Does intensive consolidation confer a clinical advantage over continued less intensive therapy in elderly patients with Acute Myeloid Leukemia in first remission following azacitidine plus venetoclax induction?

Abstract

Abstract Background The combination of venetoclax with azacitidine (VEN-AZA) has been widely utilized to treat newly diagnosed patients with acute myeloid leukemia (AML) who are elderly or ineligible for intensive chemotherapy (IC). In certain patients who were unfit at diagnosis, IC might become tolerable as their performance status improves after achieving complete remission (CR) or CR with incomplete hematologic recovery (CRi). However, the clinical benefit of switching to intensive chemotherapy for consolidation remains undefined. In this retrospective study, we compared outcomes in AML patients who either switched to intensive consolidation or were maintained on VEN-AZA therapy. Methods Patients aged 55–74 years with AML from 14 Chinese centers were included if they achieved CR/CRi after 1–2 cycles of VEN-AZA therapy and subsequently became eligible for IC consolidation due to improvement of performance status (ECOG PS < 2). Patients chose to either switch to IC consolidation or continue on VEN-AZA therapy based on personal preference. Cumulative incidence of relapse (CIR) was estimated with Fine-Gray test with non-relapse mortality (NRM) being the competing risk. Relapse-free survival (RFS) and survival were estimated with the log-rank test. Fine-Gray proportional hazards models and Cox regression models were used to identify prognostic factors. Propensity score matching was performed to compare the outcome switching to IC consolidation and continuous VEN-AZA therapy. Results 214 patients were included in this study. 98 (46%) patients were male. Median age was 66 years (interquartile range [IQR], 62‒70 years). According to the ELN 2022 or 2024 recommendation, 62 (29%), 57 (27%), and 95 (44%) patients or 138 (65%), 63 (29%), and 13 (6%) patients were in favorable, intermediate and adverse risk, respectively. 57 patients switched to IC consolidation (IC cohort) for 2‒3 cycles—15 receiving modified “3+7” regimens and 42 receiving intermediate- or high-dose cytarabine— followed by VEN-AZA maintenance, while 157 patients received continuous VEN-AZA therapy (VEN-AZA cohort). Compared with the VEN-AZA cohort, the IC cohort were younger (median age, 63 versus 67 years, P< 0.001), more frequently classified as ELN 2022 low-risk (40% versus 25%, P= 0.03), and had comparable rate of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in CR1 (12% versus 11%, P = 0.77). With a median follow-up of 15 months (IQR, 9‒24 months), there were no differences in 2-year CIR (48% [29%–66%] versus 43% [33%–53%], P =0.93), cumulative incidence of NRM (2% [0%–7%] versus 6% [2%–11%], P =0.28), RFS (53% [34%–71%] versus 51% [41%–61%], P =0.58) and survival (83% [69%–97%] versus 80% [72%–88%], P =0.61) between the IC cohort and the VEN-AZA cohort. Multivariate analysis showed that whether switching to IC consolidation or not was not associated with CIR, RFS or survival. To balance baseline characteristics, initial treatment response to VEN-AZA induction and receiving allo-HSCT or not, PSM analyses were performed at a 1:2 ratio between the IC and VEN-AZA cohorts. In the PSM analysis, 55 patients in the IC cohort and 91 patients in the VEN-AZA cohort were included. There were no significant differences in 2-year CIR and cumulative incidence of NRM and 2-year probabilities of RFS and survival between the 2 cohorts. Further stratified analyses by ELN 2022 or 2024 risk classification were conducted in the PSM population. In patients with ELN 2022 intermediate-risk, IC cohort (n = 12) had a higher 2-year CIR (78% [31%–100%] versus 24% [5%–43%], P =0.06) than the VEN-AZA cohort (n= 28). In patients with ELN 2024 intermediate-risk, IC cohort (n = 18) had a higher 2-year CIR (59% [26%–91%] versus 17% [1%–33%], P =0.02) and lower 2-year RFS rate (33% [2%–65%] versus 77% [58%–96%], P =0.02) than the VEN-AZA cohort (n = 33). However, there were no difference in outcomes between the patients classified as ELN 2022 or 2024 favorable- or adverse risk. These findings remained consistent in sensitivity analyses with censoring at the time of allo-HSCT. Conclusion Our study suggests that elderly AML patients who achieved CR/CRi after VEN-AZA induction therapy derive no benefit from switching to IC consolidation. IC consolidation even appeared to be associated with a higher relapse rate in patients classified as intermediate-risk by ELN 2022 or 2024. These findings warrant validation through prospective studies.