Page 155 - Haematologica-April 2018

Rituximab plus bendamustine or chlorambucil in CLL
In treatment-naïve CLL patients, phase II studies showed promising efficacy with rituximab plus B (R-B)7 or Clb (R-Clb),8,9 while the phase III CLL11 study demon- strated improved efficacy with R-Clb and obinutuzumab plus Clb (G-Clb) versus Clb monotherapy.10,11 G-Clb also increased progression-free survival (PFS) and complete response (CR) rates versus R-Clb,10,11 although infusion- related reactions and neutropenia were more common; infection rates were not increased, however.10 While a phase III study demonstrated superior efficacy in terms of CR and PFS with B versus Clb in treatment-naïve CLL,12,13 the activity of R-B versus R-Clb has not been directly com- pared.
Herein, we present results from the randomized, open- label, multicenter, phase IIIb MABLE study, which aimed to investigate the efficacy and safety of R-B and R-Clb in fludarabine-ineligible CLL patients.
Methods
Study design
Patients received rituximab (intravenous 375 mg/m2 Day [D] 1, Cycle [C] 1 and 500 mg/m2 D1, C2-C6) plus B (intravenous 90 mg/m2 [1L] or 70 mg/m2 [2L] D1 and D2, C1-C6) or Clb (oral 10 mg/m2 D1-D7, C1-C6) every four weeks for six cycles. R-Clb patients without CR after C6 received Clb monotherapy for ≤6 additional cycles or until CR. After treatment completion, patients were followed every three months for one year, then every six months until data cut-off. Treatment was discontinued if the patient had progressive disease.
MABLE was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws, and approved by institutional review boards and ethics committees at participating centers. All patients provided written informed con- sent.
Patients
During recruitment, the protocol was amended to permit inclu- sion of patients with progressive Binet stage A disease and to exclude 2L patients (due to slow recruitment). All 2L patients recruited before this amendment were included in the final analy- sis, as tumor response in this patient subpopulation was a second- ary study endpoint; however, as the number of 2L patients enrolled was relatively small, there was insufficient power to show statistically significant differences between study treat- ments in this patient subpopulation.
Study endpoints
The primary endpoint was CR rate (confirmed by bone marrow [BM] biopsy) after C6 in 1L patients. Secondary endpoints includ- ed CR rate after C6 in 2L patients, PFS, overall survival (OS), time to next leukemic treatment, minimal residual disease (MRD), and safety. Response was assessed after C3 and C6 as per iwCLL 2008 guidelines.14 Response was also assessed in the R-Clb arm at C12,
with treatment being discontinued for patients showing evidence of CR during C7-C12. Assessments are detailed in the Online Supplementary Information.
Safety
Adverse events (AEs) were monitored throughout the study and graded according to the National Cancer Institute Common Terminology Criteria for AEs v4.0 and coded according to the Medical Dictionary for Regulatory Activities v17.0.
Statistical analysis
Efficacy analyses were conducted on the intent-to-treat (ITT) population (all randomized patients). The safety population included all randomized patients who received treatment.
For 1L patients, the between-arm difference in response rates was tested using a one-sided continuity-corrected χ2 test. A two- sided continuity-corrected χ2 test assessed between-arm differ- ences in overall response rates (ORRs) and molecular responses. PFS and OS were summarized by Kaplan–Meier estimates and compared via the log-rank test. Hazard ratios (HRs) and 95% con- fidence intervals (CIs) were calculated based on the Cox propor- tional hazard model, with and without baseline Binet stage as a covariate.
Results
Patients
The study was conducted between 23 February 2010 and 31 March 2014. Of the 357 patients in the ITT popu- lation, comprising 241 1L patients (R-B, n=121; R-Clb, n=120) and 116 2L patients (R-B, n=57; R-Clb, n=59), 355 received treatment (R-B, n=177; R-Clb, n=178). Ninety- five patients (27%) withdrew from treatment during the study (Figure 1).
Overall, 92/120 (76.7%) 1L patients treated with R-B and 97/120 (80.8%) 1L patients treated with R-Clb received six cycles of rituximab; 92 (76.7%) and 57 (47.5%) received six cycles of B and Clb, respectively. Twelve (10.0%) patients treated with R-Clb received 12 cycles of Clb. The median number of R, B and Clb doses was six for each. The median (interquartile range) dose of rituximab was 4780.5 mg (4222.5-5346.5) in 1L patients treated with R-B and 5028.5 mg (4546.0-5349.0) in 1L patients treated with R-Clb. In total, 6/121 (5.0%) patients treated with R-B and 2/120 (1.7%) patients treated with R- Clb had a reduction or delay in their treatment schedule due to treatment-emergent toxicities.
Baseline characteristics were balanced in the 1L popula- tion (Table 1; baseline characteristics for all patients are presented in Online Supplementary Table S1). Deletion of 17p was not an exclusion criterion due to a lack of efficacy data relating to 17p deletion for the treatment combina- tions used at the time of study design. Thus, 13 1L patients (R-B, 10; R-Clb, 3) with 17p deletion were includ- ed. Median follow-up was 23.5 months (R-B) and 23.3 months (R-Clb). Median age in 1L patients was 72 years in both treatment arms; the majority of patients were aged 65 years or more. The median number of comorbidities (active medical conditions) in 1L patients was three in both arms (Table 1); the most common comorbidities were vascular disorders and metabolism disorders affect- ing 49% and 37% of patients, respectively (Online Supplementary Table S2). The great majority of all patients in the study (including 2L patients) used concomitant medication during the study (R-B, 96%; R-Clb, 94%).
Patients were aged ≥18 years, with confirmed CLL requiring treatment as per the International Workshop on CLL (iwCLL) cri- teria,14 Binet stage B/C disease, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and investigator assess- ment of ineligibility for fludarabine-based treatment (Online Supplementary Information). Exclusion criteria included transforma- tion to aggressive B-cell malignancy and previous malignancy within five years of enrollment (unless treated with curative intent). For full inclusion and exclusion criteria see the Online Supplementary Information.
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