Measurable Residual Disease Response and Prognosis in Treatment-Naïve Acute Myeloid Leukemia With Venetoclax and Azacitidine

Keith W Pratz, Brian A Jonas, Vinod Pullarkat, Christian Recher, Andre C Schuh, Michael J Thirman, Jacqueline S Garcia, Courtney D DiNardo, Vladimir Vorobyev, Nicola S Fracchiolla, Su-Peng Yeh, Jun Ho Jang, Muhit Ozcan, Kazuhito Yamamoto, Arpad Illes, Ying Zhou, Monique Dail, Brenda Chyla, Jalaja Potluri, Hartmut Döhner, Keith W Pratz, Brian A Jonas, Vinod Pullarkat, Christian Recher, Andre C Schuh, Michael J Thirman, Jacqueline S Garcia, Courtney D DiNardo, Vladimir Vorobyev, Nicola S Fracchiolla, Su-Peng Yeh, Jun Ho Jang, Muhit Ozcan, Kazuhito Yamamoto, Arpad Illes, Ying Zhou, Monique Dail, Brenda Chyla, Jalaja Potluri, Hartmut Döhner

Abstract

Purpose: There is limited evidence on the clinical utility of monitoring measurable residual disease (MRD) in patients with acute myeloid leukemia treated with lower-intensity therapy. Herein, we explored the outcomes of patients treated with venetoclax and azacitidine who achieved composite complete remission (CRc; complete remission + complete remission with incomplete hematologic recovery) and MRD < 10-3 in the VIALE-A trial.

Methods: The patients included in this report were treated with venetoclax and azacitidine. Bone marrow aspirate samples for multiparametric flow cytometry assessments were collected for central analysis at baseline, end of cycle 1, and every three cycles thereafter. MRD-negative response was defined as < 1 residual blast per 1,000 leukocytes (< 10-3 or 0.1%) with an estimated analytic sensitivity of 0.0037%-0.0027%. CRc, duration of remission (DoR), event-free survival (EFS), and overall survival (OS) were assessed. A multivariate Cox regression analysis identified prognostic factors associated with OS.

Results: One hundred sixty-four of one hundred ninety (86%) patients with CRc were evaluable for MRD. MRD < 10-3 was achieved by 67 of 164 (41%), and 97 of 164 (59%) had MRD ≥ 10-3. The median DoR, EFS, and OS were not reached in patients with CRc and MRD < 10-3, and the 12-month estimates for DoR, EFS, and OS in this group were 81.2%, 83.2%, and 94.0%. Among patients with CRc and MRD ≥ 10-3, the median DoR, EFS, and OS were 9.7, 10.6, and 18.7 months. Multivariate analysis showed that CRc with MRD < 10-3 was a strong predictor of OS (adjusted hazard ratio = 0.285; 95% CI, 0.159 to 0.510; P < .001).

Conclusion: Patients who achieved CRc and MRD < 10-3 with venetoclax and azacitidine had longer DoR, EFS, and OS, than responding patients with MRD ≥ 10-3.

Trial registration: ClinicalTrials.gov NCT02993523.

Conflict of interest statement

Keith W. PratzConsulting or Advisory Role: Astellas Pharma, Boston Biomedical, AbbVieResearch Funding: Agios (Inst), Millennium (Inst), AbbVie (Inst), Daiichi Sankyo (Inst) Brian A. JonasConsulting or Advisory Role: AbbVie, Jazz Pharmaceuticals, GlycoMimetics, Treadwell Therapeutics, Takeda, Genentech, Bristol Myers Squibb/Pfizer, PfizerResearch Funding: Daiichi Sankyo (Inst), AbbVie (Inst), Pharmacyclics (Inst), Genentech/Roche (Inst), Glycomimetics (Inst), Celgene (Inst), FORMA Therapeutics (Inst), Incyte (Inst), Arog (Inst), Roche (Inst), Jazz Pharmaceuticals (Inst), Pfizer (Inst), Sigma-Tau (Inst), Forty Seven¸ Amgen (Inst), Immune-Onc Therapeutics (Inst), Loxo (Inst), Gilead/Forty Seven (Inst)Travel, Accommodations, Expenses: AbbVie Vinod PullarkatConsulting or Advisory Role: Novartis, Amgen, Pfizer, Jazz Pharmaceuticals, AbbVie/GenentechSpeakers' Bureau: Novartis, Amgen, Jazz Pharmaceuticals, AbbVie Christian RecherConsulting or Advisory Role: Celgene, Amgen, Novartis, Jazz Pharmaceuticals, AbbVie, Janssen, Astellas Pharma, MacroGenics¸ Daiichi Sankyo, Otsuka, Novartis¸ Incyte, Pfizer¸ Roche, TakedaResearch Funding: Celgene (Inst), Amgen (Inst), Jazz Pharmaceuticals (Inst), Astellas Pharma (Inst), Agios (Inst), Daiichi Sankyo (Inst), MaaT Pharma (Inst), Roche (Inst), AbbVie (Inst), Novartis (Inst), Chugai Pharma (Inst), IQVIA (Inst)Travel, Accommodations, Expenses: Incyte, Celgene, Sanofi, Amgen, Novartis, Daiichi Sankyo, Gilead Sciences Andre C. SchuhHonoraria: Celgene, Amgen, Pfizer, Novartis, Jazz PharmaceuticalsResearch Funding: Celgene, Amgen, Agios, Pfizer Michael J. ThirmanConsulting or Advisory Role: AstraZeneca, Genentech, AbbVie, Adaptive Biotechnologies, Celgene¸ PharmacyclicsResearch Funding: AbbVie (Inst), Syndax (Inst), Merck (Inst), TG Therapeutics (Inst) Jacqueline S. GarciaConsulting or Advisory Role: AbbVie, Takeda, Astellas PharmaResearch Funding: AbbVie (Inst), Pfizer (Inst), Genentech/Roche (Inst), Lilly (Inst), AstraZeneca (Inst), Prelude Therapeutics (Inst) Courtney D. DiNardoThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Leadership: 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 Vladimir VorobyevConsulting or Advisory Role: AstraZeneca, Janssen Oncology, Sanofi, Novartis, BeiGene, Roche, AbbVie, Takeda, Gilead SciencesSpeakers' Bureau: AbbVie, AstraZeneca, Amgen, BioCad, Janssen, Sanofi, Takeda¸ Novartis, BeiGeneTravel, Accommodations, Expenses: AstraZeneca Nicola S. FracchiollaConsulting or Advisory Role: Amgen, Jazz Pharmaceuticals, Incyte, AbbVieTravel, Accommodations, Expenses: Pfizer Su-Peng YehHonoraria: Novartis, Bristol Myers Squibb, Janssen¸ Takeda, AbbVie, Amgen, Sanofi, Bayer, Astellas PharmaConsulting or Advisory Role: AbbVie, Sanofi, Novartis, Pfizer, Chugai Pharma Jun Ho JangSpeakers' Bureau: Novartis Muhit OzcanResearch Funding: Janssen, Celgene, Takeda, Bayer, Merck, Archigen Biotech, Roche, AbbVie, Acerta Pharma/AstraZeneca Kazuhito YamamotoHonoraria: Kyowa Hakko Kirin, Takeda¸ Janssen, Bristol Myers Squibb, Celgene, Sumitomo Dainippon, Ono Pharmaceutical, Chugai Pharma, Novartis, Otsuka, Mundipharma, Eisai, MSD, Meiji Seika Kaisha, Sanofi, Nippon Shinyaku, AbbVie, GlaxoSmithKline, SymBio Pharmaceuticals, Micron, Daiichi SankyoConsulting or Advisory Role: Ono Pharmaceutical, Meiji Seika Kaisha, Chugai Pharma, Bristol Myers Squibb, Kyowa Hakko Kirin, Takeda, Celgene, HUYA Bioscience International, Stemline Therapeutics, Eisai, Janssen, AstraZeneca¸ Daiichi Sankyo, AbbVie,Research Funding: Chugai Pharma (Inst), Novartis (Inst), ARIAD (Inst), Takeda (Inst), Gilead Sciences (Inst), AbbVie (Inst), Ono Pharmaceutical (Inst), Celgene (Inst), Solasia Pharma (Inst), MSD (Inst), Eisai (Inst), Zenyaku Kogyo (Inst), Bayer (Inst), SymBio Pharmaceuticals (Inst), AstraZeneca (Inst), Incyte (Inst), Mundipharma (Inst), Yakult Pharmaceutical (Inst) Arpad IllesConsulting or Advisory Role: Janssen, Takeda, Novartis, Pfizer, Roche, CelgeneResearch Funding: Takeda, Seattle GeneticsTravel, Accommodations, Expenses: Novartis, Janssen, Pfizer, Roche Ying ZhouStock and Other Ownership Interests: AbbVie Monique DailEmployment: Genentech/RocheStock and Other Ownership Interests: Roche/Genentech Brenda ChylaEmployment: AbbVieStock and Other Ownership Interests: AbbVie Jalaja PotluriEmployment: AbbVieStock and Other Ownership Interests: AbbVie Hartmut DöhnerConsulting or Advisory Role: AbbVie, Agios¸ Amgen, Astellas Pharma, Celgene, Jazz Pharmaceuticals, Janssen Oncology, Novartis, AstraZeneca, Berlin-Chemie, GEMoaB, Bristol Myers Squibb/Celgene, Gilead Sciences, SyndaxResearch Funding: Arog, Amgen, Bristol Myers Squibb, Novartis, Pfizer, Jazz Pharmaceuticals, AbbVie, Kronos BioNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Profile of patients. CR, complete remission; CRi, complete remission with incomplete marrow recovery; MRD, measurable residual disease.
FIG 2.
FIG 2.
MRD by treatment cycle and cumulative incidence. End of C1: MRD –3 from C1 day 1 to the end day of C1 + 7 days. End of C4: MRD < 10–3 from the end day of C1 + 8 days to minimum value between end day of C4 and the last dose + 7 days. End of C7: MRD < 10–3 from the end day of C4 + 1 day to minimum value between end day of C7 and last dose + 7 days. After C7: end day of C7 + 1 day and onward up to cutoff date. CR was defined as the absolute neutrophil count > 103/μL, platelets > 105/μL, red cell transfusion independence, and bone marrow with < 5% blasts; CRi was defined as all criteria for CR, except for neutropenia ≤ 103/μL or thrombocytopenia ≤ 105/μL. C, cycle; CR, complete remission; CRi, complete remission with incomplete hematologic remission; MRD, measurable residual disease.
FIG 3.
FIG 3.
(A) DoR among patients with composite complete remission. (B) Forest plot for DoR in subgroups. CR, complete remissions; CRi, complete remission with incomplete hematologic recovery; DoR, duration of remission; MRD, measurable residual disease; NR, not reached.
FIG 4.
FIG 4.
(A) EFS among patients. (B) Forest plot for EFS in subgroups. (C) Kaplan-Meier curves of EFS for patients who achieved composite complete remission and MRD-negative response by treatment cycles. CR, complete remission; CRi, complete remission with incomplete hematologic recovery; EFS, event-free survival; MRD, measurable residual disease; NE, not evaluable; NR, not reached.
FIG 5.
FIG 5.
(A) Kaplan-Meier curves of OS among patients. (B) Forest plot for OS in subgroups. (C) Multivariate Cox regression analysis for OS. (D) Kaplan-Meier curves of OS for patients who achieved CRc and MRD-negative response by treatment cycles. AML, acute myeloid leukemia; C, cycle; CR, complete remission; CRc, composite complete remission; CRi, complete remission with incomplete hematologic recovery; HR, hazard ratio; MRD, measurable residual disease; NR, not reached; OS, overall survival.

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