Combination Therapy the Future for Mantle Cell Lymphoma

Andrew D. Zelenetz, MD, PhD

The heterogeneity of mantle cell lymphoma (MCL) will require new combination strategies to improve outcomes, according to a review of recent data presented by Andrew Zelenetz, MD, at the 2015 Society of Hematologic Oncology annual meeting.

MCL currently has no standard of care, and the general population of patients has limited eligibility for high-dose therapy followed by autologous stem-cell transplant. The result is a restricted benefit for a defined subset of patients.

“There are new therapies that have significant promise for relapsed and refractory mantle cell lymphoma, and I do think that new targeted therapies will change the landscape of therapy,” Zelenetz, who is a professor of Medicine at Weill Cornell Medical College, said at SOHO.

Though heterogeneous in nature, MCL follows distinct pathways to aggressive and indolent courses. In particular, indolent MCL is characterized by lack of expression of SOX11 and hypermutation of IGHV. Aggressive MCL evolves from a molecular profile that includes expression of SOX11 and unmutated IGHV.

Proliferation factor also distinguishes indolent and aggressive forms of MCL, Zelenetz continued. Regardless of whether a patient receives chemotherapy or chemo followed by high-dose therapy, the proliferation index, reflected by Ki-67, is highly predictive of clinical course. By and large, the benefit of high-dose therapy and stem-cell rescue is limited to patients who have a proliferation index of 10% to 30%.

“If we take all of this into account, maybe 1 in 4 patients will benefit from high-dose therapy and autologous stem-cell rescue,” he said.

Clinical evaluation of alternative strategies included the phase II open-label European SPRINT trial that compared lenalidomide (Revlimid) and investigator’s choice of chemotherapy in 254 patients with relapsed/refractory MCL. Reported at the 2014 ASH Annual Meeting, the results demonstrated superiority with lenalidomide for all key outcome parameters, including objective response rate (40% vs 11%), complete response (5% vs 0%), and duration of response (16.0 vs 10.4 months).

Patients assigned to lenalidomide had a median progression-free survival of 8.7 months versus 5.2 months with chemotherapy.

Lenalidomide, and the IMID class of agents in general, leads to enhanced antibody-dependent cell-mediated cytotoxicity. As a result, lenalidomide and rituximab (Rituxan) would be a logical combination therapy to evaluate, and a phase I/II trial of the combination was carried out in 44 patients with relapsed/refractory MCL, said Zelenetz.

The combination led to objective responses in 25 (57%) patients, including complete responses in 16 (36%) patients. An additional 10 patients had stable disease. The time to first response was 2.0 months, and median overall survival was 14.3 months (Lancet Oncol. 2012;13:716-723).

The lenalidomide-rituximab combination subsequently was evaluated as frontline therapy for 38 patients in a phase II trial reported at the 2014 ASH Annual Meeting. The results showed complete responses in 21 (55%) patients and partial responses in 11 (29%) patients. The median time to partial response was 3 months and the median time to complete response was 11 months.

After a median follow-up of 26 months, the cohort had a 24-month PFS of 84.6%.

“However, there is a drop-off [in PFS] after about 24 months, and the most recent data show [PFS] at about 50%,” said Zelenetz.

B-cell signaling in MCL affords multiple opportunities for therapeutic intervention. Toward that end, ibrutinib (Imbruvica) was evaluated in a phase II trial involving 111 patients with relapsed/refractory MCL (N Engl J Med. 2013;369:507-516). The results showed an objective response rate of 68% and complete response rate of 21%. However, survival curves did not mirror those seen with ibrutinib in chronic lymphocytic leukemia, as median PFS was less than a year.

“Clinically, I can say that, outside the setting of clinical trials, it’s not a single-agent miracle drug,” said Zelenetz.

Ibrutinib was evaluated in combination with rituximab in patients with relapsed/refractory MCL, also reported at the 2014 ASH Annual Meeting. The response rate, duration of response, PFS, and overall survival were all improved as compared with ibrutinib alone.

However, patients with a high proliferation index (>50%) had a substantially lower response to the combination, whereas patients with a lower proliferation score had a complete response rate of almost 50%. Patients with a low proliferation index also had encouraging PFS and overall survival, said Zelenetz.

Recently, the second-generation BCL-2 inhibitor venetoclax has been evaluated in patients with various types of non-Hodgkin lymphoma, including relapsed/refractory MCL. Overall, 48% of patients had at least a 50% reduction in nodal mass, including 68% of the subgroup of patients with MCL. Tumor lysis syndrome and hematologic toxicity are potential adverse effects, but generally are manageable if recognized early, said Zelenetz.

“Obviously, the future is not in giving single agents forever,” Zelenetz said in conclusion. “The future is in how to figure out how to combine these agents in ways that will effectively improve outcome. There will be surprises, as they don’t always play nicely together, so we have to be very careful as we approach combination studies. However, I truly believe this is where the future lies. I believe that we have a platform that will change the natural history of mantle cell lymphoma. It will require recognizing the heterogeneity of the disease and employing these novel agents appropriately.”