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SAN DIEGO — A novel induction regimen containing bendamustine, rituximab and lower-dose cytarabine appeared highly effective and safe for older patients with mantle cell lymphoma, according to findings of a trial conducted by Fondazione Italiana Linfomi presented at the ASH Annual Meeting and Exposition.
Rituximab (Rituxan; Genentech, Biogen), bendamustine and cytarabine induction therapy is highly active in mantle cell lymphoma; however, hematologic toxicities have limited its use.
Carlo Visco, MD, of the department of hematology and cell therapy at San Bortolo Hospital in Vicenza, Italy, and colleagues investigated whether lowering the dose of cytarabine would reduce the incidence of hematologic toxicities while remaining effective.
“The rationale for combining bendamustine and cytarabine is because both drugs are very active as single agents in this patient population,” he said. “Cytarabine is recognized as being highly beneficial in younger patients with mantle cell lymphoma. These two drugs, when administered consecutively, are strongly synergistic.”
The study included 57 patients aged older than 60 years (median age, 71 years; range, 61-79; 75% men) who were treated at one of 29 centers. All patients were not eligible for autologous transplant.
Mantle Cell International Prognostic Index (MIPI) was low in 15% of patients, intermediate in 40% and high in 45%.
Patients received the R-BAC regimen, which includes 375 mg/m2 IV rituximab on day 1, 70 mg/m2 IV bendamustine on days 2 and 3, and 500 mg/m2 IV cytarabine on days 2 to 4. The dose of cytarabine was reduced from the original 800-mg/m2 dose from earlier studies.
Complete remission rate served as the primary endpoint. Molecular response using specific IGH– or BCL1–based targets, PFS and OS were secondary outcome measures.
Visco and colleagues developed a two-stage design to the study. The first stage included 19 patients and would cease if fewer than eight patients had a complete response or more than seven patients experienced toxicity. The second stage included 38 patients and would stop if fewer than 28 patients had a complete response or more than 18 patients had toxicity.
Median follow-up was 34 months (range, 28-52).
All 57 patients had at least two cycles of the regimen, including 54 patients who had at least four cycles and 38 who had at least six cycles (median, 5.3 cycles).
Results showed an ORR — which were all complete responses — of 91%. Progressive disease occurred in 4% of the cohort.
Minimal residual disease occurred in 28 patients after cycle two, 45 patients at the end of therapy and in 28 patients 12 months after the study. The molecular response rate at the end of treatment was 76% on peripheral blood and 55% on bone marrow samples.
After 2 years, OS was 86% (95% CI, 74-93), PFS was 81% (95% CI, 74-93) and durability of response was 90% (95% CI, 85-94).
In a post-hoc analysis, it was determined that MIPI was associated with inferior PFS. Elevated Ki-67 ( 30%), and the blastoid variant were the strongest independent predictors of adverse PFS. Thirty-three percent of patients had either of those features, and these patients had a significantly inferior PFS compared with patients with classical variants and low proliferative index (41% vs. 97%; P < .0001).
Grade 4 hematologic toxicities occurred in 27% of patients. Neutropenia occurred in 35%, and thrombocytopenia occurred in 36%.
Further, 72% of the cohort had at least one dose reduction and 40% had at least one episode of relevant toxicity. “The regimen was quite well tolerated,” Visco said. “We observed few episodes of grade 3 or 4 events.”
“Our results support the use of R-BAC500 in elderly patients with mantle cell lymphoma,” Visco concluded. “Hematologic toxicities exceeded our pre-specified safety boundaries but were manageable with dose reduction and a reduced dose compared with previous experience. Responses were durable without the use of maintenance therapy and PFS compares favorably with previously reported regimens.” – by Rob Volansky
For more information:
Visco C, et al. Abstract #72. Presented at: The ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosures: Visco reports speakers bureau or consultant roles with and research funding from Celgene, Gilead, Lundbeck and Mundipharma. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
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