The Future of Treatment of Mantle Cell Lymphoma

Michael L. Wang, MD:This patient relapsed in 4 years. Although we call it standard therapy, that means our standard therapy does not succeed in everybody, especially for high-risk patients such as this case. He relapsed, and our choice that was FDA approved in the past was bortezomib, also called VELCADE, from Takeda. For mantle cell lymphoma, the overall rate about 32%, and it has a lot of thrombocytopenia and neuropathy. Typically, after 2 to 4 cycles, the patient will start having pretty significant neuropathy. So, that drug was used for many years. After that, in June of 2013, another drug was approved: REVLIMID, also called lenalidomide, with a 25% response rate, 25% to 33%. In the same year, ibrutinib was approved with a 68%—unprecedented—response rate. So, in this case, we would use ibrutinib, because it has less side effects and higher efficacy. Ibrutinib was chosen in the right away.

A lot of people ask me, “Dr. Wang, what’s happening with ibrutinib? What’s new?” Well, there’s a newer BTK inhibitor called ACP-196, which is also called acalabrutinib. This medicine is a second-generation BTK inhibitor, Bruton’s tyrosine kinase inhibitor, after ibrutinib. It has a different toxicity profile, and I am going to present the primary data at the upcoming American Society of Hematology meeting in Atlanta. “Dr. Wang, what about after these BTK inhibitors?” There’s another trial of medicine from AbbVie called venetoclax. It’s a BCL-2 inhibitor. In a clinical trial published in theJournal of Clinical Oncologythis year by Matt Davids from Harvard, the response rate in 15 patients was 75%. So, this is an even better response, but it needs to be validated in a clinical trial with more patients. I would say that it needs at least 100 patients to validate this clinical trial. Venetoclax has been approved for CLL, and I’m sure in the future it could be approved for mantle cell lymphoma.

But all of those are small molecule pathway interrogators. They are not a cure. Each drug usually works for about 12 to 24 months and after that, the patient inevitably develops either intolerance or resistance. So, all of those options are not cures. Immunotherapy is coming and could provide longer remissions. There are very exciting clinical trials for CAR-T cells. There’s one dedicated FDA pivotal trial, it’s called the ZUMA-2 clinical trial, from Kite Pharma. And I’m leading this clinical trial, so far with very promising results. I hope to share this with the field, with the colleagues from academia or from the community, as soon as possible.

Our generation enjoyed the science and technology that no other generation ever enjoyed in the past many thousands of years of human history. We are blessed with so much technology and science, so we have a big opportunity to cure cancer. My lifetime dream is to cure mantle cell lymphoma. I firmly believe within my career that I am not going to single-handedly cure this disease. I’m going to make significant contributions together with colleagues, patients, families, government, and industry. Everybody who wants to cure this disease, we together need to make a big contribution, because I firmly believe within my lifetime, we will be able to cure a big fraction of patients with low-risk mantle cell lymphoma.

Transcript edited for clarity.

March 2013

• A 55-year-old male presents to his physician complaining of fatigue, unexplained weight loss, and neck swelling
• PMH: unremarkable
• Physical exam:
  • Bilateral cervical lymphadenopathy
• Laboratory findings:
  • Leukocytes, 9.0 X 10⁹/L
  • Hb, 9.8 g/dL
  • LDH, 520 U/L
  • Beta2-microglobulin; 6.4 mg/L
  • AST, 167 U/L; ALT 202 U/L
• Excisional biopsy of the right cervical node:
  • Immunophenotyping: IgM+, CD5+, CD10-, CD19+, CD20+, CD22+, CD23-, cyclin D1+
  • Cytogenetics: t(11;14)(q13;q32)
• CT imaging of the neck, chest, abdomen, pelvis: marked¹⁸F-FDG uptake and enlargement of bilateral cervical lymph nodes (right, 4.6 cm; left, 3.1 cm) and mesenteric lymph node (9.2 cm)
• Diagnosis: Mantle-cell lymphoma, Ann Arbor stage III
• The patient was started on induction therapy with R-hyper-CVAD and achieved significant reduction in tumor burden
• Consolidation with autologous stem cell transplant resulted in complete remission

March 2017

• The patient reports having symptoms of fatigue and weight loss
• PET/CT shows diffuse uptake of¹⁸F-FDG in the right lung and mediastinal lymph nodes
• The patient was started on therapy with ibrutinib