My Thoughts on Optimizing Induction Therapy for MCL

Julie M. Vose, MD, MBA

Chief, Division of Oncology and Hematology
Neumann M. and Mildred E. Harris Professor
Department of Internal Medicine
University of Nebraska Medical Center
Omaha, Nebraska

Julie M. Vose, MD, MBA, has disclosed that she has received consulting fees from AbbVie, Epizyme, Karyopharm, Legend Pharmaceuticals, Novartis, Roche, Sandoz, and Vanlam Group and funds for research support from Acerta Pharma, Bristol-Myers Squibb, Celgene, Incyte Corporation, Kite Pharmaceuticals, Merck Sharpe & Dohme, Novartis, and Seattle Genetics.

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Released: April 30, 2018

My Thoughts on Optimizing Induction Therapy for MCL

For patients with mantle cell lymphoma (MCL), there is currently a range of treatment options for induction therapy. Retrospective data have suggested that patients with MCL should receive a high-dose cytarabine‑containing regimen as induction therapy, based on an increased CR rate with these regimens. However, these combinations (eg, hyper-CVAD) are generally quite toxic, particularly for older patients but also in younger patients. Possible treatment options to decrease toxicity include omitting the methotrexate, like the Nordic trial regimen of dose‑intense R‑CHOP alternating with R-cytarabine. European trials have shown promising results from alternating R‑CHOP and R‑DHAP as well.

One question that remains is whether it is the need for a cytarabine-based regimen or the fact that the patient achieves complete remission prior to stem cell transplantation that is most important for optimal long-term outcomes.

A fairly large retrospective analysis from multiple centers in the United States, presented at the 2017 ASH Annual Meeting, showed that patients with MCL who achieved a complete remission before transplant, regardless of the induction regimen, seemed to do better following transplantation than those who did not. The patients who received BR achieved good rates of remission and reported less toxicity. Based on these data, the theory that you must use a cytarabine‑containing regimen is now back in question. At our center, we now use BR induction for most patients with MCL, although we still use R-hyper-CVAD for patients with a blastic component. In general, the BR combination is effective in MCL, has less toxicity, and produces a very high CR rate, allowing patients to proceed to autologous stem cell transplantation (ASCT) for long-term remission. Post-transplant rituximab maintenance was also found to prolong the time in remission based on this retrospective study.

Chemotherapy-Free Induction Therapy
There has been a lot of discussion recently about using chemotherapy-free regimens as induction therapy for certain patients with MCL: Targeted agents are of great interest as frontline therapy, particularly for patients who cannot tolerate chemotherapy, but these agents are not yet approved in this setting and, consequently, are not available outside of a clinical trial for most patients.

For patients who cannot tolerate frontline chemotherapy, particularly those who are older and not transplantation candidates, ibrutinib, a BTK inhibitor, may be of benefit. Following convincing evidence of substantial clinical benefit in relapsed/refractory MCL, a randomized phase III trial is currently evaluating the addition of ibrutinib to BR in patients with newly diagnosed MCL (planned N = 524; primary endpoint: PFS). In addition, a small phase II study of first‑line lenalidomide plus rituximab showed promising results in patients with MCL, a tumor mass of at least 1.5 cm, and low-risk to intermediate-risk MIPI scores.

Overall, the choice of optimal induction in MCL remains unclear. In general, the important factors to consider during induction therapy are whether patients go into remission and their MRD status at the time of transplantation.

Ongoing Clinical Trials
The ongoing phase III intergroup TRIANGLE trial is investigating whether ibrutinib increases the clinical benefit seen with traditional chemotherapy, with or without autologous transplantation in MCL. In this study, a planned 870 patients with previously untreated MCL are being randomized to:

  • Standard therapy with ASCT: R-CHOP/R-DHAP, followed by THAM or BEAM and then ASCT
  • Standard induction chemotherapy plus ibrutinib with ASCT: R-CHOP/R-DHAP plus ibrutinib as induction therapy, followed by THAM or BEAM and then ASCT, followed by ibrutinib maintenance therapy
  • Standard induction chemotherapy plus ibrutinib without ASCT: R-CHOP/R-DHAP plus ibrutinib as both induction and maintenance therapy

Another interesting trial, the phase III SHINE trial, is comparing BR with or without ibrutinib in older patients with MCL who are not suitable for aggressive chemotherapy.

Treatment Decisions for Individual Patients
As new clinical trial data emerge, treatment of MCL will continue to evolve. To help you address challenges with treatment decisions for your patients with MCL, my colleagues and I are creating a new treatment decision tool for MCL. In this tool, you will be able to enter in your own patients’ details and receive expert guidance on treatment selection based on the characteristics you submit. Check back in on the CCO Web site soon for this online tool, along with additional commentaries from the experts.

How is induction therapy for newly diagnosed MCL changing in your practice? Please share your thoughts below.

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