Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: 42-Month Follow-up of a Phase 2 Study
Authors: Furman Richard R. , Wierda William G. , Schuh Anna , Devereux Stephen , Chaves Jorge M. , Brown Jennifer R. , Hillmen Peter , Martin Peter , Awan Farrukh T , Stephens Deborah M. , Ghia Paolo , Barrientos Jacqueline C. , Pagel John M. , Woyach Jennifer , Burke Kathleen , Covey Todd , Gulrajani Michael , Hamdy Ahmed , Izumi Raquel , Frigault Melanie M. , Patel Priti , Rothbaum Wayne , Wang Min Hui , O'Brien Susan M. , Byrd John C. 
Published: November 2019

Background: Targeted inhibition of Bruton tyrosine kinase (BTK) has improved clinical outcomes for patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a highly selective, covalent BTK inhibitor. A recently completed phase 3 trial showed acalabrutinib improved progression-free survival (PFS) vs idelalisib or bendamustine + rituximab in relapsed/refractory (R/R) CLL patients (ASCEND: Ghia et al. EHA 2019;273259:LB2606). This is an updated analysis with extended follow-up of a phase 1-2 multicenter study (NCT02029443) in patients with R/R CLL/small lymphocytic lymphoma (SLL), to demonstrate the durability of response and long-term tolerability of acalabrutinib.
Methods: Patients with CLL or SLL were eligible if they were R/R after ≥1 prior treatment. Eligible patients were ≥18 years of age with an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Oral acalabrutinib 100 mg was administered twice daily. All patients were treated until progressive disease or unacceptable toxicity occurred. Study endpoints included overall response rate (ORR), PFS, duration of response (DOR) and safety, with post hoc analysis of event-free survival (EFS). Response rates were based on the International Workshop on Chronic Lymphocytic Leukemia 2008 criteria (Hallek et al., 2008) with modification for lymphocytosis (Cheson et al., 2012). Nine patients had longitudinal peripheral blood mononuclear cell samples from pre-treatment baseline, during treatment and at progression analyzed for whole exome sequencing, to assess acquired mechanisms of treatment resistance.
Results: In total, 134 patients with R/R CLL/SLL received ≥ 1 dose of acalabrutinib. The median age was 66 years (range, 42-85 years). Baseline characteristics included ECOG PS ≤1 (97%), bulky lymph nodes ≥5 cm (39%), unmutated immunoglobulin heavy chain variable region (IGHV; 73%), chromosome 17p13.1 deletion (23%), chromosome 11q22.3 deletion (18%), and complex karyotype (≥3 abnormalities; 35%). The median number of prior therapies was 2 (range, 1-13). Patients received acalabrutinib for a median of 41 months (range, 0.2-58 months).
Most adverse events (AEs) were mild to moderate, and most commonly were diarrhea (52%), headache (46%), and upper respiratory tract infection (36%). Grade ≥3 AEs occurred in 66% of patients; most commonly (≥5% of patients) neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%) and diarrhea (5%). AEs of interest included atrial fibrillation (7% all grades; 3% Grade ≥3) and major bleeding events (5% all grades; 3% Grade ≥3). Most patients (56%) remained on treatment. The most common reasons for discontinuing treatment were progressive disease (21%) and AEs (11%). AEs leading to discontinuation occurring in ≥1 patient included pneumonia (4 events), anemia, neutropenia, and thrombocytopenia (2 events each).
The ORR (partial response with lymphocytosis or above) was 94% (95% confidence interval [CI]: 89-97%); with 4% of patients having complete response, 84% having partial response and 6% having partial response with lymphocytosis (Table). The median DOR, PFS and EFS were not reached; the estimated 42-month DOR was 61% (95% CI: 49-71%), PFS was 68% (95% CI: 59-76%) and EFS was 64% (95% CI: 54-71%). Responses were similar regardless of genomic features, including unmutated IGHV, chromosomal deletions and complex karyotype (Table).
Upon relapse during acalabrutinib treatment, whole exome sequencing detected BTK mutations in 6 of 9 (67%) tested patients that were not detectable at baseline. Of the 6 patients with detectable BTK C481X mutations, 4 had expansion to high allele frequency of the BTK mutation at progression (up to 58%). In a longitudinal analysis of patients who had a sample after 6 months of treatment, the BTK mutation was not detectable. No PLCG2 gene mutations were detected using exome analysis in the 9 patients analyzed.
Conclusions: These updated results confirm the earlier reports of acalabrutinib efficacy for the treatment of CLL and provide additional data on DOR and long-term tolerability. Reported AEs indicate a tolerable and consistent safety profile, with a low rate of major bleeding events. Genomic profiling in a small subset of patients indicated that acquired mutation of BTK was the most frequent mechanism of acalabrutinib resistance.

Disclosures
Furman: Genentech: Consultancy. Wierda:Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding. Schuh:Roche: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Devereux:Servier: Speakers Bureau; Roche: Consultancy, Other: Travel expenses, Speakers Bureau; GlaxoSmithKline: Consultancy; Gilead: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; MSD: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau. Brown:Pfizer: Consultancy; Sun: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Teva: Honoraria; Sunesis: Consultancy; Pharmacyclics: Consultancy; Morphosys: Other: Data safety monitoring boards ; Sun Pharmaceuticals, Inc: Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; Dynamo Therapeutics: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Other: other; Janssen: Honoraria; Kite: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy. Hillmen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Martin:Karyopharm: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy. Awan:Sunesis: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Innate Pharma: Research Funding; Gilead: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Stephens:Acerta: Research Funding; Gilead: Research Funding; Karyopharm: Research Funding. Ghia:Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Dynamo: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy. Barrientos:Bayer: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Genentech: Consultancy; Gilead: Consultancy; Janssen: Honoraria; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Burke:AstraZeneca: Employment, Equity Ownership. Covey:Acerta Pharma: Employment, Equity Ownership; AstraZeneca: Equity Ownership. Gulrajani:AstraZeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership. Hamdy:Acerta Pharma: Employment, Equity Ownership. Izumi:Acerta Pharma: Employment, Equity Ownership. Frigault:Acerta Pharma: Employment; AstraZeneca: Employment, Equity Ownership. Patel:Acerta Pharma: Employment, Equity Ownership. Rothbaum:Acerta Pharma: Employment, Equity Ownership. Wang:AstraZeneca: Equity Ownership; Acerta Pharma: Employment. O'Brien:Eisai: Consultancy; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Gilead: Consultancy, Research Funding; Verastem: Consultancy; Vaniam Group LLC: Consultancy; Astellas: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Regeneron: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Research Funding. Byrd:Ohio State University: Patents & Royalties: OSU-2S; BeiGene: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau.

OffLabel Disclosure:
This is a Phase 1/2 investigational study of acalabrutinib in chronic lymphocytic leukemia