Comparative Analysis of Outcomes with HMA Plus Venetoclax Vs Intensive Chemotherapy in AML Patients Harboring Very-High Risk Cytogenetics

Background: Dismal survival outcomes are characteristic of pts with AML harboring very-high risk cytogenetics (vHRC), which can be attributed to aggressive disease biology and low and poorly durable response rates to conventional cytotoxic chemotherapy. Allogeneic hematopoietic stem cell transplant (alloSCT) is the preferred treatment strategy after major disease reduction with initial chemotherapy. However, it is unclear whether pts with AML-vHRC should be treated with intensive chemotherapy (IC) or hypomethylating agents plus venetoclax (HMA+ven) to achieve such responses. In this large multicenter retrospective cohort, we aimed to compare response and survival outcomes with IC vs HMA+ven in AML pts with vHRC. Methods: We analyzed a total of 1103 pts with newly diagnosed AML from across 4 large academic centers (DFCI, MSKCC, Yale and NCI in Lithuania) treated with 7+3 or CPX-351 (IC) v HMA+ven. vHRC was defined as AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2:MECOM(EVI1), t(3q26.2;v)/MECOM(EVI1)-rearranged, complex karyotype (CK) or monosomal karyotype (MK) as defined per 2022 ELN AML guidelines. Composite complete remission (cCR) was defined as CR+CR with incomplete count recovery (CRi). The Kaplan-Meier method was used to estimate OS and the log-rank test was used to compare OS between groups. Results: A total of 318 pts (29%) had AML harboring vHRC with a median age of 66 yrs (range 18-93). Of these pts, 91% (n=289) harbored a CK, 64% (n=205) harbored a MK and 10% (n=32) had chr.3-related abnormalities. Pts were stratified into 2 groups based on treatment received: IC (n=137, 43%) or HMA+ven (n= 181, 57%). Pts in the HMA+ven group were older (median age: 72 yrs vs 59 yrs, p<.001) and more likely to harbor MK (75% vs 51%, p<.001). Pts in the IC group were more likely to harbor chr.3 abn (15% vs 6.6%, p=.023), whereas pts with CK-AML equally received IC and HMA+ven (88% vs 93%, p=.16). Pts who received HMA+ven were more likely to harbor a TP53 mutation (TP53mt) (70% vs 28%, p<.001), whereas those who received IC were more likely to harbor RAS pathway and secondary splicing mutations (59% vs 26%, p<.001 and 23% vs 14%, p=.043 respectively). Of the total 318 pts, 280 (88%) were available for response assessment. cCR rates were higher with IC (66/127) than with HMA+ven (62/153) (52% vs 41%, p=.006). Among HMA+ven-treated pts, 41% (62/153) achieved a cCR as best response, 14% (22/153) attained morphologic leukemia-free state (MLFS) and 45% (69/153) had progressive disease (PD). Among pts treated with IC, 52% (66/127) achieved a cCR, 4% (5/127) MLFS and 44% (56/127) had PD. 77% (50/65) of HMA+ven pts experienced relapse vs 36% (35/96) of those treated with IC (p<.001). Significantly more pts proceeded to alloSCT after prior treatment with IC compared to HMA+ven (n=98, 53% vs 14% respectively, p<.001). The mOS for the entire vHRC cohort was 8 mos (95% CI, 6.8-10) vs 29 mos (95%CI 24-42) for those with non-vHRC (p<.001). In the AML-vHRC population, pts treated with IC had a longer mOS than pts treated with HMA+ven [11 mos (95%CI, 8.6-18) vs 6.4 mos (95%CI, 5.2-8), p<.001]. Given that HMA+ven treated pts were older, we analyzed pts aged 60-75 yrs and found that mOS was similar between IC [7 mos (95%CI 5.6-11)] and HMA+ven [6.4 mos (95%CI 5.1-9.4)], p=0.56. Additionally, the mOS among pts who received an alloSCT did not differ by treatment strategy prior to transplantation [34 mos (95%CI, 21-64) for IC vs 39 mos (95%CI, 18-NR) for HMA+ven, p=0.71]. Given that >50% of pts with vHRC carried a TP53mt, we analyzed survival outcomes based on TP53mt status and treatment strategy. The mOS of pts with vHRC and concomitant TP53mt was 6.1 mos (95%CI 5.2, 7.8) and was similar between those treated with IC [7.6 mos (95%CI 4.1-11)] compared to HMA+ven [5.8 mos (95%CI 4.8-7.8)] (p=0.30). Conversely, the mOS of pts with vHRC without concomitant TP53mt was 12 mos (95%CI 8.3-18) and was higher among pts treated with IC [14 mos (95%CI 10-30)] compared to HMA+ven [8.0 mos (95%CI 5.2-15)] (p=.007). Conclusion: In this large multicenter cohort, the survival for pts with AML-vHRC was overall poor. In pts aged 60-75, and in those who carried a TP53mt, or who underwent SCT following initial therapy, there was no significant difference in OS between those treated with HMA+ven and those treated with IC. In these pts, HMA+ven might be preferable given its comparatively lower toxicity, however, this should be explored ideally in a prospective setting.