Precision Medicine in Mantle Cell Lymphoma-Balancing Logic With Enthusiasm

John P. Leonard, MD

John P. Leonard, MD

When John P. Leonard, MD, spoke at the American Society of Hematology’s inaugural meeting on Hematologic Malignancies about mantle cell lymphoma (MCL), he balanced his enthusiasm about the emerging benefits that tumor profiling brings to this disease with an acknowledgement that many important questions about mantle cell lymphoma remain unanswered.

Leonard, the Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medical College, presented “How I Treat Mantle Cell Lymphoma” at the meeting in Chicago. He outlined two key principles of his treatment approach.

The first is to observe patients with asymptomatic MCL for as long as possible. In discussing the watch-and-wait approach, Leonard referred colleagues to data from the 2009 study that he co-authored in theJournal of Clinical Oncology, “Outcome of Deferred Initial Therapy in Mantle-Cell Lymphoma.”¹The overall survival (OS) of patients in the observation group exceeded that of patients in the early treatment group.

The second key principle that he suggested was to begin with less intensive initial treatments when needed due to their lower toxicity levels. “It’s true that less intensive treatments might have more chronic toxicity, but intensive treatments are unquestionably more toxic in the short term and can have longer-term toxicities as well,” he said.

Leonard provided a list of his standard initial treatment options, noting that MCL treatment remains officially nonstandardized. In addition to observation, he grouped R-CHOP, modified R-HyperCVAD, R-CHOP/RIT, and R-bendamustine as less intensive options. More intensive treatment options were:

• R-CHOP/DHAP/autologous stem cell transplant
• R-HyperCVAD/MTX/Ara-C
• R-HyperCVAD/MTX/Ara-C/autologous stem cell transplant
• Nordic

Leonard’s preferred initial treatment for symptomatic patients is bendamustine-rituximab. For maintenance treatment, he uses rituximab or novel approaches. He cited the 2013 study by Rummel et al in theLancet, “Bendamustine Plus Rituximab Versus CHOP Plus Rituximab as First-Line Treatment for Patients with Indolent and Mantle-Cell Lymphomas: An Open-Label, Multicentre, Randomised, Phase 3 Non-Inferiority Trial.”²Patients in the bendamustine-rituximab group experienced increased progression-free survival (PFS) with fewer toxic effects.

Leonard listed these potential novel agents for use in treating MCL:

• Bortezomib (Velcade) — FDA approved to treat multiple myeloma and relapsed and, now, treatment-naïve MCL
• Lenalidomide (Revlimid) — FDA approved to treat multiple myeloma
• Temsirolimus (Torisel) — FDA approved to treat renal cell carcinoma
• Everolimus (Afinitor) — FDA approved to treat renal cell carcinoma
• Palbociclib (Ibrance) — FDA approved to treat breast cancer
• Ibrutinib (Imbruvica) — FDA approved to treat MCL, chronic lymphocytic leukemia and Waldenstrom Macroglobulinemia
• ABT-199 — Not FDA approved

He reviewed key clinical trials for bortezomib, lenalidomide, temsirolimus, everolimus, and palbociclib, noting the status and apparent potential of each trial and agent. In discussing his choice of ibrutinib to treat patients with relapsed/refractory MCL, he directed colleagues to the 2013 study by Wang et al in theNew England Journal of Medicine, “Targeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma.”³

The primary endpoint of the phase II trial was the overall response rate (ORR). Secondary endpoints were duration of response (DOR), PFS, OS, and safety. Patients were grouped by prior bortezomib exposure: three rounds of more versus two rounds or less, although prior treatment with bortezomib showed no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months, the estimated median PFS was 13.9 months, and the median OS was not reached.

Leonard also discussed ABT-199, a selective inhibitor of the Bcl-2 protein. “ABT-199 shows a high Bcl-2 affinity but a lower affinity for Bcl-x_Land McI-1,” he said. “It is active in Bcl-2-dependent tumor cell lines (RS4; 11) and ineffective in Bcl-x_L-dependent tumor cell lines (H146).” He noted that the novel agent, which is orally bioavailable, showed greater than a hundred-fold improved functional selectivity.

Throughout his talk, Leonard emphasized the importance of assessing patients with advanced-stage MCL using the Mantle-Cell Lymphoma International Prognostic Index (MIPI). According to the MIPI, patients who score 0 to 3 points are considered low risk; those who score 4 to 5 points are intermediate risk patients, while those who score 6 to 11 points are at high risk. “Virtually all patients under age 60 and many under age 70 with good performance status, normal lactate dehydrogenase and white blood count will be low risk,” he said.

For symptomatic patients interested in transplantation, Leonard recommends autologous stem cell transplants (ASCT). He stresses to the patient that the chief benefit of ASCT is likely to be increased PFS, not OS. He considers allogeneic stem cell transplant in selected patients who have experienced multiple relapses and shortened remissions.

He encourages colleagues to consider clinical trials for patients with MCL.“We’re starting to explore the idea of tumor profiling to help us identify patients who will do better or worse with the disease or who will do better with one treatment or a combination of agents,” he said. “We want to be able to look at an individual patient’s subsets to give them a more specific treatment.”

As an example of emerging clinical benefits stemming from tumor profiling, Leonard cited the work of Chiron et al in a 2014 research article inCancer Discovery, “Cell-Cycle Reprogramming for PI3K Inhibition Overrides a Relapse-Specific C481S BTK Mutation Revealed by Longitudinal Functional Genomics in Mantle Cell Lymphoma.”⁴

In noting that ibrutinib resistance remains a major concern in the clinical management of MCL, Leonard, who is a co-author of this study, explained that it identified the first relapse-specific BTK mutation via genomic sequencing of MCL cells with primary and acquired resistance to ibrutinib. “C481S mutations are seen in some but not all MCL patients who have ibrutinib resistance, and this study showed that the mutation appeared at relapse,” he said. “This mutation has not been seen in patients with primary ibrutinib resistance.”

Leonard also discussed the group’s preclinical studies showing that a combination of the CDK4/6 inhibitor palbociclib and a PI3K inhibitor might be effective for treating patients who do not respond to ibrutinib. “With a PI3K inhibitor it [palbociclib] can overcome ibrutinib resistance with BTK C481S,” he said. “And with a PI3K inhibitor or ibrutinib, palbociclib can overcome ibrutinib with BTK_WT. Clinical trials are currently under way.”

Leonard concluded his talk by noting that, despite the gains already made in MCL treatment, the importance of tumor profiling cannot be overstated. “Right now, it’s almost as if—based on outcomes—it’s not the [available] treatment that matters, it’s the disease itself and the patient’s genetic makeup that determines overall survival,” he said. “Tumor profiling gives us a way to address that.”

References:

1. Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma.J Clin Oncol. 2009;27(8):1209-1213.

2. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial.Lancet. 2013; 381(9873):1203-1210.

3. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma.N Engl J Med. 2013;369:507-516.

4. Chiron D, Di Liberto M, Martin P, et al. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481SBTKmutation revealed by longitudinal functional genomics in mantle cell lymphoma.Cancer Disc. doi:10.1158/2159-8290.CD-14-0098.