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預防慢性淋巴細胞白血病的進展是過去兩年最重要的主題,現(xiàn)在我們發(fā)現(xiàn)了另一種有效的治療方案來治療無其它可用療法的患者。這些結果表明,我們可以通過聯(lián)合新療法和既定療法使患者達到更好的預后。
——ASCO專家Merry-Jennifer Markham博士
2015年ASCO年會將于5月29日--6月2日在美國芝加哥召開,5月30日公布的一項大型II期研究的期中分析表明,依魯替尼聯(lián)合苯達莫司汀/利妥昔單抗(BR)可改善慢性淋巴細胞白血?。–LL)患者的預后,盡管之前的療法使其惡化。
中位隨訪17個月,接受依魯替尼和BR的患者疾病進展或死亡風險比接受安慰劑和BR的患者低80%.基于這一良好獲益,患者從安慰劑組轉移至依魯替尼組。
CLL是西方國家最常見的成人白血病。幾年來,CLL的標準療法是化療法聯(lián)合靶向療法(比如利妥昔單抗)。盡管這些治療利于控制疾病多年,但是不能治愈疾病,而且最終所有患者對這一治療具有耐藥性。
直到最近,疾病惡化或復發(fā)的患者治療方案變得非常有限。去年,F(xiàn)DA批準了兩種新型靶向藥物——依魯替尼和idelalisib聯(lián)合利妥昔單抗治療這一疾病。依魯替尼是一種首創(chuàng)口服靶向藥物,每天口服一次,可抑制布魯頓酪氨酸激酶(BTK)。這種蛋白質促進淋巴細胞(受CLL損傷的白細胞)的生長。
這一研究的主要作者AsherChanan-Khan博士說:“這是治療CLL最嚴謹?shù)呐R床試驗之一,而且它確實證實依魯替尼是治療這種癌癥的重要藥物。我們發(fā)現(xiàn)依魯替尼與現(xiàn)存療法聯(lián)合可以強有力的延長緩解時間,并改善患者的健康狀況”
在這項研究中,578名先前經治療的CLL患者被隨機分配接受依魯替尼+BR或安慰劑+BR治療。中位隨訪17.2個月之后,安慰劑組和依魯替尼組的中位無進展生存期分別為13.3個月和未達到。接受依魯替尼的患者進展或死亡風險降低80%.
依魯替尼組的緩解率顯著高于安慰劑組(82.7%vs. 67.8%)。依魯替尼組的疾病相關疲勞得到改善,而且患者獲益較快(第6個月vs 14個月)。
進行期中分析時,安慰劑的90名患者已經轉移至依魯替尼組。兩組的不良反應發(fā)生率和類型相當。最常見的不良反應是血細胞計數(shù)降低和惡心。
這一研究領域的下一步包括評估依魯替尼作為單藥和聯(lián)合靶向CD20蛋白的藥物治療新診斷的,有癥狀的和無癥狀的CLL療效。
研究詳情
【背景】
III期HELIOS研究評估了首創(chuàng),口服共價BTK抑制劑+BR vs安慰劑+ BR治療先前經治療的CLL/SLL患者的療效。預先計劃的期中分析顯示達到了主要終點,根據(jù)這一點,IDMC建議對試驗揭盲。
【方法】
接受BR(≤6個療程)的患者按1:1隨機分配接受依魯替尼(420mg/天)或安慰劑。嘌呤類似物耐藥是一個分層因素。17p缺失(細胞>20%)的患者未納入其中。主要終點是***檢查委員會(IRC)評估的無進展生存期(PFS)。次要終點包括IRC評估的總生存期(OS)和總緩解率(ORR)。
【結果】
研究納入578名患者(每組289名);中位年齡為64歲;其中38%為RaiIII/IV期;先前療法中位數(shù)為2.依魯替尼組和安慰劑組分別有83%和78%的患者完成6個療程的BR.
中位隨訪17.2個月,IRC評估依魯替尼+BR的PFS顯著長于安慰劑+BR(中位未達到vs 13.3個月;HR:0.203, 95% CI: 0.150-0.276, P< 0.0001)PFS結果與高危亞組一致。ORR和CR/CRi率分別為82.7%vs 67.8%(P<0.0001)和(10.4%vs 2.8%)。中位OS未達到。安慰劑組中90名證實發(fā)生PD的患者轉移至依魯替尼組。
依魯替尼組和安慰劑組最常見的不良反應為嗜中性粒細胞減少癥(58.2%vs 54.7%)和惡心(36.9%vs 35.2%);最常見的3/4級不良反應為嗜中性粒細胞減少癥(53.7%vs 50.5%)和血小板減少癥(兩組都是15.0%)。3/4級心房顫動發(fā)生率為2.8%和0.7%,嚴重出血發(fā)生率為2.1%和1.7%.依魯替尼+BR vs安慰劑+BR,疲勞有所改善。
【結論】
依魯替尼+BR組比安慰劑+BR組的進展或死亡風險低80%.ORR顯著改善。依魯替尼+BR的安全性與已知的BR和依魯替尼一致。這一數(shù)據(jù)進一步證實依魯替尼是治療先前經治療CLL/SLL患者的重要治療方案。
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 **ysis 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 **og 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.
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