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Ibrutinib revolutionized therapy for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Real-world data on the outcome of unselected patients are still limited. We analyzed 77 R/R MCL patients receiving ibrutinib with at least one prior systemic anti-lymphoma therapy. After a median follow-up of 14.0 months, 56 patients relapsed/progressed, and 45 died. The overall response rate was 66%, with 31% of complete metabolic remissions on PET/CT. The median progression-free and overall survival (OS) rates were 10.3 and 23.1 months, respectively. The median OS from ibrutinib failure was 3.7 months. High proliferation rate by Ki67 (≥ 30%) and two or more previous therapy lines both negatively correlated with outcome (HR = 2.2, p = 0.04, and HR = 2.06, p = 0.08, respectively). Female gender borderline correlated with better outcome (HR = 0.53, p = 0.08). In multivariate analysis, Ki67 and response to ibrutinib both correlated with OS (p n = 13) or partial (n = 7) metabolic remission, none achieved remission in BM. We confirmed good efficacy of ibrutinib in unselected heavily pre-treated MCL patients. Our findings support the use of a combination of ibrutinib and rituximab in patients with BM involvement.

Mantle cell lymphoma (MCL) is a subtype of B-cell lymphoma with a large number of recurrent cytogenetic/molecular aberrations. Approximately 5&ndash, 10% of patients do not respond to frontline immunochemotherapy. Despite many useful prognostic indexes, a reliable marker of chemoresistance is not available. We evaluated the prognostic impact of seven recurrent gene aberrations including tumor suppressor protein P53 (TP53) and cyclin dependent kinase inhibitor 2A (CDKN2A) in the cohort of 126 newly diagnosed consecutive MCL patients with bone marrow involvement &ge, 5% using fluorescent in-situ hybridization (FISH) and next-generation sequencing (NGS). In contrast to TP53, no pathologic mutations of CDKN2A were detected by NGS. CDKN2A deletions were found exclusively in the context of other gene aberrations suggesting it represents a later event (after translocation t(11, 14) and aberrations of TP53, or ataxia telangiectasia mutated (ATM)). Concurrent deletion of CDKN2A and aberration of TP53 (deletion and/or mutation) represented the most significant predictor of short EFS (median 3 months) and OS (median 10 months). Concurrent aberration of TP53 and CDKN2A is a new, simple, and relevant index of chemoresistance in MCL. Patients with concurrent aberration of TP53 and CDKN2A should be offered innovative anti-lymphoma therapy and upfront consolidation with allogeneic stem cell transplantation.

Mantle cell lymphoma (MCL) is a subtype of B-cell lymphoma with a large number of recurrent cytogenetic/molecular aberrations. Approximately 5–10% of patients do not respond to frontline immunochemotherapy. Despite many useful prognostic indexes, a reliable marker of chemoresistance is not available. We evaluated the prognostic impact of seven recurrent gene aberrations including tumor suppressor protein P53 (TP53) and cyclin dependent kinase inhibitor 2A (CDKN2A) in the cohort of 126 newly diagnosed consecutive MCL patients with bone marrow involvement ≥5% using fluorescent in-situ hybridization (FISH) and next-generation sequencing (NGS). In contrast to TP53, no pathologic mutations of CDKN2A were detected by NGS. CDKN2A deletions were found exclusively in the context of other gene aberrations suggesting it represents a later event (after translocation t(11;14) and aberrations of TP53, or ataxia telangiectasia mutated (ATM)). Concurrent deletion of CDKN2A and aberration of TP53 (deletion and/or mutation) represented the most significant predictor of short EFS (median 3 months) and OS (median 10 months). Concurrent aberration of TP53 and CDKN2A is a new, simple, and relevant index of chemoresistance in MCL. Patients with concurrent aberration of TP53 and CDKN2A should be offered innovative anti-lymphoma therapy and upfront consolidation with allogeneic stem cell transplantation.

Introduction: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodkin lymphomas characterized by cyclin D1 overexpression, and other recurrent molecular-cytogenetic aberrations, including overexpression of BCL2, mutation or deletion of TP53, deletion of CDKN2A, deletion of RB1, MYC gain or breakage, and amplification of cyclin-dependent kinase (CDK) 4. The complex of upregulated cyclin D1 and CDK 4 and 6 deregulates G1/S cell cycle transition of malignant lymphocytes, which represents a rationale druggable target. Palbociclib, a CDK 4/6 inhibitor approved for the therapy of patients with breast cancer, recently demonstrated single-agent clinical activity in patients with MCL. Venetoclax, a pro-apoptotic BCL2-inhibitor, is currently being tested in combination with other agents in patients with MCL in numerous clinical trials. Interestingly, the combination of palbociclib and venetoclax showed promising results in patients with breast cancer, but has never been tested in patients with MCL. Methods: Experimental therapy aimed at inhibition of CDK and BCL2 using palbociclib and venetoclax was performed on 9 MCL cell lines and 3 patient-derived xenograft (PDX) models from patients with treatment-refractory MCL. The amount of selected cell cycle regulators, pro- and anti-apoptotic proteins was evaluated before and after exposure to palbociclib by western blotting. MCL clones with knockdown or everexpression of CDKN2A, MYC, CDK4 and RB1 were used to evaluate impact of these aberrations on the sensitivity to palbociclib and venetoclax. Results: Co-targeting CDK4/6 with palbociclib and BCL2 with venetoclax is a highly effective experimental treatment strategy with synthetic lethality observed both in vitro and in vivo. Exposure to palbociclib leads to downregulation of D-types cyclins, cyclin A and MCL-1. Molecular mechanisms of synergy include downregulation of total MCL1 protein following palbociclib exposure, and increased amount of BAK1 bound on BCL2 after 24-hour exposure of MCL cells to palbociclib. We confirmed on MCL cells, that RB1 knockdown causes resistance to palbociclib and represents a negative predictive marker. CDKN2A K/O, overexpression of MYC, and overexpression of CDK4 did not change sensitivity of MCL cells to palbociclib. Of note, overexpression of MYC and CDKN2A K/O both increased sensitivity to venetoclax. Conclusion: Our data strongly support investigation of palbociclib in combination with venetoclax as an innovative treatment strategy for chemoresistant MCL patients without RB1 deletion. Disclosures Trneny: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria.