Outcomes of relapsed mantle cell lymphoma patients after discontinuing acalabrutinib
Authors: Preetesh Jain, Rashmi Kanagal‐Shamanna, Shaojun Zhang, Chi Young OK, Lucy Navsaria, Loretta Nastoupil, Hun Ju Lee, Guilin Tang, C. Cameron Yin, Maria Badillo, Ranjit Nair, Shaoying Li, Keyur M. Patel, Christopher Flowers, Francisco Vega, Linghua Wang, Michael L. Wang
Journal: American Journal of Hematology (2021)

Acalabrutinib is an FDA approved orally available, covalent, irreversible BTK inhibitor (BTKi) in the treatment of relapsed patients with mantle cell lymphoma (MCL).1 Although head to head comparison of acalabrutinib vs ibrutinib in MCL is not reported, acalabrutinib appears to have lower incidence of side effects compared to ibrutinib due to its minimal off-target (SRC, EGFR and TEC) kinase inhibitory activity.2 Furthermore, in the 26 months follow up of ACE-LY-004 study,3 with acalabrutinib in relapsed MCL patients, the overall response (ORR) and complete response (CR) rate were 81% and 43% respectively and 51% patients discontinued acalabrutinib. Patients with MCL who progressed on BTKi have limited treatment options and post ibrutinib survival is limited to 3–10 months.4, 5 Furthermore, in contrast to ibrutinib refractory patients with chronic lymphocytic leukemia (CLL), BTK mutations were infrequent (17% in MCL5 vs 70% in CLL6) in ibrutinib refractory MCL. Non-BTK mutations (TP53, NSD2, SMARCA4, KMT2D),7 dysregulated metabolic reprogramming8 were the dominant aberrations associated with ibrutinib resistance in MCL. Since the outcomes of MCL patients after discontinuing acalabrutinib were not described, we therefore, report the outcomes, management and the mutation profile in MCL patients who discontinued acalabrutinib. Overall, 26 relapsed MCL patients were treated with acalabrutinib and of which 21 patients had discontinued acalabrutinib for various reasons and their characteristics, outcomes and subsequent management is described. For the subsequent therapies, patients were treated with various modalities including clinical trials and details from these clinical trials are not described since the patients are still on study. Informed consent was obtained from the patients to collect their information from clinical charts and perform molecular studies. The protocol was approved by the Institutional Review Board (IRB) in accordance with the Declaration of Helsinki. Kaplan–Meier survival post acalabrutinib was calculated from the date of acalabrutinib discontinuation to the date of last follow up or the date of death. Duration of acalabrutinib therapy was calculated from the date of acalabrutinib initiation to the date of discontinuation. Log rank test was used to estimate the time to event outcomes. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed in nine patients who progressed on acalabrutinib (10 samples were tumor specimens and five were matched germline samples); among these patients, four samples were collected before acalabrutinib and six were collected after progression on acalabrutinib. Only one patient had paired sample at both time points (baseline and at progression). The DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissues involved by MCL. Indexed libraries were prepared from sheared DNA using the Agilent SureSelect Reagent Kit (Agilent Technologies). Libraries were prepared for capture and exome capture was then performed using the Agilent SureSelect Human All Exon V4 kit. Following qPCR quantification, each pool was sequenced in two lanes of the HiSeq4000 sequencer, using the 76 nt paired-end format. Further details on methods for WES were as reported previously. Among the 21 patients who discontinued acalabrutinib, 15 patients (71%) discontinued due to disease progression (two patients transformed from classic to aggressive histology MCL at progression) and six patients discontinued due to intolerance [one due to worsening fatigue and worsening idiopathic encephalopathy, one due to worsening of preexisting symptomatic aortic stenosis (less likely related to acalabrutinib since the patient had long standing history of hypertension, atrial fibrillation and aortic stenosis, and was 88 years old and in complete remission on acalabrutinib), two others due to therapy related myelodysplasia (due to prior treatment with R-HCVAD regimen), one due to recurrent acute coronary syndrome (likely exacerbated by acalabrutinib, was a patient with prior coronary bypass graft, global left ventricular dysfunction 30%, prior arrythmias) and one due to worsening cardiac symptoms and recurrent atrial fibrillation (likely related to acalabrutinib, the patient had prior history of atrial fibrillation, had a pacemaker and coronary artery disease and was 80 years old)]. Characteristics of patients, their cause of discontinuation, subsequent treatments, responses and post acalabrutinib outcomes are summarized in Table S1. Overall, the median number of treatments prior to acalabrutinib was two (range, 1–3); all patients had at least one prior line of chemo-immunotherapy and none were treated with ibrutinib. The median duration on treatment with acalabrutinib was 8.3 months (1 to 50 months) and the median number of cycles of acalabrutinib treatment was eight (range, 1–53). Thirteen patients had complete remission (CR) as their best response on acalabrutinib, five were primary refractory and three patients achieved partial remission on acalabrutinib. At the time of starting acalabrutinib, 12 patients had classic and nine patients had blastoid (n = 6) or pleomorphic (n = 3) features, the median Ki-67 expression was 50% (range, 10%–100%). Patients who progressed, received acalabrutinib for a median duration of 8.3 months (range, 1–50 months) while those with intolerance, received acalabrutinib for a median duration of 9.4 months (range, 4–31 months). The median follow up after discontinuation of acalabrutinib was 38 months and the median post acalabrutinib survival was 24.3 months (not reached for progression and 7.4 months for intolerance; p = .02, Figure 1(A) and (B)). Patients who discontinued due to intolerance were not eligible to get subsequent treatment for MCL and this would have affected their poor survival after discontinuing acalabrutinib. Multiple factors existed in these six patients due to comorbidities, t-MDS and poor performance status and 5/6 patients had died (two with disease progression, one with poor performance status and comorbidities, one with progressive t-MDS and one with complications of cardiac procedure). Among the 15 patients who progressed on acalabrutinib, 14 patients received subsequent systemic therapies for progressive MCL. Seven received ibrutinib based therapies (three non responders, three achieved PR and one patient was CR but all patients progressed after ibrutinib). Among the seven patients who received ibrutinib based therapies, four got single agent ibrutinib or combination with rituximab (three non-responders and one PR with 6 months duration of response), two patients with carfilzomib-ibrutinib (one CR with 9 months duration and one PR with 2 months response duration) and one patient in PR after ibrutinib was combined with bendamustine-rituximab (4 months response). Six patients got chemo-immunotherapy with bortezomib or lenalidomide based therapies, and subsequently progressed and one patient did not receive any treatment and was lost to follow up. Furthermore, among the 14 patients who received subsequent therapies and progressed, six patients were treated with clinical trial with experimental chimeric antigen receptor (CAR-T) therapy and all of them attained CR. Among the 15 patients, nine were alive and six patients died (four with progressive MCL, one with complications of stem cell transplant and another due to a second cancer). Patients who received CAR-T therapy had significantly longer Median survival survival (not reached) compared to those who did not get CAR-T therapy (15.5 months); p = .007, Figure 1(C) and (D). The three additional patients were alive and in CR. These 3 patients were treated with other ongoing clinical trials and one is being considered for CART clinical trial. In the limited number of samples with WES, we showed that the recurrently mutated genes included ATM (6/10; 60%), TP53 (4/10; 40%), KMT2C (3/10), MYCN (2/10), NOTCH1 (2/10), NOTCH3 (2/10), and MEF2B (2/10) (Figure 1(E)). We did not detect any mutation or copy number alterations in BTK, PLCG2, TRAF2/3 and MYD88 that have been reported previously to be associated with ibrutinib resistance in CLL. In one paired sample, we compared the mutation variant allelic fractions (VAFs), between the baseline and progression samples. Mutation of MYCN, MEF2B, ATM, and NOTCH1 were identified in both tumors at similar VAFs, whereas mutation of CARD11 (two mutations), NLRC5 and B2M were detected only at progression. Although, this analysis is limited by small cohort of patients with limited molecular data, this study is the first report on post acalabrutinib outcomes in MCL and their management. We have shown that unlike post ibrutinib outcomes in relapsed MCL, patients who fail acalabrutinib have better outcomes. However, small sample size, and limited mutation data are the limitations of this report. Furthermore, since only one patient received venetoclax based therapy and did not respond, we were not able to evaluate the efficacy of venetoclax (single agent or in combination), post failure of acalabrutinib in our study. Venetoclax has demonstrated 50% responses in patients who have progressed on ibrutinib in two separate retrospective studies,9, 10 therefore the efficacy and safety of venetoclax (alone or in combination) after progression on acalabrutinib should be further investigated. Effectiveness of CAR-T therapy in BTK inhibitor refractory patients significantly improves the outcomes after progression on acalabrutinib as can be seen in this analysis where most of the long-term post acalabrutinib survivors had responded to CAR-T therapy. Advent and approval of anti CD19-CAR-T therapies11 and ongoing clinical trials have significantly improved the survival of these highly refractory patients who have progressed on acalabrutinib. In this small cohort, we did not observe BTK mutations associated with acalabrutinib resistance in MCL patients. Larger patient cohorts to study the molecular mechanisms of acalabrutinib resistant MCL are required. Clinical trials and CAR-T therapies should be considered for MCL patients who progress on acalabrutinib. Funding for these studies was provided in part by the generous philanthropy to the MD Anderson Cancer Center B-Cell Lymphoma Moon Shot Program; R21 CA202104 (Michael Wang, PI); and philanthropy funds from The Gary Rogers Foundation and the Fox Family Foundation. P.J., S.Z., R.K.S. and M.W. designed, collected, managed patients and wrote the manuscript. P.J., RKS, LN., S.Z. collected the data. All other authors provided contributions to the analysis and the interpretation of data for the work, helped in drafting the work and revised it critically for important intellectual content. All other authors gave final approval of the version to be published, and were in agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The corresponding author, M.W., had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. None of the authors declare any competing financial interests related to the patients described in this manuscript. Otherwise, no other competing conflicts are reported by other authors except for M.W. – stock or other ownership in MoreHealth; honoraria from Pharmacyclics, Janssen, AstraZeneca/Acerta Pharma, Targeted Oncology, and OMI; consultancy or advisory role for Pharmacyclics, Celgene, Janssen, AstraZeneca/Acerta Pharma, MoreHealth, Loxo Oncology, Kite, a Gilead Company, and Pulse Biosciences; research funding from Pharmacyclics, Janssen, AstraZeneca/Acerta Pharma, BioInvent, Novartis, Kite, a Gilead Company, Juno, Celgene, Loxo Oncology, and VelosBio; expert testimony for AstraZeneca/Acerta Pharma; and travel support from Janssen, Pharmacyclics, Celgene, Targeted Oncology, and OMI. Data Availability Statement - All data available with the corresponding authors and in supplemental file Table S1 Characteristics of patients who discontinued acalabrutinib treatment (n = 21) according to the cause of discontinuation and their post acalabrutinib survival. 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