Choosing Frontline Therapy for Mantle Cell Lymphoma

Michael L. Wang, MD:According to Nordic therapy, the Nordic 2 version of a clinical trial—there’s 159 patients in that 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, who were treated such as the patient we’re referring to, 12% of them had another form of malignancy we call the secondary malignancies. So, although this is a very commonly used therapy, everybody has to explain to the patient, “Yes, the median survival is over 12 years, but there is also another fatal complication that’s potentially related to the therapy.” It is the secondary malignancies, which means that we must improve on the current therapy. We cannot just 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 the complete remission followed by only 4 cycles of hyper-CVAD without any stem cell transplantation.

This therapy was presented at American Society of Hematology in 2016, and the updated trial was presented in June at the Lugano Malignant Lymphoma meeting, another international lymphoma meeting in 2017. The overall response rate was 100% before chemotherapy and the 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 everybody, 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 really think the most important therapy is the first therapy. So, for the patient, you can tell them it’s the first therapy. For the community, for the colleagues who are working in oncology, we call it frontline therapy. Frontline therapy is the most important therapy in aggressive lymphoma, and this is especially true for mantle cell lymphoma. If you mess up the first-line therapy or 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 R-bendamustine. Those are only for the elderly people who could not tolerate intensive therapy, such as stem cell transplantation.

The frontline therapy for young, fit patient has to have intensity. Why? Because, as you could imagine, the tumor is an iceberg. You can see what’s above the water with scans, blood tests, and bone marrow examinations, but what is below the water is maybe even 70% to 90% of the tumor you cannot see. So, if you use the superficial therapies—R-CHOP or R-bendamustine—you shape what’s above the water, the scans become negative, and you think the patient is doing great. And shortly after, in a year or 2, the base grew very aggressively. They are no longer chemotherapy-sensitive. They are very refractory to chemotherapy, because of the first-line therapy.

So, you want the frontline intensity. What is frontline intensity? That means that you have to use a high-powered chemotherapy, such as the Nordic therapy or 8 cycles of hyper-CVAD, to kill the tumor, to kill all of the tumors above and below the deep water. Frontline intensity is the most important principle for newly diagnosed, young patients with mantle cell lymphoma, such as this case. We were talking about the frontline intensity that’s associated with overall survival, either with Nordic or hyper-CVAD regimen, over 10 years. But, if you give the standard-of-care therapy, survival is only 3 to 5 years.

It is heaven and earth. You cannot make that mistake. So, for a young, fit patient with newly diagnosed mantle cell lymphoma, please treat the patient either with the Nordic therapy or with 6 to 8 cycles of hyper-CVAD. If you don’t know how to do it, please refer that patient to a major referral center. And for all academic colleagues, we need to make further improvements on these 2 therapies that are over 15 years old. Please refer that patient to good, well-designed clinical trials, such as the WINDOW trial.

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