Safety and Efficacy of G-CSF with Intensive Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia: A Subgroup Analysis of the Phase II Trial of Venetoclax in Combination with Cladribine, Idarubicin, and Cytarabine

Introduction

Granulocyte colony-stimulating factor (G-CSF) support is common in the treatment of acute myeloid leukemia (AML) to hasten count recovery, particularly during periods of prolonged neutropenia and infection. However, the safety and efficacy of G-CSF in combination with newer induction strategies - such as intensive chemotherapy with venetoclax - remain unclear.

Methods

This study analyzed 88 patients with newly diagnosed AML treated in the phase II trial of cladribine, idarubicin, and cytarabine in combination with venetoclax (CLIA-venetoclax, NCT02115295). The primary objective was to quantify the impact of G-CSF on the time to count recovery. Secondary objectives included comparing the incidence of grade ≥3 toxicities, overall survival (OS), and relapse-free survival (RFS) of patients treated with and without G-CSF support. An exploratory objective was to determine the molecular predictors of count recovery.

Patients received cladribine 5 mg/m² D1-5, cytarabine 1-1.5 mg/m² D1-5, idarubicin 8-10 mg/m² D1-3, and venetoclax 400 mg D2-8, with dose adjustments for CYP3A inhibitors, for up to 6 cycles. FLT3 and BCR-ABL1 inhibitors were permitted. Antimicrobial prophylaxis was administered with the regimen. The trial allowed treating physicians to use filgrastim 300-480 µg daily for prolonged neutropenia or neutropenic fever; a trial amendment integrated pegfilgrastim at a dose of 6 mg SQ once between D5-9 of each cycle. We defined count recovery as an absolute neutrophil count (ANC) ≥1000 cells/mm³ with platelets ≥100 × 10⁹/L.

Results

In the overall cohort of 88 patients, 85 (97%) had AML and 3 (3%) had MPAL. The median age at diagnosis was 49 years (range, 18-64). Twelve (14%) patients had AML-MRC; 33 (38%) harbored secondary-type mutations defined by ELN 2022 (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2). Sixteen (18%) patients had FLT3-ITD - 8 (9%) received gilteritinib and 1 (1%) received midostaurin. Forty-two (47%) patients received G-CSF support in cycle 1, and 64 (73%) received G-CSF support in any cycle.

G-CSF use in the first cycle significantly improved the time to count recovery (25 d. with G-CSF vs 29 d. without, p = 0.028). The median ANC at the best response was significantly better in the G-CSF cohort compared to those treated without (2800 vs 1560 cells/mm³, p = 0.042). G-CSF use in the first cycle was associated with a non-significantly higher proportion of patients that achieved a complete response by day 28 (82% with G-CSF vs 67% without, p = 0.203). MRD negativity by multiparameter flow cytometry at D28 was not significantly different between cohorts (76% with G-CSF vs 70% without, p = 0.783). There was no difference in the proportion of patients refractory to the first cycle (5% with G-CSF vs 14% without, p = 0.269). In a multivariate Cox model analyzing the impact of 9 mutations on the time to count recovery, only FLT3-ITD was associated with delayed count recovery (HR: 0.403, p = 0.004). In contrast, KRAS mutations were associated with swifter count recovery (HR: 3.435, p = 0.005).

G-CSF use significantly reduced the incidence of bacteremia in cycle 1 (5% with G-CSF vs 35% without, p < 0.001). Decreased rates of bacteremia appeared to be attributable, in part, to reduced rates of gram-positive infections (S. mitis/oralis, S. epidermidis, and S. aureus; 2% with G-CSF vs 24% without, p = 0.004). These findings translated to a reduction in neutropenic fever during induction that was nearly significant (64% with G-CSF vs 83% without, p = 0.057).

There were no differences in the ICU admission rate (0% with G-CSF vs 7% without, p = 0.242) or in the duration of hospitalization during cycle 1 (28 d. with G-CSF vs 25 d. without, p = 0.192). G-CSF use during any cycle did not significantly impact the overall survival (not reached [NR] in both cohorts, 2-y. OS: 78% with G-CSF vs 63% without, p = 0.201). G-CSF did not significantly impact relapse rates, with fewer relapses seen with G-CSF (NR in both cohorts, 2-y. relapse incidence: 11% with G-CSF vs 28% without, p = 0.143).

Conclusion

G-CSF support with intensive chemotherapy and venetoclax appeared to be safe and effective - significantly improving the time to count recovery. G-CSF use decreased the incidence of bacteremia, particularly for gram-positive infections. FLT3-ITD AML was associated with delayed count recovery, likely due to concurrent TKI use. G-CSF use had no impact on the incidence of AML relapse.

Kantarjian:AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Yilmaz:daiichi sankyo: Honoraria, Research Funding. Daver:Astellas: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Jazz: Consultancy; Menarini Group: Consultancy; FATE Therapeutics: Other: Consulting Fees, Research Funding; Servier: Consultancy, Research Funding; Syndax: Consultancy; Hanmi: Research Funding; Trovagene: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy; KITE: Research Funding; Shattuck Labs: Consultancy; Genentech: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Arog: Consultancy; Pfizer: Consultancy, Research Funding; Agios: Consultancy; Novartis: Consultancy; Novimmune: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Glycomimetics: Research Funding. Borthakur:Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. DiNardo:Loxo: Research Funding; Jazz: Consultancy, Honoraria; Amgen: Consultancy; Rigel: Research Funding; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; GSK: Consultancy, Honoraria; ImmuneOnc: Research Funding; Astellas: Consultancy, Honoraria; Cleave: Research Funding; Foghorn: Research Funding; Riegel: Honoraria; Schrodinger: Consultancy, Honoraria; Astex: Research Funding; Notable Labs: Honoraria; Immunogen: Honoraria; Gilead: Consultancy; GenMab: Consultancy, Honoraria, Other: data safety board; Genetech: Honoraria; BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Stemline: Consultancy. Montalban-Bravo:Rigel: Research Funding; Takeda: Research Funding. Short:NextCure: Research Funding; Pfizer Inc.: Honoraria; GSK: Consultancy, Research Funding; Stemline Therapeutics: Research Funding; Amgen: Honoraria; Novartis: Honoraria; Xencor: Research Funding; Adaptive Biotechnologies: Honoraria; BeiGene: Honoraria; Astellas Pharma, Inc.: Honoraria, Research Funding; Takeda Oncology: Honoraria, Research Funding; Sanofi: Honoraria; Autolus: Honoraria. Jain:Pharmacyclics: Consultancy, Honoraria, Other: Travel Support, Research Funding; Dialectic Therapeutics: Research Funding; CareDx: Consultancy, Honoraria, Other: Travel Support; Genentech: Consultancy, Honoraria, Other: Travel Support, Research Funding; Loxo Oncology: Research Funding; Ipsen: Consultancy, Honoraria, Other: Travel Support; Incyte: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Aprea Therapeutics: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel Support; MingSight: Honoraria, Research Funding; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Other: Travel Support; Fate Therapeutics: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support; TransThera Sciences: Research Funding; Servier: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; MEI Pharma: Consultancy, Honoraria, Other: Travel Support; Pfizer: Research Funding; NovalGen: Research Funding; Newave: Research Funding; Medisix: Research Funding; ADC Therapeutics: Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding. Pemmaraju:Incyte: Honoraria; Neopharm: Honoraria; Stemline Therapeutics: Honoraria, Other: Travel Expenses, Research Funding; ClearView Healthcare Partners: Consultancy; Protagonist Therapeutics: Consultancy; Triptych Health Partners: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Honoraria, Other: Travel Expenses; LFB Biotechnologies: Honoraria; Mustang Bio: Honoraria, Other: Travel Expenses, Research Funding; Affymetrix/Thermo Fisher Scientific: Research Funding; Roche Molecular Diagnostics: Honoraria; Springer Science + Business Media: Honoraria; Immunogen: Consultancy; Blueprint Medicines: Consultancy, Honoraria; Aptitude Health: Honoraria; Novartis: Honoraria, Research Funding; DAVA Oncology: Honoraria, Other: Travel Expenses; Pacylex: Consultancy; CareDx: Honoraria; Cellectis: Research Funding; Samus Therapeutics: Research Funding; Plexxikon: Research Funding; Daiichi Sankyo: Research Funding; Blueprint Medicines OncLive PeerView Institute for Medical Education: Consultancy, Other: advisory board; CTI BioPharma: Consultancy; Astellas: Consultancy; AbbVie: Honoraria, Other: Travel Expenses, Research Funding; ASH Committee on Communications ASCO Cancer.NET Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: uncompensated. Chien:Rigel Pharmaceuticals: Consultancy; AbbVie: Consultancy. Issa:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Astex: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Merck: Research Funding; Celgene: Research Funding; Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding. Abbas:Ascentage: Research Funding; Blueprint Medicines Corporation: Research Funding; Alamar Biosciences: Honoraria; Illumina: Honoraria, Other: Inkind Support, Research Funding; Molecular Partners: Consultancy; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Enzyme By Design: Research Funding. Jabbour:AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Garcia-Manero:Novartis: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Astex: Research Funding; Merck: Research Funding; H3 Biomedicine: Research Funding; Aprea: Research Funding; Curis: Research Funding; Janssen: Research Funding; Onconova: Research Funding; Astex: Other: Personal fees; Bristol Myers Squibb: Other: Personal fees, Research Funding; AbbVie: Research Funding; Helsinn: Research Funding; Amphivena: Research Funding; Helsinn: Other: Personal fees; Genentech: Other: Personal fees. Ravandi:Abbvie: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Prelude: Consultancy, Honoraria, Research Funding; Astyex/Taiho: Research Funding; Amgen: Research Funding; Xencor: Research Funding. Kadia:JAZZ: Research Funding; Servier: Consultancy; Rigel: Honoraria; Genentech: Consultancy, Research Funding; Sellas: Consultancy, Research Funding; BMS: Consultancy, Research Funding; DrenBio: Consultancy, Research Funding; Novartis: Honoraria; Abbvie: Consultancy, Research Funding; Regeneron: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Ascentage: Research Funding; Incyte: Research Funding; ASTEX: Research Funding; AstraZeneca: Research Funding; Cellenkos: Research Funding.