Non-Bcl2 Mutations Are Predominant in Patients (pts) with Venetoclax Resistant Mantle Cell Lymphoma (MCL) - Response and Clinical Outcomes in Ultra-Refractory MCL
Authors: Jain Preetesh , Zhao Shuangtao , Kanagal-Shamanna Rashmi , Navsaria Lucy , Hill Holly , Misra Ankita , Nomie Krystle , Jiang Changying , Yao Yixin , Zhang Liang , Nastoupil Loretta J. , Hagemeister F. B. , Westin Jason R. , Nair Ranjit , Steiner Raphael Eric , Oriabure Onyeka , Chen Wendy , Tang Guilin , Yin C. Cameron , Patel Keyur , Romaguera Jorge Enrique , Fowler Nathan H. , Wang Linghua , Wang Michael L. 
Published: November 2019

Introduction: Mantle cell lymphoma (MCL) patients (pts) who progress after ibrutinib and other lines of treatment "ultra-refractory MCL" have poor outcomes and exhibit BTK mutations infrequently (Jain P et al BJH 2018, Martin P et al Blood 2016). Venetoclax has shown promising efficacy in Phase I trial in NHL (Davids M et al JCO 2017) and is now under trials in MCL. Venetoclax response in pts with MCL after progression on ibrutinib was reported (Eyre T et al Haematologica 2018), however, genomic alterations associated with venetoclax resistance are not described. We present our experience in 24 pts with MCL treated with venetoclax and report their mutation profiles associated with progression on venetoclax.
Methods: We collected data from 24 pts with MCL who were treated with venetoclax (off clinical trial) as a salvage measure after failing multiple lines of prior therapies. Pt characteristics were collected from the time of initiating venetoclax. Progression free survival (PFS) was calculated from the time of initiating venetoclax to the date of progression or to last follow up date/date of death while overall survival (OS) was calculated from the time of initiating venetoclax to the date of last follow up date/date of death. Post venetoclax survival was calculated from the date of discontinuing venetoclax to the date of last follow up/death. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed from evaluable biopsy samples from 7 pts (5 pts at/before starting venetoclax and 6 pts after progression of venetoclax), this included 5 pts who have pairs available for analysis (pre and post venetoclax).
Results: Twenty four pts were treated with venetoclax (12 started as single agent and 8 started with combination with obinutuzumab and 3 with BTK inhibitors with/without obinutuzumab). Four pts had initial single agent venetoclax and later were rechallenged with combinations. Initial dose of venetoclax was dose escalation from 20 mg, then 50 mg then 100 mg PO daily up to 400 mg daily in 18/24 pts while in 3 pts it was 100 mg daily and in another 3 it was 400 mg daily. Median age at venetoclax start was 69 years (58-82). Median number of prior lines of therapy was 5 (range 1-11; including 17 pts who progressed on ibrutinib or other BTK inhibitors, 5 had exposure to ibrutinib and discontinued for intolerance, 4 had prior SCT and 2 had prior anti CD19 cellular therapy). At the baseline (pre/at-venetoclax start), 13 pts (54%) had blastoid/pleomorphic histology and 11 (46%) had classic variant morphology, the median Ki-67% was 60% (5-90%) and pts with Ki-67% ≥ 50 were 11 (55%), 4 pts did not have available Ki-67% values. Overall response rate (ORR) was 65% (13/20) - complete remission 25% (5/20) and partial remission 40% (8/20). Stable disease was observed in 10% (2/10), primary refractory were 25% (5/20). Four pts were not evaluable for response assessment. The median follow up after starting venetoclax was 17.5 months (1-27). The median PFS was 7.7 months (2 year 20%) and the median OS was 13.5 months (2 year 30%) Figure-1A-B. Pts in CR had a PFS of 15 months vs no CR 10 months (p=0.29). At the last follow up, 11 pts remained on venetoclax therapy (4 alive and 7 dead). Overall, 15 pts progressed and 14 pts were alive. The median post venetoclax survival was 6 months. Among 20 pts who discontinued venetoclax, 1 achieved CR and 3 PR on subsequent therapies. Among the 20 pts who discontinued venetoclax, 6 discontinued due to intolerance.
In addition, we evaluated the somatic mutation profile in pts who progressed on venetoclax using WES. Figure-1C shows mutation spectrum. In our cohort, pts with MCL who progressed on venetoclax exhibited infrequent Bcl2 mutations (one pt at progression; 14 %; p.H3D) while the mutation frequency of other genes such as TP53 (71% vs. 40%), ATM (43% vs. 20%), KMT2D (57% vs. 20%), CELSR3 (57% vs. 20%), and KMT2C (43% vs. 20%) increased by > 2-fold at progression (compared to pretreatment samples, p=N.S due to small cohort size). The mutation of CARD11 (14%) and SMARCA4 (14%) was only observed at progression. Further details on copy number abnormalities will be presented.
Conclusions: Venetoclax has promising results in refractory pts with MCL. Combination clinical trials with obinutuzumab, acalabrutinib are ongoing in MCL. We have characterized mutations and aneuploidy abnormalities in venetoclax resistant MCL pts and shown that unlike CLL, Bcl2 mutations are infrequent in venetoclax resistant MCL.

Disclosures
Nastoupil: Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Curis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding; Genentech: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Fowler:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Aviara: Research Funding; Dava Oncology: Honoraria; Juno Therapeutics: Research Funding; Celgene: Honoraria, Research Funding; BioInvent: Consultancy, Research Funding; Guidepoint Global: Consultancy; Kite Pharma: Consultancy, Research Funding; Acerta Pharma: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Loxo Oncology: Research Funding; VelosBio: Research Funding.