An initial combination chemotherapy of bendamustine (Treanda?; Cephalon, Inc) and rituximab (Rituxan?, Genentech/Biogen IDEC) more than doubled progression-free survival (PFS) compared with R-CHOP therapy, the current standard of care, among patients with previously untreated indolent or slow-growing lymphoma and mantle cell lymphoma. This outcome is based on updated long-term multicenter phase III StiL NHL1 study data.

The data presented at the 2012 annual meeting of the American Society of Clinical oncology (ASCO), being held in Chicago from June 1 ? 5, showed an increase of the median progression-free survival from 31.2 months to 69.5 months. A simpler regimen also showed that the combination therapy showed improved tolerability compared to R-CHOP, [1] a combination of rituximab, cyclophosphamide (Cytoxan), doxorubicin hydrochloride or hydroxydaunomycin (Adriamycin), vincristine sulfate and prednisone.

?This is the first randomized clinical trial to compare bendamustine and rituximab with standard chemotherapy regimen. While R-CHOP is the current standard of care, it is frequently associated with serious adverse events. The promising results of our study show that the therapy of bendamustine and rituximab (B-R) is more effective and less toxic and could eventually become the new standard first-line treatment option for patients with indolent non-Hodgkin lymphoma?s ,? said Mathias J. Rummel, M.D, PhD, Professor of Medicine at the University Hospital Giessen in Germany and lead author of the study. ?Just as important, the bendamustine-based therapy allowed patients to have a better quality of life (QoL) while undergoing therapy. These long-term findings should be strong enough to change clinical practice.?

East Germany
Bendamustine has been used for decades in Eastern Europe. It was originally developed about 50 years ago in former East Germany, but it only became available in the United States in 2008 and the European Union in 2010. While some U.S. oncologists currently use the bendamustine-based regimen based on earlier clinical data, uptake has not been universal. R-CHOP remains the established regimen of choice in the United States and much of Europe.

The investigators compared PFS in 514 patients with previously untreated indolent non-Hodgkin or mantel cell lymphomas who were randomly assigned to receive either the bendamustine-based regimen or R-CHOP.

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Significant progression-free survival
After a median follow-up of 45 months the significant PFS benefit (69.5 months vs. 31.2 months) observed in the trial extended to all risk groups, irrespective of age, including:
– Patients with follicular lymphoma, the most common form of indolent non-Hodgkin Lymphoma. This benefit was seen across all risk sub-groups independent of Follicular Lymphoma International Prognostic Index or FLIPI score.
– All other histological sub-types such as mucosa-associated lymphoid tissue, mantel cell lymphoma and small lymphocytic lymphoma. The only exception was marginal zone lymphoma, where the PFS was comparable.

In addition to PFS, the researchers observed that the complete response rate (CR) was significantly higher with the bendamustine-based regimen (39.8%) compared with R-CHOP (30.0%).

Overall survival did not differ between the two groups, partly because nearly half of the R-CHOP patients whose disease continued to progress were permitted to receive the bendamustine-based regimen, and partly because survival of indolent lymphomas tends to be very long, making PFS the most reliable measure of clinical benefit and patient QoL.

Adverse events
While there was a higher incidence of mild skin reactions in patients treated with the bendamustine-based regimen (82 vs. 38 patients), twenty secondary malignancies were observed in the bendamustine-based group compared with 23 in the CHOP-R group, with 1 hematological malignancy in each group (1 MDS in B-R, 1 AML in CHOP-R).

Rummelemphasized that there was no hair loss (alopecia) ? a side effect particularly important to patients .?It is well known that with R-CHOP patients have hair loss, but with the bendamustine-based regimen not a single patient had any hair loss,? he noted.

Moderate to severe neutropenia (severe declines in neutrophil counts), occurred in 69% of patients treated with R-CHOP versus 29% of patients treated with the bendamustine-based regimen. Treatment with G-CSF, a drug stimulating the production of white blood cells allowing higher-intensity treatment regimens, was needed in 20% of R-CHOP chemotherapy cycles but only in 4% of bendamustine-based cycles. Leukocytopenia was reported in 37% of patients in the bendamustine-arm versus 72% in R-CHOP.

Clinical perspective
John Gribben, MD, Professor and Consultant Hematologist at the Bart?s Cancer Institute on London commented: ?Should this regimen become approved, it is clear that the bendamustine-based regimen will offer an important new first-line option for all patients with indolent lymphomas ? whether fit or unfit ? and bendamustine is likely to become the new cytotoxic combination partner of choice in the treatment of these diseases.

For more information:
Protokoll NHL 1 – 2003: Bendamustin + Rituximab vs CHOP + Rituximab
NCT00991211 – Bendamustine Plus Rituximab Versus CHOP Plus Rituximab

[1] Rummel MJ, Niederle N, Maschmeyer G, Banat AG, Von Gruenhagen U, Losem C et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study. J Clin Oncol 30, 2012 (suppl; abstr 3) Plenary Session Including Science of Oncology Award and Lecture, ASCO 2012.

In Europe, bendamustine is licensed from Astellas Deutschland GmbH and marketed as Levact?, Ribomustin? or Ribovact? by Mundipharm. The drug is indicated for the treatment of first-line treatment of chronic lymphocytic leukemia (CLL, Binet stage B or C) in patients for whom fludarabine combination chemotherapy is not appropriate. The drug is also indicated as monotherapy in patients with indolent non-Hodgkin?s lymphomas who have progressed during or within 6 months following treatment with rituximab or rituximab-containing regimen. Finally, bendamustine is approved in first-line treatment of multiple myeloma (MM, Durie-Salmon stage II with progress or stage III) in combination with prednisone for patients older than 65 years of age who are not eligible for autologous stem cell transplantation and who have clinical neuropathy at time of diagnosis ? precluding treatment with thalidomide or bortezomib containing regimen.

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