The BENDALEM CLL 6 AGMT Study – Bendamustine Combined with Alemtuzumab In Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL): Results of a Planned Interim Analysis

Relapse of CLL presents a crucial problem to clinicians and patients. Improvement of the first line therapy incorporating fludarabine and monoclonal antibodies may result in relapse of disease, which might be more difficult to treat. Alemtuzumab showed efficacy in first and second line treatment and combinations of alemtuzumab with chemotherapy yielded promising results in relapsed or refractory CLL patients. We have previously reported the feasibility and efficacy of combining fludarabine and 16 weeks of alemtuzumab in pretreated CLL patients (Flusalem trial, Egle et al. EHA 2009). Bendamustine was effective in CLL as a single agent as well as in combination with rituximab. We hypothesised, that a combination of bendamustine with alemtuzumab may display little cross-resistance, given the prevalent initial treatments in our cohort.

The protocol combines 4 cycles of bendamustine (70 mg/m² i.v. 2d, q4w) with continuous alemtuzumab (30 mg s.c. 3× weekly for 16 weeks) allowing an out-patient management in pretreated CLL patients. Valganciclovir prophylaxis was mandatory for all patients with positive cytomegalovirus (CMV) serology, Valaciclovir was used for patients with negative serology. We herewith present the first 7 patients recruited into the study as result of a planned interim analysis following a Gehan design. We evaluated response rate, safety profile and toxicities with the regimen in relapsed/refractory patients. MRD analysis will be included in the follow-up phase.

Mean age of patients was 70 years (range 54–80). Three out of 7 patients had stage RAI III/IV and mean WBC count was 126 G/L. Median number of previous treatment lines was 2 (range 1–7) and the regimes included FCR, and other rituximab or alemtuzumab combinations. All patients had at least one high risk feature from CD38, FISH or IgVH mutation status. Abberations detected by FISH included 2 patients with del17p, one with del11q and one with tri12. One patient had a highly complex karyotype with >8 chromosomal aberrations in conventional cytogenetics. Regarding toxicities, almost exclusively hematological and infectious complications were observed. Grade 3 and 4 leukopenia was expected in this combination and occurred in all patients, necessitating G-CSF treatment in 6/7 patients. Two patients had grade 3 or 4 thrombocytopenia and 3 patients received transfusions. No tumor lysis syndrome was detected. The median cumulative dose of alemtuzumab was 1453 mg (maximal scheduled dose: 1483 mg), reflecting and the feasibility of the regimen. Bendamustine dose had to be reduced by greater than 25% in 3/7 patients due to hematologic toxicity. CD4 T cell depletion was profound and rapid. After 2 cycles of treatment the median CD4 count was 55/μ l. This was not relevantly different from our previous experience with the combination of fludarabine and alemtuzumab. In the current study, 3 of 7 patients had asymptomatic CMV reactivation, but no symptomatic infection was observed. Five of 7 patients had serious adverse events due to infections, including one fatal outcome due to pneumonia, 2 months after the end of treatment. Response assessment at the end of treatment (4 cycles) showed 3 complete remissions (including 1 unconfirmed CR, without bone marrow sampling), 2 partial remissions and 1 stable disease. One treatment failure with early progressive disease occurred in the patient with the very complex karyotype. This patient had received 7 prior treatment lines and had been refractory to the last two lines (FCR and Ofatumumab). The two patients with del17p achieved PR and SD, respectively. The overall response rate was 71% and slightly lower than that reported in our previous Flusalem trial. Summary/Conclusions: Bendamustine combined with 16 weeks of subcutaneous alemtuzumab was feasible in an out-patient setting in pretreated CLL patients with high risk profile. Haematological and infectious complications comprise the most important toxicities. One grade 5 toxicity was not judged to be a safety signal in this extensively pretreated patient population. In comparison to the Flusalem trial, molecular high risk features were much more common, which may explain the slightly lower rate of responses. According to the Gehan analysis this interim analysis refutes the futility hypothesis and the study currently continues to recruit patients.

Egle:Mundipharma: Honoraria, Research Funding, Speakers Bureau. Greil:Mundipharma: Honoraria, Speakers Bureau.