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Lenalidomide maintenance shows promise in high-risk patients with relapsed DLBCL
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Lenalidomide maintenance conferred high PFS among patients with relapsed diffuse large B-cell lymphoma who were ineligible for or who relapsed after autologous stem cell transplantation, according to an open-label, phase 2 study conducted in Italy published in The Lancet Haematology.
“We did not expect the excellent results of this trial,” Andrés J.M. Ferreri, MD, professor at San Raffaele Hospital in Milan, told HemOnc Today. “Usually, only 20% to 30% of these patients are alive at 1 year of follow-up; thus, to achieve a 1-year OS of 80% is an outstanding result.”
DLBCL is the most common lymphoma diagnosed in adults and the standard therapy is R-CHOP (rituximab [Rituxan; Genentech, Biogen] with cyclophosphamide, doxorubicin, vincristine and prednisone). Standard treatment for patients who relapse after R-CHOP is high-dose cytarabine-based chemotherapy or high-dose ifosfamide-based chemotherapy consolidated by autologous stem cell transplantation (ASCT), which results in a 3-year PFS of 55%.
Due to advanced age, comorbidities or unsuccessful stem cell collection, many patients are not eligible for ASCT and invariably have an additional relapse, with 1-year PFS of 30% to 40%. Further, patients who have lymphoma recurrence after a previous ASCT have a median OS of 9 months.
Coordinated by Maurilio Ponzoni, MD, a professor at San Raffaele Hospital, researchers conducted a multicenter trial to investigate the effects of lenalidomide [Revlimid, Celgene] maintenance in patients with chemotherapy-sensitive relapse of DLBCL who are not eligible for ASCT or who relapsed after ASCT.
The analysis included 46 adults (59% men; median age, 72 years; 76% advanced stage) with new or transformed DLBCL and relapsed disease responsive to conventional rituximab-containing salvage therapy from 12 oncology-hematology centers in Italy. All patients were given oral lenalidomide (25 mg/day for 21 of 28 days) until lymphoma progression or unacceptable toxicity. One-year PFS served as the primary endpoint, with an efficacy goal of 19 patients with PFS after 1 year.
Of the patients in the study, 36 (78%) had new DLBCL and 10 (22%) had transformed DLBCL. Over a median follow-up of 25 months (interquartile range, 12-56), 556 lenalidomide courses were delivered, for a mean of 12 courses (range, 3-41) per patient; 19 patients were still receiving treatments or had completed 2 years of maintenance.
One year from trial registration, 28 patients (60.9%) were progression free — which exceeded the predetermined efficacy threshold of 19 patients — and the PFS was 70% (95% CI, 57-83).
Thirty-three patients were alive at the end of data collection, with a 1-year OS of 81% (95% CI, 70-92) and 3-year OS of 71% (95% CI, 57-85).
During the entire observation period, 21 events occurred, with 19 patients developing progressive lymphoma. Overall, lenalidomide was well tolerated, with researchers reporting 10 severe adverse events in nine patients — febrile neutropenia (n = 4), diarrhea (n = 2), melena, stroke and vomiting. Six of those patients continued with lenalidomide treatment.
Death due to toxicity occurred in one patient, an 81-year-old woman, who died of intestinal infarction 11 months into lenalidomide treatment. Another patient, a 73-year-old man, developed two other cancers and died of myelodysplastic syndrome 13 months after the initiation of treatment.
Researchers noted the small size of the trial may limit its statistical power.
“Although these results are encouraging enough to recommend the use of lenalidomide maintenance in this high-risk group of patients, the efficacy of this strategy should be confirmed in a large randomized trial comparing this drug with placebo,” Ferreri said. “In the case of positive results, this will be suitable evidence to include this strategy in international guidelines and to convince regulatory bodies to approve lenalidomide for maintenance in patients with chemotherapy-sensitive relapse of DLBCL.”
In three studies, including the one by Ferreri and colleagues, lenalidomide has shown different mechanisms of action compared with rituximab monotherapy, Bertrand Coiffier, MD, professor and head of the department of hematology at Hospices Civils de Lyon, noted in an accompanying editorial.
“With all these data in mind, should we use lenalidomide in the maintenance setting?” Coiffier wrote. “If yes, it would be outside the current label of lenalidomide, which is only approved for multiple myeloma, myelodysplastic syndrome and mantle cell lymphoma in Europe and the United States.
“The major problem is that we do not have data describing the characteristics of patients who relapse once in complete response,” Coiffier added. “Almost all patients in complete response or partial response after relapse will die of lymphoma progression. A confirmatory randomized study of lenalidomide maintenance vs. placebo in relapsed patients who responded to salvage therapy would be easy to do. If lenalidomide maintenance therapy is found to be effective, it could then be given to relapsing patients or first-line patients who are at high risk.” – by Chuck Gormley
For more information:
Andrés J.M. Ferreri, MD , can be reached at Unit of Lymphoid Malignancies, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; email: ferreri.andrews@hsr.it.
Disclosure: Ferreri reports consultant/advisory roles with Acerta, Celgene, Gilead, Italfarmaco and Mundipharma and grant support from Celgene and Mundipharma. Please see the full study for a list of all other researchers’ relevant financial disclosures. Coiffier reports grants and personal fees from Celgene and personal fees from Roche during the conduct of the study. He also reports personal fees from Celltrion, Gilead, Mundipharma, Novartis and Pfizer outside the submitted work.
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