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. 2024 Jul 9;8(13):3345-3359.
doi: 10.1182/bloodadvances.2023011307.

Acalabrutinib-based regimens in frontline or relapsed/refractory higher-risk CLL: pooled analysis of 5 clinical trials

Matthew S Davids  1 , Jeff P Sharman  2 , Paolo Ghia  3   4 , Jennifer A Woyach  5 , Toby A Eyre  6 , Wojciech Jurczak  7 , Tanya Siddiqi  8 , Paulo Miranda  9 , Mina Shahkarami  10 , Anna Butturini  10 , Ugochinyere Emeribe  9 , John C Byrd  11
Affiliations

Acalabrutinib-based regimens in frontline or relapsed/refractory higher-risk CLL: pooled analysis of 5 clinical trials

Matthew S Davids et al. Blood Adv. .

Abstract

Before targeted therapies, patients with higher-risk chronic lymphocytic leukemia (CLL), defined as del(17p) and/or TP53 mutation (TP53m), unmutated immunoglobulin heavy chain variable region genes (uIGHV), or complex karyotype (CK), had poorer prognosis with chemoimmunotherapy. Bruton tyrosine kinase inhibitors (BTKis) have demonstrated benefit in higher-risk patient populations with CLL in individual trials. To better understand the impact of the second-generation BTKi acalabrutinib, we pooled data from 5 prospective clinical studies of acalabrutinib as monotherapy or in combination with obinutuzumab (ACE-CL-001, ACE-CL-003, ELEVATE-TN, ELEVATE-RR, and ASCEND) in patients with higher-risk CLL in treatment-naive (TN) or relapsed/refractory (R/R) cohorts. A total of 808 patients were included (TN cohort, n = 320; R/R cohort, n = 488). Median follow-up was 59.1 months (TN cohort) and 44.3 months (R/R cohort); 51.3% and 26.8% of patients in the TN and R/R cohorts, respectively, remained on treatment at last follow-up. In the del(17p)/TP53m, uIGHV, and CK subgroups in the TN cohort, median progression-free survival (PFS) and median overall survival (OS) were not reached (NR). In the del(17p)/TP53m, uIGHV, and CK subgroups in the R/R cohort, median PFS was 38.6 months, 46.9 months, and 38.6 months, respectively, and median OS was 60.6 months, NR, and NR, respectively. The safety profile of acalabrutinib-based therapy in this population was consistent with the known safety profile of acalabrutinib in a broad CLL population. Our analysis demonstrates long-term benefit of acalabrutinib-based regimens in patients with higher-risk CLL, regardless of line of therapy.

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Conflict of interest statement

Conflict-of-interest disclosure: M.S.D. reports consultancy fees from AbbVie, Adaptive Biotechnologies, Ascentage Pharma, AstraZeneca, BeiGene, Bristol Myers Squibb (BMS), Eli Lilly, Genentech, Genmab, Janssen, Merck, MingSight Pharmaceuticals, Secura Bio, Takeda, TG Therapeutics, and Zentalis; research funding from AbbVie, Ascentage Pharma, AstraZeneca, Genentech, MEI Pharma, Novartis, Surface Oncology, TG Therapeutics, and Verastem; and honoraria from Research To Practice. J.P.S. reports employment with The US Oncology Network; research funding from Pharmacyclics, Genentech, Celgene, Acerta Pharma, AstraZeneca, Gilead Sciences, Seattle Genetics, TG Therapeutics, Merck, Takeda, BeiGene, and Lilly; and consulting/advisory roles in Pharmacyclics, Celgene, TG Therapeutics, Genentech, AbbVie, Acerta Pharma, AstraZeneca, BeiGene, Pfizer, BMS, and VelosBio. P.G. reports research funding from AbbVie, Gilead, Janssen, Novartis, and Sunesis; honoraria from AbbVie, AstraZeneca, ArQule/Merck Sharp and Dohme, BeiGene, Celgene/Juno/BMS, Gilead, Janssen, Lilly/Loxo, Adaptive, and Roche; and consulting/advisory roles in AbbVie, AstraZeneca, ArQule/Merck Sharp and Dohme, BeiGene, Celgene/Juno/BMS, Gilead, Janssen, Lilly/Loxo, Adaptive, and Roche. J.A.W. reports consulting/advisory roles in Pharmacyclics, Janssen, AstraZeneca, BeiGene, Loxo, Newave Pharmaceutical, and Genentech, and research funding from Janssen, Karyopharm, MorphoSys, AbbVie, and Schrodinger. T.A.E. reports honoraria from Roche, Gilead, Kite, Janssen, AbbVie, AstraZeneca, Loxo Oncology, BeiGene, Incyte, Secura Bio, and Autolus; travel fees from Roche, Gilead, AbbVie, and AstraZeneca; research support from Gilead, AstraZeneca, and BeiGene; and trial steering committee membership in Loxo Oncology. W.J. reports research funding from GlaxoSmithKline, Acerta, AstraZeneca, BeiGene, Nordic Nanovector, Incyte, Debiopharm, Incyte, Genentech, Janssen, Loxo, MEI Pharma, MorphoSys, Takeda, and TG Therapeutics, and consulting/advisory roles in MEI Pharma, Debiopharm, Loxo, Takeda, AstraZeneca, and BeiGene. T.S. reports research funding from Ascentage, AstraZeneca, BeiGene, BMS, Juno Therapeutics, Kite, Oncternal, Pharmacyclics, and TG Therapeutics; membership on an entity’s board of directors or advisory committees in AstraZeneca, BeiGene, BMS, Celgene, Kite, and AbbVie; and speakers bureau fees from AstraZeneca, BeiGene, and BMS. P.M., M.S., A.B., and U.E. report stock and employment with AstraZeneca. J.C.B. reports stock and other ownership interests with Vincerx Pharma; honoraria from Pharmacyclics, AstraZeneca, Novartis, Syndax, and Trillium Therapeutics; consulting/advisory roles in Acerta Pharma, Janssen, Kura Oncology, Novartis, Syndax, and AstraZeneca; research funding from Acerta Pharma, Pharmacyclics, and Zencor; patents, royalties, and other intellectual property with The Ohio State University patents; and travel, accommodations, and expenses from Gilead Sciences, Janssen, Novartis, Pharmacyclics, and TG Therapeutics.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
PFS in TN CLL by higher-risk genomic feature. Shown are acalabrutinib-based regimens for (A) del(17p)/TP53m, (B) uIGHV, (C) CK overall, and (D) CK without del(17p)/TP53m. A, acalabrutinib; O, obinutuzumab.
Figure 2.
Figure 2.
OS in TN CLL by higher-risk genomic feature. Shown are acalabrutinib-based regimens for del(17p)/TP53m (A), uIGHV (B), or CK (C). A, acalabrutinib; O, obinutuzumab.
Figure 3.
Figure 3.
PFS in R/R CLL with acalabrutinib monotherapy for del(17p)/TP53m, uIGHV, CK overall, and CK without del(17p)/TP53m.
Figure 4.
Figure 4.
OS in R/R CLL with acalabrutinib monotherapy for del(17p)/TP53m, uIGHV, or CK.
Figure 5.
Figure 5.
ORR in TN and R/R CLL. Shown are ORR by higher-risk genomic feature in the TN CLL cohort (acalabrutinib-based regimens) (A) and R/R CLL cohort (acalabrutinib monotherapy) (B). CR includes CRi; PR includes nPR. CRi, CR with incomplete blood count recovery; nPR, nodular PR; PD, progressive disease; SD, stable disease.
Figure 6.
Figure 6.
PFS in TN and R/R CLL by higher-risk vs lower-risk genomic feature. Shown are PFS in TN CLL with acalabrutinib-based regimens for del(17p)/TP53m vs no del(17p)/TP53m (A), uIGHV vs mIGHV (B), and CK vs no CK (C) and PFS in R/R CLL with acalabrutinib monotherapy for del(17p)/TP53m vs no del(17p)/TP53m (D), uIGHV vs mIGHV (E), and CK vs no CK (F).
Figure 6.
Figure 6.
PFS in TN and R/R CLL by higher-risk vs lower-risk genomic feature. Shown are PFS in TN CLL with acalabrutinib-based regimens for del(17p)/TP53m vs no del(17p)/TP53m (A), uIGHV vs mIGHV (B), and CK vs no CK (C) and PFS in R/R CLL with acalabrutinib monotherapy for del(17p)/TP53m vs no del(17p)/TP53m (D), uIGHV vs mIGHV (E), and CK vs no CK (F).
Figure 7.
Figure 7.
OS in TN and R/R CLL by higher-risk vs lower-risk genomic feature. Shown are OS in TN CLL with acalabrutinib-based regimens for del(17p)/TP53m vs no del(17p)/TP53m (A), uIGHV vs mIGHV (B), and CK vs no CK (C) and OS in R/R CLL with acalabrutinib monotherapy for del(17p)/TP53m vs no del(17p)/TP53m (D), uIGHV vs mIGHV (E), and CK vs no CK (F).
Figure 7.
Figure 7.
OS in TN and R/R CLL by higher-risk vs lower-risk genomic feature. Shown are OS in TN CLL with acalabrutinib-based regimens for del(17p)/TP53m vs no del(17p)/TP53m (A), uIGHV vs mIGHV (B), and CK vs no CK (C) and OS in R/R CLL with acalabrutinib monotherapy for del(17p)/TP53m vs no del(17p)/TP53m (D), uIGHV vs mIGHV (E), and CK vs no CK (F).
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