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Mantle cell lymphoma treatment: plus ça change…

Monday, June 27, 2016

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. Peter Martin, M.D., wrote an editorial accompanying the study in the Lancet. Below is an excerpt - read the original here, and additional coverage by HemOnc Today here.

Photo of Peter Martin, M.D.Peter Martin, M.D. In their article in The Lancet, Olivier Hermine and colleagues from the European Mantle Cell Lymphoma Network report the results of a landmark clinical trial that are likely to cement in place the role of cytarabine in front-line therapy for younger patients with mantle cell lymphoma for years to come.

Since mantle cell lymphoma was proposed as an entity 25 years ago, patient outcomes have changed considerably. Compared with the benchmark median time to treatment failure of 14 months of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), it was helpful to see that the addition of rituximab to more intensive induction regimens and consolidation with autologous stem-cell transplantation could extend progression-free survival beyond 5 years in patients who can tolerate aggressive therapy. However, most studies were phase 2 trials; although their findings frequently changed local practice, they could not provide sufficient proof to define optimal therapy.

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By almost all measures, the trial was a success. But a lingering question remains: why was there no difference in survival? Despite a doubling of the median time to treatment failure, 5 year overall survival was similar in the two groups (69% [95% CI 62–74] in the control group vs 76% [70–81] in the cytarabine group; p=0·12).

Since the start of the rituximab era, more than ten phase 3 trials have been done in mantle cell lymphoma. These trials have assessed different chemotherapy regimens, the addition of rituximab to chemotherapy, the use of rituximab after chemotherapy, and the role of autologous stem-cell transplantation; targeted agents have been compared with chemotherapy and with each other. In all of these trials, despite an improvement in response depth and duration, only the addition of rituximab in some settings and the avoidance of fludarabine have evidence of a significant survival benefit. Indeed, it sometimes seems like the more things change, the more they stay the same.

Since survival has not been improved, two important questions arise. Are patients benefiting from all of this research? And what is the optimal endpoint of future trials? The answer to the first question is not straightforward. Although patients seem to be living longer than they did in the past, results from observational studies suggested that real-world outcomes remain poor. The improvement might be more perceived than real if we are doing a better job of correctly diagnosing the disease, overcoming a historical selection bias, or diagnosing patients earlier in the course of their disease compared with the past, resulting in lead-time bias. Conversely, perhaps our ability to manage relapsed lymphoma has improved as the number of available therapies has increased, as suggested by the increase in the average number of prior therapies in recent trials. The availability of new drugs might have an effect beyond the proven improvement in remission duration compared with another single agent. If this is true, it suggests that front-line therapies without curative potential must evolve to become less toxic so that subsequent lines of therapy remain feasible.

The second issue is even more challenging to address. Phase 3 trials that target overall survival remain the gold standard but face feasibility issues or irrelevance if they take too long. 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. 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.