Cure for Mantle Cell Lymphoma Within Reach, Says Expert

Fran Lowry

January 19, 2016

Clinical trials in mantle cell lymphoma (MCL) conducted during the past 2 decades have led to a better understanding of the biology as well as treatment of this disease and have given researchers cause to hope that a cure is within reach.

"Mantle cell lymphoma is a rare disease, which has made it a challenge to study in clinical trials, but rapid advances have been achieved in the past 2 decades, and the future is very bright," Michael L. Wang, MD, professor, Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, told Medscape Medical News.

"Clinical trials have flourished, new trials are appearing rapidly, and we have a much better understanding of this disease. It's very exciting. We are within reach of curing mantle cell lymphoma within a shorter period of time, much sooner than we expected," Dr Wang said.

MCL is an uncommon subtype of non-Hodgkin's lymphoma previously considered to be associated with a poor prognosis. There are currently 700,000 patients in the United States who are living with lymphoma, and of these, about 5% have MCL.

Knowledge of the biology and natural history of MCL, including knowledge of the many mutations and signal pathways that are important for this lymphoma, is increasing, Dr Wang said.

Dr Michael L. Wang

"This greater understanding of the molecular pathophysiology of mantle cell lymphoma has resulted in an explosion of specifically targeted new, efficacious agents, including the proteasome inhibitor bortezomib [Velcade, Millennium Pharmaceuticals, Inc], the immunomodulator lenalidomide [Revlimid, Celgene Corporation], and Bruton's tyrosine kinase inhibitor, ibrutinib [Imbruvica, Pharmacyclics, Inc], which were recently approved by the US Food and Drug Administration," he said.

Dr Wang and his colleagues published a comprehensive, up-to-date review of the current research and recommendations for treatment of MCL in the Journal of Clinical Oncology.

The review emphasizes the fact that patient age and comorbidities are the primary factors that should dictate the initial approach to treatment.

Intensive Therapy for Young, Fit Patients

For patients with MCL who are aged 65 years or younger and who are without significant comorbidities, the best results have been seen with intensive therapy with regimens that contain high-dose cytarabine (HDAC) consolidated with high-dose chemotherapy and autologous stem cell transplantation (ASCT).

When ASCT is planned, the options for induction include the Nordic Lymphoma Group MCL2 regimen (rituximab with dose-escalated cyclophosphamide and doxorubicin, vincristine, prednisone [R-maxi- CHOP] alternating with HDAC) and alternating cycles of R-CHOP and dexamethasone, cisplatin, cytarabine (DHAP).

An alternative approach without ASCT for younger, fit patients is hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate, and cytarabine with rituximab (R-hyper-CVAD/MA).

"These two intensive therapies have produced overall survival exceeding 10 years. Such overall survival has not been achieved by salvage therapies, such as R-CHOP or bendamustine," Dr Wang said.

 
If you mess up with the frontline therapy, you have missed the chance for long-term remission. Dr Michael L. Wang
 

"This is based on the theory that mantle cell lymphoma is most vulnerable to frontline attack. This is most important for young and fit patients. If you mess up with the frontline therapy, you have missed the chance for long-term remission. If you give young, fit patients salvage therapy, their disease will relapse quickly, they will get into a pattern of constant therapies, and they will die from their disease much sooner than 10 years," he said.

To improve on the tolerability of such intensive therapy, MD Anderson has designed a phase 2 study in younger, treatment-naive patients that uses a lead-in chemotherapy-free window period with rituximab and ibrutinib for 6 to 12 months followed by abbreviated, response-adapted R-hyper-CVAD/MA, Dr Wang said.

"The aim of this study is to keep the same efficacy of the intensive therapies but to dramatically decrease their toxicities. After we use the rituximab and ibrutinib, then the chemotherapy will be cut from 6-8 cycles to 4-6 cycles," he said.

Intensive therapy is too toxic for patients with MCL who are older than 65 years at diagnosis. For these patients, the choices currently are R-CHOP followed by maintenance rituximab or bendamustine/rituximab (BR) salvage therapies, Dr Wang said.

However, R-CHOP and BR are being phased out, because better therapeutic choices have emerged for this group of patients.

"R-CHOP plus ibutrinib is showing good results. Also, bendamustine/rituximab plus ibutrinib is being studied in phase 3 clinical trials in 550 patients from 350 centers worldwide. Results are expected to be available in the middle of 2016," he said.

Median Survival Has Been Doubled

"We have made so much progress in treating mantle cell lymphoma. It used to have a median survival of 3 to 5 years, but in younger patients treated with intensive regimens, the overall survival now exceeds 10 years," Dr Wang said.

In elderly patients, the gains have not been as dramatic, but the use of maintenance rituximab after R-CHOP results in a 4-year overall survival of 79%. BR appears at least as effective and has less toxicity, although longer follow-up is needed to establish the impact of BR on overall survival, as are studies that confirm survival benefit from rituximab maintenance after BR.

"Advances in the treatment of patients with relapsed/refractory MCL have been made with the approval of bortezomib, lenalidomide, and ibrutinib. These agents are now incorporated into frontline treatment strategies and should further improve response rates and survival," he said.

Dr Wang has financial relationships with Janssen Pharmaceuticals, Acerta Phrma, Celltrion, Pharmacyclics, and Onyx.

J Clin Oncol. Published online January 11, 2016. Abstract

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