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Efficacy and Safety of Front-Line Therapy with Fludarabine-Cyclophosphamide-Rituximab Regimen for Chronic Lymphocytic Leukemia O

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Efficacy and Safety of Front-Line Therapy with Fludarabine-Cyclophosphamide-Rituximab Regimen for Chronic Lymphocytic Leukemia O ARTICLES Chronic Lymphocytic Leukemia Efficacy and safety of front-line therapy with fludarabine-cyclophosphamide-rituximab regimen for chronic lymphocytic leukemia outside clinical trials: the Israeli CLL Study Group experience Yair Herishanu, Neta Goldschmidt, Osnat Bairey, Rosa Ruchlemer, Riva Fineman, Naomi Rahimi-Levene, Lev Shvidel, Tamar Tadmor, Aviv Ariel, Andrea Braester, Mika Shapiro, Erel Joffe and Aaron Polliack and on behalf of the Israeli CLL Study Group ABSTRACT This study aimed to evaluate the efficacy and safety of the fludarabine-cyclophosphamide-rituximab regimen for young physically fit patients with chronic lymphocytic leukemia in the "real-life" setting. We specifically focused on the impact of dose reduction on patient outcomes. The patient cohort consisted of 128 patients with chronic lymphocytic leukemia (≤70 years) treated at 10 Israeli centers with front-line fludarabine-cyclophosphamide-rit- uximab. We defined reduced chemotherapy as two-thirds or less of the total indicated dose. Patients treated with rituximab were divided into two groups and compared: those who received full dosages of 375 mg/m2 or 500 mg/m2, and patients given less than six cycles with either dose. Overall and clinical complete response rates (92.8% and 70.4%), as well as toxicities and overall survival (median not reached at 6 years), were similar to other reported clinical trials, but progression-free survival was shorter (42.5 months). Almost 50% of patients had some dose reduction of chemotherapy, 21% receiving less than two-thirds of the indicated dose, while close to 30% did not complete six cycles of rituximab. Reduced doses of chemotherapy and rituximab were independently associ- ated with shorter progression-free survival (hazard ratio 3.6, P<0.0001 for reduced chemotherapy; hazard ratio 2.5, P=0.003 for incomplete-treatment with rituximab). Achieving a complete response was associated with longer overall survival but was not linked to the given dose of chemoimmunotherapy. In younger physically fit patients, front-line fludarabine-cyclophosphamide-rituximab therapy in the "real-life" setting achieves long remissions (albeit shorter than in clinical trials) and prolonged overall survival. However, dose reductions are commonly administered and may impact outcome. Introduction with better complete response rates, progression-free survival (PFS) and overall survival (OS).10 In the light of these data, The treatment of chronic lymphocytic leukemia (CLL) has FCR has become the mainstay of treatment for physically fit evolved impressively over the years. For more than three patients with CLL. decades, patients with CLL were treated mostly with alkylat- Despite its proven efficacy, FCR is associated with signifi- ing agents as monotherapy, particularly chlorambucil.1 In this cant toxicities, in particular myelosuppression and a higher regard, the first real advancement occurred during the 1980s, incidence of infections.10 As a result, outside of formal clinical with the introduction of the purine analogs fludarabine,2-4 trials, patient adherence to the protocol is often compro- cladribine,5 and pentostatin6 which were used effectively. mised, and treating physicians are frequently tempted to Fludarabine (F) is the most extensively studied purine analog decrease drug doses or reduce the number of treatment in patients with CLL. When used in combination with cycles.11 Furthermore, the therapeutic concerns about toxici- cyclophosphamide (C) in the FC regimen, F was clearly ties become more problematic in older patients with comor- shown to be more effective than when given alone.7 More bidities and renal dysfunction who have been under-repre- recently, the addition of rituximab (R) to the FC combination sented in earlier clinical trials. Thus, there may be significant (FCR) was also studied in CLL.8-10 A single arm study in previ- differences in outcome in patients treated with FCR within ously untreated patients with CLL conducted at the MD the framework of a clinical study when compared to patients Anderson Cancer Center in Houston, showed that six cycles treated in everyday life. In an attempt to reduce associated of rituximab (375 mg/m2 cycle 1 and 500 mg/m2 cycles 2-6) toxicity, some investigators used modified FCR-based regi- given together with fludarabine (25 mg/m2, days 1-3) and mens, employing protocols with reduced doses of cyclophosphamide (250 mg/m2, days 1-3) achieved a high chemotherapy and increased amounts of rituximab,12 sequen- complete remission rate and prolonged duration of tial F C R regimen,13 and even substitution of fludarabine response.8,9 Similarly, a large phase III study from the German by pentostatin→ → 14 or cladribine.15,16 CLL Study Group (CLL8) in previously untreated physically The present study aimed to evaluate the efficacy and safety fit patients, demonstrated the superiority of FCR over FC of the FCR regimen for physically fit CLL patients under 70 ©2014 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2014.115808 The online version of this article has a Supplementary Appendix. Manuscript received on October 5, 2014. Manuscript accepted on January 29, 2015. Correspondence: [email protected] 662 haematologica | 2015; 100(5) FCR treatment in CLL outside clinical trials years of age in the "real-life" setting. We specifically Table 1. Demographic data and base-line characteristics. focused on the impact of dose reduction on patient sur- Parameter N. patients (%) vival and outcomes. In addition, we also examined treat- Total n=128 ment-related side-effects, including the rate of infections, degree of myelosuppression, frequency of autoimmune Median age, years (range) 57.9 (18-69) hemolytic anemia (AIHA) and the development of second- Age >65 years 18 (14.1%) ary malignancies. Sex (male) 93 (72.7%) Binet stage: A 11 (8.6%) Methods B 71 (55.5%) C 46 (35.9%) Patients and study design Splenomegaly (n=124) 102 (82.3%) This was a retrospective cohort study of 128 young patients Bulky disease (lymph node≥5cm) (n=126) 29 (22.0%) with CLL (≤70 years) from 10 Israeli medical centers who were treated with the intravenous FCR regimen as front-line therapy Positive CD38 (n=96) 43 (44.8%) during the years 2002-2013. We extracted data from the patients’ ZAP70- positivity (n=69) 33 (47.8%) medical records including: complete blood count (CBC), creatinine Unmutated IGHV (n=61) 42 (68.9%) clearance, Binet stage, available imaging results (abdominal ultra- Chromosomal aberration by FISH: (n=96) sound or CT scan of neck, chest and abdomen), analyses of del (13q) 22 (22.9%) genomic aberrations (fluorescent in situ hybridization, FISH), trisomy 12 14 (14.6%) mutational status of immunoglobulin heavy-chain variable-region del (11q) 21 (21.9%) (IgHV) genes (using a cut off of 98% homology to the germ-line del (17p) 7 (7.3%) + 17 sequence), CD38 level (using a cut off of 30% CD38 -CLL cells ), Absolute lymphocyte count (x109/L, mean±SD) 130±101 and ZAP70 expression (determined by flow cytometry as previ- 18 Hemoglobin (gr/dL, mean±SD) 11.7±2.2 ously described by Crespo et al. using a cut off of 20% ZAP70+- CLL cells). We obtained data regarding: dose modifications of Platelets (x109/L, mean±SD) 148±67 chemotherapy and rituximab, number of treatment cycles, severe Creatinine clearance (mL/min, mean±SD) 82±22 adverse events documented according to the Common Toxicity Median time to treatment (months) 34.5 Criteria for Adverse Events Classification (CTC-AE), use of antivi- ral and pneumocystis prophylaxis, the administration of granulo- cyte-colony stimulating factor (G-CSF), late-onset neutropenia (defined in the Online Supplementary Appendix),19 and the occur- rence of secondary malignancies. The study was approved by the Jonckheere-Terpstra test for non-normally distributed variables in institutional ethics committee of each participating center accord- ordered categories. Exploratory analyses for PFS and OS were per- ing to the principles of the Declaration of Helsinki. formed using a univariate Cox proportional hazard models for continuous predictors and the Kaplan-Meier and log rank tests for Dose intensity categorical covariates. We then evaluated variables collectively We defined reduced dose of chemotherapy as two-thirds or less using a multivariate Cox proportional hazard model. Two-sided of the total indicated dose. We also evaluated the subgroup of statistical significance was set at P=0.05. All analyses were per- patients who received a total dose of less than 90% of the total formed using SPSS (IBM, USA). indicated dose. Regarding rituximab, we divided the patient pop- ulation into three subgroups: those who had completed a first Results cycle with rituximab 375 mg/m2 followed by five subsequent cycles of rituximab 500 mg/m2 (R-500); patients who had received Patients’ characteristics six cycles of rituximab 375 mg/m2 (R-375); and patients who did Patients’ characteristics are shown in Table 1. A total of not receive the full six cycles of either regimen (R-incomplete). 128 CLL patients (≤70 years of age) from 10 medical cen- ters treated with FCR as front-line therapy were reviewed. Analysis of outcomes The majority of patients were males (72.7%, n=93) and Overall response rate was assessed as clinical complete response under 65 years of age (85.9%, n=110). Eleven patients (CR), CR with incomplete bone marrow recovery (CRi), partial (8.6%) had Binet stage A disease, 71 (55.5%) were stage B, response (PR), or failure. Assessment of response followed the rec- and 46 (35.9%) were stage C. Results of FISH analysis ommendations of the International Workshop on CLL 2008 were available for 96 patients, with high-risk cytogenetics (IWCLL2008) for general practice,20 which includes physical exam- of del(11q) in 21 patients (21.9%) and del(17p) in 7 cases ination, complete blood count (CBC), and a bone marrow biopsy (7.3%). The majority of patients (55.9%, n=71) initially and aspiration in patients with cytopenia of uncertain cause.
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