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446 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemias: Clinical and Epidemiological: Frailty, Age, and Care Provisions-Impact on AML Outcomes
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, Clinical trials, Research, AML, Clinical Research, Supportive Care, Diseases, Treatment Considerations, Adverse Events, Myeloid Malignancies
Sunday, December 8, 2024: 9:45 AM

Ian M. Bouligny, MD1, Hagop M. Kantarjian, MD1, Musa Yilmaz, MD1*, Naval Daver, MD2, Gautam Borthakur, MD3, Courtney D. DiNardo, MD, MSc1, Guillermo Montalban-Bravo, MD1, Nicholas J. Short, MD1, Yesid Alvarado Valero, MD1, Nitin Jain, MD1, Naveen Pemmaraju, MD1, Danielle Hammond, MD1, Kelly S. Chien, MD4, Koichi Takahashi, MD, PhD5, Ghayas C. Issa, MD1, Hussein A. Abbas, MD, PhD1, Elias Jabbour, MD1, Guillermo Garcia-Manero, MD1, Farhad Ravandi, MBBS6 and Tapan M. Kadia, MD1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2MD Anderson Cancer Center, Houston, TX
3Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, MD Anderson, Houston, TX
5Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
6Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX

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.

Disclosures: 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; Amgen: Research Funding; Astellas: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; Prelude: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; BMS: Consultancy, Honoraria; Astyex/Taiho: Research Funding; Syndax: Honoraria. 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.

*signifies non-member of ASH