本帖最后由 橙色雨丝 于 2018-4-21 08:55 编辑
Improving on R-ICE in relapsed DLBCL 改进复发弥漫大B细胞淋巴瘤的R-ICE方案
Sarit Assouline
In this issue of Blood, Sauter et al report the results of a multicenter phase 1 study of rituximab, ifosfamide,carboplatin, and etoposide (R-ICE) in combination with ibrutinib inrelapsed/refractory diffuse large B-cell lymphoma. 1 This combination was well tolerated and resulted in high response rates. 在本期的《血液》杂志中，Sauter等报告了一项关于在复发/难治弥漫大B细胞淋巴瘤上使用R-ICE+伊布替尼方案的多中心I期临床研究结果。这个方案的耐受性良好并且取得了很高的缓解率。 Therapies to improve survival among patients with relapsed and refractory (R/R) diffuse large B-cell lymphoma(DLBCL) are greatly needed, notwithstanding the newly approved chimeric antigen receptor T cell for second relapse of DLBCL. 2DLBC Lis the most common lymphoma in the Western world. Only 60% of patients arecured with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone–like chemoimmunotherapy. 3 Patients with R/R DLBCL who are transplant-eligible have an approximately 50% chance of responding to salvage therapy and receiving an autologous stem cell transplant(ASCT). Overall only 40% of these patients are long-term survivors. 4, 5 尽管针对二次复发的弥漫大B细胞淋巴瘤的嵌合抗原受体T细胞疗法已经得到批准，能够改善复发/难治弥漫大B细胞淋巴瘤患者生存的治疗方案仍然存在迫切的需求。弥漫大B细胞淋巴瘤是西方世界最常见的淋巴瘤。大约只有60%的患者可以通过R-CHOP样的方案治愈。可移植的复发/难治弥漫大B细胞淋巴瘤患者大约有50%的机会对挽救性方案应答并接受自体干细胞移植。总的来说这部分患者中只有40%可以长期生存。 Since the comparative studies of Gisselbrecht et al 4 and Crump et al, 5 which established R-ICE and rituximab, gemcitabine, dexamethasone, and cisplatinum(R-GDP), respectively, as acceptable salvage therapies prior to ASCT, there have been no further significant improvements in this curative approach. Also,the great progress in our understanding of molecular drivers of DLBCL and its resistance to chemoimmunotherapy in both frontline and relapse settings has yielded few biomarker-driven therapeutic improvements. However, the report in this issue of Blood provides some promising, though very early phase data of a biomarker-driven salvage regimen for relapsed and refractory DLBCL. 自从Gisselbrecht等和Crump等的比照性研究发表后，R-ICE和R-GDP分别成为自体干细胞移植之前的可接受的挽救性化疗方案，之后，这方面再无显著改进。另外，对弥漫大B细胞淋巴瘤在分子层面上的驱动因素，以及在初治和复发时对免疫化疗耐药的机制的理解上的巨大进步，也未能带来以生物标记物为主导的治疗方法上的改进。然而，本期《血液》杂志中这份报告提供了一个很有希望，但仍处于早期研究的以生物标记物为主导的复发/难治弥漫大B细胞淋巴瘤的挽救性方案。 Herein, Sauter and colleagues report on a21-patient, phase 1 study combining ibrutinib with R-ICE in patients with R/RDLBCL, primary mediastinal B-cell lymphoma (PMBCL), and Richter’s transformation (RT). The trial is a classic 3 + 3 design, with 3 dose levels for ibrutinib added to the standard doses of R-ICE, which is given for up to 3cycles. Ibrutinib is tested at 420 mg, 560 mg, and 840 mg orally, daily for days 1 to 21. No dose-limiting toxicities were reported at any dose level. In particular, no patients required dose delays beyond 1 week. Fifteen patients were enrolled in the dose-expansion phase at the 840-mg dose of ibrutinib.Overall, the regimen was tolerable, with rates of infection and febrile neutropenia similar to those observed with R-ICE. 4 Adverse events of concern with ibrutinib were few: only 1 patient had atrial fibrillation and was removed from the study early; there were no significant bleeding complications; and both the cardiac complications and infections were not specific to ibrutinib. The absence of added toxicity, in part, relates tothe short exposure to ibrutinib. Lastly, stem cell collection was successful in 14 of 15 patients in whom it was attempted. 这里，Sauter及同事报告了一项包含21位患者，用伊布替尼联合R-ICE治疗复发/难治弥漫大B细胞淋巴瘤、原发纵隔B细胞淋巴瘤和Richter转化淋巴瘤的I期临床试验的结果。试验采用经典的3+3设计，在标准剂量的R-ICE基础上分别加上3个剂量水平的伊布替尼，最多进行三个疗程的治疗。伊布替尼口服的剂量分别是420mg，560mg和840mg每天，从第1天到第21天。在任何剂量水平下均未发现剂量限制性毒性反应。尤其是，没有一位患者需要将剂量推迟超过一周。15位患者在剂量爬坡期过渡到了840mg剂量组。总的来说，这个方案是可耐受的，发热性粒缺的比例基本上与R-ICE相当。涉及伊布替尼的不良反应极少：只有一位患者出现房颤并且在初期就退出试验；没有发生明显的出血并发症；心脏和感染的并发症与伊布替尼不直接相关。伊布替尼没有额外增加毒性，部分原因是暴露时间较短。最后，在进行了干细胞提取的15位患者中，14位获得了成功。 The most important result of this trial is the tolerability of ibrutinib in combination with R-ICE, something not to be taken lightly given the prohibitive dose-limiting toxicities of ibrutinib in combination with R-GDP 6 and rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP). 7 The second important finding is the high rate of response of 90% (complete response[CR] = 11, partial response = 7) in a cohort comprising 17 patients with primary refractory disease. These are patients who fare the poorest with salvage regimens. 4 Lastly,the results are notable for the higher rate of response in the non–germinal center (non-GC) versus GC DLBCL, in which all evaluable non-GC patients had a complete response by positron emission tomography–computed tomography in comparison with 1 of 3 GC patients. This stark split is reassuringly consistent with the difference in single-agent activity of ibrutinib noted for non-GC versus GC DLBCL reported time and again. 这项试验的最重要的结果就是伊布替尼联合R-ICE方案的可耐受性，相比之下伊布替尼联合R-GDP和R-DHAP则存在明显的剂量限制性毒性。第二个重要的发现就是在原发耐药的17位患者中高达90%的缓解率（CR=11，PR=7）。这种患者通常是在挽救性化疗中表现最差的那些。最后，结果显示这个方案在非生发中心亚型（Non-GCB）中具有比生发中心亚型（GCB）明显更高的缓解率，所有可评估的Non-GCB患者都获得了PET/CT评估的CR，而GC的患者中只有1位获得CR。这种显著的差别与先前多次报告的伊布替尼单药分别在Non-GCB和GCB患者中有效率的差别相符。 As the authors state, a complete metabolic remission pre-ASCT is associated with greater long-term survival after transplant. 8 However,does this hold true if the rate of CR is increased because of the addition of a nonchemotherapeutic/targeted agent? The quality of the response to salvage chemotherapy may simply be a reflection of the sensitivity of the tumor to chemotherapy or may provide a state of minimal residual disease allowing thetransplant to be more effective. If the latter is true, then the addition of ibrutinib during salvage only should improve survival of transplant patients with R/R DLBCL. However, it is possible that the targeted agent is needed throughout and even beyond the salvage and transplant period to provide the maximal benefit, as was seen with the advantage in overall survival obtained from maintenance rituximab post-ASCT in mantle cell lymphoma. 9 Studies examining the addition of targeted agents, such as ibrutinib, venetoclax,immunotherapies, and others, in transplant-eligible R/R DLBCL will have to consider this possibility. 正如作者们所说，自体干细胞移植前获得完全代谢缓解与移植后的长期生存是正相关的。但是，如果完全缓解率的提高，是因为加入了非化疗药物/靶向药物引起的，这个论断是否还正确呢？对挽救性化疗应答的质量也许只是反映了肿瘤对化疗的敏感性，或者提供了一个最小疾病残余的状态以便让自体干细胞移植更加有效。如果是后者，那么在挽救性化疗中加入伊布替尼应该只会改善做移植的复发/难治弥漫大B细胞淋巴瘤患者的生存。然而，也有可能靶向药物从一开始就需要，甚至超出挽救性化疗和移植的阶段，这样才能提供最大的获益，就好比自体干细胞移植后的套细胞淋巴瘤患者用美罗华维持治疗可以在总生存上获益一样。在可移植的复发/难治弥漫大B细胞淋巴瘤的治疗中加入靶向药物，例如伊布替尼、Venetoclax、免疫疗法以及其它的临床试验中应该考虑这种可能性。 An important ethical point that comes to mind while reviewing this study pertains to the enrollment of transplant-eligible patients. Although this regimen proved to be safe,transplant-eligible patients enrolled in phase 1 studies of salvage therapy may miss a chance at transplant if the experimental salvage regimen proves too toxic. Interestingly, this trial has a large proportion of patients with refractory and early-relapsed DLBCL, as well as patients with relapsed RT and PMBCL, lymphomas with low response rates to salvage therapy, suggesting that there may have been a selection bias toward patients less likely to respond to R-ICE alone. (Despite this, response rates were impressively high.) 在回顾这项研究的时候，一个关于入组可移植患者的伦理问题涌入脑海。尽管这个方案被证明是安全的，但是入组这项试验的可移植患者也许会因为试验方案的毒性太大而错失移植机会。有意思的是，这项试验有很大比例的耐药和早期复发的患者，以及复发的转化淋巴瘤和原发纵隔大B，这些患者通常对挽救性化疗的应答率较低，说明在入组的时候存在一个对单纯的R-ICE方案应答不良的患者的选择偏向。（尽管如此，应答率之高令人印象深刻）。 With these questions in mind, we look forward to both the results of the phase 2 study of ibrutinib and R-ICE and to the design of future studies hoping to improve on salvage chemotherapy and transplant for patients with relapsed and refractory DLBCL. 带着这些问题，我们热切的期待伊布替尼+R-ICE的II期临床试验结果，并希望未来有更多的临床试验来进一步改进复发/难治弥漫大B细胞淋巴瘤的挽救性化疗和移植。
Conflict-of-interest disclosure: The author declares no competing financial interests. © 2018 by The American Society of Hematology
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