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Clinical Trial
. 2021 Sep 1;39(25):2768-2778.
doi: 10.1200/JCO.20.03736. Epub 2021 May 27.

Venetoclax Combined With FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia

Courtney D DiNardo  1 , Curtis A Lachowiez  2 , Koichi Takahashi  1 , Sanam Loghavi  3 , Lianchun Xiao  4 , Tapan Kadia  1 , Naval Daver  1 , Maria Adeoti  1 , Nicholas J Short  1 , Koji Sasaki  1 , Sa Wang  3 , Gautam Borthakur  1 , Ghayas Issa  1 , Abhishek Maiti  1 , Yesid Alvarado  1 , Naveen Pemmaraju  1 , Guillermo Montalban Bravo  1 , Lucia Masarova  1 , Musa Yilmaz  1 , Nitin Jain  1 , Michael Andreeff  1 , Elias Jabbour  1 , Guillermo Garcia-Manero  1 , Steven Kornblau  1 , Farhad Ravandi  1 , Marina Y Konopleva  1 , Hagop M Kantarjian  1
Affiliations
Clinical Trial

Venetoclax Combined With FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia

Courtney D DiNardo et al. J Clin Oncol. .

Abstract

Purpose: Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving frontline therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refractory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic options. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML.

Materials and methods: The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-escalation algorithm for identification of maximum tolerated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML.

Results: Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events occurring in ≥ 10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a composite CR. Measurable residual disease-negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improvement in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML.

Conclusion: Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep remissions and a high rate of transition to successful transplantation.

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Conflict of interest statement

Courtney D. DiNardoLeadership: Notable LabsStock and Other Ownership Interests: Notable LabsHonoraria: Agios, Celgene, AbbVie, Jazz Pharmaceuticals, Daiichi Sankyo, Novartis, TakedaConsulting or Advisory Role: Celgene, Agios, AbbVieResearch Funding: AbbVie, Agios, Celgene, Daiichi Sankyo Koichi TakahashiHonoraria: Celgene, Novartis, GlaxoSmithKline, SymBio Pharmaceuticals, DAVA PharmaceuticalsConsulting or Advisory Role: SymBio Pharmaceuticals, Novartis, GlaxoSmithKline, CelgeneResearch Funding: Onconova TherapeuticsTravel, Accommodations, Expenses: SymBio Pharmaceuticals, Celgene, GlaxoSmithKline, DAVA Pharmaceuticals Sanam LoghaviStock and Other Ownership Interests: AbbVie, PureTechHonoraria: Curio ScienceConsulting or Advisory Role: Seattle Genetics, Gerson Lehrman Group, Guidepoint GlobalTravel, Accommodations, Expenses: Curio Science Tapan KadiaConsulting or Advisory Role: Novartis, Jazz Pharmaceuticals, Pfizer, AbbVie/Genentech, AgiosResearch Funding: Bristol Myers Squibb, Celgene, Sanofi, Amgen, BiolineRx, Incyte, Genentech/AbbVie, Pfizer, Jazz Pharmaceuticals, AstraZeneca, Astellas Pharma, Ascentage Pharma, Genfleet, Cyclacel Naval DaverHonoraria: BMS, Jazz Pharmaceuticals, Novartis, Incyte, Otsuka, Immunogen, Pfizer, Astellas Pharma, AbbVieConsulting or Advisory Role: Celgene, Agios, Jazz Pharmaceuticals, Pfizer, AbbVie, Astellas Pharma, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Otsuka, Incyte, Karyopharm Therapeutics, Sunesis Pharmaceuticals, Amgen, Immunogen, Genentech, Servier, Syndax, Trillium TherapeuticsResearch Funding: Bristol Myers Squibb, Pfizer, Immunogen, Genentech, Nohla Therapeutics, AbbVie, Astellas Pharma, Servier, Daiichi Sankyo, Novartis, Karyopharm Therapeutics, Incyte, Sunesis Pharmaceuticals, Sobi Nicholas J. ShortHonoraria: AmgenConsulting or Advisory Role: AstraZenecaResearch Funding: Takeda, Astellas Pharma Koji SasakiHonoraria: OtsukaConsulting or Advisory Role: Novartis, Pfizer, TakedaResearch Funding: NovartisTravel, Accommodations, Expenses: Otsuka Sa WangConsulting or Advisory Role: Boston Biomedical, GlaxoSmithKline, Blueprint Medicines, CapricoResearch Funding: GlaxoSmithKline, Autolus Ltd, Genmab Gautam BorthakurConsulting or Advisory Role: Argenx, PTC Therapeutics, BiolineRx, BioTheryX, Nkarta, Treadwell Therapeutics, Novartis, Catamaran Bio, TakedaResearch Funding: Incyte, GlaxoSmithKline, Cyclacel, BiolineRx, MedImmune, Lilly, Oncoceutics, Ryvu Therapeutics, Janssen Scientific Affairs, Bristol Myers Squibb, AbbVie, Novartis, AstraZeneca, Mundipharma Research, PTC Therapeutics, BioTheryX, XBiotech, Arvinas, Astex Pharmaceuticals, TCR2 Therapeutics, Nkarta, Treadwell Therapeutics, Cellestia Biotech Ghayas IssaConsulting or Advisory Role: Novartis, Kura OncologyResearch Funding: Novartis, Syndax, Kura Oncology Abhishek MaitiResearch Funding: Celgene Yesid AlvaradoResearch Funding: Jazz Pharmaceuticals, FibroGen, Sun Pharma, BerGenBio, Daiichi Sankyo/Lilly, Astex Pharmaceuticals Naveen PemmarajuEmployment: MD Anderson Cancer CenterLeadership: ASH, ASCOHonoraria: Incyte, Novartis, LFB Biotechnologies, Stemline Therapeutics, Celgene, AbbVie, MustangBio, Roche Molecular Diagnostics, Blueprint Medicines, DAVA Pharmaceuticals, SpringerConsulting or Advisory Role: Blueprint Medicines, Pacylex, Immunogen, Bristol Myers SquibbResearch Funding: Novartis, Stemline Therapeutics, Samus Therapeutics, AbbVie, Cellectis, Affymetrix/Thermo Fisher Scientific, Daiichi Sankyo, PlexxikonTravel, Accommodations, Expenses: Stemline Therapeutics, Celgene, AbbVie, DAVA Oncology, MustangBioUncompensated Relationships: Dan's House of Hope, Oncology Times Guillermo BravoResearch Funding: IFM Therapeutics Musa YilmazResearch Funding: Daiichi Sankyo, Pfizer Nitin JainHonoraria: Pharmacyclics, ADC Therapeutics, Adaptive Biotechnologies, AbbVie/Genentech, Janssen, AstraZeneca/MedImmune, Servier, Precision Biosciences, BeiGene, TG Therapeutics, Cellectis, Bristol Myers Squibb/CelgeneConsulting or Advisory Role: Pharmacyclics, ADC Therapeutics, Adaptive Biotechnologies, AbbVie/Genentech, Janssen, AstraZeneca/MedImmune, Servier, Precision Biosciences, BeiGene, TG Therapeutics, Cellectis, Bristol Myers Squibb/CelgeneResearch Funding: Pfizer, Pharmacyclics, AbbVie, Genentech/Roche, Incyte, Infinity Pharmaceuticals, Bristol Myers Squibb, Seattle Genetics, Celgene, ADC Therapeutics, Servier, AstraZeneca/MedImmune, Cellectis, Adaptive Biotechnologies, Precision Biosciences, Aprea Therapeutics, Fate Therapeutics, Kite, a Gilead company Michael AndreefStock and Other Ownership Interests: Reata Pharmaceuticals, Aptose Biosciences, Eutropics, Senti Biosciences, Oncoceutics, OncolyzeConsulting or Advisory Role: Daiichi Sankyo, Jazz Pharmaceuticals, Celgene, Amgen, AstraZenecaResearch Funding: Daiichi Sankyo, Breast Cancer Research Foundation, United Therapeutics, Ono Pharmaceutical, Karyopharm Therapeutics, CPRIT, NIH/NCI, Amgen, AstraZenecaPatents, Royalties, Other Intellectual Property: Patent with ReataTravel, Accommodations, Expenses: Aptose Biosciences, Oncoceutics, Amgen, AstraZeneca Elias JabbourConsulting or Advisory Role: Pfizer, Takeda, Amgen, AbbVie, Bristol Myers Squibb, Incyte, Adaptive Biotechnologies, Astellas Pharma, GenentechResearch Funding: Pfizer, AbbVie, Amgen, Takeda, Adaptive Biotechnologies, Ascentage Pharma Group Guillermo Garcia-ManeroHonoraria: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Helssin, AbbVieConsulting or Advisory Role: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Jazz Pharmaceuticals, Bristol Myers Squibb, Helsinn TherapeuticsResearch Funding: Celgene, Astex Pharmaceuticals, Amphivena, Helsinn Therapeutics, Novartis, AbbVie, Bristol Myers Squibb, Onconova Therapeutics, H3 Biomedicine, Merck Farhad RavandiHonoraria: Amgen, Pfizer, Astellas Pharma, Orsenix, Celgene, Agios, AbbVie/Genentech, AstraZeneca, Bristol Myers Squibb, Takeda, Jazz Pharmaceuticals, NovartisConsulting or Advisory Role: Amgen, Astellas Pharma, Orsenix, Celgene, Jazz Pharmaceuticals, Agios, AbbVie/Genentech, Bristol Myers Squibb, AstraZeneca, Taiho Oncology, Syros Pharmaceuticals, Certara IncResearch Funding: Bristol Myers Squibb, Amgen, Macrogenics, Xencor, Selvita, Cellerant Marina Y. KonoplevaHonoraria: AbbVie, Genentech, Roche, Amgen, Stemline Therapeutics, KisoJi BiotechnologyConsulting or Advisory Role: AbbVie, Genentech/Roche, Stemline Therapeutics, Amgen, Forty Seven, KisoJi Biotechnology, Roche, JanssenResearch Funding: AbbVie, Genentech, Roche, Lilly, Cellectis, Calithera Biosciences, Ablynx, Agios, Ascentage Pharma, AstraZeneca, SanofiPatents, Royalties, Other Intellectual Property: Novartis—Pending, Eli Lilly—Research Funding; Issued/Licensed, Reata Pharmaceutical—Research Funding (Issued, Licensed, Royalities) Hagop M. KantarjianHonoraria: AbbVie, Amgen, ARIAD, Bristol Myers Squibb, Immunogen, Orsenix, Pfizer, Agios, Takeda, Actinium PharmaceuticalsResearch Funding: Pfizer, Amgen, Bristol Myers Squibb, Novartis, ARIAD, Astex Pharmaceuticals, AbbVie, Agios, Cyclacel, Immunogen, Jazz PharmaceuticalsNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Adverse events by (A) AML type and (B) cohort. AML, acute myeloid leukemia; ND-AML, newly diagnosed acute myeloid leukemia; R/R-AML, relapsed or refractory acute myeloid leukemia; SSTI, skin and soft tissue infection.
FIG 2.
FIG 2.
(A) Swimmers plot of all study participants and (B) response across study cohorts. Horizontal arrows indicate patients remaining on study. CR, complete response; CRc, composite CR; CRh, CR with partial hematologic recovery; CRi, CR with incomplete count recovery; HSCT, hematopoietic stem-cell transplantation; MLFS, morphologic leukemia-free state; MRD, measurable residual disease; ND-AML, newly diagnosed acute myeloid leukemia; NR, not reached; PD, progressive disease; R/R-AML, relapsed or refractory acute myeloid leukemia.
FIG 3.
FIG 3.
(A) EFS and (B) OS by cohort. EFS, event-free survival; ND-AML, newly diagnosed acute myeloid leukemia; OS, overall survival; R/R-AML, relapsed or refractory acute myeloid leukemia.
FIG 4.
FIG 4.
Outcomes in R/R-AML on the basis of (A) salvage number and (B) 3-month landmark analysis of HSCT in patients attaining CRc. Outcomes in R/R-AML with versus without mutations in (C) tumor suppressor and (D) active signaling genes. alloHSCT, allogeneic hematopoietic stem-cell transplantation; HSCT, hematopoietic stem-cell transplantation; ND-AML, newly diagnosed acute myeloid leukemia; OS, overall survival; R/R-AML, relapsed or refractory acute myeloid leukemia.
FIG A1.
FIG A1.
Genomic landscape of AML cohorts. AML, acute myeloid leukemia; CR, complete response; CRh, CR with partial hematologic recovery; CRi, CR with incomplete count recovery; MLFS, morphologic leukemia-free state; NR, not reached.
FIG A2.
FIG A2.
Median time to count recovery (ANC ≥ 500; platelet count ≥ 50,000 cells/µL) by (A-C) cycle and (D-F) study cohort. ANC, absolute neutrophil count.
See this image and copyright information in PMC

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