在既往未经治疗的慢性淋巴细胞白血病患者中，使用氟达拉滨、大剂量环磷酰胺和利妥昔单抗进行序贯治疗可产生高质量的反应：分子缓解预示着持久的完全缓解。
Sequential therapy with fludarabine, high-dose cyclophosphamide, and rituximab in previously untreated patients with chronic lymphocytic leukemia produces high-quality responses: molecular remissions predict for durable complete responses.
作者信息
Lamanna Nicole, Jurcic Joseph G, Noy Ariela, Maslak Peter, Gencarelli Alison N, Panageas Katherine S, Heaney Mark L, Brentjens Renier J, Golde David W, Scheinberg David A, Zelenetz Andrew D, Weiss Mark A
机构信息
Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA.
出版信息
J Clin Oncol. 2009 Feb 1;27(4):491-7. doi: 10.1200/JCO.2008.16.4459. Epub 2008 Dec 15.
PURPOSE
Modern combination strategies are active in chronic lymphocytic leukemia (CLL) but can have significant myelosuppression and immunosuppression that may require dose attenuation for safety. We explored a sequential treatment strategy to allow safe delivery of active agents at full doses. Previously, we studied sequential therapy with fludarabine followed by cyclophosphamide (F-->C). In that study, cyclophosphamide consolidation improved the frequency of complete response (CR) four-fold. Subsequently, rituximab was added to this regimen (F-->C-->R).
PATIENTS AND METHODS
Thirty-six previously untreated CLL patients received therapy with fludarabine 25 mg/m(2) on days 1 through 5 every 4 weeks for six cycles, followed by consolidation with cyclophosphamide 3,000 mg/m(2) administered every 3 weeks for three cycles, followed by consolidation with weekly rituximab 375 mg/m(2) for four cycles. Evaluation for minimal residual disease included flow cytometry and a highly sensitive clonotypic polymerase chain reaction (PCR). The median age was 59 years (range, 37 to 71 years), 61% of patients had high-risk disease, and 58% had unmutated IgV(H) genes.
RESULTS
There were 32 responses (89%), including 22 CRs (61%). Consolidation with cyclophosphamide improved responses in 13 patients (36%); nine patients (25%) further improved their response with rituximab. Twenty patients (56%) achieved flow cytometric CRs, and 12 patients (33%) achieved a molecular CR (PCR negative). Patients achieving molecular CRs had an excellent prognosis with a plateau in the response duration curve, and 90% remain in clinical CR at 5 years. For the entire group, 5-year survival rate is 71% compared with a rate of 48% with our prior F-->C regimen (P = .10).
CONCLUSION
Sequential therapy with F-->C-->R yields improvement in quality of response, with many patients achieving a PCR-negative state.
目的
现代联合治疗策略在慢性淋巴细胞白血病（CLL）治疗中具有活性，但可能会导致显著的骨髓抑制和免疫抑制，为了安全起见可能需要调整剂量。我们探索了一种序贯治疗策略，以允许全剂量安全地给予活性药物。此前，我们研究了氟达拉滨序贯环磷酰胺（F→C）的治疗方法。在该研究中，环磷酰胺巩固治疗使完全缓解（CR）率提高了四倍。随后，利妥昔单抗被加入到该方案中（F→C→R）。
患者与方法
36例既往未接受过治疗的CLL患者接受治疗，每4周的第1至5天给予氟达拉滨25mg/m²，共6个周期，随后每3周给予环磷酰胺3000mg/m²巩固治疗，共3个周期，接着每周给予利妥昔单抗375mg/m²巩固治疗，共4个周期。微小残留病的评估包括流式细胞术和高灵敏度克隆型聚合酶链反应（PCR）。中位年龄为59岁（范围37至71岁），61%的患者患有高危疾病，58%的患者IgV(H)基因未发生突变。
结果
有32例患者出现缓解（89%），其中22例为CR（61%）。环磷酰胺巩固治疗使13例患者（36%）的缓解情况得到改善；9例患者（25%）使用利妥昔单抗后缓解情况进一步改善。20例患者（56%）达到流式细胞术CR，12例患者（33%）达到分子学CR（PCR阴性）。达到分子学CR的患者预后良好，缓解持续时间曲线呈平台期，90%的患者在5年时仍处于临床CR状态。对于整个队列，5年生存率为71%，而我们之前的F→C方案的生存率为48%（P = 0.10）。
结论
F→C→R序贯治疗可改善缓解质量，许多患者达到PCR阴性状态。
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