We thank Opat and Hawkes¹ for their letter to the editor in response to our recent article in Journal of Clinical Oncology titled “Chemoimmunotherapy Is Not Dead Yet in Chronic Lymphocytic Leukemia.”² In particular, we appreciate that they agree with the ongoing role of chemoimmunotherapy (CIT) in the treatment of chronic lymphocytic leukemia (CLL) and with our cautious approach to major shifts in therapy on the basis of limited short-term data. Their primary concerns focus on the role of fludarabine plus cyclophosphamide plus rituximab (FCR) and its toxicity, although they acknowledge the superiority of FCR among fit patients with CLL with mutated immunoglobulin heavy-chain variable-region. Indeed, one of our goals was to remind the community that the long-term efficacy data with FCR demonstrate a plateau on the progression-free survival (PFS) curve at > 12 years in patients with mutated immunoglobulin heavy-chain variable-region, with those who were tested negative for minimal residual disease, raising the possibility of cure. These data establish the superiority of FCR to other CIT regimens, none of which show a PFS plateau, and indicate that, as stated in our commentary, FCR is the regimen of choice when appropriate. Opat and Hawkes raise extremely valid concerns about acute toxicity when FCR is inappropriately used in unfit older patients. However, their concerns about appropriate patient selection and management apply to all therapies, including ibrutinib, which has proven more toxic in community use than expected from clinical trials,^3,4 the so-called real world effect. Indeed, with FCR, the clear eligibility criteria of the German CLL Study Group trials provide unusually specific and sound guidance in defining which patients are sufficiently fit for FCR.⁵ Furthermore, most published studies on FCR have unfortunately not mandated the use of supportive care, which we commonly use and which mitigates toxicity, including anti-infective prophylaxis and prophylactic myeloid growth factors. Their argument that FCR dose reductions are associated with reduced PFS is not relevant, because these patients do not fare more poorly than patients receiving less effective CIT regimens. In fact, the median PFS for patients with FCR dose reduction in the study by Kovacs et al⁶ cited by Opat and Hawkes is still better than the median PFS for those treated with upfront bendamustine and rituximab.⁵

中文翻译：

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回复S. Opat等

感谢Opat和Hawkes ¹写给编辑的信，以回应我们最近在《临床肿瘤学杂志》上发表的文章“化学免疫疗法在慢性淋巴细胞白血病中尚未消亡”。^2个特别是，我们赞赏他们同意化学免疫疗法（CIT）在治疗慢性淋巴细胞性白血病（CLL）中的持续作用，并同意我们基于有限的短期数据对治疗的重大转变持谨慎态度。他们的主要关注点是氟达拉滨加环磷酰胺加利妥昔单抗（FCR）的作用及其毒性，尽管他们承认FCR在患有免疫球蛋白重链可变区突变的CLL患者中的优势。确实，我们的目标之一是提醒社区，FCR的长期疗效数据表明，免疫球蛋白重链可变区突变，那些被检验为最小残留病阴性的人，增加了治愈的可能性。这些数据确立了FCR优于其他CIT方案的优势，但没有一个显示PFS平稳期，并且表明，如我们的评论所述，在适当的情况下FCR是首选方案。当不适当的FCR在不适合的老年患者中使用时，Opat和Hawkes对急性毒性提出了极为有效的担忧。但是，他们对适当患者选择和治疗的担忧适用于所有疗法，包括依鲁替尼，该疗法在社区使用中已证明比临床试验预期的毒性更大，^3，4所谓的现实世界效应。确实，对于FCR，德国CLL研究小组试验的明确资格标准为确定哪些患者足够适合FCR提供了异常特殊而合理的指导。⁵此外，不幸的是，大多数已发表的有关FCR的研究并未强制要求使用支持性护理，这是我们通常使用的支持性护理，可减轻毒性，包括抗感染性预防和预防性髓样生长因子。他们认为FCR剂量减少与PFS降低相关的论点是不相关的，因为这些患者的病情不会比接受无效CIT方案的患者病情更糟。实际上，Kovacs等[ ^6]的研究显示FCR剂量降低的患者的中位PFS对于使用前苯达莫司汀和利妥昔单抗治疗的患者，Opat和Hawkes引用的PFS仍优于中位PFS。⁵