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Immunochemotherapy, autologous HSCT double time to treatment failure in mantle cell lymphoma
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Immunochemotherapy with high-dose cytarabine, followed by autologous hematopoietic stem cell transplantation, doubled time to treatment failure and should be considered the standard of care for younger patients with mantle cell lymphoma, according to the results of an open-label, randomized phase 3 study conducted by the European Mantle Cell Lymphoma Network.
“Although the median OS has doubled in the past 3 decades, mantle cell lymphoma remains incurable, with a median OS of only 4 to 5 years,” Martin Dreyling, MD, professor of medicine at Ludwig Maximilians University in Munich and coordinator of the European Mantle Cell Lymphoma Network, and colleagues wrote. “Results from a meta-analysis showed that the addition of rituximab [Rituxan; Genentech, Biogen] to conventional chemotherapy improves OS, but complete remission rate remains below 50% and time to treatment failure shorter than 2 years after treatment with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone).”
Peter Martin
Dreyling and colleagues sought to determine whether the addition of high-dose cytarabine to immunochemotherapy, followed by autologous HSCT, would improve outcomes in this patient population.
The analysis included 497 patients aged 65 years or younger (median age, 55 years; interquartile range, 49-60) with untreated stage II to stage IV mantle cell lymphoma from Germany, France, Belgium or Poland.
Patients were randomly assigned to six cycles of R-CHOP, followed by myeloablative radiochemotherapy and autologous HSCT (control group; n = 234); or six courses of alternating R-CHOP and R-DHAP (rituximab plus dexamethasone, high-dose cytarabine and cisplatin), followed by a high-dose conditioning regimen including cytarabine and autologous HSCT (cytarabine group; n = 232).
Time to treatment failure served as the primary endpoint. Secondary endpoints included complete remission rate, overall response rate, PFS, OS and adverse events.
Median follow-up was 6.1 years (95% CI, 5.4-6.4).
Treatment failure occurred in 143 patients in the control group and 85 patients in the cytarabine group.
Median time to treatment failure was 9.1 years (95% CI, 6.3-not reached) in the cytarabine group vs. 3.9 years (95% CI, 3.2-4.4) in the control group. More patients in the cytarabine had not failed treatment by 5 years (65% vs. 40%; (HR = 0.56; P = .038).
More patients in cytarabine group achieved complete remission than the control group (55% vs. 39%; P = .0005). ORR after autologous HSCT was similar in each arm (98% vs. 97%).
More patients assigned cytarabine tested negative for minimal residual disease in the peripheral blood (79% vs. 47%; P < .0001) and in the bone marrow (61% vs. 26%; P < .0001).
Median PFS from the time of randomization was 9.1 years in the cytarabine arm and 4.3 years in the control arm (HR = 0.55; 95% CI, 0.42-0.71).
Median OS did not significantly differ between the cytarabine and control arms (9.8 years vs. not reached; HR = 0.78; 95% CI, 0.57-1.07).
More patients assigned high-dose cytarabine experienced grade 3 or worse hematological toxicity, including severe febrile neutropenia (17% vs. 8%), and affected hemoglobin (29% vs. 8%) and platelets (73% vs. 9%).
More patients assigned cytarabine also had grade 1 or grade 2 renal toxicity (43% vs. 10%).
Eight patients in both groups died of complications related to autologous HSCT.
“As a result of our trial, a high-dose cytarabine-containing therapy, followed by autologous HSCT, represents the current standard of care in patients aged 65 years or younger, with which innovative approaches have to be compared in future trials,” Dreyling and colleagues wrote. “Additionally, the assessment of minimal residual disease should be considered in clinical response assessment.”
The lack of survival benefit seen in this and other studies raises important questions for future research, Peter Martin, MD, associate professor of medicine at Weill Cornell Medicine and associate attending physician at NewYork–Presbyterian Hospital, wrote in an accompanying editorial.
“By almost all measures, the trial was a success,” Martin wrote. “But a lingering question remains: Why was there no difference in survival? Despite a doubling of the median time to treatment failure, 5-year OS was similar in the two groups.”
Although OS remains the gold standard for phase 3 trials, these studies face feasibility issues and irrelevance if they take too long, Martin added.
“Trialists should take heart that Hermine and colleagues’ study started in 2004, yet it yielded results that are as relevant today as when the study was first conceived,” Martin wrote. “Treatments that improve response depth or duration but not survival might have value that is not immediately apparent, but results must be assessed in the context of toxicity and effect on subsequent therapies.” – by Cameron Kelsall
Disclosure: The European Commission, Lymphoma Research Foundation and Roche provided funding for this study. Dreyling reports grants and personal fees from Roche outside the submitted work. Please see the full study for a list of all other researchers’ relevant financial disclosures. Martin reports consulting fees from Acerta, Celgene, Gilead, Janssen and Novartis.
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