Randomized phase 2 study of otlertuzumab and bendamustine versus bendamustine in patients with relapsed chronic lymphocytic leukaemia
Tadeusz RobakAndrzej HellmannJanusz KłoczkoJavier LoscertalesEwa Lech‐MarańdaJohn M. PagelAnthony R. MatoJohn C. ByrdFarrukh T. AwanHolger HebartJose A. García‐MarcoBrian T. HillMichael HallekAmy J. EisenfeldScott StromattUlrich Jaeger
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Otlertuzumab (TRU-016) is a humanized anti-CD37 protein therapeutic that triggers direct caspase-independent apoptosis of malignant B cells and induces antibody-dependent cell-mediated cytotoxicity. Patients with relapsed chronic lymphocytic leukaemia (CLL) received either otlertuzumab (20 mg/kg) weekly by IV infusion for two 28-day cycles then every 14 days for four 28-day cycles and IV bendamustine (70 mg/m2 ) on Days 1 and 2 of each cycle for up to six 28-day cycles or bendamustine alone. Thirty-two patients were treated with otlertuzumab and bendamustine and 33 with bendamustine alone. Overall response rate according to the International Workshop on Chronic Lymphocytic Leukaemia criteria was 69% in the otlertuzumab and bendamustine arm and 39% in the bendamustine alone arm (P = 0·025). Median progression-free survival (PFS) was 15·9 months in the otlertuzumab and bendamustine arm and 10·2 months in the bendamustine alone arm (P = 0·0192). There was a higher incidence of pyrexia (34% vs. 12%) and neutropenia (59% vs. 39%) with the combination but this did not result in a higher incidence of severe (grade 3/4) infections (13% vs. 27%). This combination significantly increased the response rate and prolonged the PFS over single agent bendamustine in patients with relapsed or refractory CLL.Keywords:
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OBJECTIVE: To report outcomes in patients with chronic lymphocytic leukemia (CLL) presenting with CNS and leptomeningeal involvement (CNS CLL) treated with intravenous (IV) rituximab and bendamustine (R-benda). BACKGROUND: Chronic Lymphocytic Leukemia (CLL) is a hematologic malignancy characterized by small mature and malignant B lymphocyte proliferation. Autopsy studies have demonstrated CNS involvement in 8-12% of patients, usually as leptomeningeal disease (LMD), or more rarely as parenchymal involvement, though presentations with clinical symptoms are rare. This likely reflects transformation to diffuse large B cell lymphoma in the majority of cases. The prognosis of CNS CLL is poor, with an average survival of 12 months and no standard treatment. R-benda is a highly effective regimen in CLL, but penetration through the blood-brain barrier is suboptimal, and the use of this regimen to treat CNS CLL has not been reported. DESIGN/METHODS: Institutional databases were searched to identify patients with CNS involvement by CLL that were treated with R-Benda. RESULTS: Three patients met the inclusion criteria. The first (#1) was a 55 year-old man with optic neuropathy and thoracic myelopathy, with a clinical presentation resembling multiple sclerosis. Neuroimaging showed periventricular and spinal cord lesions. The second (#2) was a 53-year-old woman presenting with seizures and a left frontal lesion. The third (#3) was a 73 year-old woman presenting with thoracic and lumbar multi-radiculopathy. All patients had pleocytosis and CSF involvement by CLL, confirmed by flow cytometry or gene rearrangement studies. Patients received 5-6 cycles of R-benda, which were well tolerated and resulted in a complete response in all, as measured by follow up imaging and CSF analysis. The progression-free survival from diagnosis was 20 months for patient #1, 44+ months for #2 and 8+ months for #3. The overall survival was 42 months (#1), 47+ months (#2) and 8+ months (#3). CONCLUSIONS: In this selected group of patients with CNS CLL, the R-benda regimen was safe and efficacious, warranting further investigation. Study Supported by: NA
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Abstract: As the most prevalent form of adult leukemia, chronic lymphocytic leukemia (CLL) affects thousands of patients each year. Given the indolent nature of the disease, symptomatic patients frequently experience multiple relapses throughout their clinical course. Better therapeutic options are needed, particularly for the elderly population that characterizes the majority of affected patients. Bendamustine, a hybrid alkylating agent, has demonstrated remarkable activity in CLL in conjunction with a tolerable safety profile. Although historically used in relapsed and refractory disease, it has recently gained a role in the front-line setting, including younger, physically fit patients. Current investigatory efforts are focused on exploring the combination of bendamustine with novel therapies in CLL. Keywords: chronic lymphocytic leukemia, overall survival, aspartate aminotransferase, chlorambucil, bendamustine
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Introduction: Chronic lymphocytic leukemia (CLL) often has an extended disease course. With a median age at diagnosis of 72 years, newer treatment options with less toxicity than standard nucleoside analogue-based regimens are needed. Historically, few therapy options are available once CLL has become refractory to nucleoside analogues. Bendamustine has emerged as a feasible therapy for older and less fit CLL patients, with clinical efficacy in previously untreated and refractory CLL.
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Background: Bendamustine is now approved in the US for the treatment of chronic lymphocytic leukemia and low grade non-Hodgkin's lymphoma, and is currently being explored in the treatment of several solid tumor types. Objective: The bi-functionality of bendamustine was used to provide a therapeutic understanding of both its benefit as well as adverse effects. Methods: Pertinent biochemistry and molecular biology pathways are reviewed with regards to bendamustine activity. In view of these pathways bendamustine was reviewed in human clinical trials. Results/conclusion: Bendamustine combines alkylating properties with purine analogue properties making it an effective drug in chronic lymphocytic leukemia where agents that affect these pathways have proven useful. There is limited evidence of cross-reactivity with this agent and other pure purine analogues and alkylators.
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