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Wang Discusses Treatment Options for Patients With Intermediate-Risk Mantle Cell Lymphoma

Published Online: Mar 15,2018

Michael L. Wang, MD
Michael L. Wang, MD, a professor in the Department of Lymphoma and Myeloma at MD Anderson Cancer Center, explains the biologic underpinnings of mantle cell lymphoma (MCL) as well as the treatment options for patients with MCL. The discussion was framed around a case scenario of a patient with stage III intermediate-risk disease, and the factors that Wang would use when deciding on treatment for this patient.

TARGETED ONCOLOGY: Explain the disease background of MCL.

Wang: MCL is a rare subtype of B-cell lymphoma. In the United States, 1 million citizens live with lymphoma. Overall, lymphoma has 2 parts: Hodgkin lymphoma and non-Hodgkin lymphoma. Non-Hodgkin lymphoma includes T-cell lymphoma, [with a frequency of] about 5% to 10%, but the vast majority is B-cell lymphoma, which is about 85% to 90%. Within B-cell lymphoma, which is the most common type of lymphoma, there are many subtypes. Large cell lymphoma is most common, followed by follicular lymphoma and then marginal zone lymphoma. MCL is a rare subtype of B-cell lymphoma that is not yet curable, but much progress has been made in this eld. There are specific medicines approved by the FDA just for MCL.

MCL is driven by cyclin D1. With the 11;14 translocation, there’s also cyclin D1, which is supposed to drive the pathogenesis of MCL. And when there’s a translocation of this gene from the 11th chromosome on to the 14th chromosome, where there’s a heavy chain promoter—heavy chain is around the most number of proteins, there is a lot of it in our body, so this promoter has a lot of work to do—it drives the B cell to make a lot of heavy chain antibodies. So, if any protein gene is placed after this promoter, it overdrives the protein expression. In this case, it happens under genetic environmental factors. The cyclin D1 gene is misplaced on the 14th chromosome, just after the heavy gene promoter. That’s overproduction of cyclin D1, which could drive the pathogenesis of MCL together with many factors on the molecular and cell pathway levels.

With morphologic variants, there’s a controversy, but most variants are nodular, morphologically diffuse, pleomorphic, and blastoid. Nodular has the slowest growth rate, and diffuse is a little faster. The slowest is indolent MCL—the nodular. Pleomorphic is very aggressive, and blastoid is the most aggressive. Sometimes, people think the slowest MCL is mantle zone lymphoma, as described by a hematopathologist from The University of Texas MD Anderson Cancer Center, but it’s not overly used.

TARGETED ONCOLOGY: What is the prognosis for this patient?

Wang: The MIPI (Mantle Cell Lymphoma International Prognostic Index) score for this patient is over 6, and MIPI scores are often used in publications. When you publish something on MCL, you have to use the MIPI score, but not all doctors calculate a MIPI score before they give therapy. For example, this patient needs therapy because he has symptoms and a big tumor. You do not need a MIPI score to tell you that this patient needs immediate therapy.

This patient has a big tumor, tumors above and below the diaphragm, and is young. The regular therapies—R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) or BR (bendamustine [Treanda] plus rituximab)—are inadequate for this patient. This patient has to get intensive therapy.
If you’re very familiar with the therapy and natural history of MCL, you don’t need a MIPI score. But if you don’t treat it yearly—on average, community doctors in their entire oncological career treat 1 to 2 patients with MCL—please calculate the MIPI. The MIPI calculation is rather complicated if you do it manually, but there’s an online formula.

TARGETED ONCOLOGY: What are the choices for induction therapy for this patient?

Wang: According to the Nordic 2 clinical trial, the median survival was 12.5 years, so it was a great trial and people got to live for more than 12 years. However, chemotherapies are DNA breakers. They attack the tumor DNA, but at the same time, these intensive therapies also attack the normal, human DNA. Of the patients on the Nordic trial, 12% of them had another form of malignancy we call the secondary malignancies. We cannot use this therapy forever without improvement. At The University of Texas MD Anderson Cancer Center, we did a clinical trial, called the WINDOW-2 clinical trial, which used ibrutinib with rituximab to induce CR followed by 4 cycles of hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin (Adriamycin), dexamethasone, with methotrexate and cytarabine) without stem cell transplantation (NCT02427620).

This therapy was presented at the 2016 American Society of Hematology (ASH) Annual Meeting, and the updated trial was presented in June at the 2017 International Malignant Lymphoma meeting. The overall response rate (ORR) was 100% before chemotherapy and the complete remission (CR) rate was 90% before chemotherapy, so we do not need a lot of chemotherapy to get long-term survival. Although I have to caution, the WINDOW-2 clinical trial follow-up time is still short. So, I wouldn’t say that these patients were treated in a standard-of-care way. But if this patient presented at MD Anderson, I would put him into the WINDOW clinical trial.

I think the most important therapy is the first therapy. Frontline therapy is the most important therapy in aggressive lymphoma, and this is especially true for MCL. If you mess up the frontline therapy, you could mess up a long-term remission. If you treat the patient with a good therapy, the patient can be therapy free for 10 years. But you shouldn’t treat a young patient, such as this case, with an inadequate therapy, such as R-CHOP for 6 cycles or BR. Those are only for elderly people who could not tolerate intensive therapy, such as stem cell transplantation.

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Wang Discusses Treatment Options for Patients With Intermediate-Risk Mantle Cell Lymphoma
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