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Chlorambucil, rituximab and lenalidomide in CLL
imab (375 mg/m2 i.v. cycle 1, day 1; 500 mg/m2 i.v. cycles 2-6, day 1) and lenalidomide (induction-I). The dose of lenalidomide was escalated from 2.5 mg to 10 mg during induction-I. Subsequently patients were treated with six cycles of lenalido- mide 10 mg p.o. daily (induction-II) (Figure 1). The criteria for discontinuation and restarting lenalidomide and prophylactic treatment are presented in Online Supplementary Tables S2, S3, and S4, respectively.
Study phase 1
This phase of the study focused on determining the maximum tolerated dose and the recommended dose level of chlorambucil in combination with rituximab and lenalidomide. Six patients started combination treatment with chlorambucil at dose level 1 (7 mg). If no more than one dose-limiting toxicity occurred (Online Supplementary Table S5), the dose was escalated to 10 mg (dose level 2) for the subsequent patients, on the basis of which the recommended dose level was established.
Study phase 2
The aim of this phase was to evaluate the efficacy of chloram- bucil, at the recommended dose level, in combination with rit- uximab and lenalidomide, in terms of overall response rate.
Endpoints
The protocol endpoints are presented in Online Supplementary Table S6. Responses were determined according to the 2008 International Workshop on CLL criteria17 and evaluated after cycle 3 (clinically), after cycle 6, at the end of the study treat- ment and during follow-up. The presence of minimal residual disease, as measured in the peripheral blood, was determined centrally using six-color flow cytometry.18 Toxicity was reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The Cairo-Bishop grading classification19 and CTCAE version 3.020 were used to grade tumor lysis syndrome and tumor flare reaction, respectively.20
Statistical analysis
All analyses were performed according to the intention-to- treat principle but, in agreement with the protocol, excluding patients not considered eligible in hindsight. The patients’ char- acteristics and treatment toxicity were summarized by descrip- tive cross-tabulations. Responses were tabulated according to the fraction of the optimal dose of lenalidomide in each cycle (<90% versus ≥90%). The Kaplan-Meier method was used for time-to-event analysis. All statistical analyses were performed using STATA Statistical Software version 14.
Ethics
Written informed consent was obtained before enrollment in the trial. The study was approved by an accredited Ethical Committee and Institutional Review Board and was performed according to the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice Guidelines and the European Union Clinical Trial Directive (2001/20/EG). The study was registered with EuraCT number 2010-022294-34.
Results
Between September 20, 2011 and October 18, 2015, 63 previously untreated patients with CLL from 26 centers in the Netherlands were enrolled in this study.
Maximum tolerated dose and recommended dose level of chlorambucil given in combination with rituximab and lenalidomide
Twelve patients were included in phase 1 of this study aimed at determining the recommended dose level of chlorambucil in combination with rituximab and lenalidomide. In the first dose level group 7 mg/m2 chlo- rambucil), no dose-limiting toxicity was observed. Subsequently, six patients were included in the second dose level, of 10 mg/m2, of chlorambucil. Again, no dose- limiting toxicities were observed at this dose level. There were no differences in the proportions of adverse or severe adverse events between the groups treated with the two different doses. Lenalidomide dose modifications were more frequently applied in the second dose level group. Despite the lack of significant differences in toxic- ity between the two groups treated with different chlo- rambucil dosages, the principal investigators, with sup-
Figure 2. Flowchart of number of patients through the study protocol and off protocol, with reasons. Chlor 7: chlorambucil 7 mg/m2; Chlor 10: chlorambucil 10 mg/m2; SLL: small lymphocytic leukemia.
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