HCEMM-SE Molecular Oncohematology Research Group, Budapest, Hungary; 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary.
Pathology. 2022 Feb;54(1):95-103. doi: 10.1016/j.pathol.2021.04.008. Epub 2021 Jul 28.
Richter syndrome (RS) represents the development of high-grade lymphoma in patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) and presents a diagnostic and therapeutic challenge with an adverse prognosis. The genetic background and morphology of RS in CLL patients treated with chemoimmunotherapy is extensively characterised; however, our knowledge about RS in patients treated with targeted oral therapies should be extended. To understand the morphologic and molecular changes leading to RS in CLL patients treated with the Bruton's tyrosine kinase inhibitor, ibrutinib, and the BCL2 inhibitor, venetoclax, sequential samples from six CLL/SLL patients undergoing RS were collected in both the CLL and RS phases. A detailed immunophenotypic analysis of formalin-fixed, paraffin-embedded tissue specimens of RS phase was performed, followed by extensive molecular characterisation of CLL and RS samples, including the immunoglobulin heavy chain gene (IGH) rearrangement, TP53 mutations, drug-induced resistance mutations in BTK and BCL2 genes and various copy number changes and point mutations detectable with multiplex ligation-dependent probe amplification (MLPA). Rare, non-diffuse large B-cell lymphoma phenotypes of RS were observed in 3/6 cases, including plasmablastic lymphoma and a transitory entity between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. The majority of cases were clonally related and harboured an unmutated variable region of the immunoglobulin heavy chain gene. Abnormalities affecting the TP53 gene occurred in all patients, and every patient carried at least one genetic abnormality conferring susceptibility to RS. In the background of RS, 2/5 patients treated with ibrutinib showed a BTK C481S resistance mutation. One patient developed a BCL2 G101V mutation leading to venetoclax resistance and RS. In conclusion, our findings contribute to better understanding of RS pathogenesis in the era of targeted oral therapies. Rare phenotypic variants of RS do occur under the treatment of ibrutinib or venetoclax, and genetic factors leading to RS are similar to those identified in patients treated with chemoimmunotherapy. To our best knowledge, we have reported the first BCL2 G101V mutation in an RS patient treated with venetoclax.
Richter 综合征（RS）代表慢性淋巴细胞白血病（CLL）或小淋巴细胞淋巴瘤（SLL）患者中高级别淋巴瘤的发展，具有诊断和治疗挑战，预后不良。在接受化疗免疫治疗的 CLL 患者中，RS 的遗传背景和形态学已得到广泛描述；然而，我们对接受靶向口服治疗的患者中 RS 的了解应该扩展。为了了解接受 Bruton 酪氨酸激酶抑制剂伊布替尼和 BCL2 抑制剂维奈托克治疗的 CLL 患者中 RS 的形态学和分子变化，在 CLL 和 RS 阶段，从 6 例接受 RS 的 CLL/SLL 患者中连续采集样本。对 RS 期福尔马林固定石蜡包埋组织标本进行详细的免疫表型分析，然后对 CLL 和 RS 样本进行广泛的分子特征分析，包括免疫球蛋白重链基因（IGH）重排、TP53 突变、BTK 和 BCL2 基因中药物诱导的耐药突变以及可通过多重连接依赖性探针扩增（MLPA）检测到的各种拷贝数变化和点突变。在 3/6 例中观察到 RS 的罕见非弥漫性大 B 细胞淋巴瘤表型，包括浆母细胞淋巴瘤和弥漫性大 B 细胞淋巴瘤与经典霍奇金淋巴瘤之间的短暂实体。大多数病例具有克隆相关性，并且携带未突变的免疫球蛋白重链基因可变区。所有患者均发生影响 TP53 基因的异常，每个患者均携带至少一种导致 RS 易感性的遗传异常。在 RS 的背景下，5 例接受伊布替尼治疗的患者中有 2 例显示 BTK C481S 耐药突变。1 例患者发生 BCL2 G101V 突变导致维奈托克耐药和 RS。总之，我们的研究结果有助于更好地了解靶向口服治疗时代的 RS 发病机制。在接受伊布替尼或维奈托克治疗时确实会发生 RS 的罕见表型变异，导致 RS 的遗传因素与接受化疗免疫治疗的患者相似。据我们所知，我们报道了首例接受维奈托克治疗的 RS 患者中 BCL2 G101V 突变。
