S52 EXABS-139-LYM Major Advances in the Fight Against Mantle Cell Lymphoma Michael Wang, MD1,* 1University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA *Corresponding author: miwang@mdanderson.org Keywords Chemotherapy, immunotherapy, CAR-T cell therapy, targeted therapy, BTK Introduction Mantle cell lymphoma is a distinct subtype of B-cell non-Hodgkin lymphoma that is characterized by t(11;14) translocation or Cyclin D1 overexpression. For many years, MCL was the most difficult lymphoma to treat, with a very short survival. But today, the treatment for MCL has progressed to the point that we have many FDA-approved agents for targeted therapies and immunotherapies. In the past, we treated MCL mainly with intensive chemotherapy followed by autologous stem cell therapy for patients younger than 65 years old, which has been the standard therapy internationally. But at MD Anderson, rather than using intensive chemotherapy followed by autologous stem cell therapy, we used Hyper-CVAD rituximab alternating with rituximab plus methotrexate-cytarabine. For elderly patients over 65 years old, we formerly used R-CHOP, but now the international standard is bendamustine-rituximab. All of those are chemotherapies. With so many new FDA-approved therapies, and so many more high-quality therapies in ongoing clinical trials, we could now afford to use rational combinations of these novel therapies, aiming to move away from chemotherapy to a chemotherapyfree combination therapy. In the past 20 years, the FDA has approved many therapies for relapsed mantle cell lymphoma, including the protease inhibitor bortezomib, the cereblon-binding immunomodulator lenalidomide, the first-ever Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, and the second-generation BTK inhibitors acalabrutinib and zanubrutinib. All three of those BTK inhibitors bind to the BTK protein in a covalent, irreversible fashion. The FDA also approved brexucabtagene autoleucel, a CD19-targeted CAR-T cell therapy and, in January 2023, approved the novel non-covalent reversible BTK inhibitor pirtobrutinib. MD Anderson has played leadership roles in the majority of these approvals. With the availability of those agents, we designed clinical trials to reduce chemotherapy and move towards chemo-free therapy. For example, in the WINDOW-1 clinical trial, we used a rituximab-ibrutinib combination for a period of 6–12 months to achieve complete remission before we ever used chemotherapy. This trial has been quite successful.1 Building on this success, we designed the WINDOW-2 clinical trial,2 in which we added a third chemo-free agent, the Bcl2 inhibitor venetoclax. After achieving complete remissions in this trial, we have a riskstratified approach: in the high-risk patients, we still use four cycles of chemotherapy, but for the low-risk patients, we use no chemotherapy. We have now moved into the immunotherapy era. Most recently, triple therapies have been widely studied in clinical trials with very good preliminary results without any chemotherapy, even in younger patients. These included our Window approach, the acalabrutinib-venetoclax-rituximab trial,3 and the acalabrutiniblenalidomide-rituximab (ARL) trial.4 We now have many clinical trials employing rational combinations with targeted agents. We have been heavily studying the normal CAR-T cell therapies in mantle cell lymphoma, and we also have many clinical trials with bispecific and trispecific antibodies; those immunotherapies are also very promising. With many samples available from patients with mantle cell lymphoma, we have been busy doing translational research. We profiled ibrutinib-sensitive and -resistant samples and found that the oxidative phosphorylation pathway was upregulated in ibrutinib-resistant samples. In subsequent functional studies we found that inhibition of this pathway could overcome ibrutinib resistance in vitro and in vivo in PDX models.5 We developed a gene signature that clearly separated the sensitive and resistant samples. We then used bulk and single-cell RNA sequencing on clinical samples and discovered that survivin was upregulated in ibrutinib resistant samples. In subsequent functional studies we found that inhibition of survivin could overcome ibrutinib resistance in vitro and in vivo in PDX models.6 In our single-cell RNA sequence analysis of CAR T cell resistant samples, we found the immune checkpoint TIGIT was over-expressed in post-CAR T cell therapy samples.7 The mission of the Mantle Cell Lymphoma Program of Excellence at MD Anderson Cancer Center is to cure this disease. We work closely with patients and their families, industry, NIH, and many collaborators within and outside of our institution. We are in the process of saving many lives from mantle cell lymphoma.
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