Clinical Outcomes of Non-Hodgkin Lymphoma Patients on Acalabrutinib Including Off-Label Utilization
Authors: Namoglu Esin C. , Hughes Mitchell E. , Landsburg Daniel J. , Schuster Stephen J. , Svoboda Jakub , Chong Elise A. , Gerson James N. , Barta Stefan K. , Dwivedy Nasta Sunita 
Published: November 2019

Introduction: Acalabrutinib (acala), a Bruton's Tyrosine Kinase inhibitor (BTKi), received accelerated FDA approval for treatment of mantle cell lymphoma (MCL) in 2017. Since approval, there has been limited "real world" data, especially in the setting of off-label utilization. We performed an analysis of the safety and efficacy of acala in non-Hodgkin lymphoma (NHL) at our institution for both on- and off-label indications.
Methods: We performed a retrospective analysis of all patients (pts) who had received acala for NHL at the University of Pennsylvania between 1/2017 and 5/2019. We examined best response to therapy, duration of response, and progression free survival. Response assessments were determined by treating physician using standard, disease-specific criteria. We collected clinical and demographic data such as genetic risk factors, staging, previous and concomitant therapies. We analyzed adverse events (AEs) and toxicities associated with acala. Survival analyses were completed as described by Kaplan and Meier; all other analyses were descriptive in nature.
Results: We identified 23 pts treated with acala at our institution. The cohort consisted of 83% males (n=19). Diagnoses were chronic lymphocytic leukemia (CLL) (n=10; 44%), MCL (n=9; 39%), and diffuse large B-cell lymphoma (DLBCL) (n=4; 17%). One DLBCL was GCB subtype and three were ABC subtype; two of four DLBCL pts were transformed from marginal zone lymphoma and two were de novo. The median age at diagnosis was 61 years, median age at acala start was 69 years. Sixteen (70%) of the pts were Ann Arbor or Rai stage III or IV at diagnosis. The median number of therapies prior to acala was 3 (range 0-12). Of note, the GCB-DLBCL patient had previously undergone both allogeneic (alloSCT) and autologous (autoSCT) stem cell transplants and four of the MCL patients (44%) also had prior allo and/or autoSCTs. The majority (65%) of pts received acala 100 mg twice daily, with the rest of the patients receiving 100 mg once daily. The median time to best response was 2 months (mos). All CLL pts (n=10; 100%) had at least a partial response (PR), including 1 complete response (CR) by iwCLL criteria. In the MCL cohort of 9 pts, 8 (88%) had at least a PR (including 1 CR), and one patient (11%) had stable disease (SD). One MCL pt achieved a CR and moved to alloSCT. One (25%) of the DLBCL pts had a PR (pt was ABC subtype), and three (75%) had SD (one GCB and two ABC-DLBCL pts.) At the time of last follow up, two DLBCL pts had SD and remain on acala, one progressed after 10 months on acala and was switched to obinutuzumab, and one died due to disease progression. The 12 mo progression free survival (PFS) was 89% for CLL and 83% for MCL; 12 mo overall survival (OS) was 89% for CLL and 100% for MCL respectively. (Figure 1).
Of note, 16 pts (70%) had been on ibrutinib previously and all pts discontinued (d/c) ibrutinib due to intolerance. Acala related toxicities included: 26% (n=6) arthralgias/myalgias, 13% (n=3) infection, 13% (n=3) bruising/ bleeding, 9% (n=2) rashes, and 4% (n=1) diarrhea. Two pts required dose adjustment of acala and one patient had to d/c acala due to fatigue and bleeding/bruising. Ten (43%) of pts tolerated acala without any side effects. Of note, there were 6 pts with a history of atrial fibrillation (afib) or an afib-related toxicity of ibrutinib, and none of our pts experienced new afib while on acala. In total, six pts d/c acala: 1 patient moved to alloSCT, 3 had disease progression, 1 d/c due to toxicity, and 2 pts died. One death was unrelated to lymphoma progression (renal cancer).
Conclusion: Our "real world" experience with acala demonstrates its efficacy and tolerability in the setting of NHL, supporting previously published literature (ACE-LY-004 and ACE-CL-001 trials). In our analysis of 23 patients, the response rates in our CLL and MCL cohorts were 100% and 88% respectively and only one patient discontinued acala for intolerance. There is limited information on the off-label utilization of acala in the relapsed/refractory DLBCL setting. However, the response in our cohort may warrant further evaluation of acala as a possible therapeutic agent in this aggressive/refractory patient population. Acala continues to demonstrate a favorable toxicity profile, especially in pts who were unable to tolerate ibrutinib. Our experience with acala supports pilot data showing efficacy and thus further research in other B-cell malignancies, especially DLBCL, is warranted.
Figure 1

Disclosures
Hughes: Genzyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta Pharna/HOPA: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding. Schuster:Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Chong:Merck: Research Funding; Novartis: Consultancy; Tessa: Consultancy. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Barta:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Merck: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria. Dwivedy Nasta:Rafael: Research Funding; Millenium/Takeda: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Roche: Research Funding; 47 (Forty Seven): Research Funding; Debiopharm: Research Funding.

OffLabel Disclosure:
FDA label indication for acalabrutinib is only for patients with CLL. Utilization in DLBCL and CLL populations is beyond the specified indication.