibodies, alkylating agents, purine analogs, proteasome inhibitors, immunomodulatory drugs, and mammalian target of rapamycin inhibitors. However, the highest-quality evidence from rigorously conducted randomized clinical trials remains scant. CONCLUSIONS AND RELEVANCE: Recognizing the paucity of data, we advocate participation in clinical trials, if available, at every stage of WM. Specific indications exist for initiation of therapy. Outside clinical trials, based on the synthesis of available evidence, we recommend bendamustine-rituximab as primary therapy for bulky disease, profound hematologic compromise, or constitutional symptoms attributable to WM. Dexamethasone-rituximab-cyclophosphamide is an alternative, particularly for nonbulky WM. Routine rituximab maintenance should be avoided. Plasma exchange should be promptly initiated before cytoreduction for hyperviscosity-related symptoms. Stem cell harvest for future use may be considered in first remission for patients 70 years or younger who are potential candidates for autologous stem cell transplantation. At relapse, retreatment with the original therapy is reasonable in patients with prior durable responses (time to next therapy ≥3 years) and good tolerability to previous regimen. Ibrutinib is efficacious in patients with relapsed or refractory disease harboring MYD88 L265P mutation. In the absence of neuropathy, a bortezomib-rituximab-based option is reasonable for relapsed or refractory disease. In select patients with chemosensitive disease, autologous stem cell transplantation should be considered at first or second relapse. Everolimus and purine analogs are suitable options for refractory or multiply relapsed WM. Our recommendations are periodically updated as new, clinically relevant information emerges.
91Plasma exchange: a selective form of blood-letting.PubMed
J P Isbister
Med J Aust. 1979 Aug 25;2(4):167-73. doi: 10.5694/j.1326-5377.1979.tb142022.x.
The technique of, and indications for, plasma exchange are presented. This selective form of plasma removal has re-established "blood-letting" in medical therapeutics on a scientific basis. It is the most appropriate therapy when hyperviscosity or haemostatic failure complicate immunoproliferative disease. Plasma exchange is also a significant advance in the management of fulminant forms of autoimmune disease, but in many other conditions it must be regarded as experimental.
92Therapeutic apheresis in hyperleukocytosis and hyperviscosity syndrome.PubMed
William Blum, Pierluigi Porcu
Semin Thromb Hemost. 2007 Jun;33(4):350-4. doi: 10.1055/s-2007-976170.
Therapeutic apheresis (TA), as a way of rapidly eliminating harmful or excessive blood components such as plasma proteins (plasma exchange) or cells (leukapheresis and platelet apheresis), has found broad application in a vast array of hematologic disorders. The most common hematologic indications for TA are leukocytosis in acute leukemias and hyperviscosity syndrome secondary to plasma cell dyscrasia. Leukapheresis is indicated in the initial management of leukostasis in patients with hyperleukocytosis in acute leukemias, particularly myeloid leukemias, or in patients who are at high risk of developing such a complication. Patients with lymphoid malignancies rarely develop leukostasis but may undergo cytoreduction with leukapheresis as prophylaxis for tumor lysis. The use of leukapheresis in acute promyelocytic leukemia is discouraged, given the possibility of increased risk of coagulopathy and bleeding. Similarly, therapeutic plasma exchange (TPE) represents an effective but temporary way of managing hyperviscosity syndrome secondary to immunoglobulin M paraproteins in patients with Waldenström macroglobulinemia. This review provides an overview of the pathophysiology of leukostasis and its management with leukapheresis. The use of TPE in the management of hyperviscosity syndrome is also discussed.
93Monoclonal Gammopathy-Associated Peripheral Neuropathy: Diagnosis and Management.PubMed
Hafsa M Chaudhry, Michelle L Mauermann, S Vincent Rajkumar
Mayo Clin Proc. 2017 May;92(5):838-850. doi: 10.1016/j.mayocp.2017.02.003.
Monoclonal gammopathies comprise a spectrum of clonal plasma cell disorders that include monoclonal gammopathy of undetermined significance, multiple myeloma, and Waldenström macroglobulinemia. In this review, we outline the epidemiology, etiology, classification, diagnosis, and treatment of monoclonal gammopathy-associated peripheral neuropathy. Monoclonal gammopathy of undetermined significance is relatively common in the general population, with a prevalence of 3% to 4% among individuals older than age 50 years. Therefore, the presence of M protein in a patient with neuropathy does not automatically indicate a causal relationship. Monoclonal gammopathy-associated peripheral neuropathy is often a difficult diagnosis with limited treatment options. Studies addressing the optimal approach to diagnosis and management of this entity are limited. In addition to a review of the literature, we present a diagnostic approach to patients with monoclonal gammopathy-associated peripheral neuropathy and discuss available data and options for treatment.
94CANOMAD: a neurological monoclonal gammopathy of clinical significance that benefits from B-cell-targeted therapies.PubMed
Marie Le Cann, Françoise Bouhour, Karine Viala, et al.
Blood. 2020 Nov 19;136(21):2428-2436. doi: 10.1182/blood.2020007092.
CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.
95Canomad: report of a case with a 40-year history and autopsy. Is this a sensory ganglionopathy with neuromuscular junction blockade?PubMed
Penelope A McKelvie, Peter C Gates, Timothy Day
Muscle Nerve. 2013 Oct;48(4):599-603. doi: 10.1002/mus.23897. Epub 2013 Jun 26.
INTRODUCTION: An 80-year-old man had a 40-year history of chronic sensory ataxic neuropathy and 11 years of relapsing/remitting episodes of rapid deterioration with perioral paresthesiae and weakness of bulbar, respiratory, and limb muscles. METHODS: An immunoglobulin M (IgM) paraprotein was detected 12 years before death, and Waldenstrom macroglobulinemia was diagnosed on bone marrow biopsy 3 years before death. Chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins, and anti-disialyl antibodies (CANOMAD) was diagnosed. RESULTS: Comprehensive autopsy showed severe dorsal column atrophy and dorsal root ganglionopathy. A different pathology was identified in cranial and peripheral nerves, dorsal roots, and cauda equina, comprising infiltration of clonal B-lymphocytes within the endoneurium, perineurium, and leptomeninges. CONCLUSIONS: The autopsy provides evidence of the pathogenesis of the relapsing remitting component of CANOMAD, and we postulate that this may relate to the presence of clonal IgM anti-disiayl gangliosides secreting B-lymphocytes within nerves.
96Waldenström macroglobulinemia in hepatitis C: case report and review of the current literature.PubMed
Ryan Nipp, Aaron Mitchell, Allyson Pishko, et al.
Case Rep Oncol Med. 2014;2014:165670. doi: 10.1155/2014/165670. Epub 2014 Aug 27.
Background. Recent literature has associated hepatitis C virus with the development of non-Hodgkin lymphoma. Hepatitis C virus infection appears to promote lymphoproliferation, providing a plausible mechanism for a causative association; however, despite prior reports of patients with comorbid hepatitis C infection and Waldenström macroglobulinemia, the literature is in disagreement regarding whether there exists an association between these two conditions. Case Presentation. This case report describes a 57-year-old African-American male with chronic hepatitis C infection and cryoglobulinemia who presented with several episodes of transient confusion and paralysis and was found to have symptomatic hyperviscosity. The recognition of his condition was facilitated by characteristic findings on ophthalmologic examination. He was subsequently diagnosed with Waldenström macroglobulinemia on bone marrow biopsy. Conclusions. An up to date, comprehensive review of the literature suggests an association between hepatitis C and Waldenström macroglobulinemia. Data on optimal treatment of patients with comorbid hepatitis C infection and Waldenström macroglobulinemia is limited. We have provided a comprehensive review of previously explored treatment options to guide management of other similar patients. Our patient has since been treated with repeated plasmapheresis with a plan to pursue antiviral therapy.
97A case with acute renal failure complicated by Waldenström's macroglobulinemia and cryoglobulinemia.PubMed
K Yonemura, T Suzuki, K Sano, et al.
Ren Fail. 2000;22(4):511-5. doi: 10.1081/jdi-100100892.
We encountered a 53-year-old man associated with acute renal failure caused by Waldenström's macroglobulinemia and type I cryoglobulinemia. Treatment with prednisolone and cyclophosphamide induced a rapid recovery from acute renal failure. Renal histology revealed endocapillary proliferation and lobular formation with scattered subendothelial, amorphous and periodic acid-Schiff (PAS)-positive materials in the glomerular capillaries which were positive for IgM on immunofluorescence study. Although the exact mechanism for pathophysiology of acute renal failure remains unknown, treatment with prednisolone and cyclophosphamide could induce a rapid recovery from acute renal failure accompanied by Waldenström's macroglobulinemia and type I cryoglobulinemia.
98[Waldenström's macroglobulinemia, cryoglobulinemia type I and membranous glomerulonephritis].PubMed
M I González Anglada, J González García, A del Arco, et al.
Med Clin (Barc). 1991 Oct 26;97(14):539-41.
Renal complications in Waldenström's macroglobulinemia (WM) are infrequent and are characterized by the presence of PAS positive amorphous hyaline deposits in the capillary lumen, infiltrated with lymphoplasmatic cells with PAS positive inclusions in the interstices and intratubular hyaline cylinders. Membranous glomerulonephritis may be a paraneoplastic manifestation of the lymphoproliferative processes. A 67-year-old male was diagnosed of WM, type-I cryoglobulinemia with renal insufficiency without proteinuria. Renal histological examination revealed changes characteristic of nephropathy associated to WM as well as membranous glomerulonephritis. This association has not been described previously. The coexistence of two pathogenic mechanisms with a common base, lymphoproliferative disease, may explain this association.
99Cryoglobulinemia and other dysproteinemias, familial Mediterranean fever, and POEMS syndrome.PubMed
M L Cuéllar, C García, J F Molina
Curr Opin Rheumatol. 1995 Jan;7(1):58-64.
The introduction of newer technology in the past few years, especially the use of second-generation enzyme-linked immunosorbent assays, recombinant immunoblot assays, reverse transcriptase, and DNA amplification, have clearly defined the role of hepatitis C virus as the most important etiologic factor in the development of mixed cryoglobulinemia. This has led to a better understanding of the pathogenic mechanisms involved in disease expression, particularly vasculitis, and also has provided a rationale for the use of interferon alfa and other antiviral drugs in the therapy of these disorders. The clinical manifestations of the syndrome also have been well characterized, as well as some of the risk factors. There also has been an improvement in our understanding of the pathogenic mechanisms involved in multiple myeloma and related monoclonal gammopathies, as well as several attempts to improve early recognition of bone disease with magnetic resonance imaging. The susceptibility gene for familial Mediterranean fever has been better characterized, as have risk factors for colchicine toxicity. The role of cytokines has been better delineated for both monoclonal gammopathies and POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome.
100A Focus on Waldenström Macroglobulinemia and AL Amyloidosis.PubMed
Rebecca Lu, Tiffany Richards
J Adv Pract Oncol. 2022 Jul;13(Suppl 4):45-56. doi: 10.6004/jadpro.2022.13.5.14. Epub 2022 Jul 28.
Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma that is characterized by the overproduction of an IgM monoclonal protein. It may cause adenopathy, hepatomegaly, splenomegaly, as well as other disease-related complications such as cold agglutinin anemia, cryoglobulinemia, hyperviscosity, and neuropathy. While light chain amyloidosis in patients with WM only occurs in about 10% of patients, it is important that advanced practitioners are able to recognize concurrent AL amyloidosis, which will affect the patient's treatment trajectory. Diagnosis of WM with AL amyloidosis is based on bone marrow biopsy and a fat pad biopsy. If AL amyloidosis is suspected, the bone marrow and fat pad biopsy should undergo Congo red staining. If it is negative, and there is a strong suspicion of AL amyloidosis, then an organ biopsy can be considered. Treatment of WM uses rituximab-based therapy in combination with a variety of other agents, including proteasome inhibitors, alkylating agents, and BTK inhibitors. Treatment of light chain amyloidosis uses bortezomib as the backbone of therapy and can be administered with cyclophosphamide, dexamethasone, and now daratumumab, which was recently approved. Waldenström macroglobulinemia and light chain amyloidosis are both rare diseases and can lead to a variety of disease-related complications. Fortunately, many options exist for both diseases. This article will highlight a case of WM with amyloidosis and a case of a patient with relapsing WM with considerations for advanced practitioners managing this patient population.
101Autologous stem cell transplant after heart transplant for light chain (Al) amyloid cardiomyopathy.PubMed
Martha Q Lacy, Angela Dispenzieri, Suzanne R Hayman, et al.
J Heart Lung Transplant. 2008 Aug;27(8):823-9. doi: 10.1016/j.healun.2008.05.016. Epub 2008 Jul 3.
BACKGROUND: Historically, patients with AL amyloidosis and overt congestive heart failure have had an ominous prognosis with median survival of approximately 6 months. METHODS: Between 1994 and 2005, 11 patients underwent sequential orthotopic heart transplantation (HT) followed by autologous peripheral blood stem cell transplantation (SCT) for treatment of AL amyloidosis. Patients were accepted for this approach if they had heart-dominant AL with minimal/no other organ impairment and no evidence of multiple myeloma. Conditioning chemotherapy consisted of melphalan 200 mg/m(2) (6 patients) or melphalan 140 mg/m(2) (5 patients). RESULTS: Two patients died of complications from the SCT (18% transplant-related mortality). Nine patients survived both the HT and the SCT. Three patients subsequently died from progressive amyloidosis at 66, 56.7 and 55 months after SCT. The 1- and 5-year survival for HT was 82% and 65%. The median survival was 76 months from HT and 57 months from SCT. CONCLUSIONS: These data suggest that aggressive treatment of the underlying plasma cell clone after HT may improve long-term outcomes in patients with cardiac amyloid. HT followed by SCT is feasible and offers the possibility of remission for carefully selected patients with cardiac amyloidosis.
102Prognostic factors in symptomatic Waldenstrom's macroglobulinemia.PubMed
Giampaolo Merlini, Luca Baldini, Chiara Broglia, et al.
Semin Oncol. 2003 Apr;30(2):211-5. doi: 10.1053/sonc.2003.50064.
We analyze the prognostic value of the presenting features of a series of patients with symptomatic Waldenstrom's macroglobulinemia who were homogeneously treated. A total of 215 patients (119 males) with a median age of 62.6 years (range, 24.9 to 91.6) were retrospectively analyzed. The median overall follow-up was 57.6 months (range, 0.6 to 281): 58 (0.9 to 281) for living patients and 52.2 (0.6 to 261.3) for those who died. All patients were treated with alkylating agent-based chemotherapy. The overall median survival was 77.2 months, without significant differences based on the duration of the previous monoclonal gammopathy of undetermined significance (MGUS) phase. The multivariate Cox analysis performed on the whole population showed that age, hemoglobin level, and serum albumin level predicted survival. The addition of beta(2)-microglobulin, available in the subgroup of 60 patients diagnosed after 1990, in a Cox stepwise selection showed that this parameter was by far the main prognostic determinant. Application of the Dhodapkar, Morel, and Gobbi scoring systems to this population of patients showed that all three stratified the population into groups with significantly distinct prognoses. A prognostic index based on age, hemoglobin, and albumin is capable of identifying various groups of patients with different therapeutic needs.
103Onsets of progression and second treatment determine survival of patients with symptomatic Waldenström macroglobulinemia.PubMed
Stephanie Guidez, Julien Labreuche, Elodie Drumez, et al.
Blood Adv. 2018 Nov 27;2(22):3102-3111. doi: 10.1182/bloodadvances.2018021287.
Few reports assess prognosis during follow-up of patients with symptomatic Waldenström macroglobulinemia (WM). In 121 WM patients treated between 1993 and 2016, we analyzed the prognostic role during the clinical course of the initial International Prognostic Scoring System for WM (IPSSWM). Then, we assessed onset of response, progression, and second treatment initiation coded as time-dependent covariates. High-risk IPSSWM was an adverse prognostic factor for survival after first treatment initiation (SAFTI). Nevertheless, the corresponding Dxy concordance index obtained in multiple landmark analyses decreased from 0.24 to 0.08 during the first 6 years, in accordance with a departure from the proportional hazard assumption. By contrast with onset of response (whatever its level), onset of progression and initiation of second-line treatment retained prognostic value for SAFTI ( = .02 and = .006, respectively). These findings were confirmed in cause-specific Cox models for deaths related to WM, but not for unrelated deaths. Time to progression after first-line treatment and time to initiation of second-line treatment had no prognostic value for survival after these 2 events. These results were confirmed in an independent series of 119 patients homogeneously treated with chemoimmunotherapy. Finally, after second-line and third-line treatment, onset of progression had significant prognostic value for subsequent risk of related death only. Thus, taking initial IPSSWM and delayed response to treatment into account, only onset of progression and second treatment initiation provided additional prognostic information for SAFTI. Therefore, progression-free survival or time to next treatment may be satisfactory surrogate end points of SAFTI in WM.
104Real-world data on the survival outcome of patients with newly diagnosed Waldenström macroglobulinemia.PubMed
Jang Ho Cho, Joon-Ho Shim, Sang Eun Yoon, et al.
Korean J Intern Med. 2021 May;36(3):668-678. doi: 10.3904/kjim.2019.367. Epub 2020 Aug 14.
BACKGROUND/AIMS: Waldenström macroglobulinemia (WM) is a rare lymphoproliferative disorder that usually follows an indolent clinical course. However, some patients show an aggressive clinical course leading to death. We explored the risk factors predicting poor prognosis in WM patients. METHODS: We retrospectively analyzed 47 patients diagnosed with WM between 2000 and 2018 to explore risk factors predicting poor prognosis using various clinical and laboratory parameters and risk models including the International Prognostic Staging System for WM (IPSS-WM). RESULTS: Over a median follow-up duration of 80.4 months, 29 patients died. The main causes of death were disease progression, organ failure related to amyloidosis, and infection. The median overall survival (OS) was 55.1 months, and 14 patients, including three with amyloidosis, died within 2 years. Serum β2-microglobulin level higher than 4 mg/dL was significantly associated with poor OS. Accordingly, the IPSS-WM showed a significant association with poor prognosis compared with other risk models, and the low-risk group had better OS than intermediate- and high-risk groups. In the retrospective analysis using the results of targeted sequencing in two cases representing good and bad prognosis, different patterns of mutation profiles were observed, including mutations of MYD88, TP53, ARID1A, and JAK2 in a refractory case. CONCLUSION: Serum β2-microglobulin could be a single biomarker strongly predictive of poor survival of WM patients, and the low-risk group of the IPSS-WM risk model including serum β2-microglobulin has better prognostic value than other risk models. Mutation analysis also might provide additional information to predict high-risk patients.
105Current approach to Waldenström Macroglobulinemia.PubMed
Gayathri Ravi, Prashant Kapoor
Cancer Treat Res Commun. 2022;31:100527. doi: 10.1016/j.ctarc.2022.100527. Epub 2022 Feb 2.
Waldenström Macroglobulinemia (WM) is a unique, low grade, IgM lymphoplasmacytic lymphoma with a heterogeneous clinical course. A paucity of high-grade evidence from large phase 3 trials remains a major issue in the field despite a rapidly expanding therapeutic armamentarium against WM. Prior knowledge of the patients' MYD88 and CXCR4 mutation status aids in treatment decision making if Bruton's tyrosine kinase (BTK) inhibitor therapy is being considered. Head-to head comparative data to inform optimal approach are lacking, and a particularly vexing issue for the clinicians is choosing between fixed-duration bendamustine-rituximab (BR) therapy and an indefinite BTK inhibitor-based regimen, given that both approaches are well tolerated and effective, particularly for the patient population harboring MYD88 mutation. For the patients with MYD88 genotype, chemo-immunotherapy such as BR is preferred, although zanubrutinib, a potent second generation BTK inhibitor, with its reduced off target effects and greater BTK occupancy compared to its predecessor, ibrutinib, has also recently shown activity in MYD88 WM. This review summarizes the current literature pertaining to the diagnosis, prognosis, and the treatment of WM.
106Cytogenetic and molecular abnormalities in Waldenström's macroglobulinemia patients: Correlations and prognostic impact.PubMed
Daphné Krzisch, Nayara Guedes, Clémentine Boccon-Gibod, et al.
Am J Hematol. 2021 Dec 1;96(12):1569-1579. doi: 10.1002/ajh.26339. Epub 2021 Sep 27.
While Waldenström macroglobulinemia (WM) is characterized by an almost unifying mutation in MYD88, clinical presentation at diagnosis and response to therapy can be widely different among WM patients. Current prognostic tools only partially address this clinical heterogeneity. Limited data compiling both molecular and cytogenetic information have been used in risk prognostication in WM. To investigate the clinical impact of genetic alterations in WM, we evaluated cytogenetic and molecular abnormalities by chromosome banding analyses, FISH and targeted NGS in a retrospective cohort of 239 WM patients, including 187 patients treated by first-line chemotherapy or immunochemotherapy. Most frequent mutations were identified in MYD88 (93%), CXCR4 (29%), MLL2 (11%), ARID1A (8%), TP53 (8%), CD79A/B (6%), TBL1XR1 (4%) and SPI1 (4%). The median number of cytogenetic abnormalities was two (range, 0-22). Main cytogenetic abnormalities were 6q deletion (del6q) (27%), trisomy 4 (tri4) (12%), tri18 (11%), del13q (11%), tri12 (7.5%) and del17p (7%). Complex karyotype (CK) was observed in 15% (n = 31) of cases, including 5% (n = 12) of highly CK (high-CK). TP53 abnormalities (TP53abn) were present in 15% of evaluable patients. TP53abn and del6q were associated with CK/high-CK (p < .05). Fifty-three percent of patients with hyperviscosity harbored CXCR4 mutations. Cytogenetic and molecular abnormalities did not significantly impact time to first treatment and response to therapy. Prognostic factors associated with shorter PFS were del6q (p = .01), TP53abn (p = .002) and high-CK (p = .01). These same factors as well as IPSSWM, tri4, CXCR4 frameshift and SPI1 mutations were significantly associated with lower OS (p < .05). These results argue for integration of both cytogenetic and molecular screening in evaluation of first-line WM patients.
1076q deletion in Waldenström macroglobulinaemia negatively affects time to transformation and survival.PubMed
Ramón García-Sanz, Irene Dogliotti, Gian Maria Zaccaria, et al.
Br J Haematol. 2021 Mar;192(5):843-852. doi: 10.1111/bjh.17028. Epub 2020 Aug 11.
Deletion of the long arm of chromosome 6 (del6q) is the most frequent cytogenetic abnormality in Waldenström macroglobulinaemia (WM), occurring in approximately 50% of patients. Its effect on patient outcome has not been completely established. We used fluorescence in situ hybridisation to analyse the prevalence of del6q in selected CD19+ bone marrow cells of 225 patients with newly diagnosed immunoglobulin M (IgM) monoclonal gammopathies. Del6q was identified in one of 27 (4%) cases of IgM-monoclonal gammopathy of undetermined significance, nine of 105 (9%) of asymptomatic WM (aWM), and 28/93 (30%) of symptomatic WM (sWM), and was associated with adverse prognostic features and higher International Prognostic Scoring System for WM (IPSSWM) score. Asymptomatic patients with del6q ultimately required therapy more often and had a shorter time to transformation (TT) to symptomatic disease (median TT, 30 months vs. 199 months, respectively, P < 0·001). When treatment was required, 6q-deleted patients had shorter progression-free survival (median 20 vs. 47 months, P < 0·001). The presence of del6q translated into shorter overall survival (OS), irrespective of the initial diagnosis, with a median OS of 90 compared with 131 months in non-del6q patients (P = 0·01). In summary, our study shows that del6q in IgM gammopathy is associated with symptomatic disease, need for treatment and poorer clinical outcomes.
1086q deletion in Waldenström macroglobulinemia is associated with features of adverse prognosis.PubMed
E M Ocio, R F J Schop, B Gonzalez, et al.
Br J Haematol. 2007 Jan;136(1):80-6. doi: 10.1111/j.1365-2141.2006.06389.x.
Fluorescence in situ hybridisation (FISH) is an effective technique for the cytogenetic analysis of Waldenström macroglobulinemia (WM), but the potential impact of molecular cytogenetics on disease evolution and as a prognostic marker is still unknown. Deletion of the long arm of chromosome 6 (6q-) is the most frequent cytogenetic abnormality in WM. This study analysed the prevalence of this aberration in 102 WM patients, and correlated it with disease characteristics. The incidence of 6q21 deletion was 7% by conventional cytogenetics and 34% when analysed by FISH (54% when cytoplasmic immunoglobulin M-FISH was used). Patients with deletion of 6q displayed features of adverse prognosis, such as higher levels of beta2-microglobulin and monoclonal paraprotein and a greater tendency to display anaemia and hypoalbuminemia. Interestingly, there was a correlation between the presence of 6q deletion and the International Staging System prognostic index (incidence of 6q- among patients stratified in stages 1, 2 and 3 was 24%, 42% and 67% respectively). Those patients diagnosed with smouldering WM who displayed the abnormality showed a trend to an earlier requirement of treatment. Finally, the survival analysis did not show differences between the two groups of patients, probably due to the short follow up of our series.
109Prognostic relevance of 6q deletion in Waldenström's macroglobulinemia: a multicenter study.PubMed
Hong Chang, Connie Qi, Young Trieu, et al.
Clin Lymphoma Myeloma. 2009 Mar;9(1):36-8. doi: 10.3816/CLM.2009.n.008.
The deletion of the long arm of chromosome 6 is the most common cytogenetic abnormality in Waldenstrom's macroglobulinemia (WM), but its prognostic significance is unclear. We investigated 77 patients with WM by interphase cytoplasmic immunoglobulin M fluorescence in situ hybridization (cIgM-FISH) and correlated the 6q status with the patients' clinical features and survival. cIg-FISH detected hemizygous 6q deletions in 32 patients (41.6%). The 6q deletions were correlated with higher C-reactive protein levels (P = .02) and CD23 expression (P = .03) but not with other clinical laboratory features of WM. There was no significant difference in time to the initial treatment between deleted and non-deleted groups (median, 5.6 months vs. 2.6 months; P = .46), or overall survivals in patients with and without del (6q) (163 months vs. not reached; P = .83). Our study confirms that the 6q deletion is a frequent event, but it does not appear to affect the clinical outcome of WM.
110Analysis of 6q deletion in Waldenstrom macroglobulinemia.PubMed
Hong Chang, Xiaoying Qi, Wei Xu, et al.
Eur J Haematol. 2007 Sep;79(3):244-7. doi: 10.1111/j.1600-0609.2007.00903.x. Epub 2007 Jul 26.
The frequency and prognostic significance of chromosome 6q deletion were investigated in a cohort of patients with Waldenstrom macroglobulinemia (WM). By interphase cytoplasmic fluorescence in situ hybridization with probes for 6q21 and 6q25, we detected hemizygous 6q deletions in the clonal lymphoplasmacytic cells in 13 (38%) out of 34 patients. Patients with 6q deletions had a lower IgM paraprotein levels than non-deleted patients (P = 0.04). There was no correlation between 6q deletion and other clinical features of WM. There was no significant difference in overall survival between 6q deleted and non-6q deleted groups (P = 0.92). Our study confirms that 6q deletion is a frequent event, but it does not appear to be a prognostic marker for patients with WM.
111Highly sensitive mutation detection by droplet digital polymerase chain reaction in Waldenström macroglobulinemia.PubMed
Daniela Drandi, Elisa Genuardi, Irene Dogliotti, et al.
Haematologica. 2018 Jun;103(6):1029-1037. doi: 10.3324/haematol.2017.186528. Epub 2018 Mar 22.
We here describe a novel method for mutation detection and minimal residual disease monitoring in Waldenström macroglobulinemia, by droplet digital polymerase chain reaction, in bone marrow and peripheral blood cells, as well as in circulating cell-free DNA. Our method shows a sensitivity of 5.00×10, which is far superior to the widely used allele-specific polymerase chain reaction (1.00×10). Overall, 291 unsorted samples from 148 patients (133 with Waldenström macroglobulinemia, 11 with IgG lymphoplasmacytic lymphoma and 4 with IgM monoclonal gammopathy of undetermined significance) were analyzed: 194 were baseline samples and 97 were followup samples. One hundred and twenty-two of 128 (95.3%) bone marrow and 47/66 (71.2%) baseline peripheral blood samples scored positive for To investigate whether detection by droplet digital polymerase chain reaction could be used for minimal residual disease monitoring, mutation levels were compared with -based minimal residual disease analysis in 10 patients, and was found to be as informative as the classical, standardized, but not yet validated in Waldenström macroglobulinemia, -based minimal residual disease assay (r=0.64). Finally, detection by droplet digital polymerase chain reaction on plasma circulating tumor DNA from 60 patients showed a good correlation with bone marrow findings (bone marrow median mutational value 1.92×10, plasma circulating tumor DNA value: 1.4×10, peripheral blood value: 1.03×10). This study indicates that droplet digital polymerase chain reaction assay of is a feasible and sensitive tool for mutation screening and minimal residual disease monitoring in Waldenström macroglobulinemia. Both unsorted bone marrow and peripheral blood samples can be reliably tested, as can circulating tumor DNA, which represents an attractive, less invasive alternative to bone marrow for detection.
112MYD88 L265P Mutation Detection by ddPCR: Recommendations for Screening and Minimal Residual Disease Monitoring : ddPCR for Highly Sensitive Detection of MYD88 L265P Mutation.PubMed
Daniela Drandi, Martina Ferrante, Michela Borriero, et al.
Methods Mol Biol. 2023;2621:57-72. doi: 10.1007/978-1-0716-2950-5_5.
MYD88 is a gain-of-function mutation, arising from the missense alteration c.794T>C, that frequently occurs in B-cell malignancies such as Waldenstrom macroglobulinemia and less frequently in IgM monoclonal gammopathy of undetermined significance (IgM-MGUS) or other lymphomas. MYD88 has been recognized as a relevant diagnostic flag, but also as a valid prognostic and predictive biomarker, as well as an investigated therapeutic target. Up until now, allele-specific quantitative PCR (ASqPCR) has been widely used for MYD88 detection providing a higher level of sensitivity than Sanger sequencing. However, the recently developed droplet digital PCR (ddPCR) shows a deeper sensitivity, compared to ASqPCR, that is necessary for screening low infiltrated samples. Actually, ddPCR could represent an improvement in daily laboratory practice since it allows mutation detection in unselected tumor cells, allowing to bypass the time-consuming and costly B-cell selection procedure. ddPCR accuracy has been recently proved to be suitable also for mutation detection in "liquid biopsy" samples that might be used as a noninvasive and patient-friendly alternative to bone marrow aspiration especially during the disease monitoring. The relevance of MYD88, both in daily management of patients and in prospective clinical trials investigating the efficacy of novel agents, makes crucial to find a sensitive, accurate, and reliable molecular technique for mutation detection. Here, we propose a protocol for MYD88 detection by ddPCR.
113Incidence and Risk of Secondary Malignancy in Patients with Waldenström Macroglobulinemia: A Population-Based Analysis.PubMed
Mohammad Ebad Ur Rehman, Maha Hameed, Zunairah Shah, et al.
Clin Hematol Int. 2024 Jan 5;6(1):3-12. doi: 10.46989/001c.90436. eCollection 2024.
Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma which may predispose individuals to development of secondary malignancies (SMs). The Surveillance, Epidemiology, and End Results (SEER) database is a comprehensive registry of cancer patients in the United States reporting on a wide set of demographic variables. Using the SEER-18 dataset, analyzing patients from 2000 to 2018, we aimed to assess the incidence of SMs in WM patients. Patient characteristics such as gender, age, race, and latency were identified, and respective standardized incidence ratios (SIRs) and absolute excess risks (AERs) were calculated to compare to the general population. Of the 4,112 eligible WM patients identified, SMs were reported in 699 (17%) patients. The overall risk of developing SM, second primary malignancy, and secondary hematological malignancy was significantly higher in WM patients compared to the general population. Our findings show that WM patients had a 53% higher risk of SMs relative to the general population, and an AER of 102.69 per 10,000. Although the exact mechanism is unclear, the risk of SM development may be due to genetic predisposition, immune dysregulation, or treatment-induced immune suppression.
114Incidence of secondary malignancies among patients with Waldenström macroglobulinemia: An analysis of the SEER database.PubMed
Jorge J Castillo, Adam J Olszewski, Zachary R Hunter, et al.
Cancer. 2015 Jul 1;121(13):2230-6. doi: 10.1002/cncr.29334. Epub 2015 Mar 10.
BACKGROUND: Waldenström macroglobulinemia (WM) is an indolent malignancy that predominantly affects older individuals who are at risk for secondary malignancies (SMs). The objective of this study was to characterize the incidence of SMs after a diagnosis of WM with the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: With SEER-13 data (1992-2011), standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated for the rates of solid and hematologic SMs in WM patients versus the general population. The analysis was stratified by age, sex, race, year of diagnosis, and latency from the WM diagnosis. RESULTS: Among 4676 patients with WM, 681 SMs were recorded. The overall SIR was 1.49 (95% CI, 1.38-1.61), and the median time to an SM was 3.7 years. The cumulative incidence of SMs was 10% at 5 years and 16% at 10 years. The risk was significantly increased for cancers of the lungs, urinary tract, and thyroid; melanoma; aggressive lymphoma; and acute leukemia. The SIR for SMs in patients with WM was increased, regardless of age, sex, race, or year of diagnosis. CONCLUSIONS: Patients with WM had a 49% higher risk of SMs than the general population. The selectively increased risk for hematologic SMs and certain solid SMs may be associated with transformation, therapy, and immune dysregulation.