Combined epigenetic and immunotherapy for blastic and classical mantle cell lymphoma
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Francis R. LeBlanc1,*, Zainul S. Hasanali1,*, August Stuart2, Sara Shimko2, Kamal Sharma3, Violetta V. Leshchenko4, Samir Parekh4, Haiqing Fu5, Ya Zhang5, Melvenia M. Martin5, Mark Kester6, Todd Fox6, Jiangang Liao7, Thomas P. Loughran8, Juanita Evans9, Jeffrey J. Pu10, Stephen E. Spurgeon11, Mirit I. Aladjem5 and Elliot M. Epner12
1 Department of Medicine, Pennsylvania State University College of Medicine and Penn State Hershey Cancer Institute, Hershey, PA 17033, USA
2 Department of Hematology/Oncology, Penn State Hershey Cancer Institute, Hershey, PA 17033, USA
3 BayCare Medical Group, Cassidy Cancer Center, Winter Haven, FL 33881, USA
4 Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
5 Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA
6 Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
7 Department of Public Health Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
8 Department of Medicine/Hematology-Oncology, UVA Cancer Center, Charlottesville, VA 22908, USA
9 Department of Anatomic Pathology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
10 Department of Medicine and Cancer Center, University of Arizona College of Medicine, Tucson, AZ 85724, USA
11 Department of Medicine, Oregon Health and Science University, Portland, OR 97239, USA
12 Beverly Hills Cancer Center, Beverly Hills, CA 90211, USA
* Co-first authors
|Francis R. LeBlanc,||email:||[email protected]|
Keywords: epigenetics; blastic mantle cell lymphoma; cladribine
Received: May 05, 2022 Accepted: July 01, 2022 Published: August 16, 2022
Classical MCL (cMCL) constitutes 6–8% of all B cell NHL. Despite recent advances, MCL is incurable except with allogeneic stem cell transplant. Blastic mantle cell lymphoma (bMCL) is a rarer subtype of cMCL associated with an aggressive clinical course and poor treatment response, frequent relapse and poor outcomes. We treated 13 bMCL patients with combined epigenetic and immunotherapy treatment consisting of vorinostat, cladribine and rituximab (SCR). We report an increased OS greater than 40 months with several patients maintaining durable remissions without relapse for longer than 5 years. This is remarkably better then current treatment regimens which in bMCL range from 14.5-24 months with conventional chemotherapy regimens. We demonstrate that the G/A870 CCND1 polymorphism is predictive of blastic disease, nuclear localization of cyclinD1 and response to SCR therapy. The major resistance mechanisms to SCR therapy are loss of CD20 expression and evasion of treatment by sanctuary in the CNS. These data indicate that administration of epigenetic agents improves efficacy of anti-CD20 immunotherapies. This approach is promising in the treatment of MCL and potentially other previously treatment refractory cancers.
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