Real World Outcomes of Patients (Pts) with Acute Myeloid Leukemia, Myelodysplasia-Related (AML-MR) or Therapy-Related AML (t-AML) Receiving Venetoclax-Based Therapies
Authors: Pugh Kelly , Walker Michael C , Nicolet Deedra , Klein Victoria , Mrózek Krzysztof , Behbehani Gregory K , Blachly James S. , Borate Uma , Grieselhuber Nicole R. , Koenig Kristin L , Larkin Karilyn T. , Long Meixiao , Srisuwananukorn Andrew , Eisfeld Ann-Kathrin , Mims Alice 
Published: December 2024

Introduction
AML-MR is defined by cytogenetic and/or molecular abnormalities associated with myelodysplastic neoplasms or arising from a known history of myelodysplastic/ myeloproliferative neoplasms. T-AML is characterized by prior cytotoxic, radiation, or immunosuppressive therapy for an unrelated disease. Pts with AML-MR and t-AML have worse outcomes historically (Granfeldt Ostgard et al. J Clin Oncol 2015;33:3641). In the VIALE-A trial, only about 25% of pts had secondary AML (DiNardo et al. N Engl J Med 2020;383:617). In the VIALE-C trial, pts with secondary AML (38%) had worse survival than those with de novo AML (Wei et al. Blood 2020;135:2137). Both studies excluded pts with prior hypomethylating agent (HMA) exposure for prior MDS/MPN.
Methods
This study was a single-center, retrospective analysis of pts with AML-MR or t-AML, defined according to WHO 2022 classification (Khoury et al. Leukemia 2022;36:1703), who were treated with a venetoclax-based regimen from 10/2016 to 5/2023. Clinical, cytogenetic and molecular data were collected to establish diagnosis of AML-MR and t-AML. CRh, CRi, and CR were determined based on the 2022 ELN guidelines. Measurable residual disease (MRD) status measured by multiparameter flow cytometry was collected after cycles 2 and 3, with an MRD-positive threshold of ≥0.1%. Overall survival (OS) was calculated from time of venetoclax initiation. Early mortality was defined as death within 30 days after diagnosis. Kaplan-Meier method and the log-rank test were used to assess survival differences between AML-MR vs non-AML-MR and t-AML vs non-t-AML pts.
Results
Ninety-five pts who received venetoclax-based therapy were included. Median age was 67 years (range, 23-92), and 40 (42%) were female. Sixty-nine pts (73%) had AML-MR and 22 pts (23%) had t-AML. Fifteen pts had both AML-MR and t-AML.
There was no significant difference in age, sex, or ECOG performance status between pts with AML-MR and those with non-AML-MR. Venetoclax first line was received by 30% of pts with AML-MR and 35% of those with non-AML-MR. Venetoclax was combined with HMA in 88% of pts with AML-MR and 96% of pts with non-AML-MR. The AML-MR group completed a median of 2 cycles (range, 1-14) and the non-AML-MR group completed a median of 4 cycles (range, 1-56) of venetoclax-based therapy. There were no significant differences in CRh, CRi, and CR rates between AML-MR vs non-AML-MR (composite CR/CRh/CRi 35% vs 46%). Among 25 pts with AML-MR who had MRD assessment at cycles 2 or 3, 12 (48%) were MRD-positive and 13 (52%) MRD-negative, whereas among 15 pts with non-AML-MR, 6 (40%) were MRD-positive and 9 (60%) MRD-negative. After excluding pts post-allogeneic transplant, there was no significant difference in the number of pts who proceeded to transplant [11/18 (61%) for AML-MR v. 54/70 (77%) for non-AML-MR, p = .23]. There was no significant difference in OS (median, 35.1 vs 41.3 months, p=0.85). Three pts with AML-MR and 0 with non-AML-MR suffered early mortality (p=0.56).
There was no significant difference in age, sex or ECOG performance status between pts with t-AML and those with non-t-AML. Fifty percent of pts with t-AML and 33% with non-t-AML received venetoclax first line. Venetoclax with HMA was administered to 91% of pts with t-AML and 90% with non-t-AML. Pts with t-AML completed a median of 2 cycles (range, 1-13) and those with non-t-AML completed a median of 3 cycles (range, 1-56) of venetoclax-based therapy. There was no significant difference in CRh, CRi, and CR rate between t-AML vs non-t-AML (composite CR/CRh/CRi 27% vs 41%). Of the pts with t-AML who had MRD assessment at cycles 2 or 3, 5 (56%) were MRD-positive and 4 (44%) MRD-negative. Among pts with non-t-AML, 13 (42%) were MRD-positive and 18 (58%) were MRD-negative. After excluding pts post-allogeneic transplant, there was no significant difference in the number of pts who proceeded to transplant [4/22 (18%) with t-AML v. 14/66 (21%) with non-t-AML, p=1.00]. There was no significant difference in OS (median, 41.3 vs 35.1 months, p=0.74). One pt with t-AML and 2 pts with non-t-AML suffered early mortality.
Conclusions
In our real-world cohort, pts with AML-MR and those with t-AML treated with venetoclax had no significant differences in outcomes (CR, OS, and early death) compared with pts with non-AML-MR and non-t-AML, respectively. This data supports further investigation into the treatment of AML-MR and t-AML with venetoclax-based regimens.