Mantle cell lymphoma (MCL), one of the 70 subtypes of non-Hodgkin lymphoma, results from a malignant change of a B lymphocyte within a lymph node. It is a particularly aggressive disease, with a short remission from standard therapies and a median overall survival of four to five years. LLS is supporting multiple approach to address the unmet need in this disease.
Approximately 10-15% of MCL patients are considered low risk and these patients can be managed with a watch and wait approach to monitor the disease. Other patients will need treatment more immediately.
Younger, fit patients may be suitable candidates for the most promising approach of intensive high-dose chemotherapy and stem cell transplantation. The combination of cytarabine + rituximab (Rituxan ®) followed by transplant; or a regimen known as hyper-CVAD (combination of chemotherapy drugs cyclophosphamide, vincristine, adriamycin, and dexamethasone given together to for one "course" of treatment, alternating with a course or combination of the chemotherapy drugs methotrexate and cytarabine is generally used for these patients. Nevertheless, the treatment does not cure most patients, and some patients can develop secondary cancers or blood disorders as a result of these regimens. The transplant process itself also carries some risk of death.
In the summer of 2020, the FDA approved the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel (Tecartus) for treatment of adults with relapsed or refractory MCL. Read more about this approval and our $50M investment in CAR T-cell therapy here.
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LLS has funded work for the pre-clinical and clinical development of rituximab dating as far back as the 1980s. While much of this work has centered on other types of lymphoma, the funded work does impact MCL by showing that rituximab improves drug combination therapy. LLS-funded researchers including David G. Maloney, M.D., Ph.D. and Margaret Shipp, M.D., have shown that rituxumab added to a four drug regimen improves outcomes; and Aaron Rapoport, M.D. and Omer Koc, M.D. showed it improved outcomes after after transplants.
However, since the average age of patients with MCL is 60 years old, many patients are unable to tolerate these intensive therapy regimens. There is, in general, no accepted “standard” therapy for these older patients.
Approximately 70% of these older patients will experience a complete response (CR), which means that all signs of cancer disappear, but MCL eventually returns in most patients. The three-year overall survival rate 72-88%.
LLS funded researchers including Owen O’Conner, M.D., Ph.D., Andrew Zelenetz, M.D., Ph.D. and others showed that bortezomib (Velcade®) has clinical activity in MCL. Another option is to use bendamustine with rituximab which shows similar efficacy with better quality of life.
The BTK inhibiting drug, ibrutinib (Imbruvica®), advanced with LLS-funded research, is showing high response rates of up to 75% in relapsed/refractory (R/R) MCL patients. The data are clearly strong but not all patients respond to the drug. Second generation drugs similar to ibrutinib are in development. Recently, acalabrutinib (Calquence) was approved by the FDA for R/R MCL patients. In a phase II trial, 81% of the patients treated with acalabrutinib achieved an overall response with 49% CR, which is better than has been achieved historically with ibrutinib (23% CR) in this patient population. The findings warrant further clinical work. LLS funded many investigators involved in the development of ibrutinib for other types of lymphomas but specifically for MCL, LLS-funded researcher Jonathan Friedberg, M.D., showed that the drug could kill MCL cells that were even resistant to Velcade. Also, LLS-funded work by Peter Martin, M.D. showed activity of the drug in a Phase II clinical trial in MCL patients.
A recent clinical trial shows great promise for the use of CD19 CAR T immunotherapy (KTE-X19) in relapsed or resistant MCL. LLS has supported the development of the CAR T therapeutic approach for more than 25 years and continues to fund multiple projects to improve CAR T technology and expand the application of this powerful therapy in MCL and all blood cancers.
Novel drug combinations and alternative cytotoxic-free regimens are being explored in MCL. The goals are to find new avenues of therapies and to overcome resistance to existing therapies. Recently it was shown that the drug venetoclax (Venclexta®) had ORR and CR rates of 75% and 21%, respectively in R/R MCL patients. Sarah-Jane Dawson, MBBS, Ph.D., and her colleagues in Australia are pursuing the use of ibrutinib + venetoclax in R/R MCL patients in work supported by an LLS Quest For Cures grant. In R/R MCL, ibrutinib plus venetoclax given for 16 weeks induced a CR rate of 42%, which was higher than the historical response rate of 9% at this time point with ibrutinib. Similar to ibrutinib, LLS has had a major impact in the development of venetoclax especially through multiple Specialized Center of Research grants led by Professor Jerry Adams and his team at Walter and Eliza Hall Institute of Medical Research.
Another novel approach under investigation is development of a new a new monoclonal antibody directed therapy called cirmtuzumab, which targets a protein called ROR1. The work was funded by an LLS SCOR grant to Thomas Kipps, M.D., Ph.D. (UC San Diego Moores Cancer Center) ROR1 is an overexpressed protein located on the surface CLL and MCL tumor cells.
LLS’s current research portfolio contains seven grants heavily focused on MCL. Two grants in this portfolio support a synergistic team of researchers (led by Larry Kwak M.D., Ph.D., and Selina Chen-Kiang, Ph.D.). Dr. Kwak’s grant program will 1) develop a novel monoclonal antibody for MCL, 2) explore the activity of combination therapy of CD19-CAR T-cell therapy with oral agents, and 3) investigate if agents that target CD25 have clinical activity in MCL. Dr. Chen-Kiang’s program will 1) define the mechanism of resistance to ibrutinib beyond the already known point mutation (C481S), 2) target the cell cycle with inhibitors of CDK4/6 and PI3K, and 3) explore the utility of a novel inhibitor of protein arginine methyl transferase 5 (PRMT5).
Other grants are exploring ways to overcome resistance to ibrutinib (Alexey Danilov, M.D., Ph.D. at City of Hope) and predict disease progression risk in aggressive lymphomas (Ash Alizadeh M.D., Ph.D. at Stanford).
The image was originally published in ASH Image Bank. Maryam Asif, Girish Venkataraman and Dan Arber. Mantle cell lymphoma with mantle zone pattern. ASH Image Bank. 2019;62363 © the American Society of Hematology.