High-Risk Myelodysplastic Syndrome (HR-MDS) Treated with a Hypomethylating Agent (HMA) and Venetoclax - Focus on Antifungal (AF) Prophylaxis and Molecular Subset Outcomes
Authors: DiGennaro Jeremy V. , Drekolias Dimitrios , Al Ali Najla H. , Chan Onyee , Yun Seongseok , Walker Alison R. , Xie Zhuoer , Padron Eric , Lancet Jeffrey E , Komrokji Rami S. , Sallman David 
Published: December 2024

Background
Outcomes in HR-MDS remain suboptimal with HMA with a high morbidity and mortality and overall survival (OS) &lt; 2 years. The addition of the oral BCL-2 inhibitor venetoclax (Ven) has been investigated in HR-MDS (Garcia J et al., ASH 2023) and the VERONA Phase 3 data are eagerly awaited. There is paucity of data regarding the need for AF prophylaxis in HR-MDS treated with HMA/Ven as well as OS data in molecular subsets.
Methods
In the current study, we retrospectively reviewed HR-MDS patients treated with HMA/Ven between 2018 - 2024 (n=96; 15 managed at Moffitt Cancer Center, 81 co-managed with outside providers), focusing on AF use, incidence of fungal infections, time to absolute neutrophil count (ANC) recovery, and impact on OS.
Results
96 HR-MDS patients (68.7% male) received at least one cycle of HMA/Ven. The median age at diagnosis was 71 years (range of 23 - 92 years). 82.3% were at least intermediate risk per IPSS-R and 100% were higher risk per IPSS-M. 37 (39%) were HMA-naïve and 59 (62%) were HMA relapse/refractory (R/R). Next generation sequencing data were available for 96% of patients (n=92) at diagnosis. Epigenetic mutations occurred in 56% (n=51), followed by spliceosome mutations in 29% (n=27), and RAS pathway in 12% (n=11). TP53 mutations were present in 17% (n=16). The median bone marrow myeloid blast percentage at the time of initiation of HMA/Ven was 11% (range: 1.5% - 18%). Ven was used with azacitidine in 36.5% (n=35) vs. decitabine in 63.5% (n=61). The median number of HMA/Ven cycles was 3 (range: 1-30 ). HMA dose adjustments were not observed in any patient during C1/C2 with one patient having dose adjustment in C3 for neutropenia. Median duration of Ven was 21 days (d) during C1 (range: 14-28d),14d during C2 (range: 5-28d) and 14d during C3 (range: 4-28d). Venetoclax was dose-adjusted based on interactions with concurrent medications in 47% (n=45) of patients having AF use in C1 (56% prior to start of HMA/Ven and 38% with development of G4 neutropenia. Only one culture-proven invasive fungal infection (IFI) was reported in our cohort during C1 (none in C2/C3).
Median time to ANC recovery for frontline HMA/Ven was 30d (range 7-75d) with AF prophylaxis compared to 31d (range 7-90d ) with no AF use in C1 (P=0.411). ANC recovery for relapsed/refractory (R/R) MDS was 38.5d (SD 22) with AF prophylaxis vs 40d (SD 18) with no AF prophylaxis C1 (P=0.38). In C2, there was a trend towards prolonged ANC recovery with AF use in both frontline (41.5d with AF vs 26d without AF; P=0.39) and R/R patients (35.5d with AF vs 22d without AF; P=0.25).
OS data were available for 89 patients with median OS (mOS) being 26.2 months (m) for patients receiving frontline HMA/Ven compared to 13.2m for patients with R/R MDS who had HMA prior to HMA/Ven. No difference in OS was observed based on AF use in either frontline or R/R MDS (P=0.4).
Mutational analysis for frontline patients showed mOS of 9.6m in patients with TP53 mutations, 24m in splicing mutations (P=0.347 compared to TP53, 25.1m for epigenetic mutations (P=0.195), 34m for RAS pathway mutations (P=0.154), and 35.7m in patients with none of the prior 4 mutations (P=0.075). Mutational analysis for R/R showed: mOS of 6.2m in patients with TP53 mutations, 12.2m in splicing mutations (P=0.048 when compared to TP53), 11.5m for epigenetic mutations (P=0.053), 27.1m for RAS pathway mutations (P=0.019), and 21.6m in patients with none of the prior 4 mutations (P=0.024).
29 patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT ). Regarding HSCT, the mOS in frontline patients who underwent HSCT was 39.7m vs 24.1m in non-HSCT patients (P=0.04). mOS in R/R patients was 36.2m vs 9.1m in HSCT vs non-HSCT patients, respectively (P &lt;0.001). There was a trend for improved mOS in 14d vs 21d Ven in both frontline patients (29.2m vs 18.7m, respectively; P=0.204) and R/R patients (28.2m vs 9.8m ; P= 0.0987). Median number of cycles in patients not transplanted was 3 (range 1-30). Regarding TP53 mutations: N=2 went to allo-HSCT with mOS of 5.9m compared to mOS 7.9m (n=15) in non-HSCT (P=0.269).
Conclusion
IFI was rare and independent of prophylactic AF use. No detriment in outcomes based on time to ANC recovery or survival was observed based on AF use. TP53 patients had inferior OS with HMA/Ven irrespective of frontline or R/R setting with no other molecular subgroups prognostic of OS. Long term outcomes are significantly improved with HMA/Ven, particularly in patients bridged to allo-HSCT.