There is no established standard therapy for the treatment of mantle cell lymphoma (MCL). Instead, there is a range of treatment options and, to date, there has been a dearth of data to assist in clinical decision-making.
However, recent insights into the molecular and genomic diversity and pathogenesis of the disease have given rise to the development of many new biologically targeted therapies that are under active investigation in clinical trials at Memorial Sloan Kettering (MSK).
The most common treatment modalities for newly diagnosed MCL include intensive chemotherapy regimens followed by consolidation with high-dose therapy and autologous stem cell transplant. Rituximab is given for maintenance in young patients; more-tolerable chemotherapy programs, such as bendamustine and rituximab, are given for elderly patients.
To improve outcomes for MCL patients, clinical trials with novel agents are always a consideration. We offer a number of innovative clinical trials enrolling MCL patients that are incorporating these biologically targeted therapies at time of initial presentation or at relapse.
MCL is a rare subtype of B cell non-Hodgkin lymphoma, representing around 5 percent of all non-Hodgkin lymphomas. It is a lymphoma that most often presents in older individuals and is more common in men than in women. Classically, patients have advanced-stage disease at time of presentation, often with extranodal sites of involvement such as the gastrointestinal tract or bone marrow. MCL is characterized by the chromosomal translocation between chromosome 11 and 14 resulting in the CCDN1/IGH rearrangement and increased cyclin D1 expression.
MSK participated in the development of ibrutinib for the treatment of relapsed or refractory B cell non-Hodgkin lymphomas. (1) Ibrutinib was FDA approved for relapsed, refractory MCL in 2013 and has dramatically improved survival outcomes for patients with recurrent MCL. There are, however, a number of novel drugs that are clinically active in MCL that are expanding the therapeutic landscape, including PI3Kinase inhibitors, CDK inhibitors, BCL-2 inhibitors, histone deacetylase inhibitors, and immune-modulatory drugs such as lenalidomide.
MSK researchers along with other colleagues led the phase I clinical trial of venetoclax, a BCL-2 inhibitor, in relapsed or refractory B cell non-Hodgkin lymphoma. Because of its remarkable efficacy in MCL, venetoclax is now included in National Comprehensive Cancer Network guidelines for treatment of relapsed, refractory MCL. (2)
Frontline Phase II Study with Lenalidomide
We are currently enrolling patients with untreated MCL in a novel phase II clinical trial incorporating the highly active immunomodulatory agent lenalidomide. In this study, we aim to evaluate if the addition of lenalidomide to standard sequential induction chemotherapy followed by rituximab (R) and lenalidomide maintenance will result in improvement in outcomes for untreated MCL. In this study, after induction therapy (lenalidomide-RCHOP x 4 cycles and R-high dose cytarabine x 2 cycles), patients receive R-lenalidomide maintenance for six months. We hypothesize that this maintenance therapy will be equally or potentially more efficacious compared with high-dose therapy and autologous stem cell transplant in eradicating microscopic residual tumor cells at the end of therapy, resulting in deep and prolonged remission durations. In this clinical trial, we will assess early biomarkers for response, including post-induction PET/CT and minimal residual disease assessment using a novel deep-sequencing platform.
Bendamustine, Rituximab, Ibrutinib, and Venetoclax
Bendamustine and rituximab (BR) is an efficacious chemotherapy platform for the treatment of relapsed, refractory MCL as well as for the frontline treatment of MCL. (3) (4) Both ibrutinib and venetoclax have demonstrated promising efficacy as single agents and in combination for the treatment of relapsed, refractory (R/R) MCL population. (2) (5)There are ongoing efforts to combine these biologically targeted therapies with BR for the frontline treatment of MCL, such as the randomized phase III SHINE study that compares BR with BR-ibrutinib. In the current phase I study, we seek to build upon the BR-ibrutinib combination by adding the BCL-2 inhibitor venetoclax. There is a strong biologic rationale for combining ibrutinib and venetoclax given preclinical data demonstrating that ibrutinib therapy leads to increased BCL-2 dependence and enhances sensitivity to venetoclax, in addition to recent phase I data demonstrating the clinical synergy of the ibrutinib-venetoclax combination. In this phase I study, we will determine the maximum tolerated dose and safety profile of venetoclax in combination with BR-ibrutinib in patients with relapsed, refractory MCL. If the MTD and safety is established in this phase I study, we plan to test the combination of BR-ibrutinib-venetoclax in newly diagnosed MCL patients.
Buparlisib and Ibrutinib
Ibrutinib is an irreversible covalent inhibitor of Bruton’s tyrosine kinase (BTK) and demonstrates clinical activity in MCL. In relapsed/refractory MCL, ibrutinib has an overall response rate of 68 percent, with the majority of responses being partial responses (47 percent). (5) Strong preclinical data demonstrates synergism between BTK and PI3K inhibitors since BTK and PI3K are parallel survival pathways for lymphoma. Combining ibrutinib with PI3K inhibitors can potentially increase the depth and duration of response to therapy and prevent development of resistant subclones. We have two early-phase studies investigating this combination. The first clinical trial, which is completing enrollment, is a phase I/IB clinical trial that is enrolling MCL patients for treatment with buparlisib and ibrutinib. Preliminary results of this study, presented at the International Conference on Malignant Lymphoma 2017, demonstrate that the combination of ibrutinib and buparlisib has a promising clinical activity in MCL with an increased complete response rate associated with the combination compared with historical data for single-agent ibrutinib. A follow-up study will investigate the combination of copanlisib and ibrutinib in relapsed MCL patients.
Other novel treatments for relapsed, refractory MCL
There are a number of other active early-phase clinical trials testing novel approaches for the treatment of relapsed, refractory MCL patients at MSK including a novel antibody-drug conjugate (ADCT-301), bispecific antibody (BTCT4465A) designed to target both CD20 on B cells and CD3 on T cells, CD19-directed chimeric antigen receptor (CAR) T cell therapy, and a novel protein arginine methyltransferase-5 inhibitor (GSK3326595) which has been shown to have potent preclinical antitumor activity in MCL.