Haddadin, Michael

Abstract Background: Hypomethylating agent (HMA) with venetoclax (VEN) is used in clinical practice for frontline management of patients with myelodysplastic syndrome (MDS) based on encouraging data from phase 1 clinical trial (Garcia JS et al. Blood 2025). While the randomized clinical trial (VERONA-NCT04401748) did not show a survival benefit of azacitidine-VEN, the study had important differences such as exclusion of therapy related MDS and being conducted in several non-academic US centers. To better understand the impact of this regimen and its effects in subgroups, we conducted a real-world analysis of frontline MDS patients treated mainly at academic medical centers with HMA-VEN and compared to HMA monotherapy. Methods: This is a multicenter retrospective study of 19 US academic medical centers. We included contemporary cohorts of adults (age≥18 years) with MDS (intermediate, high or very high risk by IPSS-R) who were treated outside of clinical trials with either upfront combination of HMA-VEN or HMA monotherapy. Data on patient-related, disease-related and treatment-related variables were collected through chart review. Descriptive statistics were used for baseline characteristics. Overall survival (OS) and event free survival (EFS: progression, leukemic transformation, death as events) analysis was conducted using Kaplan-Meier method. Determinants of outcomes were analyzed using multivariable regression models. All analyses were conducted at a significance level of p<0.05. Results: Among 1198 patients with intermediate, high or very-high risk MDS, 313 patients received upfront VEN in combination with HMA [HMA-VEN] and 885 patients received HMA monotherapy. Median age was 70 (63-76) years and majority of patients had MDS with excess blasts-1 (34% overall, HMA-VEN=26%, HMA=37%) or MDS with excess-blasts-2 (41% overall, HMA-VEN=60%, HMA=34%). Disease risk by IPSS-R was intermediate (29% overall, HMA-VEN=18%, HMA=33%), high (30% overall, HMA-VEN=31%, HMA=30%) or very-high risk (41% overall, HMA-VEN=51%, HMA=37%, p<0.001). Therapy related MDS (t-MDS) was seen in 27% of patients (HMA-VEN=33%, HMA=25%, p=0.004), 34% had TP53 mutation (HMA-VEN=40%, HMA=32%, p=0.005) and 33% underwent allogeneic hematopoietic stem cell transplantation (AHSCT) (HMA-VEN=42%, HMA=30%, p<0.001). The most common mutations detected at baseline included TP53 (34%), ASXL1 (22%), DNMT3A (16%), RUNX1 (16%), TET2 (14%), SRSF2 (13%), and U2AF1 (11%). The response rate by IWG 2006 criteria was significantly higher with HMA-VEN than HMA monotherapy (overall 81% vs 39%, CR: 17% vs 9.6%; marrow CR: 56% vs 14%, p<0.001). In multivariable analysis accounting for upfront treatment, AHSCT, genomic mutations, baseline bone marrow blasts and t-MDS, patients treated with HMA-VEN in the upfront setting had significantly improved EFS (median EFS 10.7 vs. 7.8 mon, HR 0.83, 95%CI 0.72-0.96, p=0.01) and OS (median OS 22.4 vs. 18.1 mon, HR 0.79, 95%CI 0.64-0.97, p=0.02). In addition, TP53 mutation status (OS: HR 1.88, 95% CI 1.57-2.26, p<0.001, EFS: HR 1.43, 95% CI 1.23-1.65, p<0.001), subsequent AHSCT (OS: HR 0.34, 95% CI 0.27-0.41, p<0.001; EFS: HR 0.47, 95% CI 0.40-0.54, p<0.001), and therapy related MDS (OS: HR 1.20, 95% CI 1.00-1.44, p=0.04, EFS: HR 1.10, 95% CI 0.96-1.27, p=0.2) were significant predictors on multivariable analysis. When separately investigated in subgroups, an OS benefit of HMA-VEN over HMA was seen in patients undergoing subsequent AHSCT (median OS 40.6 vs. 30 mon, p=0.05), bone marrow blast 10-19% (median OS 25.1 vs. 17.4 mon, P=0.01), de novo MDS (median OS 30 vs. 20.1 mon, P=0.003) and absence of TP53 mutation (median OS 34.9 mon vs. 23.1 mon, p=0.004). The benefit of HMA-VEN over HMA was also seen across molecular mutations including presence of ASXL1 mutation (median OS 35.2 vs 20.9 mon, p=0.03). Conclusions: In this large multicenter retrospective analysis from US academic medical centers, we found that HMA-VEN therapy significantly improved OS in certain subsets of high risk MDS including patients with 10-19% blasts, denovo MDS, subsequent AHSCT and those without TP53 mutation. While our analysis is limited by its retrospective design, prospectively exploring subgroups of MDS patients who could benefit from HMA-VEN therapy is needed.

Background: Hypomethylating agents (HMA) with venetoclax (VEN) have shown encouraging clinical efficacy in single arm clinical trials for patients with myelodysplastic syndrome (MDS) (Garcia JS et al. ASH 2023, Zeidan AM et al. Am J Hematol. 2023). Many centers have started utilizing HMA-VEN in the clinical management of MDS due to unmet need, pending results of the ongoing phase 3 randomized clinical trial (VERONA) using this combination. However, real world studies with large sample size investigating the use of these agents in MDS, practice patterns and clinical outcomes are lacking. Methods: This is a multicenter retrospective study of 13 US academic medical centers. We included contemporary cohorts of adults (age≥18 years) with MDS who were treated with upfront combination of HMA-VEN, upfront HMA monotherapy, or VEN added after inadequate response or progression on HMA (post-HMA failure VEN). Outcomes analyzed includes clinical response, adverse events (AE) of interest, dose administration and survival. Descriptive statistics were used for baseline characteristics. Overall survival and event free survival (EFS: progression, leukemic transformation, death as events) analysis was conducted using Kaplan-Meier method. Determinants of outcomes were analyzed using multivariable regression models. All analyses were conducted at a significance level of p<0.05. Results: Among 454 patients included, 258 patients received VEN in combination with HMA [upfront HMA-VEN (n=175), post-HMA failure VEN (n=83)] and 196 patients received HMA monotherapy. Median age was 69 (59-77) years and majority of patients had MDS with excess blasts (75%), high risk (31.9%) or very-high (41.8%) risk disease by IPSS-R, 23.7% had therapy related disease, 33% had deletion17p or TP53 mutation and 40.9% underwent allogeneic stem cell transplantation. VEN was predominantly started in outpatient setting (78.6%) with tumor lysis syndrome (TLS) prophylaxis and VEN doses ranged from 70-400mg, adjusted for concomitant antifungal drugs. Incidence of TLS was minimal (No TLS- 92.9%, lab-only TLS 6.2%, 1 pt with clinical TLS). Neutropenic fever was the main AE noted [upfront VEN-HMA (34.2%), HMA monotherapy (22.5%), post-HMA VEN (44.5%)]. In the upfront setting, response rate was significantly higher with HMA-VEN than HMA monotherapy (CR: 33% vs 12%; marrow CR: 40% vs 27%, p<.001). VEN given in the post HMA failure setting also resulted in encouraging response rates (CR 10%, marrow CR 32%). After adjusting for covariates in multivariable analysis, patients treated with HMA-VEN in the upfront setting had significantly improved event free survival as compared to HMA monotherapy (HR 0.59, HR 0.44-0.78, p<0.01), but overall survival did not reach statistical significance (overall survival HR 0.77, 95%CI 0.57-1.04, p=0.08). Conclusions: In this large multicenter retrospective analysis from US academic medical centers, we found that VEN in combination with HMA resulted in encouraging clinical outcomes and was effectively administered in the outpatient setting with minimal TLS. Infection risk management and supportive measures would be important to improve the ability to use this treatment widely, pending results of the ongoing phase 3 randomized clinical trial. Updated results with additional variables will be available at the main meeting.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

Abstract Large-scale sequencing studies of hematologic malignancies have revealed notable epistasis among high-frequency mutations. One of the most striking examples of epistasis occurs for mutations in RNA splicing factors. These lesions are among the most common alterations in myeloid neoplasms and generally occur in a mutually exclusive manner, a finding attributed to their synthetic lethal interactions and/or convergent effects. Curiously, however, patients with multiple-concomitant splicing factor mutations have been observed, challenging our understanding of one of the most common examples of epistasis in hematologic malignancies. In this study, we performed bulk and single-cell analyses of patients with myeloid malignancy who were harboring ≥2 splicing factor mutations, to understand the frequency and basis for the coexistence of these mutations. Although mutations in splicing factors were strongly mutually exclusive across 4231 patients (q < .001), 0.85% harbored 2 concomitant bona fide splicing factor mutations, ∼50% of which were present in the same individual cells. However, the distribution of mutations in patients with double mutations deviated from that in those with single mutations, with selection against the most common alleles, SF3B1K700E and SRSF2P95H/L/R, and selection for less common alleles, such as SF3B1 non-K700E mutations, rare amino acid substitutions at SRSF2P95, and combined U2AF1S34/Q157 mutations. SF3B1 and SRSF2 alleles enriched in those with double-mutations had reduced effects on RNA splicing and/or binding compared with the most common alleles. Moreover, dual U2AF1 mutations occurred in cis with preservation of the wild-type allele. These data highlight allele-specific differences as critical in regulating the molecular effects of splicing factor mutations as well as their cooccurrences/exclusivities with one another.