Poor Overall Survival of Patients with Ibrutinib-Resistant Mantle Cell Lymphoma
Authors: Martin Peter , Maddocks Kami J. , Noto Katherine , Christian Beth , Furman Richard R. , Andritsos Leslie A. , Flynn Joseph M , Jones Jeffrey A. , Ruan Jia , Chen-Kiang Selina , Di Liberto Maurizio , Leonard John P. , Blum Kristie A. 
Published: October 2019

Abstract
Introduction
The United States Food and Drug Administration approved ibrutinib for treatment of patients with mantle cell lymphoma (MCL) that have received at least one prior therapy based on a phase II trial demonstrating a 68% response rate with a median progression-free survival of 13.9 months (Wang et al, NEJM 2013). Despite this significant efficacy, recent data suggest that primary or secondary resistance to ibrutinib is common and the mechanisms of ibrutinib resistance are varied (Chiron et al, Cancer Discovery 2014). The outcomes of MCL patients with ibrutinib resistance have not been previously reported, and the ideal management of patients with ibrutinib-resistant MCL is not known.
Methods
Following IRB approval, we performed a retrospective cohort study of all patients with MCL at WCMC and OSU that had experienced disease progression while receiving ibrutinib in a clinical trial or in routine clinical use. We evaluated historical medical records for clinical, pathological, and radiological data. Time-to-event statistics were estimated using the Kaplan-Meier method.
Results
We identified 32 subjects (19 male, 13 female) with primary or acquired ibrutinib resistant MCL. The median age at start of ibrutinib was 70 years (range 50-83), and the median number of prior therapies was 3 (0-9), including 2 patients with no prior therapy. The median time from diagnosis to start of ibrutinib was 32.5 months (range 0-223). Of the 30 patients that had received prior treatment, all had received rituximab, 21 had received bendamustine, 19 received bortezomib, 10 received an IMiD, 5 had received cytarabine, 5 had received methotrexate, 4 had received a purine analog, 2 received a PI3K inhibitor, and 1 had received an mTOR inhibitor. Five had undergone prior stem cell transplantation (3 auto, 2 allo). Only 11/30 patients had responded to their prior treatment, with a median time of 2.5 months between the prior treatment and ibrutinib. Four of 18 patients with morphology evaluated within 6 months of start of ibrutinib had blastoid MCL, and 11/19 patients had a previously reported Ki67 of >30%. The MIPI scores were as follows: 18 high risk, 5 intermediate risk, and 8 low risk, 1 not evaluable. Best response to ibrutinib was reported as follows: PD 20, SD 2, PR 6, CR 2, not evaluable 2. The median time on ibrutinib was 2.5 months (range 0-11). Among 27 patients with available follow-up data, 19 received treatment following ibrutinib with a median time of 0 months between stopping ibrutinib and starting subsequent treatment. The MIPI scores at start of subsequent therapy were as follows: 11 high risk, 3 intermediate risk, 3 low risk, and 2 unknown. Subsequent treatments included the following: 11 rituximab, 6 lenalidomide, 6 alkylator, 3 bendamustine, 2 anthracycline, 1 bortezomib, 1 purine analog. Two patients underwent allogeneic stem cell transplantation. Six of 17 patients evaluated for response demonstrated an objective response to subsequent treatment, including 2 patients that received bendamustine, 2 patients that received lenalidomide (one in combination with bendamustine), one that received an anthracycline, and one that received a purine analog. The median overall survival following cessation of ibrutinib was 4 months (95% CI 2-10 months). Both patients that underwent allogeneic stem cell transplantation died, one at 4 months from toxicity and one at 5 months from disease progression. Twelve patients were still alive, including four patients with more than 6 months of follow up (17, 22, 25, and 32+ months). There was no clear association between number of prior therapies, response to ibrutinib, morphology, Ki67 prior to ibrutinib, response to ibrutinib, duration of ibrutinib, or choice of subsequent therapy and OS.
Conclusions
In a group of patients with highly treatment-resistant MCL, primary and secondary ibrutinib resistance was associated with poor clinical outcomes, with limited duration of response to subsequent therapy and short overall survival. As yet, there are no identifiable predictors of clinical outcome following development of ibrutinib resistance, nor are there any clear signs that specific therapies might be particularly effective in this setting. Additional investigation into the outcomes of these patients is warranted. Clinical trials evaluating combinations with ibrutinib should be prioritized, as should trials of novel agents in the post-ibrutinib setting.

Disclosures
Martin: Janssen: Honoraria. Maddocks:Pharmacyclics: Advisory Board Other, Research Funding. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Jones:Pharmacyclics: Consultancy, Research Funding. Ruan:Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau. Blum:Janssen, Pharmacyclics : Research Funding.