Long‐term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib

Abstract

Long term outcomes and mutations in patients with mantle cell lymphoma (MCL) who discontinued ibrutinib have not been described. Using deep targeted next generation sequencing, we performed somatic mutation profiling from 15 MCL patients (including 5 patients with paired samples; before and after progression on ibrutinib). We identified 80 patients with MCL who discontinued ibrutinib therapy for various reasons. Median follow-up after ibrutinib discontinuation was 38 months. The median duration on ibrutinib was 7·6 months. Forty-one (51%) patients discontinued ibrutinib due to disease progression/transformation, 20 (25%) for intolerance, 7 (9%) due to patient choice, 5 (6%) for stem cell transplant, 4 (5%) due to second cancers and 3 (4%) other causes. The median survival after ibrutinib was 10 and 6 months for disease progression and transformation, respectively, and 25 months for patients with ibrutinib intolerance. Overall, BTK mutations were observed in 17% patients after progression on ibrutinib. Notably, TP53 alterations were observed after progression in 75% patients. Among the 4 patients with blastoid transformation, 3 (75%) had NSD2 mutations (co-existing with TP53). Ibrutinib-refractory MCL patients had a short survival. Demonstration of TP53 and NSD2 mutations in patients who developed blastoid transformation and ATM and TP53 mutations in patients who progressed, opens the door for future investigations in ibrutinib-refractory MCL.

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

“…Our group has been involved in various clinical trials with ibrutinib, acalabrutinib, venetoclax (a Bcl2 inhibitor), and their combinations with anti‐CD20 monoclonal antibodies (mAb), rituximab, or with obinutuzumab. Furthermore, we are characterizing ibrutinib, acalabrutinib, and venetoclax‐refractory MCL and championing the CAR‐T cell clinical trials (Zuma‐2) in MCL in the United States.…”

“…However, we recognize that even after the emergence of ibrutinib or acalabrutinib or venetoclax resistance, intolerance of these agents, management after their discontinuation, disease transformation, and MRD‐positive disease remain a constant challenge in MCL.…”

“…Overall, the advent of ibrutinib is a “great leap forward” in the treatment of MCL; however, problems with ibrutinib discontinuation, management of ibrutinib‐refractory disease, and mechanisms of ibrutinib resistance pose new challenges. In contrast with SLL/CLL, where the C481S mutation is commonly associated with ibrutinib resistance, this mutation is infrequent in ibrutinib‐resistant MCL, and other mechanisms of ibrutinib resistance and ways to overcome ibrutinib resistance must be explored. A detailed discussion about the molecular aspects of ibrutinib resistance is beyond the scope of the current article.…”

Drug Resistance in Non-Hodgkin Lymphomas

“…Ibrutinib-resistant MCL cells also appear to be more dependent on BCL2 antiapoptotic signaling and the combination of ibrutinib and venetoclax has emerged as a highly promising combination [131]. Mutations of TP53 and NSD2 have developed in 3 out of 4 patients with blastoid transformation of MCL on ibrutinib [132]. In addition to somatic mutations, complex adaptive changes in response to microenvironmental factors play an important role in contributing to acquired ibrutinib resistance [126].…”

Low-dose radiation (4 Gy) with/without concurrent chemotherapy is highly effective for relapsed, refractory mantle cell lymphoma

“…9,10 Yet, patients who fail ibrutinib are resistant to further therapies and have poor outcomes, with median survival of 3 to 10 months. [11][12][13] Although effective, radiation therapy (RT) is not commonly used for MCL, except for early-stage disease or palliation. 14 Reports indicate local control (LC) and CR rates of 91% to 100% and 64% to 69%, respectively, with traditional doses of 30 Gy.…”