Division of Hematology and Hemostaseology, Department of Internal Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria.
Blood. 2018 Aug 16;132(7):694-706. doi: 10.1182/blood-2017-10-810739. Epub 2018 Jun 14.
Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of MPN with JAK1/2 inhibitors. We assessed 626 patients with MPN, including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4 (5.8%) of 69 patients receiving JAK1/2 inhibition compared with 2 (0.36%) of 557 with conventional treatment (16-fold increased risk). A similar 15-fold increase was observed in an independent cohort of 929 patients with MPN. Considering primary myelofibrosis only (N = 216), 3 lymphomas were observed in 31 inhibitor-treated patients (9.7%) vs 1 (0.54%) of 185 control patients. Lymphomas were of aggressive B-cell type, extranodal, or leukemic with high MYC expression in the absence of V617F or other MPN-associated mutations. Median time from initiation of inhibitor therapy to lymphoma diagnosis was 25 months. Clonal immunoglobulin gene rearrangements were already detected in the bone marrow during myelofibrosis in 16.3% of patients. Lymphomas occurring during JAK1/2 inhibitor treatment were preceded by a preexisting B-cell clone in all 3 patients tested. Sequencing verified clonal identity in 2 patients. The effects of JAK1/2 inhibition were mirrored in mice: 16 of 24 mice developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B cells. Transplantations of bone marrow from diseased mice unmasked the outgrowth of a malignant B-cell clone evolving into aggressive B-cell leukemia-lymphoma. We conclude that JAK/STAT1 pathway inhibition in myelofibrosis is associated with an elevated frequency of aggressive B-cell lymphomas. Detection of a preexisting B-cell clone may identify individuals at risk.
Janus 激酶 1/2（JAK1/2）的抑制是治疗骨髓增生性肿瘤（MPN）的主要方法。偶然观察到在使用 JAK1/2 抑制剂治疗 MPN 时，会同时发生 B 细胞非霍奇金淋巴瘤。我们评估了 626 名 MPN 患者，其中 69 名患有骨髓纤维化的患者接受了 JAK1/2 抑制剂治疗以评估淋巴瘤的发展情况。在接受 JAK1/2 抑制治疗的 69 名患者中，有 4 名（5.8%）出现 B 细胞淋巴瘤，而在接受常规治疗的 557 名患者中，有 2 名（0.36%）出现这种情况（风险增加 16 倍）。在另一项由 929 名 MPN 患者组成的独立队列中，也观察到了类似的 15 倍风险增加。仅考虑原发性骨髓纤维化（N=216），在 31 名接受抑制剂治疗的患者中观察到 3 例淋巴瘤（9.7%），而在 185 名对照患者中观察到 1 例（0.54%）。这些淋巴瘤为侵袭性 B 细胞型、结外或白血病型，且在缺乏 V617F 或其他 MPN 相关突变的情况下，高表达 MYC。从抑制剂治疗开始到淋巴瘤诊断的中位时间为 25 个月。在 16.3%的患者中，骨髓纤维化期间已经在骨髓中检测到克隆性免疫球蛋白基因重排。在所有 3 例接受检测的患者中，在接受 JAK1/2 抑制剂治疗期间发生的淋巴瘤之前均存在预先存在的 B 细胞克隆。2 例患者的测序证实了克隆的同一性。在小鼠中，JAK1/2 抑制的作用也得到了反映：24 只小鼠中有 16 只自发发展为髓样增生，同时存在异常 B 细胞。移植患病小鼠的骨髓揭示了恶性 B 细胞克隆的生长，发展为侵袭性 B 细胞白血病-淋巴瘤。我们的结论是，在骨髓纤维化中抑制 JAK/STAT1 通路与侵袭性 B 细胞淋巴瘤的频率增加有关。检测到预先存在的 B 细胞克隆可能会识别出处于风险中的个体。
