Prognostic value of measurable residual disease after venetoclax and decitabine in acute myeloid leukemia

Abstract

Assessment of measurable residual disease (MRD) provides prognostic information in acute myeloid leukemia (AML). However, the utility of MRD with venetoclax-based lower intensity regimens is unknown. We analyzed the prognostic value of achieving a negative MRD in older/"unfit" patients with AML receiving first-line therapy with 10-day decitabine and venetoclax. MRD was evaluated in bone marrow specimens using multicolor flow cytometry (sensitivity 0.1%). Ninety-seven patients achieving either a complete remission (CR) or CR with incomplete hematologic recovery (CRi) or morphologic leukemia-free state were included. Median age was 72 years (interquartile range, 68-78 years), and 64% had adverse-risk AML. Eighty-three patients achieved CR/CRi, and 52 (54%) became MRD negative. Median time to becoming MRD negative was 2.0 months (interquartile range, 0.9-3.1 months). Patients becoming MRD negative by 2 months had longer relapse-free survival (RFS) compared with those remaining MRD positive (median RFS, not reached vs 5.2 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.12-0.78; P = .004), longer event-free survival (EFS) (median EFS, not reached vs 5.8 months; HR, 0.25; 95% CI, 0.12-0.55; P < .001), as well as longer overall survival (OS) (median OS, 25.1 vs 7.1 months; HR, 0.23; 95% CI, 0.11-0.51; P < .001). Patients achieving an MRD-negative CR had longer OS compared with those with an inferior response (median OS, 25.1 vs 11.6 months; HR, 0.33; 95% CI, 0.19-0.58; P < .0005). Patients becoming MRD negative within 1 month had an improved OS compared with MRD-positive patients (median OS, 25.1 vs 3.4 months; HR, 0.15; 95% CI, 0.03-0.64; P < .0001). Differential impact of MRD status on survival outcomes persisted at a later 4-month time point of evaluation. In conclusion, MRD-negative status at 1, 2, and 4 months after starting therapy confers significantly better survival in older/unfit patients with AML receiving first-line therapy with 10-day decitabine and venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT03404193.

Conflict of interest statement

Conflict-of-interest disclosure: A.M. reports research funding from Celgene. C.D.D. reports personal fees from AbbVie, Agios, Novartis, Immune-Onc, Daiichi Sankyo, Celgene, Jazz Pharmaceuticals, and Notable Labs, outside the submitted work. N.G.D. reports grants from AbbVie, Genentech, Astellas, Daiichi Sankyo, Pfizer, BMS, ImmunoGen, Novimmune, and Forty Seven; and personal fees from AbbVie, Genentech, Astellas, Daiichi Sankyo, Pfizer, BMS, ImmunoGen, Jazz Pharmaceuticals, Trillium, Forty Seven, Gilead, Kite, and Novartis. N.J.S. reports grants from Takeda Oncology and Astellas; and personal fees from Takeda Oncology, AstraZeneca, and Amgen. N.P. reports personal fees from Pacylex Pharmaceuticals, Incyte, LFB Biotechnologies, Roche Diagnostics, and Blueprint Medicines; grants and other from Affymetrix; grants from SagerStrong Foundation; personal fees and other from Novartis; personal fees, nonfinancial support, and other from Stemline Therapeutics and AbbVie; personal fees and nonfinancial support from Celgene, Mustang Bio, and DAVA Oncology; and other from Samus Therapeutics, Cellectis, Daiichi Sankyo, and Plexxikon, outside the submitted work. G.B. has received research funding from AbbVie, Incyte, Janssen, GSK, Cyclacel, and Oncoceutics, Inc.; consultancy and research funding from BioLineRx; and consultancy for NKarta and PTC Therapeutics. P.B. reports research grant and personal fees from Incyte, Celgene, CTI Biopharma, Kartos Therapeutics, and Blueprint Medicines; and research grants from Constellation Pharmaceuticals, NS Pharma, Promedior, Pfizer, and Astellas. G.C.I. received research funding from Celgene; and served on an advisory board for Novartis. E.J.J. reports consultancy research funding from Takeda, BMS, Adaptive, Amgen, AbbVie, Pfizer, and Cyclacel Ltd; and research grants with Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer and Adaptive. N.J. reports the following: consultancy, honoraria, or membership on an entity’s Board of Directors or advisory committees, and research funding from AbbVie, Pharmacyclics, an AbbVie company, Genentech, Pfizer, ADC Therapeutics, AstraZeneca, Servier, Verastem, Precision Biosciences, and Adaptive Biotechnologies; consultancy, honoraria, or membership on an entity’s Board of Directors or advisory committees from Janssen Pharmaceuticals, Inc.; and research funding from BMS, Incyte, and Cellectis. K.T. has received personal fees for service on advisory boards of Symbio Pharmaceuticals, GSK, and Celgene. P.A.T. reports research funding to institution and consultancy/honorarium paid to institution from Pharmacyclics, AbbVie, and Amgen; consultancy/honorarium paid to institution from Genentech, Gilead Sciences, and Janssen-Cilag; and research funding to institution from Pfizer. K.S. reports honoraria from Otsuka; and consultancy for Pfizer. M.A. reports consultancy, patents, and royalties from Daiichi Sankyo, Inc.; patents licensed, royalty bearing, and research funding from Jazz Pharmaceuticals; consultancy for Celgene, Amgen, AstraZeneca, and 6 Dimensions Capital; equity ownership in Reata, Aptose, Eutropics, Oncoceutics, and Oncolyze; equity ownership and membership on an entity’s Board of Directors or advisory committees for Senti Biosciences; research funding from the Breast Cancer Research Foundation, CPRIT, and the NCI/National Institutes of Health; and membership on an entity’s Board of Directors or advisory committees for the Center for Drug Research & Development, Cancer UK, NCI-CTEP, German Research Council, Leukemia Lymphoma Society, NCI-RDCRN (Rare Diseases Clinical Research Network), CLL Foundation, and BioLineRx. H.M.K. reports grants and other from AbbVie, Agios, Amgen, ImmunoGen, and Pfizer; grants from Ariad, Astex, BMS, Cyclacel, Daiichi Sankyo, Jazz Pharmaceuticals, and Novartis; and other from Actinium and Takeda, outside the submitted work. M.Y.K. has received grants from the National Institutes of Health, the NCI, AbbVie, Genentech, Stemline Therapeutics, Forty Seven, Eli Lilly, Cellectis, Calithera, Ablynx, and AstraZeneca; consulting/honorarium from AbbVie, Genentech, F. Hoffmann–La Roche, Stemline Therapeutics, Amgen, Forty Seven, and Kisoji; clinical trial support from Ascentage; and stocks/royalties in Reata Pharmaceutical. F.R. reports personal fees and research grants from AbbVie. The remaining authors declare no competing financial interests.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Schema showing overall population and patients included in this analysis.

Figure 2.

Rates of negative MRD and survival outcomes. Assessment of patients in clinical subgroups (A) and mutational subgroups (B) of AML treated with DEC10-VEN; outcomes according to MRD status at 2 months, including competing risk analysis for cumulative incidence of relapse (CIR) with death as a competing event (C), RFS (D), EFS (E), and OS (F). CG, cytogenetics; NR, not reached; pts, patients; sAML, secondary AML from antecedent hematologic disorder; t-AML, therapy-related AML.

Figure 3.

Survival according to SCT. (A) OS of responding patients according to allogeneic SCT. Outcomes with censoring at SCT, including RFS (B), EFS (C), OS (D), OS according to MRD status in patients achieving response at 1 month (E), and OS in patients achieving CRwith negative MRD (CR MRD–) at any time compared with any other response (F). NR, not reached.