Clinical Implications of TP53 Mutations/Allelic State in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) Treated with Hypomethylating Agents (HMA)- a Multicenter, Retrospective Analysis from the Validate Database

TK and JPB Co-first; RK, DS, and AMZ are Co-senior authors. Introduction MDS with TP53 mutations ( TP53 MT) are associated with high-risk disease features and rapid progression to AML. Effective treatment for this aggressive subtype is still not available. As compared to monoallelic TP53 MT, biallelic MT have been associated with adverse outcomes and worse overall survival (OS), but the impact of allelic status on treatment response and OS after HMA therapy are not well established. In this study, we analyzed TP53 allelic state for a large well annotated cohort of pts with MDS who were treated with HMAs. Methods The VALIDATE database includes pts with MDS treated with frontline HMA from 14 specialized centers. Pts were considered to have biallelic TP53 MT according to the ICC definition (Arber et al. 2022, Blood) if they meet any of the following: a. two TP53 MT (variant allelic frequency [VAF]>10% for each) b. single TP53 MT with copy neutral loss of heterozygosity (CN-LOH, available for 308 pts) c. TP53 MT with del17p and d. Single TP53 MT with VAF >50%. Time to event analyses were estimated using Kaplan-Meier estimator and groups were compared by the log-rank test from the time of HMA initiation. Only higher risk (HR)-MDS pts (IPSS>1 or IPSS-R>3.5) with BM biopsy within 180 days after HMA initiation were assessed for complete response (CR) and overall response rate (ORR) according to the IWG 2023 criteria (Zeidan et al, Blood 2023) (n=480). OS was calculated from time of HMA therapy initiation. This study was supported by an independent research grant from AbbVie. Results A total of 816 pts met eligibility and were included in this analysis. Median age was 68 years (IQR: 61-74) and 64% were men. MDS excess blast (EB) 1/2 was the most common MDS subtype (62%). Overall, 78% of the pts were treated with HMA monotherapy (26% decitabine [DEC] and 74% azacitidine [AZA]) and 22% received HMA as part of combination therapy. In total, 40% of the pts underwent allogenic HSCT. Median HMA treatment time was 5 months (mo), IQR:3-11. Median follow up time was 17 mo (IQR:9-31). TP53 MT were detected in 253 pts (31%) at time of MDS diagnosis, of whom 153 (60%) pts had biallelic TP53 MT and 100 (40%) pts had monoallelic TP53 MT. Missense MTs were identified in 80% of pts with monoallelic TP53 MT. TP53 MT/del17p (33%), TP53 MT/CN-LOH (28%), and multiple TP53 MT (25%) were the most common combinations in pts with biallelic TP53 MT. Pts with TP53 MT had higher rates of MDS-EB (74% vs. 61%, p<0.001). Complex karyotype was observed in 112 (73%) pts with biallelic TP53 MT and 81 (81%) pts with monoallelic TP53 MT (p=0.154). Median number of HMA cycles among pts with TP53 MT was 8 (IQR:5-12) and higher compared to pts without TP53 MT (5 cycles, IQR:3-9), p=0.032 ( Panel-A). In a logistic regression model for CR, TP53 MT was not associated with probability of achieving CR (1.4, 0.89-2.29). CR rates for pts with biallelic TP53 MT (18%) and monoallelic TP53 MT (14%) were not significantly different, p=0.37. There were also no significant differences in ORR observed between biallelic TP53 MT (59%) and monoallelic TP53 MT (54%) pts, p=0.39. Among TP53 MTpts treated with HMA monotherapy, pts treated with AZA compared to DEC had similar odds for ORR (OR:1.1, 95%CI: 0.7-1.6)/CR (OR: 0.8, 95%CI: 0.4-1.3) and hazard for OS (HR: 1.1, 0.9-1.4). As expected, the median OS (mo, 95%CI) for pts with TP53 MT (12, 10-13) was significantly lower than pts without TP53 MT (28, 25-31), p<0.001. Importantly, pts with biallelic TP53 MT (11, 9-14) had no significant difference in median OS compared to monoallelic TP53 MT (13, 11-17), p=0.268 (Panel-B). In a multivariable cox proportional hazard regression model for OS (hazards ratio, 95%CI) adjusted for age (1.0, 0.9-1.0), HSCT (0.4, 0.3-0.4), IPSS-M score (1.2, 1.1-1.3), and complex karyotype (1.4, 1.1-1.8), TP53 MT status (1.8, 1.4-2.3) was still associated with OS. However, biallelic TP53 MT had comparable risk to monoallelic TP53 MT (1.2, 0.9-1.7). Conclusions To our knowledge, VALIDATE is the largest database of MDS pts with TP53 MT who were treated with HMA. We confirm that TP53 MT have significant negative impact on survival, but not on response to HMA therapy. Importantly, we did not observe OS differences between monoallelic and biallelic TP53 MT. We also show that the type of HMA monotherapy used does not impact outcome of these pts. Overall, pts with TP53 MT have very poor outcomes and are in desperate need of new, effective therapies

Evaluation of the Molecular International Prognostic Scoring System (IPSS-M) in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) with Missing Molecular Data

TK and JPB Co first; RK and AMZ are Co senior authors. Introduction The IPSSM incorporates molecular features to improve outcome prediction for pts with MDS. However, IPSSM requires assessment of 31 genetic mutations to classify pts into 6 risk groups. Importantly, IPSSM accounts for missing data and provides best, average, and worst IPSSM scores. Here, we used a large cohort of pts with MDS to analyze the performance of IPSSM if molecular data were missing to better understand the performance of the tool in this frequently encountered clinical setting. Methods For this study, we combined data from a publicly available dataset (Kewan et al. 2023 Nat com) with our multicenter VALIDATE database to increase sample size. Only pts with available molecular data were included and IPSSM was calculated twice: a. using TP53 mutation ( TP53 MT) only and assuming that all other molecular mutations are missing (missing molecular data [IPSSM MM]) and b. using the full molecular panel (available molecular data [IPSSM AM]). TP53 MT were included in all IPSSM calculations given frequency and significant impact on survival. Time-to-event analysis from the time of diagnosis was conducted using Kaplan-Meier estimator. The performance of different scores was evaluated by Harrell's c-index. This study was supported by an independent research grant from AbbVie. Results Of 2,789 pts, 2,489 had molecular data and were included. Median age was 72 years (IQR: 65-78). MDS with excess blast 1/2 (42%) was the most common subtype. Overall, 39% of pts treated with HMA and 15% of underwent transplantation. In total, 16% of pts had complex karyotypes. The most prevalent mutations were SF3B1 (21%), ASXL1 (20%), TP53 (15%), SRSF2 (15%), DNMT3A (12%), and RUNX1 (10%), 39% of the pts had >1 gene mutation. Based on IPSSR, pts were classified as very low (13%), low (47%), intermediate (13%), high (13%), and very high (14%) risk. First, we calculated IPSSM score assuming that all molecular data were missing (IPSSM MM) except TP53 MT. Accordingly, pts were classified as very low (4%), low (33%), moderate low (19%), moderate high (14%), high (17%), and very high (14%) risk. IPSSM MM resulted in the re-stratification of 1623 (66%) pts of which 1104 (68%) pts were up-staged, and 519 (32%) pts were down-staged. When applying actual molecular data (IPSS-M AM), pts were classified as very low (14%), low (30%), moderate low (12%), moderate high (10%), high (17%), and very high (17%) risk. When compared with IPSSR, IPSSM AM resulted in re-stratification of 1218 pts (50%) of which 868 pts (71%) were upstaged ( Panel A). When comparing IPSSM MM with IPSSM AM, 1243 pts (51%) were assigned to the same risk group and 1186 pts (49%) were assigned to different risk groups. Amongst reclassified pts, 431 (36%) were upstaged and 755 (64%) were down staged. Only 109 pts (5%) were reclassified with more than one shift. Median follow-up time was 24 (IQR:10-77) months (mo) with a median overall survival (OS) of 50 mo (95% CI: 47-55). The probability of OS based on IPSSM MM and IPSSM AM risk groups was significantly different (p-value: <0.0001 for both), Panel B. Median OS (mo) based on IPSSM MM vs. IPSSM AM were as follows: very low (not reached vs. 125), low (103 vs. 82), moderate low (63 vs. 58), moderate high (46 vs. 43), high (27 vs. 24), and very high (13 vs.15). Median OS based on IPSSR were: very low (not reached), low (78), intermediate (36), high (24), and very high (14). The median LFS (n=1100 pts) based on IPSSM MM vs. IPSSM AM were as follows: very low (41 vs. 78), low (63 vs. 54), moderate low (39 vs. 33), moderate high (26 vs. 29), high (18 vs. 15), and very high (11 vs. 13). IPSSM MM showed comparable performance to IPSSM AM with c-index (95%CI): 0.713 (0.697 -0.728) vs. 0.714 (0.699-0.729) for OS and 0.645 (0.622-0.669) vs. 0.623 (0.599-0.647) for LFS. When used as continuous scores, IPSSM MM continues to be comparable to IPSSM AM for OS (c-index:0.721 vs. 0.730) and LFS (c-index:0.655 vs. 0.641). IPSS-R had a lower c-index for OS (0.688) and LFS (0.622). Conclusions Our study supports prognostic and clinical value of IPSSM even if most molecular data are missing, confirming that IPSSM adjusts well for missing molecular data and can be used in clinical practice if molecular data are largely missing. While molecular testing remains optimal for accurate risk stratification in MDS, our data suggest that clinical, pathological and cytogenetic data continue to be the main determinant of outcome prediction for pts with MDS

Validation of the Molecular International Prognostic Scoring System (IPSS-M) in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) Who Were Treated with Hypomethylating Agents (HMA)

TK and JPB Co-first; RK and AMZ are Co-senior authors. Introduction Recognition of the growing importance of genetic mutations in prognostication for pts with MDS prompted the development of IPSS-M to improve outcome prediction. Subsequent validation studies included a heterogenous groups of pts; treated & untreated pts with lower & higher risk (HR) disease, and thus the value of IPSS-M in predicting outcomes of pts with HR-MDS treated with HMA remains unclear. We aimed to evaluate the ability of IPSS-M to predict outcomes of pts with HR-MDS who were treated with HMA in a large multicenter cohort. Methods Using the multi-center VALIDATE database, we included pts with HR-MDS (Defined as IPSS score >1 or IPSS-R score > 3.5) who were treated with any HMA in the frontline setting and had available molecular data before HMA initiation. Time-to-event analysis used Kaplan-Meier estimator and the log-rank tests. Survival was measured from time of HMA initiation. We compared the different scoring systems by Harrell's c-index. Best response to HMA was assessed using the IWG 2023 response criteria in HR pts (n=480) who had a marrow evaluation within 180 days of HMA initiation. This study was supported by an independent research grant from AbbVie. Results A total of 925 pts were included in the analysis. Median age was 68 years (IQR: 62-75) and 66% of the pts were men. MDS excess blast 1/2 accounted for 65% of the diagnosis. Overall, 76% of pts were treated with HMA monotherapy (29% decitabine and 71% azacitidine), 24% received HMA combination therapy, and 39% of pts had HSCT. The most common mutations (MT) were TP53 (32%), ASXL1 (20%), TET2 (13%) and SRSF2 (12%); 36% of pts had MDS harboring >1 gene MT. As anticipated, the cohort was enriched with high risk (26%) and very high risk (46%) IPSS-R groups. According to pre-therapy IPSS-M, pts were classified into very low (2%), low (9%), moderate low (11%), moderate high (14%), high (29%) and very high (36%) risk groups. IPSS-M reclassified 54% of pts, of whom 184 (37%) were up-staged and 317 (63%) were down-staged. Specifically, 38%/21% of pts with intermediate risk IPSS-R MDS, and 30%/36% of pts with high risk IPSS-R MDS were up-staged/down-staged, respectively. In addition, 44% of pts with very high risk IPSS-R MDS were down-staged. The median follow-up time was 19 (IQR:10-35) months (mo). Median overall survival (OS) was 19 (95% CI: 17-22) mo. Overall, 35% of the pts progressed to AML during follow up. IPSS-M groups showed significant differences for both OS and LFS (p-value: <0.0001 for both). The median OS (mo, 95%CI) based on IPSS-M categories were: low (37, 25-62), moderate low (30, 23-47), moderate high (29, 22-35), high (17, 14-20), and very high (14, 12-15) (Panel A). The 3-year LFS (%) were: low (20%), moderate low (48%), moderate high (41), high (50%), and very high (59%). IPSS-M was significantly associated with OS in a multivariable model adjusted for age, sex, type of HMA, number of HMA cycles and receiving allogeneic HSCT (HR: 1.4, 95% CI:1.2-1.5). However, IPSS-M showed comparable performance when compared with the IPSS-R with c-index (95%CI): 0.599 (0.557-0.622) vs. 0.619 (0.560-0.641) for OS. In addition, IPSS-M showed similar performance for LFS: 0.583 (0.560-0.606) vs. 0.588 (0.565-0.610) (Panel B). When IPSS-M/IPSS-R were used as continuous scores, the c-indices (95%CI) for OS and LFS were: 0.617 (0.592-0.640) vs. 0.6400 (0.616-0.664) for OS and 0.598 (0.575-0.622) vs. 0.606 (0.581-0.632) for LFS. We then analyzed the performance of IPSS-R/IPSS-M in pts with HR MDS (IPSS ≥1.5). Both IPSS-R and IPSS-M had comparable performance for OS prediction (c-index:0.548 vs. 0.566) and LFS (0.551 vs. 0.538). Based on the proposed IWG 2023 response criteria, complete remission rate (CR)/ overall response rate (ORR) were 12/47%, 9/58%, 13/47%, and 17/57% of pts assigned to moderate low, moderate high, high, and very high IPSS-M risk groups. No significant association was observed between IPSS-M and ORR (OR: 1.1, p=0.475) or CR (1.1, p=0.286). Conclusions In our multi-center large cohort of pts with HR MDS treated with frontline HMA, IPSS-M significantly stratified pts for OS and LFS. However, when compared with IPSS-R, IPSS-M did not seem to substantially improve prediction of outcomes among HMA-treated pts. Our results emphasize the high predictive prognostic power of clinical features and cytogenetic alterations among HR-MDS pts treated with HMA

Validation of the Molecular International Prognostic Scoring System (IPSS-M) in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) Who Underwent Allogenic Stem Cell Transplantation (HSCT)

TK and JPB Co-first; RK and AMZ are Co-senior authors. Introduction MDS are genetically heterogenous neoplasms with diverse prognoses. While hypomethylating agents (HMA) can improve outcomes, HSCT remains the only potentially curative therapy. The IPSS-M incorporates clinical and molecular features to improve outcome prediction beyond traditional risk stratification tools. The IPSS-M has been validated in studies that either variably included pts who underwent HSCT, were limited by sample size, or were single-institution analyses. We aimed to validate the performance of the IPSS-M in predicting outcomes among pts with MDS who were treated with HMAs and subsequently underwent HSCT. Methods The VALIDATE database includes MDS pts treated with frontline HMA from 14 specialized centers. Only pts with available molecular data pre-HMA therapy and subsequently underwent HSCT were included. Time-to-event analyses used Kaplan-Meier estimator and the log-rank test. Overall survival (OS) was measured from time of HSCT. Multivariate-adjusted survival analysis used Cox proportional hazards. We compared the different scoring scores by Harrell's c-index. This study was supported by an independent research grant from AbbVie. Results A total of 350 pts met eligibility ( Panel A). Median age was 63 years (IQR: 58-68). MDS with excess blasts 1/2 (66%) was the most common type. Overall, 74% of pts received HMA monotherapy (27% decitabine; 73% azacitidine), while 26% received HMA in a combined therapy. The most prevalent mutations were TP53 (29%), ASXL1 (21%), RUNX1 (13%), STAG2 (12%), SRSF2 (12%), and DNMT3A (11%); 53% of pts had disease harboring >1 gene mutation. Only 44% had TP53 CN-LOH and 40% had MLL-PTD testing. The most common donor types were matched unrelated donors (MUD, 46%), haploidentical donors (21%), and matched related donors (MRD, 17%). Myeloablative, non-myeloablative, and reduced-intensity conditioning were used in 38%, 27%, and 27% of the pts, respectively. Only 14% of pts received post-HSCT maintenance therapy. Our cohort was enriched with very high risk (41%) and high risk (30%) IPSS-R groups at time of diagnosis, while very low (1%), low (9%), and intermediate (20%) IPSS-R risk groups accounted for remaining 29% of pts. According to the IPSS-M, pts were classified into very low (2%), low (10%), moderate low (13%), moderate high (14%), high (27%) and very high (34%) risk groups. The IPSS-M re-stratified 198 (57%) pts, of whom 77 (39%) pts were up-staged and 121 (61%) pts were down-staged. More specifically, 35% and 26% of pts with intermediate risk IPSS-R MDS, and 32% and 35% of pts with high risk IPSS-R MDS were up-staged and down-staged, respectively. Importantly, 45% of pts with very high risk IPSS-R MDS were down-staged. Median follow-up time was 20 (IQR:8-36) months (mo). The median OS for the entire cohort was 32 mo (IQR:10-Not reached [NR]). The IPSS-M groups showed significantly different OS (p-value= 0.001, Panel B)withmedian OS (mo, 95%CI) of: very low (NR, 11.5-NR), low (55, 22-NR), moderate low (48, 25-NR), moderate high (35, 22-NR), high (29, 23-NR), and very high (20, 13-28). The 5-year OS (%) were as following: very low (56%), low (47%), moderate low (37%), moderate high (40), high (43%), and very high (17%). IPSS-M risk (HR: 1.3, 95% CI:1.1-1.5) was significantly associated with OS in a multivariable model (HR, 95%CI) adjusted for age (1.01, 1.00-1.03), sex (1.2, 0.9-1.7), type of HMA used before HSCT (1.0, 0.9-1.1), number of HMA cycles (1.0, 0.9-1.05), donor type (1.0, 0.9-1.1), and conditioning regimen used (1.3, 1.1-1.5). For OS, the IPSS-M significantly stratified pts assigned to the very high risk IPSS-R subgroup (p=0.009). However, the IPSS-M showed comparable performance to IPSS-R with c-index (95%CI): 0.597 (0.555-0.640) vs. 0.599 (0.554-0.643), respectively, for OS. When IPSS-M/IPSS-R were analyzed as continuous scores, the c-index (95%CI) for OS were: 0.606 (0.561-0.651) vs. 0.611 (0.559-0.662). When focusing on the higher risk group defined as IPSS ≥.1.5, the IPSS-M (c-index: 0.584) still had performance comparable to the IPSS-R (c-index: 0.606). Conclusions To our knowledge, this is the largest reported cohort in which IPSS-M performance was evaluated among pts with HMA-treated MDS and subsequently underwent HSCT. While the IPSS-M subgroups showed significant OS differences, the IPSS-M did not seem to substantially improve prediction when compared to the IPSS-R

Validation of the Composite Complete Response (cCR) Definitions in the International Working Group (IWG) 2023 Criteria in Patients (Pts) with Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) Treated with Hypomethylating Agents (HMA) - a Large, Multicenter, Retrospective Analysis from the Validate Database

JPB and TK are co-first authors; RK and AMZ are co-senior authors Introduction: Efficacy of therapies used in HR-MDS pts has long been assessed using IWG 2006 MDS criteria, but important limitations in clinical utility and practical application of these criteria have become apparent. The revised IWG response criteria for HR-MDS were proposed in 2023 (Zeidan et al., Blood 2023) were proposed to address these gaps. IWG 2023 re-defined CR by lowering hemoglobin (Hb) threshold from 11 to 10 g/dL and bone marrow [BM] blasts from ≤5% to 3.5 (n=213 pts excluded). Pts were excluded (N=90) if age at diagnosis was 180 days after HMA initiation, except in cases of overt disease progression. Best responses were assessed based on IWG 2006 and 2023 criteria. Kaplan-Meier analysis estimated OS from HMA initiation, and the log-rank test was used to compare subgroups. Cox multivariable regression models identified predictors of OS. This study was supported by an independent research grant from AbbVie. Results: Of 1,223 pts in VALIDATE database, 629 were met eligibility. Median age was 68 years, 27.7% and 27.4% were red blood cell and platelet transfusion-dependent, respectively, 38.1% had TP53 mutations, and 45.3% underwent allogeneic transplantation (allo-HCT). Most pts (71.6%) received HMA monotherapy (51.7% azacitidine, 19.9% decitabine), while 28.4% received HMA-based combinations. Median duration of therapy was 4 cycles (Range: 1-94). Median OS of different subgroups pts are shown in Figure 1. Median OS for pts with IWG 2023-defined cCR (CR+CR-L+CRh+CRequ; N = 230) was 26.5 months (mo; 95% CI: 20.7 - 32.2 mo) vs 14.3 mo (95% CI: 12.5 - 16.9 mo) for pts who did not achieve cCR (p=0.002). Median OS for pts who achieved IWG 2023-defined CR (N = 90) was 29.8 (95% CI: 23.1 - 41.8) vs. 26.4 mo (95% CI: 22.0 - 41.3) for IWG 2006-defined CR (p=0.71). The 124 pts (19.7%) who achieved CR-L had a median OS of 26.4 mo (95% CI: 17.6 - 36.2 mo); of those 67 pts achieved CRbi and had a median OS of 29.1 mo (95% CI: 20.7 - not reached), while 57 pts achieved CRuni and had a median OS of 18.7 mo (95% CI: 15.5 - 54.4 mo), with no significant difference in OS between CRbi and CRuni (Hazard ratio: 1.24; 95% CI: 0.78-1.98, p=0.71). Given the hierarchical prioritization of CR-L designation over CRh in IWG 2023 if a pt meets both response definitions, only 6 pts achieved CRh which precluded a reliable estimate of their OS. Similarly, CRequ was achieved only in 10 pts limiting a reliable assessment of OS in these pts. In a multivariable Cox model that adjusted for sex, HMA type, age, allo-HCT, complex karyotype, TP53 mutation, and IPSS-M risk group, achieving a cCR per IWG 2023 criteria was statistically significantly associated with improved OS was associated with improved OS compared to those who did not achieve cCR (HR: 1.64; 95% CI: 1.30 - 2.08; p<0.001, Figure 2). Discussion: In this real-world analysis of HR-MDS pts treated with HMA-based therapy, cCR according to IWG 2023 were associated improved OS. In particular, CR and CRL (including CRbi and CR uni) were associated with improved OS, supporting their inclusion in the overall response rate in clinical trials. The number of pts who achieved CRh and CRequ was too small to reliably assess their specific association with OS. Additional pts are being added to the database and detailed analyses will be presented in the meeting

Impact of Type of Hypomethylating Agent (HMA) Used on Outcomes of Patients (Pts) with Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) - a Large, Multicenter, Retrospective Analysis

JPB and TK Co-first; RK and AMZ are Co-senior authors Introduction HMAs remain the mainstay for frontline treatment of HR-MDS. Azacitidine (AZA) and decitabine (DEC; including oral cedazuridine/decitabine) are the only FDA-approved HMAs. However, AZA and DEC have not been compared directly in randomized trials. In this study, we aimed to assess the clinical outcomes of pts with HR-MDS treated with different HMA regimens, focusing on overall survival (OS) and treatment responses. Methods The VALIDATE database includes pts with HR-MDS treated with HMA-based therapies in the frontline setting from 14 specialized MDS centers. HR-MDS pts treated with HMA-based therapies in the frontline setting were included. HR-MDS was defined as having an IPSS ≥1.5 or IPSS-R >3.5 (n=213 pts excluded). Pts were excluded from the survival analysis if age at diagnosis was <18 years (n=1), bone marrow (BM) blasts ≥20% or unknown at HMA initiation (n=61), or if survival status, follow-up time, date of HMA initiation, or HMA type was unknown (n=28). To be included in the analysis of response based on IWG 2023 criteria (Zeidan A et al, Blood 2023), pts had to have a BM response assessment within 180 days after HMA initiation to allow determination of response (n=290 pts excluded). Time to event analyses were estimated using the Kaplan-Meier method and treatment groups (AZA vs DEC monotherapy) were compared by log-rank test and assessed from the time of HMA initiation. Multivariable Cox regression models were performed among pts treated with AZA and DEC monotherapy to identify predictors of response and OS. This study was supported by an independent research grant from AbbVie. Results 1,223 pts were screened of whom 919 were included in the survival analysis. Median age was 68 years (Range [R]: 19-95) with 66% males. Our cohort was enriched for pts with adverse genetic features including complex karyotype (38%) and TP53 mutations (36%). Overall, 76% of pts were treated with HMA monotherapy (56% AZA, 20% DEC) and 24% received HMA-based combination therapy (HMA/VEN: 15%, other HMA combinations: 9%). 38.2% underwent allogeneic hematopoietic cell transplant (allo-HCT). The median HMA duration was 5 cycles (R: 1 - 94). Due to the small number and the heterogeneity of pts receiving HMA combinations, as well the multiple partner drugs used in these pts ( Table), we compared OS and responses only between pts treated with AZA (n = 512 pts) or DEC monotherapy (n = 186 pts). In unadjusted analyses, median OS differed by treatment type (p = 0.002) and was 19.8 months (mo) with AZA (95% CI: 17.0 - 23.1 mo) and 14.3 mo with DEC (95% CI: 11.2 - 18.5 mo). Among 629 pts evaluable for response, rates of complete remission (CR) and overall response (ORR) were 14.8% and 48.6% for AZA monotherapy and 5.6% and 50.4% for DEC monotherapy, respectively. In a Cox multivariable regression model ( Figure) adjusted for age, sex, TP53 mutation status, complex karyotype, IPSS-M category (compared to very high risk), and receipt of allo-HCT, there was no difference in OS when comparing AZA and DEC monotherapy (Hazard ratio [HR]: 0.95, 95% CI: 0.72 - 1.26; p = 0.740). Variables associated with adverse OS were male sex (HR: 1.52; 95% CI: 1.16 - 2.00; p = 0.002) and presence of TP53 mutation (HR: 1.50, 95% CI: 1.05 - 2.14; p = 0.027). Conversely, receipt of allo-HCT (HR: 0.26, 95% CI: 0.19 - 0.37; p<0.001) and IPSS-M moderate-high (HR: 0.57, 95% CI: 0.37 - 0.87; p=0.009) and moderate-low (HR: 0.58, 95% CI: 0.36 - 0.95; p = 0.031; both compared to IPSS-M very high risk) were associated with improved OS. Similarly, there were no statistically significant differences in ORR between AZA and DEC (OR: 1.05, 95% CI: 0.66 - 1.68; p = 0.832) in a Cox multivariable regression model adjusted for age, sex, TP53 mutation, complex karyotype, IPSS-M category, and treatment type. Conclusions: Among pts included in the real-world VALIDATE database, there were no significant difference in OS or ORR (IWG 2023) between AZA- and DEC-treated pts in adjusted analyses. Other factors (e.g., TP53 mutations, complex karyotype) are substantially more relevant to outcomes than the specific HMA used. The small number of pts and heterogeneity of partner drugs in HMA-based combinations precluded robust analyses or conclusions regarding differences in efficacy. Additional analyses evaluating the impact of combinations and molecular subtypes on response and survival will be presented during the meeting as more pts are added to the database