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预防慢性淋巴细胞白血病的进展是过去两年最重要的主题，现在我们发现了另一种有效的治疗方案来治疗无其它可用疗法的患者。这些结果表明，我们可以通过联合新疗法和既定疗法使患者达到更好的预后。
——ASCO专家Merry-Jennifer Markham博士

2015年ASCO年会将于5月29日--6月2日在美国芝加哥召开，5月30日公布的一项大型II期研究的期中分析表明，依鲁替尼联合苯达莫司汀/利妥昔单抗（BR）可改善慢性淋巴细胞白血病（CLL）患者的预后，尽管之前的疗法使其恶化。

中位随访17个月，接受依鲁替尼和BR的患者疾病进展或死亡风险比接受安慰剂和BR的患者低80%。基于这一良好获益，患者从安慰剂组转移至依鲁替尼组。

CLL是西方国家最常见的成人白血病。几年来，CLL的标准疗法是化疗法联合靶向疗法（比如利妥昔单抗）。尽管这些治疗利于控制疾病多年，但是不能治愈疾病，而且最终所有患者对这一治疗具有耐药性。

直到最近，疾病恶化或复发的患者治疗方案变得非常有限。去年，FDA批准了两种新型靶向药物——依鲁替尼和idelalisib联合利妥昔单抗治疗这一疾病。依鲁替尼是一种首创口服靶向药物，每天口服一次，可抑制布鲁顿酪氨酸激酶（BTK）。这种蛋白质促进淋巴细胞（受CLL损伤的白细胞）的生长。

这一研究的主要作者AsherChanan-Khan博士说：“这是治疗CLL最严谨的临床试验之一，而且它确实证实依鲁替尼是治疗这种癌症的重要药物。我们发现依鲁替尼与现存疗法联合可以强有力的延长缓解时间，并改善患者的健康状况”

在这项研究中，578名先前经治疗的CLL患者被随机分配接受依鲁替尼+BR或安慰剂+BR治疗。中位随访17.2个月之后，安慰剂组和依鲁替尼组的中位无进展生存期分别为13.3个月和未达到。接受依鲁替尼的患者进展或死亡风险降低80%。

依鲁替尼组的缓解率显著高于安慰剂组（82.7%vs. 67.8%）。依鲁替尼组的疾病相关疲劳得到改善，而且患者获益较快（第6个月vs 14个月）。

进行期中分析时，安慰剂的90名患者已经转移至依鲁替尼组。两组的不良反应发生率和类型相当。最常见的不良反应是血细胞计数降低和恶心。

这一研究领域的下一步包括评估依鲁替尼作为单药和联合靶向CD20蛋白的药物治疗新诊断的，有症状的和无症状的CLL疗效。

研究详情

【背景】

III期HELIOS研究评估了首创，口服共价BTK抑制剂+BR vs安慰剂+ BR治疗先前经治疗的CLL/SLL患者的疗效。预先计划的期中分析显示达到了主要终点，根据这一点，IDMC建议对试验揭盲。

【方法】

接受BR（≤6个疗程）的患者按1:1随机分配接受依鲁替尼（420mg/天）或安慰剂。嘌呤类似物耐药是一个分层因素。17p缺失（细胞>20%）的患者未纳入其中。主要终点是独立检查委员会（IRC）评估的无进展生存期（PFS）。次要终点包括IRC评估的总生存期（OS）和总缓解率（ORR）。

【结果】

研究纳入578名患者（每组289名）；中位年龄为64岁；其中38%为RaiIII/IV期；先前疗法中位数为2。依鲁替尼组和安慰剂组分别有83%和78%的患者完成6个疗程的BR。

中位随访17.2个月，IRC评估依鲁替尼+BR的PFS显著长于安慰剂+BR（中位未达到vs 13.3个月；HR:0.203, 95% CI: 0.150-0.276, P< 0.0001）PFS结果与高危亚组一致。ORR和CR/CRi率分别为82.7%vs 67.8%（P<0.0001）和（10.4%vs 2.8%）。中位OS未达到。安慰剂组中90名证实发生PD的患者转移至依鲁替尼组。

依鲁替尼组和安慰剂组最常见的不良反应为嗜中性粒细胞减少症（58.2%vs 54.7%）和恶心（36.9%vs 35.2%）；最常见的3/4级不良反应为嗜中性粒细胞减少症（53.7%vs 50.5%）和血小板减少症（两组都是15.0%）。3/4级心房颤动发生率为2.8%和0.7%，严重出血发生率为2.1%和1.7%。依鲁替尼+BR vs安慰剂+BR，疲劳有所改善。

【结论】

依鲁替尼+BR组比安慰剂+BR组的进展或死亡风险低80%。ORR显著改善。依鲁替尼+BR的安全性与已知的BR和依鲁替尼一致。这一数据进一步证实依鲁替尼是治疗先前经治疗CLL/SLL患者的重要治疗方案。

英文摘要：

Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): First results from arandomized, double-blind, placebo-controlled, phase III study.（AbstractNo: LBA7005）

Session Type：Oral Abstract Session

Background: The phase III HELIOS study evaluated the first-in-class, oral covalent BTK inhibitor ibrutinib in combination with BR(BR+ibr) vs BR plus placebo (BR+plb) in patients (pts) with previously treated CLL/SLL. The preplanned interim analysis reported here showed that the primary end point was met, upon which the IDMC recommended unblinding the study.

Methods: Pts received BR ( ≤ 6 cycles) and were randomized 1:1 to ibr (420 mg daily) or plb. Purine analog refractoriness was a stratification factor. Pts with del17p ( > 20% of cells) were excluded.Primary end point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end points included overall survival(OS) and overall response rate (ORR) per IRC.

Results: 578 pts were randomized (289 per arm); median age 64 yrs; 38% Rai Stage III/IV; median 2 prior therapies. 6 cycles of BR were completed in 83% and 78% of ptsin the ibr and plb arms, respectively. At a median follow-up of 17.2 months, IRC-assessed PFS was significantly longer with BR+ibr vs BR+plb (median not reached vs 13.3 months; HR: 0.203, 95% CI:0.150-0.276, P< 0.0001); PFS results were consistent across high-risk subgroups. ORR and CR/CRi rates were 82.7% vs 67.8% (P<0.0001) and 10.4% vs 2.8%. Median OS was not reached. 90 pts (31%) in the BR+plb arm with confirmed PD crossed over to receive ibr, as permitted per the protocol. Incidence of most AEs was similar between arms. The most common all-grade AEs with BR+ibr and BR+plb were neutropenia (58.2% vs54.7%) and nausea (36.9% vs 35.2%); most common grade 3/4 AEs were neutropenia(53.7% vs 50.5%) and thrombocytopenia (15.0% each arm). Rates of grade 3/4 a trial fibrillation were 2.8% and 0.7%, and major hemorrhage were 2.1% and1.7%. Fatigue (FACIT-Fatigue) was improved with BR+ibr vs BR+plb.

Conclusions: The addition of ibr to BR reduced the risk of progression or death by 80% compared with BR+plb. ORR was also significantly improved. Safety of BR+ibr was consistent with the known profiles for BR and ibr. The data further support ibr as an important treatment option for pts with previously treated CLL/SLL.

更多精彩>>>2015美国临床肿瘤学会（ASCO2015）