Ibrutinib Maintenance (I-M) Following Frontline Intensive Induction in Mantle Cell Lymphoma (MCL): Interim Safety, Response and Sequential MRD Evaluation
Authors: Karmali Reem , Abramson Jeremy S. , Stephens Deborah M. , Barnes Jeffrey A. , Kaplan Jason , Winter Jane N. , Ma Shuo , Gao Juehua , Petrich Adam M. , Hochberg Ephraim , Takvorian Ronald W. , Kuhr Frank , Nelson Valerie , Gordon Leo I. , Pro Barbara 
Published: November 2019

Background: MCL carries a poor overall prognosis despite high response rates to induction chemotherapy. Maintenance strategies have impacted survival in MCL but optimal strategies have yet to be defined. Despite profound activity of ibrutinib, a selective BTK inhibitor, in relapsed/refractory MCL, ibrutinib maintenance (I-M) following induction for treatment-naive MCL has not been explored. We report preliminary results of a multicenter phase II trial assessing efficacy and safety of I-M for MCL after frontline induction.

Methods: Patients (pts) with MCL with complete or partial response (CR/PR) to frontline chemo-immunotherapy +/- autologous stem cell transplantation (autoSCT) received I-M 560 mg daily for up to 4 years. The primary objective was 3 year PFS rate with I-M. Secondary objectives were PR to CR conversions, median OS after 4 years and toxicity. Measurable residual disease (MRD) assessments using an NGS-MRD Assay (detection resolution of < 1 cell per million; Adaptive Biotechnologies) on peripheral blood and/or PBMCs were planned at 4 time points: prior to I-M initiation and at 1, 6 and 18-24 mo(s) after initiation of I-M.

Results: Accrual is complete (n=36). Median age was 60 (range 46-90), 28 pts (78%) were males, 28 (78%) had advanced stage and 9 (25%) had extranodal disease. 18 (50%), 7 (19%) and 11 (31%) had low vs intermediate vs high risk MIPI respectively. For induction, 17 (47%) received bendamustine-rituximab (BR), 18 (50%) a cytarabine-based regimen, and 1 (3%) R-CHOP. 18 (50%) had autoSCT in CR1 prior to enrollment. 33 (92%) and 3 (8%) had CR and PR with induction respectively with 1 PR to CR conversion on I-M. Median follow-up from initiation of induction therapy was 33 mos. With a median follow-up of 24.5 mos from initiation of I-M, 1 pt had disease progression (PD) and 2 others died, 1 from hepatic cholangiocarcinoma 2 years after I-M discontinuation for toxicity (atrial fibrillation) and 1 from unknown cause. 20/36 (56%) pts remain on I-M (median 24 cycles, range 1-52). Sixteen pts discontinued ibrutinib, including 3 for completion of 4 years of I-M. Of the remaining 13 who discontinued, TRAEs accounted for 10 (77%) and the other 3 were for uterine cancer (n=1), PD (n=1), and death of unknown cause (n=1) (Table 1). Atrial fibrillation/atrial flutter accounted for 50% (n=5) of TRAEs that led to I-M discontinuation. 9 (25%) pts required permanent dose reductions for TRAEs with neutropenia (n=3), myalgias (n=2), and fatigue (n=2) being the most common. Collectively, TRAEs led to dose reductions/ interruptions/ discontinuations in 25 (69%) pts. At time of data cut-off, (July 2019), using a trackable dominant clone identified from tissue at diagnosis, MRD was assessed in 12 patients at varying time points (Figure 1). In these 12 pts, 6 were induced with BR, 5 with a cytarabine-based regimen, and 1 with R-CHOP and 5 were consolidated with autoSCT prior to enrollment. Prior to I-M initiation, 9 pts were MRD (-) and 3 had indeterminate MRD status. Indeterminate results corresponded with total cell counts below the level of detection and quantification with our assay. Those with indeterminate MRD status were confirmed to be MRD (-) with subsequent evaluation after 1 month of I-M. 3 of 12 (25%) pts became MRD (+) on I-M. The first reverted back to MRD (-) status and remains MRD (-) with clinical CR on > 3 years of I-M. The second pt was treated with hyperCVAD with PR prior to I-M. This patient required several dose interruptions for neutropenia just prior to MRD detection with clinical PD leading to discontinuation of therapy after 9 months of I-M. The third pt was treated with R-CHOP + autoSCT with PR prior to I-M and maintains a PR despite MRD conversion on > 2 years of I-M. Further analysis of dynamic changes in dominant and non-dominant clones associated with I-M is ongoing.

Conclusions: I-M is feasible in MCL pts who respond to frontline chemo-immunotherapy +/- autoSCT with manageable toxicities consistent with the known safety profile of ibrutinib. Guidelines to discontinue I-M for atrial fibrillation were strictly upheld in this protocol though not typical of current practice. NGS can be used to assess MRD with induction and maintenance therapy and demonstrates that most pts are MRD negative after intensive induction. Longer follow-up, evaluation of dynamic changes in MRD, and PFS and OS data are needed to assess clinical relevance of I-M and importance of MRD status, and may support larger, controlled studies.

Disclosures

Karmali: Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution; Astrazeneca: Speakers Bureau. Abramson:AbbVie Inc, Amgen Inc, Bayer HealthCare Pharmaceuticals, Celgene Corporation, EMD Serono Inc, Genentech, Gilead Sciences Inc, Janssen Biotech Inc, Juno Therapeutics, a Celgene Company, Karyopharm Therapeutics, Kite Pharma Inc, Merck, Novartis, Seattle Gen: Consultancy. Stephens:Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Winter:Merck: Consultancy, Research Funding. Ma:Genentech: Consultancy; Gilead: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Acerta: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Janssen: Consultancy, Speakers Bureau; Kite: Consultancy; Juno: Research Funding; Xeme: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Beigene: Research Funding; Bioverativ: Consultancy; Novartis: Research Funding. Petrich:Abbvie: Employment, Equity Ownership. Kuhr:Adaptive Biotechnologies: Employment, Other: shareholder. Gordon:Zylem LLC: Other: co-founder; research in nanoparticles in cancer; Bayer: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Gilead: Other: Advisory Board. Pro:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding.

OffLabel Disclosure:

We will discuss results of our trial looking at ibrutinib maintenance in frontline MCL