Efficacy and safety of frontline FCR(fludarabine, cyclophosphamide, rituximab) with dose reduction of rituximab in chronic lymphocytic leukemia
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摘要: 目的 分析利妥昔单抗减量(375 mg/m2固定剂量)的氟达拉滨+环磷酰胺+利妥昔单抗(FCR)方案一线治疗慢性淋巴细胞白血病(CLL)的疗效，并探讨影响疗效的预后因素。方法 回顾性分析2009年9月—2021年6月在我院接受一线利妥昔单抗减量FCR方案治疗的35例CLL患者的临床资料。结果 35例患者中男25例，女10例，中位年龄58(42~75)岁，中位疗程数为6(2~6)个，总反应率为91.4%(32/35)，15例(42.9%)达完全缓解，3例(8.6%)达骨髓未恢复的完全缓解，14例(40.0%)达部分缓解，2例(5.7%)疾病稳定，1例(2.9%)疾病进展。20例患者进行了骨髓微小残留病(MRD)检测，14例(70.0%)MRD阴性(MRD < 0.01%)。中位随访60.7(6.6~153.4)个月，中位无进展生存期为61.7(95%CI57.7~106.9)个月，中位总生存期未达到。Cox回归分析发现，患者血清β2-微球蛋白>3.5 mg/L和伴有TP53异常是影响无进展生存期的独立不良预后因素(P< 0.05)，未发现对总生存期有意义的影响因素。单因素分析发现，治疗前IgA缺乏患者的总生存期显著缩短(P< 0.05)；治疗后达骨髓MRD阴性患者的无进展生存期显著延长(未达到vs 35.6个月，P=0.016)。治疗后7例(20.0%)发生≥3级感染，15例(42.9%)发生≥3级血液学不良反应，除1例发生5级不良反应，其余不良反应均可恢复。结论 利妥昔单抗减量的FCR方案一线治疗CLL患者的总反应率、MRD转阴率及远期生存获益较理想，安全性可控。患者治疗前血清β2-微球蛋白>3.5 mg/L和伴有TP53异常影响无进展生存期，治疗前IgA缺乏可能影响总生存期；治疗后达骨髓MRD阴性的患者更易获得长期无进展生存。Abstract: Objective To investigate the efficacy and safety of the FCR regimen(fludarabine, cyclophosphamide and rituximab) with dose reduction of rituximab(375 mg/m2fixed dosage) in treatment-naive patients with chronic lymphocytic leukemia(CLL).Methods The clinical data of 35 CLL patients treated with frontline rituximab-reduced FCR regimen in our hospital from September 2009 to June 2021 were collected and analyzed.Results The median age before treatment initiation was 58(42-75) years in 35 patients, with 25 males and 10 females. The median treatment course was 6(2-6). The overall response rate was 91.4%(32/35), 15 cases(42.9%) achieved complete response, 3 cases(8.6%) achieved complete response with incomplete marrow recovery, 14 cases(40.0%) achieved partial response, 2 cases(5.7%) were in stable disease and 1 case(2.9%) had progressive disease. The bone marrow measurable residual disease(MRD) was detected in 20 patients, of which 14 cases(70.0%) achieved MRD negative(MRD < 0.01%). The median follow-up time was 60.7(6.6-153.4) months, the median progression-free survival was 61.7(95%CI57.7-106.9) months, and median overall survival was not reached. Cox regression analysis showed that serum β2-microglobulin>3.5 mg/L and TP53 abnormalities before treatment initiation were independent prognostic factors of progression-free survival(P< 0.05). No independent prognostic factors of overall survival were identified, but IgA deficiency was significantly correlated with shorter overall survival in univariate analysis(P< 0.05). Patients achieved bone marrow MRD negative post-treatment had a significant prolongation in progression-free survival(not reached vs 35.6 months,P=0.016). Seven cases(20.0%) experienced ≥grade 3 infection post-treatment and 15 cases(42.9%) experienced ≥grade 3 hematologic adverse events. All adverse events were resolved and recovered other than 1 case of grade 5 adverse events.Conclusion FCR regimen with does reduction of rituximab results in a high response rate and undetectable MRD rate with good long-term survival, and toxicities are acceptable, as frontline treatment for young CLL patients. Serum β2-microglobulin>3.5 mg/L and TP53 abnormalities before treatment initiation are independent prognostic factors of progression-free survival, and IgA level before treatment may have an impact on overall survival. To achieve bone marrow MRD negative post-treatment results in prolongation of progression-free survival.
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Key words:
- chronic lymphocytic leukemia /
- fludarabine /
- cyclophosphamide /
- rituximab /
- drug tapering
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表 1 影响患者PFS的预后因素分析
变量 单因素 多因素 χ2 P HR 95% CI P Binet A期vs B~C期(1 vs 34) 1.189 0.276 Rai Ⅰ期vs Ⅱ~Ⅳ期(11 vs 24) 1.176 0.278 β2-微球蛋白≤3.5 mg/L vs > 3.5 mg/L(22 vs 7) 6.064 0.014 5.778 1.292~25.837 0.022 TP53正常vs异常(20 vs 4) 5.030 0.025 6.056 1.307~28.050 0.021 治疗前IgA正常vs缺乏(16 vs 19) 0.829 0.362 
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表 2 影响患者OS的预后因素分析
变量 单因素 χ2 P Binet A期vs B~C期(1 vs 34) 0.316 0.574 Rai Ⅰ期vs Ⅱ~Ⅳ期(11 vs 24) 5.057 0.025 β2-微球蛋白≤3.5 mg/L vs > 3.5 mg/L(22 vs 7) 0.964 0.326 TP53正常vs异常(20 vs 4) 0.788 0.375 治疗前IgA正常vs缺乏(16 vs 19) 6.204 0.013
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