Alemtuzumab in T-cell large granular lymphocytic leukaemia: interim results from a single-arm, open-label, phase 2 study.
Alemtuzumab in T-cell large granular lymphocytic leukaemia: interim results from a single-arm, open-label, phase 2 study.
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DOI：
10.1016/s2352-3026(15)00227-6
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发表时间：
2016-01
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影响因子：
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通讯作者：
Scheinberg P
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作者：
Dumitriu B;Ito S;Feng X;Stephens N;Yunce M;Kajigaya S;Melenhorst JJ;Rios O;Scheinberg P;Chinian F;Keyvanfar K;Battiwalla M;Wu CO;Maric I;Xi L;Raffeld M;Muranski P;Townsley DM;Young NS;Barrett AJ;Scheinberg P
T细胞大颗粒淋巴细胞白血病（T-LGL）是一种以免疫介导的血细胞减少为主要表现的淋巴细胞增生性疾病，其特征是细胞毒性CD 3 + CD 8+淋巴细胞的克隆性扩增。甲氨蝶呤、环孢霉素或环磷酰胺作为首次治疗可改善50%患者的血细胞减少症，但抗CD 52单克隆抗体Alemtuzumab的活性在T-LGL中未确定。2006年10月至2015年3月，在美国国立卫生研究院（www.clinicaltrials. gov-NCT 00345345）入组了25例连续T-LGL受试者。Alemtuzumab以10 mg/天静脉给药，持续10天。主要终点是3个月时的血液学应答。在此，我们报告了一项使用Alemtuzumab治疗T-LGL的II期临床试验的方案规定的中期基准。在该异质性既往接受过治疗的队列中，14/25例（56%; 95% CI，37-73%）受试者在3个月时出现血液学缓解。在与骨髓增生异常或骨髓移植无关的T-LGL病例中，缓解率为14/19（74%; 95% CI，51-86%）。首次给药输注反应常见，对症治疗后改善。EBV和CMV再激活是常见和亚临床的。仅2例患者进行了预防性抗CMV治疗。无EBV或CMV疾病病例。根据TCRBV受体表型鉴定，Alemtuzumab诱导细胞毒性T淋巴细胞绝对克隆群持续减少，但异常克隆偶然持续存在于应答者中。在10名受试者中发现的SH 2结构域中的STAT 3突变与缓解无关。与健康志愿者相比，T-LGL受试者在治疗前显示出不同的血浆细胞因子和JAK-STAT特征，但两者均与应答无关。这是迄今为止报告的接受Alemtuzumab治疗的T-LGL受试者的最大和唯一前瞻性队列。在主要复发和难治性患者中，淋巴细胞毒性剂单疗程的高活性表明，无需继续使用口服免疫抑制剂即可实现血液学应答结局。这项研究得到了NIH，国家心脏，肺和血液研究所的校内研究计划的支持。
T-cell large granular lymphocytic leukemia (T-LGL) is a lymphoproliferative disease presenting with immune-mediated cytopenias and characterized by clonal expansion of cytotoxic CD3+CD8+ lymphocytes. Methotrexate, cyclosporine, or cyclophosphamide improve cytopenias in 50% of patients as first therapy, but the activity of an anti-CD52 monoclonal antibody, alemtuzumab, is not defined in T-LGL. Twenty-five consecutive subjects with T-LGL were enrolled from October 2006 to March 2015 at the National Institutes of Health (www.clinicaltrials.gov-NCT00345345). Alemtuzumab was administered at 10 mg/day intravenously for 10 days. The primary endpoint was haematologic response at 3 months. Analysis was intention to treat. Here we report the protocol specified interim benchmark of a phase II clinical trial using alemtuzumab in T-LGL. In this heterogeneous, previously treated cohort, 14/25 (56%; 95% CI, 37–73%) subjects had a haematological response at 3 months. In T-LGL cases not associated with myelodysplasia or marrow transplantation, the response rate was 14/19 (74%; 95% CI, 51–86%). First dose infusion reactions were common which improved with symptomatic therapy. EBV and CMV reactivations were common and subclinical. In only 2 patients pre-emptive anti-CMV therapy was instituted. There were no cases of EBV or CMV disease. Alemtuzumab induced sustained reduction of absolute clonal population of T-cytotoxic lymphocytes, as identified by TCRBV-receptor phenotype, but the abnormal clone serendipitously persisted in responders. STAT3 mutations in the SH2 domain, identified in ten subjects, did not correlate with response. When compared with healthy volunteers, T-LGL subjects showed a distinct plasma cytokine and JAK-STAT signature prior to treatment, but neither correlated to response. This is the largest and only prospective cohort of T-LGL subjects treated with alemtuzumab yet reported. The high activity with a single course of a lymphocytotoxic agent in a mainly relapsed and refractory suggests that haematologic response outcomes can be accomplished without the need for continued use of oral immunosuppression. This research was supported by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute.