From Minimal Residual Disease to Maintenance Therapy: Optimizing Tools for Treatment of Mantle Cell Lymphoma

April 15, 2016

Overall, the future of patients with MCL is promising, since therapeutic options have widened. The implementation of universal aggressive treatment is challenged by novel regimens, targeted agents, the use of MRD to guide treatment decisions, and new trials that will directly compare transplant vs non-transplant approaches.

Since the relatively recent discovery in 1992 that mantle cell lymphoma (MCL) is a subtype of B-cell lymphoma, significant therapeutic advances have lengthened the expected median survival time for the majority of patients, from 3 to 5 years to more than a decade.[1] Despite progress, cure remains elusive, and this unfortunate fact underlies many of the controversies in management of this malignancy. The review article by Chen and colleagues in this issue of ONCOLOGY provides valuable insight and updates regarding diagnostic, prognostic, and clinical trial data in MCL.[2] However, a few issues warrant further discussion as we evaluate how to incorporate the relevant data into daily practice.

First, as Chen and colleagues describe, a variety of prognostic tools are embedded within therapeutic trials, including the Mantle Cell Lymphoma International Prognostic Index (MIPI), the five-gene (RAN, MYC, TNFRSF10B, POLE2, and SLC29A2) panel, and proliferation indices obtained via gene expression profiling. However, these are prognostic but not predictive tools, limiting their utility in individual patients. The tool with the greatest potential for individual applicability is minimal residual disease (MRD), which has been assessed via flow cytometry, quantitative polymerase chain reaction (PCR), and next-generation sequencing (NGS) of DNA and RNA. MRD negativity is a potent independent predictor of favorable prognosis, trumping both MIPI score and the specific treatment administered.[3] Given the robust prognostic role of MRD status, can therapy be intensified, extended, or halted based on MRD results? Studies to date have been promising but have also uncovered limitations of various MRD detection techniques. For example, one study of preemptive rituximab therapy for MRD relapse could only identify a PCR marker in half of enrolled patients; among the patients with a detectable marker, one-third had concurrent clinical relapse necessitating more intensive therapy, rendering identification of MRD moot.[4] Several planned and ongoing trials will prospectively implement “MRD-based” treatment algorithms. A US Intergroup study in active development will use MRD status to allocate therapy, likely informing practice patterns in the near future. The most important aspect of any MRD assessment will require a rapid, reliable, and reproducible assay that is sensitive enough to detect disease prior to clinical relapse; NGS holds significant promise in this regard.

A second issue raised by Chen and colleagues is the concept of maintenance therapy. In a disease for which relapse is inevitable, maintenance strategies are an attractive means to achieve prolonged control over progression. However, it is important to note that maintenance rituximab has only shown improved progression-free survival (PFS) and a trend towards improved overall survival (OS) after patients have been treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Since both RB (rituximab and bendamustine) and VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) have been shown to be superior to R-CHOP in separate randomized trials, the added value of maintenance rituximab after patients have been treated with these regimens is unknown. In addition, prolonged lymphopenia with increased viral and mycobacterial infections is more common with RB than with other regimens, and maintenance therapy with rituximab can be associated with increased neutropenia and infections with prolonged B-cell depletion.[5] Complicating the questions of indicators for, and duration of, maintenance therapy is the advent of ibrutinib, a highly active single-agent drug. Currently, several trials are evaluating ibrutinib maintenance, including a planned US Intergroup study, a National Cancer Institute–sponsored trial, and a Swiss trial (ClinicalTrials.gov identifier: NCT02356458). The TRIANGLE study (ClinicalTrials.gov identifier: NCT00209222), ongoing in Europe, will explore the effect of transplant vs maintenance therapy on OS and PFS. The trial, which will help clinicians to further delineate the role of maintenance with novel agents, randomizes patients with MCL to one of three arms: R-CHOP/R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin), followed by autologous stem cell transplantation (ASCT); R-CHOP/R-DHAP with ibrutinib, followed by ASCT with ibrutinib maintenance; and R-CHOP/R-DHAP with ibrutinib, followed by ibrutinib maintenance.

A third issue highlighted by Chen et al is that the inevitable likelihood of relapse challenges the need to use aggressive tools such as ASCT universally in all young patients. While ASCT yields a clear and robust prolonged PFS, there are currently no randomized trials comparing ASCT against a non-transplant approach. Furthermore, MCL remains incurable despite upfront ASCT and there is no proven overall survival advantage to this approach over non-transplant approaches. Biologic doublets, as reflected by the promising activity of combination therapy with lenalidomide and rituximab, may offer patients with MCL an alternative to both transplant and chemoimmunotherapy.[6] The TRIANGLE study, which includes an arm replacing ASCT with ibrutinib, will directly address the value of high-dose chemotherapy in patients with MCL who respond after intensive chemotherapeutic induction.

Recent registry data from the Center for International Blood and Bone Marrow Transplant Research evaluating use of ASCT in MCL at relapse adds complexity to the debate on timing and value of intensive therapy in the front-line setting.[7] Although patients undergoing ASCT as part of initial therapy had the best outcomes, among 132 patients with MCL who underwent ASCT at relapse, the rate of relapse/progression at 5 years was approximately 50% and the 5-year OS rate was 44%. Considering that these patients had received multiple lines of prior therapy, these data are provocative. The ability to achieve long-term disease control in relapsed MCL challenges the role of upfront transplant, suggesting that some patients can derive benefit if ASCT is postponed to the relapsed setting.

Finally, despite impressive single-agent activity observed with ibrutinib, the reported salvage rates after failure of ibrutinib are alarmingly poor. Two separate series have shown a dismal median OS of 8 months and 3 months after ibrutinib discontinuation, with low rates of response to almost any salvage regimen.[8,9] However, it is important to note that all analyzed patients were heavily pretreated and may not be reflective of post-ibrutinib outcomes that might be achieved if ibrutinib were used earlier in the disease course. In addition, insight into mechanisms of ibrutinib resistance has improved, and drug development-targeting Bruton tyrosine kinase (BTK) mutations, phosphoinositide 3-kinase (PI3K)/AKT activation, and other BTK-related resistance mechanisms-is underway.

Overall, the future of patients with MCL is promising, since therapeutic options have widened. The implementation of universal aggressive treatment is challenged by novel regimens, targeted agents, the use of MRD to guide treatment decisions, and new trials that will directly compare transplant vs non-transplant approaches. The ability to put these results into daily practice is on the horizon and will move us closer towards personalized treatment approaches for our patients with MCL.

Financial Disclosure:Dr. Smith serves as a consultant to Celgene, Genentech, and Pharmacyclics. Dr. Tallarico has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Howlader N, Noone AM, Krapcho M, et al, editors. SEER Cancer Statistics Review, 1975–2012, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER website, April 2015.

2. Chen R, Sanchez J, Rosen ST. Clinical management updates in mantle cell lymphoma. Oncology (Williston Park). 2016;30:353-60.

3. Pott C, Macintyre E, Delfau-Larue MH, et al. MRD eradication should be the therapeutic goal in mantle cell lymphoma and may enable tailored treatment approaches: results of the Intergroup Trials of the European MCL Network. Blood. 2014;124:abstr 2147.

4. Andersen NS, Pedersen LB, Laurell A, et al. Pre-emptive treatment with rituximab of molecular relapse after autologous stem cell transplantation in mantle cell lymphoma. J Clin Oncol. 2009;27:4365-70.

5. Cheson BD, Wendtner CM, Pieper A, et al. Optimal use of bendamustine in chronic lymphocytic leukemia, non-Hodgkin lymphomas, and multiple myeloma: treatment recommendations from an international consensus panel. Clin Lymphoma Myeloma Leuk. 2010;10:21-7.

6. Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373:1835-44.

7. Fenske TS, Zhang MJ, Carreras J, et al. Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma: analysis of transplantation timing and modality. J Clin Oncol. 2014;32:273-81.

8. Cheah CY, Chihara D, Romaguera JE, et al. Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes. Ann Oncol. 2015;26:1175-9.

9. Martin P, Maddocks K, Leonard JP, et al. Post-ibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016 Jan 13. [Epub ahead of print]