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ATLANTA -- Adding lower-dose lenalidomide (Revlimid) to rituximab maintenance therapy extended progression-free survival (PFS) in older mantle cell lymphoma (MCL) patients ineligible for transplant, but came at the price of added toxicity, a randomized trial found.

In MCL Elderly R2, median PFS with first-line maintenance treatment improved from 3 years with rituximab alone to 5.1 years with rituximab plus lenalidomide, dubbed the R2 regimen (RR 0.579, 95% CI 0.429-0.781, P=0.003), reported Vincent Ribrag, MD, of Institut Gustave Roussy in Villejuif, France.

"So far we have no difference in overall survival [OS]," he said during his presentation at the American Society of Hematology annual meeting.

Virtually all patients responded to either of the two maintenance strategies, and complete responses were seen in 43% of patients who received rituximab alone and 49% of those assigned to rituximab-lenalidomide.

Starting in 2013, MCL Elderly R2 first randomized 620 previously untreated MCL patients, ages 60 and older, who were ineligible for autologous transplant to one of two induction regimens: eight cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or six cycles of an alternating regimen of R-CHOP and rituximab, high-dose cytarabine (Ara-C), and dexamethasone (R-HAD).

Eligible responders were then randomized to 2 years of maintenance therapy with rituximab alone or to rituximab with lenalidomide at dose of 15 mg.

Suchitra Sundaram, MD, of the Icahn School of Medicine at Mount Sinai in New York City, told 名媛直播 that she does not anticipate that the study will change practice due to the lack of OS benefit combined with the higher rates of hematotoxicity in the rituximab-lenalidomide arm.

With R2, 58.8% of patients experienced adverse events (AEs) involving the blood and lymphatic system versus 27.2% of those in the rituximab arm. Other AEs that were higher with R2 included neutropenia (50% vs 19%, respectively), infections (14% vs 2%), and secondary primary malignancies (13% vs 10%).

Sundaram, who was not involved in the research, noted that despite the lower 15-mg dose, further lenalidomide dose reductions were required in 46% of patients on the R2 arm.

"It would be crucial to review the quality-of-life metrics and patient-reported outcomes," for the two study arms, she said.

Deaths during the maintenance phase were similar between arms (43 with R2, 47 with rituximab), most of which were due to disease progression, though one patient in the R2 arm died of a treatment-related AE.

During his presentation, Ribrag noted that while no international standard of care exists for older MCL patients unfit for high-dose therapy with autologous stem cell transplant, induction chemoimmunotherapy remains the backbone of treatment.

In the U.S., Sundaram pointed out that R-CHOP induction is not typically used even for elderly MCL patients, making the maintenance findings in the study somewhat more difficult to extrapolate.

Study Details

The multicenter study was performed across seven countries in Europe. Inclusion criteria for the start of the trial included MCL as defined by World Health Organization classification, with cyclin D1 overexpression or t(11;14)(q13;q32), Ann Arbor stage II-IV disease, and an Eastern Cooperative Oncology Group performance status of 0-2.

After induction therapy, the 514 patients (87%) who had at least a partial response by Cheson 1999 criteria were eligible for maintenance therapy. Of those, 495 were randomized to 2 years of rituximab or rituximab plus lower-dose lenalidomide. Exclusion criteria for the maintenance portion included patients who received fewer than six cycles of R-CHOP or fewer than four cycles of R-CHOP/R-HAD during induction, creatinine clearance below 30 mL/min, platelet count less than 50,000 cells/mm³, and an absolute neutrophil count lower than 1,000 cells/mm³.

The maintenance group was a median age of 71, 70.5% were men, nearly all had Ann Arbor stage IV disease (90%), and lactate dehydrogenase was greater than the upper limit of normal in 38%.

Maintenance randomization was stratified by induction regimen, country, MCL International Prognostic Index risk group, and response to induction (complete response, unconfirmed complete response, or partial response). Median follow-up time for OS was 32.4 months since the time of induction and 25.2 months from maintenance.

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