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Induction regimen associated with durable response, low toxicity in mantle cell lymphoma
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.
Perspective
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A number of groups around the world are looking at combining bendamustine and rituximab with other agents. For example — through the Eastern Cooperative Oncology Group — we have the E1411 study, which combines bendamustine and rituximab with or without bortezomib (Velcade, Takeda Oncology) in the frontline setting. The NORDIC group published its results evaluating bendamustine–rituximab plus lenalidomide (Revlimid, Celgene). The SHINE trial, sponsored by Janssen, evaluates bendamustine and rituximab with or without ibrutinib (Imbruvica; Pharmacyclics, Janssen) and recently completed accrual; we’re still waiting on those data.
The Fondazione Italiana Linfomi’s study evaluated bendamustine and rituximab with intermediate-dose cytarabine. Cytarabine is a particularly active agent in mantle cell lymphoma. It makes sense that we should capitalize on that, along with the favorable activity and tolerability profile of bendamustine and rituximab. An earlier version of this trial used 800 mg/m2 of cytarabine and showed that it was very active, but it was also plagued by considerable myelosuppression. So, the Italian group went back to the drawing board and dropped the cytarabine dose to 500 mg/m2 for four doses and instituted some dose-modification schemas for different types of toxicity.
Investigators found that the results were quite promising, with a complete response rate of 91%, which is essentially unprecedented in mantle cell lymphoma. The results look very good. However, it is, importantly, a phase 2 trial. It’s very challenging to change the standard of care on the basis of a phase 2 trial. There hopefully will be a phase 3 trial of RBAC500 compared with bendamustine–rituximab alone. I suspect we will see that it does, in fact, have improved efficacy at the expense of some toxicity.
Every one of the other regimens under evaluation likely would promise something very similar. At some point in the next 5 to 10 years, we will have a number of bendamustine–rituximab plus drug X combinations that show that they are active. It will be interesting from the clinician’s perspective to choose a regimen that seems to fit the patient best, and it will be interesting from an investigator’s perspective to choose the regimens that look the most promising and move those forward into phase 3 trials.
Beyond that, before we even get a chance to decide what the optimal combination is, we may see nonchemotherapy combinations moving forward, as well. The next 5 to 10 years will be very interesting in mantle cell lymphoma.
Perspective
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This is an important study for mantle cell lymphoma. At this point in time, there is really no standard of care for how we treat our patients with mantle cell lymphoma. The patients in the presented study were older patients who are not eligible for transplant. We know that bendamustine is a very active drug in mantle cell lymphoma, and we have seen have seen that bendamustine and rituximab (Rituxan; Genentech, Biogen), compared with R-CHOP, can result in prolonged PFS . We also know that the addition of cytarabine plays an important role in the management of patients with mantle cell lymphoma.
The investigators here present a slightly modified study with a lower dose of cytarabine than they used previously. They used a 500-mg/m2 dose as opposed to the 800-mg/m2 dose that was used in the previous study. Although that regimen had excellent response rates, there was a significant degree of toxicity, particularly hematological toxicity like neutropenia and thrombocytopenia, which is why they reduced the dose of cytarabine. Here again, researchers showed excellent outcomes with a very high response rate and, importantly, a very high molecular response rate. We know that this can be a surrogate marker for long-term survival, so we know how important it is to achieve deep molecular remission in patients with mantle cell lymphoma.
Although this regimen was less toxic, we still see that a quarter of the patients were not able to continue all six cycles. Although this study confirms that bendamustine and rituximab with cytarabine can lead to deep responses, we still don’t know exactly how to use these drugs. For example, giving cytarabine together with bendamustine and rituximab may not be the best way to use them. It might be better to do it in an alternating or consecutive way. These are questions we need to look at.
Furthermore, especially patients with a high Ki67 and the blasted variant of mantle cell lymphoma — who had worse outcomes than their counterparts — it would be interesting to know if it is possible to add novel biological agents such as proteasome inhibitors or BCR inhibitors, or Bcl2 inhibitors to bendamustine and rituximab instead of cytarabine. That might make it somewhat less toxic for older patients while preserving efficacy or even improving outcomes for the high-risk patients. It also may be interesting to see if we can bring this regimen to younger patients who traditionally are treated with intensive regimens followed by an autologous stem cell transplant.
