Three-Year Follow-up of the Ascend Trial: Acalabrutinib Vs Rituximab Plus Idelalisib or Bendamustine in Relapsed/Refractory Chronic Lymphocytic Leukemia

Abstract

Background: Bruton tyrosine kinase (BTK) inhibitors are a preferred treatment option in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Acalabrutinib (acala) is a next-generation, highly selective, covalent BTK inhibitor approved for the treatment of patients with CLL including those with R/R disease. In the primary analysis of the ASCEND study with a median follow-up duration of 16.1 months, acala monotherapy demonstrated superior progression-free survival (PFS) compared with idelalisib (Id) plus rituximab (R) (IdR) or bendamustine (B) plus R (BR) and favorable safety in patients with R/R CLL (Ghia et al. J Clin Oncol. 2020;38:2849-2861). Herein we report results of the ASCEND study at 3 years of follow-up. Methods: In this randomized, multicenter, open-label, phase 3 study (NCT02970318), patients with R/R CLL were randomized 1:1 to receive acala 100 mg orally (PO) twice daily or investigator's (INV) choice of IdR (Id: 150 mg PO twice daily; R: 375 x1 then 500 mg/m 2 intravenously [IV] for 8 total infusions) or BR (B: 70 mg/m 2 IV and R: 375 x1 then 500 mg/m 2 IV for 6 total cycles) until disease progression or unacceptable toxicity. Crossover to the acala monotherapy arm was permitted in patients who progressed on IdR or BR. Assessments included INV-assessed PFS, overall survival (OS), INV-assessed overall response rate (ORR), and safety. Results: A total of 310 patients (acala, n=155; IdR, n=119; BR, n=36) were enrolled (median age: 67 y; del(17p) 16%, unmutated IGHV 78%, Rai stage 3/4 42%). At a median (range) follow-up of 36.0 (0.5-44.0) and 35.2 (0.03-42.5) months (data cutoff: October 26, 2020) for acala and IdR/BR, respectively, acala significantly prolonged INV-assessed PFS vs IdR/BR (median: not reached [NR] vs 16.8 months, respectively; hazard ratio [HR]: 0.29; 95% confidence interval [CI]: 0.21, 0.41; P<0.0001); 36-month PFS rates were 63% for acala vs 21% for IdR/BR (Figure 1). Similar PFS benefits were observed for acala vs IdR (median: 16.2 months [HR: 0.31; P<0.0001]) and vs BR (median: 18.6 months [HR: 0.25; P<0.0001]) when assessed separately (Figure 2). PFS benefit was also consistently shown in high-risk subgroups; in patients with the del(17p) mutation, median PFS was NR vs 13.8 months (HR: 0.13; 95% CI: 0.06, 0.3; P<0.0001); 36-month PFS rates were 66% and 5% for acala and IdR/BR, respectively. In patients with unmutated IGHV, median PFS was NR vs 16.1 months (HR: 0.30; 95% CI: 0.21, 0.42; P<0.0001); 36-month PFS rates were 61% and 17% for acala and IdR/BR, respectively. Median OS was NR in both arms; the 36-month OS rate was 80% for acala vs 73% for IdR/BR (Figure 3). ORR was 83% with acala vs 85% with IdR/BR (ORR including partial response with lymphocytosis was 92% vs 88%, respectively). Adverse events (AEs) occurring in ≥15% of patients in any treatment arm are shown in the Table; the most commonly reported all-grade AEs (≥20%) with acala were headache (23%), neutropenia (23%), diarrhea (21%), and upper respiratory tract infection (20%); with IdR, diarrhea (53%) and neutropenia (47%); and with BR, neutropenia (34%), fatigue (23%), infusion-related reaction (23%), and nausea (20%). Serious AEs (SAEs) were reported in 38% of acala, 63% of IdR, and 26% of BR patients; SAEs reported in ≥5% of patients in any treatment arm were pneumonia (acala 8%, IdR 9%, BR 3%), pyrexia (acala 2%, IdR 7%, BR 3%), and diarrhea (acala 1%, IdR 15%, BR 0%). AEs led to drug discontinuation in 21% of acala, 65% of IdR, and 17% of BR patients. Events of clinical interest included all-grade atrial fibrillation/flutter (acala 6%, IdR/BR 3%), all-grade hypertension (acala 7%, IdR/BR 4%), all-grade major hemorrhage (acala 3%, IdR/BR 3%), grade ≥3 infections (acala 25%, IdR/BR 27%), and all-grade second primary malignancies excluding non-melanoma skin cancer (acala 7%, IdR/BR 3%). Conclusions: At 3 years of follow-up, the efficacy of acala monotherapy was maintained, showing a significant PFS benefit over standard-of-care regimens in patients with R/R CLL. Acala also maintained an acceptable tolerability profile with no new safety findings identified with longer-term follow-up. Figure 1 Figure 1. Disclosures Jurczak: AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees; European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy; Jagiellonian University: Ended employment in the past 24 months; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment. Pluta: Celgene, Servier, Takeda, Novartis: Honoraria; Celgene: Other: Travel, Accommodations, Expenses; Janssen-Cilag, Kartos Therapeutics, Iqvia, Roche, Acerta Pharma, Pharmacyclics, BeiGene, Takeda: Research Funding; National University of Sanok: Current Employment; Szpital Specjalistyczny w Brzozowie: Ended employment in the past 24 months. Lysak: Novartis, Janssen-Cilag, AbbVie; AstraZeneca: Honoraria, Research Funding. Šimkovič: AbbVie, AstraZeneca, Janssen-Cilag, Gilead, Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Kriachok: Takeda, Roche, Abbivie, Janssen, MSD: Consultancy; Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau. Illes: Novartis, Janssen, Pfizer, Roche: Other: Travel, Accommodations, Expenses; Takeda, Seattle Genetics: Research Funding; Janssen, Celgene, Novartis, Pfizer, Takeda, Roche: Consultancy. de la Serna: ABBVIE, ASTRAZENECA,ROCHE: Research Funding; AbbVie, AstraZeneca, Beigene, Gilead, GSK, Janssen, Jazzpharma, Novartis, Roche: Consultancy; AbbVie, AstraZeneca, Roche: Speakers Bureau. Campbell: Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; CSL Behring: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy, Research Funding; BMS/Celgene: Research Funding; Roche: Consultancy, Research Funding. Musuraca: Janssen, Roche, Incyte: Honoraria; Janssen, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen, Incyte, Roche: Consultancy. Jacob: Astrazeneca, GlaxoSmithKilne: Current equity holder in publicly-traded company; Horizon Discovery, Oxford Biomedica: Divested equity in a private or publicly-traded company in the past 24 months; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Clinical Haematology Services: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astrazeneca: Honoraria. Avery: Macrogenics, Moderna: Divested equity in a private or publicly-traded company in the past 24 months. Wang: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Yu: AstraZeneca: Current Employment; EMD Serono Research Institute: Ended employment in the past 24 months; AstraZeneca, Johnson and Johnson, AbbVie, Abbott: Current equity holder in publicly-traded company; Merck KGaA: Divested equity in a private or publicly-traded company in the past 24 months. Ghia: AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding.

Orelabrutinib in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma patients: Multi‐center, single‐arm, open‐label, phase 2 study

“…4,5,7,18,19 At similar follow-up times, CR rates following treatments of ibrutinib, acalabrutinib, and zanubrutinib were 9%, 5%, and 6.6%, respectively. [20][21][22] The CR/CRi rates have been raised during orelabrutinib monotherapy as time went on (3.8% to 21.3%). The relatively high and durable responses translated into clinically meaningful survival bene ts, as demonstrated by PFS and DOR in this group of patients (Fig.…”

“…Moreover, the 36‐month PFS rate was 59% when treated with ibrutinib 23 . Results of the ASCEND study demonstrated that the ORR for acalabrutinib was 93%, the percentage of patients achieving CR/CRi was 5%, and the 36‐month PFS rate showed 63% as evaluated by investigator 24 . In the BGB‐3111‐205 study, after a median follow‐up of 34 months, response was achieved in 87.9% of zanubrutinib‐treated patients, and the CR/CRi was 6.6% based on IRC assessments, with 68.1% PFS at 36 months 22 .…”

Real-world management of targeted therapies in chronic lymphocytic leukemia

“…29,30 The ASCEND trial randomized patients aged 18 years or older with relapsed or refractory CLL to receive either acalabrutinib monotherapy or investigator's choice [idelalisib plus rituximab (IR) or BR] (n = 310). 31,32 Acalabrutinib 100 mg orally twice daily was associated with significantly longer median PFS compared in investigator's choice (not reached vs. 16.8 months, p < 0.0001), with 36-month PFS rates of 63% and 21%, respectively. Patients with del(17p), TP53 mutations, del(11q), and unmutated IGHV demonstrated a consistent PFS benefit with acalabrutinib in prespecified subgroup analyses.…”

Management of relapsed/refractory Chronic Lymphocytic Leukemia

“…FDA approval for acalabrutinib in relapsed CLL came as result of the ASCEND study, which compared acalabrutinib versus dealers choice of idelalisib/rituximab versus bendamustine/rituximab 12,13 . In this trial, 36 month PFS rate was 63% for acalabrutinib versus 21% for standard of care, with bendamustine/rituximab and idelalisib/rituximab performing similarly.…”