AUTHORS
Kuo-Kai Chin, MD, Ying Huang, MA, MS2, Tara L. Lin, MD3, Shivani Handa, MD4, Ann-Kathrin Eisfeld, MD5, Ronan Swords, MD6, Curtis Lachowiez, MD7, Elie Traer, MD, PhD8, Wendy Stock, MD9, Olatoyosi Odenike Jr, MD10, Anand Ashwin Patel, MD11, Maria R. Baer, MD12, Vu Duong, MD13, Eytan M Stein I, MD14, William Blum, MD15, Colin Vale16, Emily Curran, MD17, Yazan F. Madanat, MD18, Rebecca L Olin, MD19, Gary J. Schiller, MD20, Angela Nichols, NP21, Lacey Williams, MD22, Nyla Heerema, MD23, Timothy Chen, PhD24, Sonja Marcus, MPH25, Molly Martycz26, Mona Stefanos, MD, MBChB27, John Byrd, MD28, Brian Druker, MD29, Ross L. Levine, Prof. Dr.30, Ashley Yocum, PhD31, Joshua F. Zeidner, MD32, Uma Borate, MBBS, MSc33, Alice Scott Mims, MD34
AFFILIATIONS
1 Memorial Sloan Kettering Cancer Center, New York City, New York, United States
2 The Ohio State University, Columbus, Ohio, United States
3 University of Kansas Medical Center, Kansas City, Kansas, United States
4 The Ohio State University, Columbus, Ohio, United States
5 The Ohio State University, Columbus, Ohio, United States
6 Oregon Health & Science University, Portland, Oregon, United States
7 Oregon Health & Science University, Portland, Oregon, United States
8 Oregon Health & Science University, Portland, Oregon, United States
9 University of Chicago Comprehensive Cancer Center, Chicago, Illinois, United States
10 The Ohio State University, Columbus, Ohio, United States
11 University of Chicago Comprehensive Cancer Center, Chicago, Illinois, United States
12 University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, United States
13 University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, United States
14 Memorial Sloan Kettering Cancer Center, New York City, New York, United States
15 Winship Cancer Institute of Emory University, Atlanta, Georgia, United States
16 Winship Cancer Institute of Emory University, Atlanta, Georgia, United States
17 University of Cincinnati, Cincinnati, Ohio, United States
18 University of Texas Southwestern Medical Center, Dallas, Texas, United States
19 University of California San Francisco, San Francisco, California, United States
20 David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States
21 University of North Carolina, Chapel Hill, North Carolina, United States
22 University of North Carolina, Chapel Hill, North Carolina, United States
23 The Ohio State University, Columbus, Ohio, United States
24 The Ohio State University, Columbus, Ohio, United States
25 Blood Cancer United, Washington, District of Columbia, United States
26 The Ohio State University, Columbus, Ohio, United States
27 The Ohio State University, Columbus, Ohio, United States
28 University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
29 Oregon Health & Science University, Portland, Oregon, United States
30 Memorial Sloan Kettering Cancer Center, New York City, New York, United States
31 Blood Cancer United, Washington, District of Columbia, United States
32 University of North Carolina, Chapel Hill, North Carolina, United States
33 The Ohio State University, Columbus, Ohio, United States
34 The Ohio State University, Columbus, Ohio, United States
ABSTRACT
Background: Azacitidine-venetoclax (AZA/VEN) is standard for older or unfit patients (pts) with newly diagnosed AML. European LeukemiaNet (ELN) 2022 guidelines recommend that response assessment utilize the best hematologic response achieved after a bone marrow biopsy (BmBx) and prior to the next cycle without a specified time window for hematologic recovery. In contrast, US clinical trials have generally followed FDA guidance requiring response assessment within 14 days (D) of bone marrow biopsy (BmBx); however, this may underestimate response and necessitate repeated BmBx to characterize best response.
OPTI-AML (NCT03013998) was a prospective, randomized phase 2 trial comparing AZA with 28D VEN (AV28) versus 14D VEN (AV14). The primary endpoint was CR within 2 cycles. Response criteria were per modified ELN-2017, requiring hematologic recovery within 14D of a D21(+4D) BmBx each cycle (D35-39 from treatment start). This stringent window may underestimate CR rates in pts with delayed hematologic recovery. We performed an exploratory analysis of OPTI-AML data to characterize delayed count recovery and associated outcomes.
Methods: We defined stringent CR (sCR) as <5% marrow blasts with full hematologic recovery (ANC≥1 and PLT≥100) within 14D of the D21(+4D) BmBx and delayed CR (dCR) as full hematologic recovery 15-28D after that same BmBx. PFS and OS were calculated from date of full count recovery.
Results: From 5/2023-9/2025, 175 pts were randomized and 169 were treated (AV28 n=83, AV14 n=86). After cycle 1 (C1), 27% of pts (n=45) achieved sCR (sCR1) and 24% (n=41) achieved dCR1. All dCR1 pts had full hematologic recovery between D15-28 but were formally classified as CRh (4.7% , n=8), CRi (13%, n=22), and MLFS (6.5%, n=11). Median time to ANC≥0.5 and PLT≥25 in the dCR1 group was 38 days (range 25–50). At the traditional phase 1 C1D42 assessment timepoint, 10 dCR1 pts did not have documented count recovery and would have potentially met DLT criteria for prolonged cytopenias, despite subsequently achieving CR-level recovery. C1 G-CSF use was low (sCR 13%, dCR 20%).
MRD negativity by flow cytometry (MRD-, sensitivity 0.02%) was similar between sCR1 and dCR1 (68% vs 67%, p=0.89). The distribution of sCR1 and dCR1 was similar between AV28 and AV14 (sCR1: 49% vs 51%; dCR1: 49% vs 51%, respectively; p=0.99).
Baseline demographics, counts, mutations, cytogenetics, and ELN risk were balanced between sCR1 and dCR1. The rates of grade 3+ AEs (78% vs 78%), serious AEs (24% vs 17%), infectious AEs (47% vs 32%), and bleeding AEs (16% vs 27%) were similar between sCR1 and dCR1 (all p>0.05). Median PFS and OS were not significantly different between sCR1 and dCR1 (PFS: NR vs. 12.4, p=0.32; OS: NR vs. 22, p=0.30).
Of 142 patients receiving C2, 49 pts achieved sCR (sCR2, 34%) and 26 pts achieved dCR (dCR2, 18%; formally, 18 CRh [13%], 6 CRi [4%], 2 MLFS [1%]). Rates of MRD- favored dCR2 vs sCR2 (90.9%, n=20 vs 70.8%, n=34, p=0.06). C2 G-CSF use remained low (sCR 12%, dCR 3.9%). No differences were observed in the distribution of sCR2 and dCR2 between AV28 and AV14 (sCR2: 57% vs 43%; dCR2: 42% vs 58%; p=0.22).
Baseline demographics, mutations, cytogenetics, and ELN risk remained balanced between sCR2 and dCR2. sCR2 and dCR2 AEs remained similar. Grade 3+ AEs (sCR2 57% vs dCR2 77%, p=0.09) and infection AEs (27 vs 8%, p=0.05) differences approached significance. Median PFS and OS remained similar between sCR2 and dCR2 (PFS: 21.1 vs. 19.2 months, p=0.85; OS: NR vs. 20.3 months, p=0.61).
Response categories shifted between cycles: sCR1 (n=45) was followed by 16 sCR2 (36%), 12 dCR2 (17%), and 17 (38%) neither. dCR1 (n=41) was followed by 24 sCR2 (59%), 7 dCR2 (17%), and 10 neither (24%). Of the 169 treated pts, 78 achieved sCR in C1 and/or 2, and 24 achieved dCR in cycles 1 or 2 without ever achieving sCR (AV28 n=10, AV14 n=14, p=0.35). Survival outcomes between these groups were similar. 46% of patients achieved sCR within 2 cycles and 60% of patients achieved sCR or dCR within 2 cycles (AV28, n=51 [61%], AV14 n=51 [59%], p=0.78).
Conclusion: In this exploratory analysis of OPTI-AML, many pts with marrow clearance achieved full hematologic recovery after the mandated 14D window from BmBx after C1 and C2 and achieved similar outcomes to patients with hematologic recovery within 14D. These findings suggest that existing timing requirements for hematologic recovery may underrecognize meaningful responses to low-intensity AML therapies.
DISCLOSURES
Kuo-Kai Chin, MD: Syndax Pharmaceuticals - Research Funding; Seres Therapeutics - Research Funding; Servier - Consultancy (Includes expert testimony); Syndax Pharmaceuticals - Consultancy (Includes expert testimony); Qualified Health - Consultancy (Includes expert testimony)