Rao V Koneti, Pittaluga Stefania, Uzel Gulbu
National Institutes of Health (NIH), Bethesda, MD.
Hematology Am Soc Hematol Educ Program. 2024 Dec 6;2024(1):126-136. doi: 10.1182/hematology.2024000537.
Refractory autoimmune mutilineage cytopenias can present in childhood associated with chronic nonmalignant lymphoproliferation (splenomegaly, hepatomegaly, and/or lymphadenopathy). Cytopenias due to peripheral destruction and sequestration have been well recognized since the 1950s and are often lumped together as eponymous syndromes, such as Evans syndrome and Canale-Smith syndrome. Though their clinical and genetic diagnostic workup may appear daunting, it can provide the basis for early intervention, genetic counseling, and empirical and targeted therapies. Autoimmune lymphoproliferative syndrome (ALPS), activated phosphatidylinositol 3-kinase delta syndrome (APDS), and many other related genetic disorders are otherwise collectively known as inborn errors of immunity (IEI). They present in early childhood as refractory autoimmune cytopenias due to immune dysregulation leading to lymphadenopathy, splenomegaly, and increased susceptibility to lymphoma. More recently, controlled clinical trials have shown that some of these immune system disorders with hematological manifestations might be more readily amenable to specific targeted treatments, thus preventing end-organ damage and associated comorbidities. Over the last 20 years, both rapamycin and mycophenolate mofetil have been successfully used as steroid-sparing long-term measures in ALPS. Current therapeutic options for APDS/PASLI (phosphoinositide 3-kinase [PI3K]-associated senescent T lymphocytes, lymphadenopathy, and immunodeficiency) include the orally bioavailable PI3Kδ inhibitor, leniolisib, which was licensed by the US Food and Drug Administration (FDA) in 2023 for use in individuals older than 12 years as a targeted treatment. Paradigms learned from patients with rare genetic disorders like ALPS and APDS may help in exploring and streamlining molecular therapy strategies in the wider group of IEIs presenting with refractory cytopenias and lymphoproliferation.
难治性自身免疫性多系血细胞减少症可在儿童期出现，并伴有慢性非恶性淋巴增殖（脾肿大、肝肿大和/或淋巴结病）。自20世纪50年代以来，外周破坏和隔离导致的血细胞减少症已得到充分认识，并且常常被归为一些以人名命名的综合征，如伊文思综合征和卡纳尔-史密斯综合征。尽管它们的临床和基因诊断检查可能看起来令人生畏，但可为早期干预、遗传咨询以及经验性和靶向治疗提供依据。自身免疫性淋巴增殖综合征（ALPS）、活化磷脂酰肌醇3激酶δ综合征（APDS）以及许多其他相关的遗传疾病统称为先天性免疫缺陷（IEI）。它们在儿童早期表现为难治性自身免疫性血细胞减少症，原因是免疫失调导致淋巴结病、脾肿大以及淋巴瘤易感性增加。最近，对照临床试验表明，一些具有血液学表现的免疫系统疾病可能更容易接受特定的靶向治疗，从而预防终末器官损害和相关合并症。在过去20年中，雷帕霉素和霉酚酸酯已成功用作ALPS中替代类固醇的长期措施。APDS/PASLI（磷脂酰肌醇3激酶[PI3K]相关的衰老T淋巴细胞、淋巴结病和免疫缺陷）目前的治疗选择包括口服生物利用度高的PI3Kδ抑制剂来那度胺，该药物于2023年获得美国食品药品监督管理局（FDA）批准，用于12岁以上个体的靶向治疗。从ALPS和APDS等罕见遗传疾病患者身上学到的范例可能有助于探索和简化在表现为难治性血细胞减少症和淋巴增殖的更广泛的IEI群体中的分子治疗策略。
