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12月3日，第58届美国血液学年会（ASH，12月3日~6日）于美国圣地亚哥召开。其间，在“
Anna Maria Fink博士说，研究发现接受来那度胺维持治疗的CLL患者疾病进展风险比未接受来那度胺维持治疗的患者降低了至少80%，并且一部分患者的最小残留病变达到阴性。该研究是首个证明CLL患者可从来那度胺维持治疗中获益的研究，但对将来的治疗有无影响尚不确定。近年来，多种靶向新药为医生和患者提供了更多的方案选择，因此来那度胺维持治疗可能也会成为某部分合适患者的治疗选择。
Nadia Khan博表示，应用这项研究结果的最大挑战就是其它口服耐受性疗法的可用性。该研究证实了其它研究数据——最小残留病变阴性是预测化疗预后最强有力的预测因素。除了临床实践以外，临床试验的设计可能也非常困难。该研究应用的MRD风险评估模型可能也会用到后续研究中。
研究细节
该项CLL M1研究纳入468名至少经4周期的标准免疫化疗一线治疗的CLL患者，之前接受过的一线化疗方案包括
大多数患者（373 /468， 79.7%）因MRD 阴性或低复发或进展风险，未接受来那度胺维持治疗。接受维持治疗的患者需满足：对之前化疗响应，但有高复发风险，高 MRD ≥ 10-2，中间MRD（≥10-4 ~ <10-2）需满足具有未突变的IGHV基于状态或del（17p） or TP53突变。经筛选，89名患者符合纳入条件，其中60名患者接受了来那度胺维持治疗，29名患者接受了安慰剂治疗。来那度胺维持治疗的起始剂量为5 mg/d，持续1个疗程（为期28天），在随后的疗程中，来那度胺剂量逐渐增加为10 mg、15 mg、20 mg和25 mg，直至达到MRD阴性。18个疗程偶，所有MRD阳性的患者继续接受来那度胺25 mg治疗，直至疾病进展。安慰剂组的患者接受了匹配的安慰剂治疗。
研究结果
89名患者的中位年龄为64岁，身体状态相对较好，中位累积疾病评分2分。整体上，87% 的患者达到了部分缓解，9%的患者完全缓解。
来那度胺组的中位疗程数为11.1，安慰剂组为8.3。来那度胺组中42.9%的患者中断了维持治疗，低于安慰剂组（72.4%），并且大多因不良反应所致。而因疾病进展所致治疗中断率，安慰剂组明显高于来那度胺组，分别为44.8% vs 7.1%。共3名患者死亡，其中1名为来那度胺组，另外2名在安慰剂组。
中位随访17.7个月，来那度胺组的中位生存期明显长于安慰剂组（未达 vs 13.3个月），进展风险降低了至少80%。
对于随机化时高或中MRD的患者，来那度胺维持治疗明显延长了PFS，高MRD患者为32.3个月（安慰剂组3.7个月），中MRD的患者为未达到（安慰剂组19.4个月），但总生存期无差异。
临床意义
Fink 教授说，该研究表明，对于预后不良的患者而言，改变治疗策略可能比强化治疗产生更好地预后，但来那度胺维持治疗能否成为标准选择还有待确定。
目前临床工作中，很多患者接受了免疫化疗，但没接受维持治疗。自该研究开展以来多种靶向治疗方案已被批准治疗CLL，如依鲁替尼、 idelalisib和obinutuzumab等。随着这些药物的审批，免疫化疗用于一线治疗的情况越来越少。临床工作中，经某种治疗后进展的患者应接受另一种方案治疗，但FCR[氟达拉滨、
Fink教授说，现在的难点是这些新型无化疗方案如何改变这类患者的标准治疗方案。另外，她强调了一项有关这个问题的大型研究（CLL 13），将评估无化疗方案的活性，并与化疗方案（苯达莫司汀或氟达拉滨/阿糖胞苷联合利妥昔单抗）进行比较。
另外，Khan教授补充了另一项类似的研究（ALLIANCE），包含三个试验组，通过比较依鲁替尼、ibrutinib /利妥昔单抗和苯达莫司汀/利妥昔单抗，明确最佳一线方案。
需要强调的是，有些新型方案不定期或无限期给药，但很少有患者达到完全缓解，因此未来研究需进一步明确停药最佳时机。
摘要详情
229 Lenalidomide Maintenance after Front Line Therapy Substantially Prolongs Progression Free Survival in High Risk CLL: Interim Results of a Phase 3 Study （CLL M1 study of the German CLL Study Group）Clinically Relevant Abstract
Introduction: The combined use of genetic markers and minimal residual disease (MRD) assessment identifies CLL patients (pts) with a poor outcome after front line chemoimmunotherapy. The CLLM1 study was initiated to evaluate lenalidomide as a maintenance treatment versus (vs) placebo in a double-blind fashion. The primary endpoint was progression free survival (PFS) by an independent review.
Methods: Pts who achieved at least a partial response after at least 4 cycles of front line chemoimmunotherapy were defined as high risk for progression if they had MRD levels of ≥10-2 or MRD levels of ≥10-4 to <10-2 combined with either an unmutated IGHV gene status, del(17p) or TP53 mutation at baseline. After 2:1 randomization, treatment with lenalidomide or placebo started with 5 mg daily in the first cycle, and was subsequently escalated to the target dose of 15 mg in the 7th cycle. Further possible escalation was guided by six-monthly MRD assessments. If well tolerated, the study drug was administered until disease progression. According to their risk for thromboembolic events pts received either low dose aspirin daily, or appropriate anti-coagulation prophylactic therapies. Pts were followed for progression monthly. This formal interim analysis was conducted after 20% (24 events) of the calculated PFS events and 89 pts of the planned 200 pts were randomized. PFS was evaluated at the significance level determined using the Hwang-Shih-DeCani spending function (including stopping boundaries for both futility and efficacy). The trial was registered with clinicaltrials.gov (NCT01556776).
Results: A total of 468 pts from 62 sites in five countries (Austria, Germany, Italy, Netherlands and Spain) were screened for the study. 379 were not eligible, 347 because of MRD-negativity/low risk after frontline treatment and 32 because of progression between end of frontline and screening (11), withdrawal of consent (15) and other reasons (6). Out of 89 randomized pts, 60 received lenalidomide and 29 placebo. Randomized pts had a median age of 64 (range, 32-80), a median CIRS Score of 2 (range, 0-6), and 85.2% were male. 11.4% /20.5% of the pts had a 17p deletion/TP53 mutation, and 90.2% of the pts had an unmutated IGHV gene status at baseline. At randomization, 37% of pts had a high and 63% an intermediate MRD level, respectively. At data cut off, pts had received a median of 10 (range 0-42) treatment cycles [lenalidomide, 11 (0-42); placebo, 9 (1-35)]. Treatment was discontinued in 27 pts on lenalidomide and in 21 pts on the placebo arm due to adverse events (17 vs 6 pts), disease progression (4 vs 13 pts), withdrawal of consent (4 vs 2 pts) and other reasons (2 vs 2 pts). Treatment with lenalidomide was more frequently associated with neutropenia (30.4% vs 3.4%), gastrointestinal disorders (55.4% vs 27.6%), nervous system disorders (30.4% vs 13.8%), respiratory disorders (35.7% vs 13.8%) and skin disorders (60.7% vs 27.6%). Infections (50% vs 62.1%) and vascular disorders (14.3% vs 17.2%) were not increased in the lenalidomide compared to the placebo arm. Three deaths have been observed so far, one in the lenalidomide arm (acute lymphoblastic leukemia) and two in the placebo arm (1 progressive multifocal leukoencephalopathy; 1 Richter’s syndrome). After a median observation time of 17.7 months, the hazard ratio for PFS was 0.198 with 95% confidence interval (CI) 0.083 to 0.475 (stratified by MRD level at randomization). The median PFS in the placebo arm was 14.6 months, and was not reached in the lenalidomide arm (see figure 1). The one-sided p-value from the stratified log-rank test was 0.000059/2, thus smaller than the determined efficacy boundary 0.0006 derived from the Hwang-Shih-DeCani spending function based on 24 PFS events. Conversion to MRD negativity has been observed only in the lenalidomide arm, data will be presented at the meeting.
Conclusion: Lenalidomide is a feasible and efficacious maintenance option for high risk CLL after chemoimmunotherapy and substantially prolonged PFS in high risk CLL patients resulting in a relative risk reduction for progression of more than 80%. An independent data monitoring committee assessed the results as being robust and reliable and recommended unblinding of the study as well as continuing treatment with lenalidomide. The PFS observed in the placebo arm independently confirms the prognostic significance of the MRD based risk assessment model, which might be used in future trials.
医脉通编译自：Maintenance Lenalidomide Prolongs PFS in High-Risk CLL.Medscape.2016
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