Beyond Bruton’s tyrosine kinase inhibitors in mantle cell lymphoma: bispecific antibodies, antibody–drug conjugates, CAR T-cells, and novel agents

Jain et al. Journal of Hematology & Oncology https://doi.org/10.1186/s13045-023-01496-4 (2023) 16:99 Journal of Hematology & Oncology Open Access REVIEW Beyond Bruton’s tyrosine kinase inhibitors in mantle cell lymphoma: bispecific antibodies, antibody–drug conjugates, CAR T‑cells, and novel agents Neeraj Jain1,2, Mukesh Mamgain3, Sayan Mullick Chowdhury4, Udita Jindal1,2, Isha Sharma1, Lalit Sehgal4 and Narendranath Epperla5* Abstract Mantle cell lymphoma is a B cell non-Hodgkin lymphoma (NHL), representing 2–6% of all NHLs and characterized by overexpression of cyclin D1. The last decade has seen the development of many novel treatment approaches in MCL, most notably the class of Bruton’s tyrosine kinase inhibitors (BTKi). BTKi has shown excellent outcomes for patients with relapsed or refractory MCL and is now being studied in the first-line setting. However, patients eventually progress on BTKi due to the development of resistance. Additionally, there is an alteration in the tumor microenvironment in these patients with varying biological and therapeutic implications. Hence, it is necessary to explore novel therapeutic strategies that can be effective in those who progressed on BTKi or potentially circumvent resistance. In this review, we provide a brief overview of BTKi, then discuss the various mechanisms of BTK resistance including the role of genetic alteration, cancer stem cells, tumor microenvironment, and adaptive reprogramming bypassing the effect of BTK inhibition, and then provide a comprehensive review of current and emerging therapeutic options beyond BTKi including novel agents, CAR T cells, bispecific antibodies, and antibody–drug conjugates. Keywords BTK inhibitor resistance, Mantle cell lymphoma, CAR T cell therapies, Bispecific antibodies, Antibody–drug conjugates *Correspondence: Narendranath Epperla 1 Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India 2 Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India 3 Department of Medical Oncology and Hematology, All India Institute of Medical Sciences, Rishikesh, India 4 Division of Hematology, Department of Medicine, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA 5 The Ohio State University Comprehensive Cancer Center, Suite 7198, 2121 Kenny Rd, Columbus, OH 43221, USA Background Mantle cell lymphoma (MCL) is a subtype of B cell nonHodgkin lymphoma (NHL) characterized by overexpression of CCND1 and translocation t(11:14)(q13;q32) [1]. The most common type of MCL originates from mature B cells and is often found to become unstable and aggressive through accumulating mutations in genes related to cell cycle regulation, such as the DNA damage response pathway. They are often found to express SOX11 [2] and carry little to no immunoglobulin heavy variable (IGHV) somatic mutations [2] and include classical, blastoid, and pleomorphic variants of MCL. The second indolent subtype (10–15% cases, leukemic non-nodal variant) is less aggressive, carries © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Jain et al. Journal of Hematology & Oncology (2023) 16:99 IGHV somatic hypermutations [1], and is genetically stable with low to no SOX11 expression. Patients can potentially have asymptomatic disease with this subtype for extended periods [3]. Recently, the diagnosisto-treatment interval (DTI) was shown to be prognostic patients with newly diagnosed MCL, wherein patients with short DTI (DTI ≤ 14 days) had worse outcomes and was strongly associated with adverse clinical factors [4]. While the outcomes of MCL have been conventionally poor, there has been improvement in survival in the past decade owing to the advent of novel therapies [5]. The treatment of MCL in the frontline setting largely relies on patient-specific factors such as age, overall performance status, and underlying co-morbidities. For the young, transplant-eligible patient, treatment generally consists of induction chemotherapy, consolidation with an autologous stem cell transplantation, and maintenance with rituximab for about three years. For induction chemotherapy, no specific chemotherapy regimen has been firmly established as the standard of care, and the treatment regimen used is variable based on the institution or physician’s practice. However, it is generally accepted that the regimen should contain rituximab and cytarabine. Less toxic chemotherapy treatments are given for patients unfit for intensive chemotherapy, such as bendamustine/rituximab (BR) or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), with or without maintenance rituximab. However, patients eventually progress following frontline therapy, so establishing effective treatments for relapsed/ refractory (R/R) MCL is important. In the past decade, BTK inhibitors (BTKi) have revolutionized the management of patients with R/R MCL. However, a significant proportion of patients eventually progress with poor post-BTKi relapse outcomes. This review article focuses on three main aspects: (1) discuss the current BTKis approved for clinical use in the USA, (2) detail the various mechanisms of BTK resistance including the role of genetic alteration, cancer stem cells, tumor microenvironment, and adaptive reprogramming bypassing the effect of BTK inhibition, and (3) current and emerging therapeutic strategies beyond BTKi. BTKi in MCL Currently, there are four BTKis approved for MCL therapy. They are ibrutinib, acalabrutinib, zanubrutinib (all covalent BTKis), and pirtobrutinib (only approved noncovalent BTKi) [6–10]. Table 1 summarizes the BTKi currently approved for MCL, the study that led to their FDA approval, and the potential adverse effects reported on these studies. Page 2 of 26 Resistance to BTKis and approaches for targeting mutant BTK Although the first-generation BTKi (ibr (...truncated)