ANALYSIS OF COVID-19 INFECTIONS WITH FIXED-DURATION ACALABRUTINIB-VENETOCLAX COMBINATIONS IN TREATMENT-NAIVE CHRONIC LYMPHOCYTIC LEUKEMIA IN THE PHASE 3 AMPLIFY TRIAL
J. R. Brown, A. P. Kater, W. Jurczak, P. Ghia, B. Eichhorst, A. C. Peters, M. A. Pavlovsky, M. Yağcı, D. Lysak, K. Miller, T. Fujimori, S. Rule, M. de Borja, J. F. Seymour
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We sought to further characterize COVID-19 AEs in AMPLIFY.</p><p><b>Methods:</b> Pts with TN CLL aged ≥ 18 y with ECOG ≤ 2 and without del(17p) or <i>TP53</i> mutation were randomized 1:1:1 to receive AV (oral acalabrutinib 100 mg BID [cycles (C) 1–14]; oral venetoclax QD [C3–14 with 5-wk dose ramp-up]), AVO (AV dosing as above, + intravenous obinutuzumab 1000 mg C2 [days 1, 8, and 15] and 3−7 [day 1]), or investigator’s choice of FCR or BR (C1−6). We report incidences of COVID-19 infections and deaths (during the tx-emergent period [up to earliest of 30 d after last dose or start of subsequent therapy] and up to the time of interim analysis [30 Apr 2024]), COVID-19 vaccination status, and COVID-19 deaths by pandemic waves.</p><p><b>Results:</b> In total, 867 pts were randomized from 2019 to 2021, including 291, 286, and 290 in the AV, AVO, FCR/BR arms, respectively, among whom 53.3% (AV), 50.0% (AVO), and 38.6% (FCR/BR) had ≥ 1 COVID-19 vaccination, most commonly tozinameran (Pfizer) in 35.4%, 31.5%, and 23.4% of pts. Among the 867 randomized pts, 321 had ≥ 1 COVID-19 event anytime during the trial, including 109 (37.5%), 131 (45.8%), and 81 (27.9%) pts in the AV, AVO, and FCR/BR arms, respectively, of whom 58.7%, 52.7%, and 12.3% experienced ≥ 1 event during the tx-emergent period. Median age among pts with ≥ 1 COVID-19 event was 60 y (23.1% > 65 y) versus 61 y (26.8% > 65 y) in the overall study population. Among study-treated pts (≥ 1 dose received), COVID-19 AEs were grade ≥ 3 in 29/291 (10.0%), 65/284 (22.9%), and 38/259 (14.7%) pts in the AV, AVO, and FCR/BR arms, respectively. COVID-19 AEs led to permanent discontinuation of ≥ 1 study tx in the regimen in 2.4% (AV), 8.1% (AVO), and 1.2% (FCR/BR) of pts. Death due to COVID-19 any time during the trial occurred in 10 (3.4%), 25 (8.7%), and 21 (7.2%) pts in the AV, AVO, and FCR/BR arms, respectively (of which 80.0%, 60.0%, and 33.3%, respectively, occurred during the tx-emergent period). Vaccination rates among all pts who died from COVID-19 were 0% (AV), 24.0% (AVO), and 9.5% (FCR/BR). COVID-19 death rates were highest during the second pandemic wave, with the highest rates in the AVO and FCR/BR arms (Figure).</p><p><b>Conclusions:</b> In this post hoc analysis, COVID-19–associated deaths occurred most frequently in the AVO and FCR/BR arms, followed by the AV arm. Vaccination rates were lower among pts with COVID-19 death versus overall. COVID-19 deaths were most prevalent during the second pandemic wave, particularly in the AVO and FCR/BR arms.</p><p><b>Research</b> <b>funding declaration:</b> Study funded by AstraZeneca</p><p><b>Encore Abstract:</b> EHA 2025</p><p><b>Keywords:</b> combination therapies; chronic lymphocytic leukemia (CLL); ongoing trials</p><p><b>Potential sources of conflict of interest:</b></p><p><b>J. R. Brown</b></p><p><b>Consultant or advisory role:</b> AbbVie, Acerta/AstraZeneca, Alloplex Biotherapeutics, BeiGene, Bristol-Myers Squibb, EcoR1, Galapagos NV, Genentech/Roche, Grifols Worldwide Operations, InnoCare Pharma Inc, Loxo/Lilly, Magnet Biomedicine, Merck, Pharmacyclics</p><p><b>Other remuneration:</b> Research Funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, TG Therapeutics. Data Safety Monitoring Board: Grifols Therapeutics. Royalties: UpToDate</p><p><b>A. P. Kater</b></p><p><b>Consultant or advisory role:</b> AbbVie, AstraZeneca, BeiGene, BMS, Genentech/Roche Janssen</p><p><b>Other remuneration:</b> Research/Trial Support: AbbVie, AstraZeneca, BeiGene, BMS, Genentech/Roche Janssen. Speaker’s fee: AbbVie, Janssen, AstraZeneca, Lilly, BeiGene</p><p><b>W. Jurczak</b></p><p><b>Consultant or advisory role:</b> AbbVie/Genentech, AstraZeneca, BeiGene, Janssen-Cilag, Lilly, Takeda</p><p><b>Other remuneration:</b> Research Grant/Funding: AbbVie/Genentech, AstraZeneca, BeiGene, Janssen-Cilag, Lilly, Merck, MSD, Roche, Takeda</p><p><b>P. Ghia</b></p><p><b>Consultant or advisory role:</b> AbbVie, AstraZeneca, BeiGene, BMS, Galapagos, Johnson & Johnson, Lilly/Loxo Oncology, MSD, Roche</p><p><b>Honoraria:</b> AbbVie, AstraZeneca, BeiGene, BMS, Galapagos, Johnson & Johnson, Lilly/Loxo Oncology, MSD, Roche</p><p><b>B. Eichhorst</b></p><p><b>Honoraria:</b> Roche, AbbVie, BeiGene, AstraZeneca, MSD</p><p><b>Other remuneration:</b> Research Funding: Janssen, Gilead, Roche, AbbVie, BeiGene, AstraZeneca. Speaker's Bureau: Roche, AbbVie, BeiGene, AstraZeneca, MSD</p><p><b>A. C. Peters</b></p><p><b>Consultant or advisory role:</b> AstraZeneca, AbbVie</p><p><b>M. A. Pavlovsky</b></p><p><b>Consultant or advisory role:</b> BeiGene, AstraZeneca, Ascentage Pharma</p><p><b>Honoraria:</b> AbbVie, Janssen, AstraZeneca</p><p><b>Educational</b> <b>grants:</b> Sanofi, Roche, AstraZeneca, BeiGene</p><p><b>D. Lysak</b></p><p><b>Consultant or advisory role:</b> AstraZeneca, Johnson & Johnson, Eli Lilly</p><p><b>K. Miller</b></p><p><b>Employment or leadership position:</b> AstraZeneca</p><p><b>Stock ownership:</b> AstraZeneca</p><p><b>T. Fujimori</b></p><p><b>Employment or leadership position:</b> AstraZeneca</p><p><b>S. Rule</b></p><p><b>Employment or leadership position:</b> AstraZeneca</p><p><b>Stock ownership:</b> AstraZeneca</p><p><b>M. de Borja</b></p><p><b>Employment or leadership position:</b> AstraZeneca</p><p><b>Stock ownership:</b> AstraZeneca, Roche</p><p><b>J. F. Seymour</b></p><p><b>Consultant or advisory role:</b> Genor Bio, TG Therapeutics</p><p><b>Honoraria:</b> AbbVie, AstraZeneca, BeiGene, BMS, Gilead, Janssen, Roche</p><p><b>Other remuneration:</b> Research Funding: AbbVie, BMS, Roche. 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引用次数: 0
Abstract
Introduction: An interim analysis of the ongoing phase 3 AMPLIFY trial (NCT03836261) showed significant progression-free survival benefit with both fixed-duration acalabrutinib-venetoclax combinations (± obinutuzumab; AV and AVO) versus investigator’s choice of fludarabine-cyclophosphamide-rituximab (FCR) or bendamustine-rituximab (BR) in patients (pts) with treatment (tx)-naive (TN) chronic lymphocytic leukemia (CLL), with initial data on COVID-19 adverse events (AEs) reported (Brown JR, et al., NEJM. 2025). We sought to further characterize COVID-19 AEs in AMPLIFY.
Methods: Pts with TN CLL aged ≥ 18 y with ECOG ≤ 2 and without del(17p) or TP53 mutation were randomized 1:1:1 to receive AV (oral acalabrutinib 100 mg BID [cycles (C) 1–14]; oral venetoclax QD [C3–14 with 5-wk dose ramp-up]), AVO (AV dosing as above, + intravenous obinutuzumab 1000 mg C2 [days 1, 8, and 15] and 3−7 [day 1]), or investigator’s choice of FCR or BR (C1−6). We report incidences of COVID-19 infections and deaths (during the tx-emergent period [up to earliest of 30 d after last dose or start of subsequent therapy] and up to the time of interim analysis [30 Apr 2024]), COVID-19 vaccination status, and COVID-19 deaths by pandemic waves.
Results: In total, 867 pts were randomized from 2019 to 2021, including 291, 286, and 290 in the AV, AVO, FCR/BR arms, respectively, among whom 53.3% (AV), 50.0% (AVO), and 38.6% (FCR/BR) had ≥ 1 COVID-19 vaccination, most commonly tozinameran (Pfizer) in 35.4%, 31.5%, and 23.4% of pts. Among the 867 randomized pts, 321 had ≥ 1 COVID-19 event anytime during the trial, including 109 (37.5%), 131 (45.8%), and 81 (27.9%) pts in the AV, AVO, and FCR/BR arms, respectively, of whom 58.7%, 52.7%, and 12.3% experienced ≥ 1 event during the tx-emergent period. Median age among pts with ≥ 1 COVID-19 event was 60 y (23.1% > 65 y) versus 61 y (26.8% > 65 y) in the overall study population. Among study-treated pts (≥ 1 dose received), COVID-19 AEs were grade ≥ 3 in 29/291 (10.0%), 65/284 (22.9%), and 38/259 (14.7%) pts in the AV, AVO, and FCR/BR arms, respectively. COVID-19 AEs led to permanent discontinuation of ≥ 1 study tx in the regimen in 2.4% (AV), 8.1% (AVO), and 1.2% (FCR/BR) of pts. Death due to COVID-19 any time during the trial occurred in 10 (3.4%), 25 (8.7%), and 21 (7.2%) pts in the AV, AVO, and FCR/BR arms, respectively (of which 80.0%, 60.0%, and 33.3%, respectively, occurred during the tx-emergent period). Vaccination rates among all pts who died from COVID-19 were 0% (AV), 24.0% (AVO), and 9.5% (FCR/BR). COVID-19 death rates were highest during the second pandemic wave, with the highest rates in the AVO and FCR/BR arms (Figure).
Conclusions: In this post hoc analysis, COVID-19–associated deaths occurred most frequently in the AVO and FCR/BR arms, followed by the AV arm. Vaccination rates were lower among pts with COVID-19 death versus overall. COVID-19 deaths were most prevalent during the second pandemic wave, particularly in the AVO and FCR/BR arms.
Researchfunding declaration: Study funded by AstraZeneca
Other remuneration: Research Funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, TG Therapeutics. Data Safety Monitoring Board: Grifols Therapeutics. Royalties: UpToDate
A. P. Kater
Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, BMS, Genentech/Roche Janssen
期刊介绍：
Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged:
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