Shallis, Rory M.

Abstract Introduction: Clinical outcomes for patients (pts) with Philadelphia chromosome positive (Ph+) B-cell precursor Acute Lymphoblastic Leukemia (B-ALL) have significantly improved with the incorporation of tyrosine kinase inhibitors (TKI) and immunotherapy. Although the incidence of central nervous system (CNS) relapse in Ph+ B-ALL is rare, it has become an emerging challenge with chemotherapy-free approaches. While IKZF1, CDKN2A/B and emergence of T315I kinase domain mutations in ABL1 have been associated with worse outcomes (Foà R, JCO, 2024),further characterization of patients with CNS relapse could prove useful in risk stratification and optimizing treatment intensification. Currently, high white blood cell count (WBC) is being assessed as a marker to identify pts who may benefit from addition of CNS penetrant chemotherapy (ex. cytarabine or high-dose methotrexate (HD-MTX)) to TKI and immunotherapy protocols (Short NJ, J Hematol Oncol, 2025). Methods This is a multicenter retrospective study of relapsed/refractory Ph+ B-ALL pts under the COMMAND consortium. Age, gender, induction regimen and TKI of choice during induction were descriptively reported for the entire cohort. Categorical variables were compared, using Fisher's exact test, between pts with CNS relapse and pts with systemic relapse. Variables of interest were the presence of IKZF1 or CDKN2A/B alterations, emergence of T3151 mutation, CNS disease at diagnosis (dx), WBC >70K/microliter at dx, use of high-dose methotrexate (HD-MTX) during induction or consolidation, and use of TKI as part of the induction regimen. Odds ratio (OR) and 95% confidence intervals (CI) were reported for each variable. Results A total of 654 Ph+ B-ALL pts were initially identified across multiple centers in the United States, of whom 20 (3%) experienced a CNS relapse and 157 (24%) experienced a systemic relapse on median follow up of 29 months (range, 0-207). A total of 15 pts with CNS relapse and 114 pts with systemic relapse were used for this analysis after exclusion of pts without molecular data. The median age for the 129 pt cohort was 55 years (range 22-85), of whom 65 pts (50%) were male. Induction regimens used were intensive chemotherapy (IC)+TKI for 79 pts (61%), low-intensity chemotherapy or steroids (LDC-S)+TKI for 40 pts (31%), IC without TKI during induction for 5 pts (4%) and blinatumomab+TKI for 1 pt (1%). TKI of choice during induction included second-generation TKIs (dasatinib, nilotinib) for 77 pts (60%), imatinib for 30 pts (23%), ponatinib for 15 pts (12%) and none during induction for 5 pts (4%). CNS disease at dx was found in 6/15 pts (40%) with CNS relapse and 9/114 pts (8%) with systemic relapse, which was a statistically significant difference (p=0.002, OR= 7.57, 95% CI= 1.81 - 31.08). The systemic treatment regimens for the 15 pts with CNS disease at x were IC+TKI for 10 pts (66%) and LDC-S+TKI for 5 pts (33%), 9 of the pts (60%) received HD-MTX during induction. Intrathecal (IT) chemotherapy administration data at dx was available for 8 pts (53%) with CNS disease at dx, of whom 2 pts received <9 doses, 4 pts received 9-12 doses and 2 pts received >12 doses of IT chemotherapy. Although not statistically significant, pts with CNS relapse were more likely to have IKZF1 or CDKN2A/B alterations (p = 0.648, OR= 1.44, 95% CI= 0.14-7.78), WBC >70K/mcl (p = 0.472, OR= 1.73, 95% CI= 0.34-7.41), emergence of T3151 mutations (p = 0.123, OR= 2.54, 95% CI= 0.72-8.84) and use of HD-MTX during induction or consolidation (p = 0.262, OR= 2.15, 95% CI= 0.61-8.61); while they were less likely to have received a TKI during induction (p = 0.106, OR= 0.18, 95% CI= 0.02-2.34). Conclusion This data confirms that the presence of CNS disease at dx is associated with CNS relapse. Despite recent incorporation into clinical trials, WBC≥70K/mcl and omission of HD-MTX were not seen more frequently in pts with CNS relapse in this cohort. However, this analysis is limited by the small number of pts who experienced CNS relapse. With the rising use of chemotherapy-free regimens, prospectively trialing treatment intensification, such as with additional IT chemotherapy or HD-MTX, could be prospectively trialed in pts with CNS disease at dx to potentially improve outcomes for this subset of pts. The impact of increasing IT chemotherapy doses or additional cycles of systemic chemotherapy in this pt population is yet to be elucidated.

Abstract Introduction: HMA monotherapy (HMAm) continues to be the standard of care for HR-MDS. While the addition of VEN to azacitidine (AZA) improved overall survival (OS) and complete remission (CR) rates among older pts with acute myeloid leukemia (AML) over AZA monotherapy, the recently completed phase III VERONA trial of AZA+/-VEN in HR-MDS failed to show an OS benefit for AZA/VEN over AZA monotherapy. Using the icMDS VALIDATE database, we compared outcomes of pts with HR-MDS treated with HMA or HMA/VEN as frontline therapy. Methods: The icMDS VALIDATE database includes over 4000 adult MDS pts who received HMA-based therapy from 32 international centers in 9 countries. For this analysis, we included pts with HR-MDS defined by International Prognostic Scoring System [IPSS] ≥1.5 or IPSS-revised [IPSS-R] ≥4 (at diagnosis or HMA initiation) and treated with HMAm or HMA/VEN as frontline therapy for HR-MDS. We assessed responses based on IWG 2023 criteria (Zeidan A et al, Blood 2023). Composite complete remission (cCR) was defined as CR+CRbi+CRuni+CRh+CRequivalent. We calculated OS from time of HMA initiation to date of death from any cause. Pts lost to follow-up were censored at the date they were last known to be alive. We used Kaplan-Meier methods to calculate OS and compared OS between different groups using the log-rank test. We used Cox and logistic regression models to adjust for baseline prognostic variables as appropriate. The study was funded by an independent grant from Abbvie. Results: A total of 1907 pts met eligibility and were included (1552 AZA, 221 decitabine, 134 HMA+VEN). 479 pts subsequently underwent allogeneic stem cell transplant (allo-SCT; 430 after HMAm [32.6%]; 49 after HMA/VEN [37.1%]). Our cohort was enriched for pts with adverse disease characteristics including complex karyotype (33.6%) and TP53 mutations (28.7%). Compared to pts treated with HMA/VEN, pts treated with HMAm were more likely to be male (p=0.012), have lower baseline platelet counts (p=0.037), peripheral blood (PB) blasts (p=0.004), or bone marrow blasts (p<0.001), and were less likely to have very high risk IPSS-M (p<0.001), TP53 mutations (p<0.001), or complex karyotype (p=0.020). In unadjusted analyses, the rate of cCR was significantly lower in HMAm treated pts compared to HMA/VEN treated pts (27.7% vs. 48.8%, p<0.001). However, CR rate was not significantly different (11.7% vs. 17.1% for HMAm and HMA/VEN, respectively, p=0.22). After adjusting for age, sex, and IPSS-M, pts treated with HMA/VEN were more likely to achieve cCR compared to HMAm with an odds ratio (OR) of 2.49 (95% CI: 1.56-3.96, p<0.001). When separated by TP53 mutation status, the OR for cCR for HMA/VEN vs HMAm was 4.17 (95%CI: 2.14-8.31; p<0.001) and 1.27 (95%CI: 0.54-2.86; p=0.57) for TP53 wild-type and TP53-mutant pts, respectively. In unadjusted analyses, median OS was 17.4 months for HMAm and 19.6 months for HMA+VEN, and OS did not differ significantly by treatment type (p=0.33). For HMAm treated pts, the OS rates at year 1, 2, 3 were 0.65 (95%CI: 0.63-0.67), 0.38 (95%CI: 0.36-0.40), and 0.27 (95%CI: 0.25-0.29), respectively. For HMA/VEN treated pts, the OS rates at year 1, 2, 3 were 0.64 (95%CI: 0.56-0.73), 0.45 (95%CI: 0.36-0.56), and 0.37 (95%CI: 0.27-0.51), respectively. In a multivariate analysis adjusting for age, sex, PB blast, IPSS-M and allo-SCT as a time-varying covariate, treatment with HMA/VEN vs HMAm did not significantly influence OS (hazard ratio (HR) of OS for HMA/VEN vs HMAm: 0.89, 95%CI: 0.69-1.13, p=0.33). When stratified by TP53 mutation status, HR of HMA/VEN vs. HMAm was favorable for TP53 wild-type (HR: 0.47; 95%CI: 0.29-0.74) but not TP53-mutant pts (HR=0.96; 95%CI: 0.66-1.41). Adjusting for other variables in the model, HR for pts who underwent vs. those who did not undergo allo-SCT were 0.65 (95% CI: 0.49-0.85) and 0.36 (95%CI: 0.24-0.53) in TP53 wild-type and mutant patients, respectively. Conclusion: In this large, international retrospective analysis from the icMDS VALIDATE database, HMA/VEN was associated with higher cCR rates—but not CR rates—compared to HMAm among pts with HR-MDS, though we observed no significant differences in OS. In our analysis, clinical benefit from the addition of VEN was most clear in TP53 wild-type pts, and allo-SCT was associated with improved OS regardless of baseline TP53 status. Our analysis was limited by the relatively small number of HMA/VEN-treated pts and heterogeneous real-world treatment patterns.

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.

Abstract Background: Acute myeloid leukemia (AML) with TP53 alteration (TP53alt), including deletion (TP53del) detected by cytogenetics (CG) (karyotype, FISH, or genomic microarray) and/or TP53 mutation (TP53mut) identified by next-generation sequencing, is associated with poor prognosis. However, a subset of patients may achieve long-term survival after allogeneic hematopoietic cell transplantation (allo-HCT). Patient-, disease-, and transplant-related variables may inform risk stratification and improve treatment decision-making in this high-risk population. We used the CIBMTR registry to investigate outcomes of patients with TP53alt AML undergoing allo-HCT. Methods: We included adult patients with 2017 ELN adverse-risk AML who underwent first allo-HCT between 2013–2019 and had available CG and molecular data. TP53del was centrally reviewed by expert cytogeneticist. Patients were stratified into three TP53alt groups: Group 1 (TP53mut+/ TP53del+), Group 2 (TP53mut −/ TP53del+), and Group 3 (TP53mut+/ TP53del −). The control group comprised patients with 2017 ELN adverse-risk AML negative for both TP53mut and TP53del. Patients from embargoed centers, lacking consent or comprehensive research data, or missing CG and molecular information were excluded. Results: Of 6,474 patients with adverse-risk AML, 703 patients with TP53alt met inclusion criteria: Group 1 (n=203), Group 2 (n=271), Group 3 (n=229). The control group included 2,763 patients. Median age was 58 years (44% ≥60); 44% were female; 16% had Karnofsky score <90, and 52% had HCT-CI ≥3. Secondary AML was more frequent in TP53alt groups (32%, 27%, 27%) versus control (21%) (p<.01). Complex and monosomal karyotypes were most common in Group 1 (61%), followed by Group 2 (54%), Group 3 (31%), and control (6%), p<.01. More patients in Groups 1 and 2 (28% each) underwent HCT in primary induction failure/relapse (PIF/Rel) versus Group 3 (19%) and control (19%), p<.01. Median time from diagnosis to transplant was 5 months (1-331). Donor type was matched related in 23%, matched or mismatched unrelated in 50%, haploidentical in 18%, and umbilical cord blood in 7%. Conditioning intensity was myeloablative (MA) in 51%; reduced-intensity (RIC) in 36% , and 13% non-MA (NMA). Post-transplant cyclophosphamide (PTCy) was used in 27%; and in vivo T-cell depletion (ATG or alemtuzumab) in 26%. After median follow-up of 66 months (3-130), 5-yr OS was 18% (Group 1), 18% (Group 2), 35% (Group 3) vs 46% in controls (p<0.001). 5-yr LFS was 14%, 15%, and 28%, respectively, vs 38% (p<0.001). 5-yr CIR was 69%, 66%, and 52% vs 43% (p<0.001). Transplant-related mortality (TRM) was similar across groups (1-year: 12–16%). On multivariate analysis, compared with controls, TP53del (with or without TP53mut) was independently associated with higher relapse risk: Group 1 HR 1.97, Group 2 HR 1.91, Group 3 HR 1.45 (all p<0.001). These findings translated into inferior OS (HR 1.94, 1.87, and 1.45, respectively, p<0.001). PIF/Rel and CR2+ were also associated with worse survival (HR 2.58 (p<0.001) and 1.18 (p<0.001, respectively). No significant difference was observed between MA and RIC for relapse, while non-myeloablative regimens (HR 1.65; p<0.001) were associated with higher CIR. In vivo T-cell depletion increased relapse risk (HR 1.22; p=0.004). TRM was not influenced by TP53alt status; it was impacted by age, KPS, time from diagnosis to HCT, and GVHD prophylaxis regiment (non-PTCy). Conclusions: This large, registry-based study with long term median follow-up showed that among patients with adverse-risk AML, TP53alt is a strong independent predictor of poor post-HCT outcomes in AML, particularly when TP53del is present. Patients with TP53del , with or without concurrent TP53mut, experienced the worst outcomes, followed by those with isolated TP53mut. Despite the limitations of registry data including lack of information on timing of TP53mut, variant allele frequency (VAF), number of mutations, or accurate information on measurable residual disease (MRD), these findings reinforce the adverse prognostic impact of TP53alt and support its inclusion in risk stratification frameworks. While some patients with TP53alt —particularly those with isolated mutations—may benefit from allo-HCT, relapse remains the dominant cause of failure. Future studies incorporating TP53 functional status, VAF, clonal architecture, specific CG, MRD, and novel transplant approaches are warranted.

Abstract Introduction TP53MT are associated with poor outcomes in MDS, especially in the context of biallelic MT. We have previously reported on outcomes of pts with HR-MDS with TP53MT who received HMA in the VALIDATE dataset (Kewan T et al, ASH 2023). Here we provide expanded analyses focusing on outcomes post allo-HCT, and we explore the prognostic significance of different classification methods for biallelic TP53MT. Methods The VALIDATE database includes 4,732 pts with MDS who received HMA-based frontline therapy from 32 international centers in 9 countries. For this study, only pts with HR-MDS with molecular data at time of diagnosis were included. Biallelic TP53MT status was assessed using three classification schemes: WHO 2022, ICC 2022, and a VAF-based Cleveland Clinic Foundation (CCF) method.1TP53 copy neutral loss of heterozygosity (CN-LOH) was evaluable in 386 pts (118 had TP53MT). Treatment responses were evaluated using IWG 2023 criteria (Zeidan A et al, Blood 2023). Composite complete remission (cCR) was defined as CR+CRbi+CRuni+CRh+CRequivalent. We calculated OS from time of HMA initiation to date of death or last follow up. Unsupervised clustering (MOSAIC framework) was applied to identify molecular subgroups within the TP53MT cohort. The study was funded by an independent grant from Abbvie. Results A total of 1,485 pts were included. Median age was 69 years (IQR: 62–76), with 66% male pts. Median bone marrow blast was 7%, and 28% had a complex karyotype. Treatment regimens included azacitidine (68%), decitabine (15%), HMA/Venetoclax (8%), and other HMA combinations (9%); 34% underwent allo-HCT. Overall, 392 (26%) had TP53MT with 430 TP53 mutations (missense: 316; truncating: 89). Biallelic TP53MT % varied by classification: 72% (WHO), 84% (ICC), and 85% (CCF). Compared to TP53 wild-type (TP53WT) pts, pts with TP53MT had worse OS (median: 11.5 vs. 23.9 months [mo], p< 0.001), were younger (68 vs. 70 years, p=0.039), and had lower counts at diagnosis. Complex karyotype (81% vs. 14%) and chromosomal abnormalities were more frequent in TP53MT pts. Pts with TP53MT also had fewer co-mutations in other genes. Response to HMA was evaluable in 1,094 pts: cCR and CR were 32% and 13%, respectively. TP53MT pts had higher cCR (39% vs. 29%, p=0.001) than TP53WT, but similar CR rates (16% vs. 12%, p=0.093). According to WHO 2022, biallelic TP53MT had higher CR rates than monoallelic TP53MT (18% vs. 8%, p=0.03), but similar cCR. ICC and CCF classifications did not differentiate response rates. Median OS did not differ by TP53MT allelic status using WHO or ICC definitions. However, using the CCF method, pts with biallelic TP53MT had shorter OS than monoallelic TP53MT (10.4 vs. 17.2 mo, p=0.038). In multivariable models adjusted for age, gender, and allo-HCT, only the CCF-defined biallelic TP53MT group had significantly worse OS (HR: 1.6; 95% CI: 1.1–2.4). TP53MT pts undergoing allo-HCT had improved OS regardless of allelic status. Median OS for TP53MT pts with allo-HCT was 18.9 vs. 9.2 mo without all-HCT. This benefit was observed across WHO, ICC, and CCF classifications. However, a TP53MT VAF ≥19% predicted worse OS even post allo-HCT (14.6 vs. 47.1 mo, p<0.001). At 1 year, the survival rate was 78% (95%CI: 69-89%) in TP53MT pts who underwent allo-HCT and had cCR vs. 68% (95%CI: 55-84%) in pts who did not have cCR. However, 1 year survival rate was significantly higher for pts with TP53MT who did not have allo-HCT and achieved cCR (60%, 95%CI: 48-76%) vs. no cCR (26%, 95%CI: 20-35%). Unsupervised clustering of 335 TP53MT pts identified 9 molecular clusters (MCs). MC2, characterized by low TP53MT VAF (median 17%), fewer co-mutations, and frequent del17p, was associated with significantly improved OS (17.9 mo) and predicted favorable outcome (HR for death: 0.6; 95% CI: 0.4–0.8). Other clusters were enriched for adverse features (e.g., high VAF, multi-hit TP53MT).Conclusions The CCF method appears to best classify biallelic TP53MT pts with worse survival in the absence of accurate assessment of LOH status. Treatment response per IWG 2023 for TP53MT pts was associated with OS only in non-transplanted pts. Allo-HCT improved survival across TP53MT subsets, but TP53 VAF ≥19% at diagnosis remained a strong negative prognostic factor. Integrative clustering revealed a less aggresive molecular subset among TP53MT pts, suggesting refined risk stratification may guide therapy in this high-risk population. Ref: 1.Bahaj et al. J Hematol Oncol 2023.

Abstract Introduction: Marrow complete remission (mCR) in 2006 IWG criteria for MDS (Cheson B et al, Blood 2006) reflects achieving bone marrow (BM) blast percentage below 5% but is frequently not associated with meaningful count recovery. While mCR + hematologic improvement (HI) does reflect wide ranges of count improvement or transfusion reductions, HI is difficult to measure accurately in routine clinical practice. The 2023 International Working Group (IWG) response criteria (Zeidan A et al, Blood 2023) eliminated the mCR category without meaningful count recovery and reclassified mCR associated with meaningful count recovery into specific “less-than-CR” categories. Still, many clinical trials continue to use mCR as a secondary efficacy endpoint or as a part of overall response rate (ORR). Within the icMDS VALIDATE database, we assessed the association of mCR with OS in hypomethylating agent (HMA)-treated higher risk (HR)-MDS patients among both (1) transplanted and (2) non-transplanted patients. Methods We included patients with HR-MDS (defined as IPSS ≥1.5 and/or IPSS-R >3.5) who received HMA-based therapies from the international icMDS VALIDATE dataset. We evaluated the best response by IWG 2006 criteria into CR, mCR, or no CR/mCR. We then reclassified patients with mCR per IWG 2023 criteria into either (A) having achieved a composite CR (cCR) defined as CR + CR equivalent (CRequ) + CR with bilineage count recovery (CRbi) + CR with unilineage count recovery (CRuni) + CR with partial hematologic recovery (CRh) or (B) not having achieved cCR (no cCR). OS was calculated from time of HMA initiation to date of death or last follow-up by using 6-month landmark analyses. We used Kaplan-Meier methods to estimate OS, and the Log-rank test to compare OS. VALIDATE is supported by an independent grant from AbbVie. Results A total of1049 patients met eligibility.Median age of patients was 69 (range 21-95), 64% were men. While 61% received azacitidine, 17% received decitabine, and 22% received HMA-based combination therapy. In total, 37% underwent subsequent allogenic stem cell transplantation (allo-HCT). Based on IWG 2006 criteria, 17%, 33%, and 50% achieved CR, mCR, and no CR/mCR as their best response, respectively. Patients achieving CR had superior median OS (25 months, 95% CI: 21-34 months) compared to those with mCR (16 months, 95% CI: 13-18 months; p=0.038) and no CR/mCR (15 months, 95% CI: 12-17 months; p=0.001). In patients who received a subsequent allo-HCT, the median OS for patients with mCR (30 months, 95% CI: 21-54 months; 1 year OS: 71%, 2 year OS: 55%) did not significantly differ compared to patients with CR (59 months, 95% CI: 25 months-not reached, p=0.80; 1 year OS: 73%, 2 year OS 62%) and patients with no CR/mCR (32 months, 95% CI: 21-45 months, p=0.46; 1 year OS: 69%, 2 year OS 54%). In contrast, in patients treated with HMA therapy alone without subsequent allo-HCT, median OS for patients with mCR (11 months, 95% CI: 9-15 months; 1 year OS: 46%, 2 year OS: 23%) did not significantly differ compared to patients with no CR/mCR (11 months, 95% CI: 9-14 months, p=0.85; 1 year OS: 47%, 2 year OS: 22%) but was significantly shorter compared to patients with CR (20 months, 95% CI: 17-28 months, p<0.001; 1 year OS: 69%, 2 year OS: 46%). Patients with mCR by IWG 2006 (N=347) were reclassified per IWG 2023 into having either achieved a cCR (N=219, 63%) or no cCR (N=128, 37%). Specifically, patients with mCR were reclassified per IWG 2023 into CR (4.9%), CRequ (0.6%), CRbi (26.8%), CRuni (29.4%), CRh (1.4%), PR (0%), HI (10%), no response (21.9%) and PD (4.9%). Patients with mCR who were reclassified into cCR had an improved median OS (16 months, 95% CI: 15-26 months; 1 year OS: 62%; 2 year OS: 43%) compared to patients reclassified into no cCR per IWG 2023 (13 months, 95% CI: 11-17 months, p=0.023; 1 year OS: 52%; 2 year OS: 31%). Conclusions Using the large icMDS VALIDATE dataset, we found that achievement of mCR by 2006 IWG criteria was not associated with improved OS compared to patients who did not achieve CR/mCR. Reclassification of mCR using IWG 2023 highlights the heterogeneity within the mCR group and suggests that IWG 2023 criteria stratifies outcomes in patients previously labeled as mCR by IWG 2006. IWG 2023 should be the standard used for ORR assessment in all future clinical trials involving patients with HR-MDS.

6538 Background: TP53 mutated ( TP53 mt ) high-risk myeloid neoplasm (HR-MN) confers a dismal prognosis in the contemporary era with only a subset of eligible patients (pts) able to achieve long-term remission with allogeneic stem cell transplantation (allo-HCT). Owing to poor outcomes, many physicians believe it is futile to treat older pts with disease-directed therapy, since curative intent allo-HCT cannot be offered. We sought to describe the outcomes of older pts with TP53 mt HR-MN receiving disease directed treatment. Methods: We conducted a multicenter observational study in collaboration with 11 U.S. academic centers under the COMMAND consortium. We reviewed the data of 451 older (≥ 60 years [yrs]) TP53 mt HR-MN (n= 282 acute myeloid leukemia [AML], n= 91 MDS transformed AML, n= 50 myeloproliferative neoplasm blast phase (MPN-BP) and n= 28 high-risk myelodysplastic syndromes [HR-MDS]) pts to analyze their outcome with disease directed treatment. Results: The median age was 70 yrs (range [R],60-90) and 58% were male. Proportions of pts with age ≥ 70 yrs were 47.5%. Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was available in 68% (n= 306) of pts; 10.5%, 49%, 32% and 8.5% had ECOG-PS 0-3, respectively. The median bone marrow (BM) blast % was 32 (R, 5-99) and TP53 variant allele frequency (VAF) was 45% (R, 2-97). The proportion of pts with multi-hit (MH) TP53 mt and complex cytogenetics (CG) was 83% and 82%, respectively. 43 %, 31%, 20% and 6% received hypomethylating agent (HMA) + venetoclax, intensive chemotherapy, HMA and other low-intensity therapy, respectively. The complete remission rate with or without count recovery (CR/CRi) amongst evaluable patients (n= 356) was 37%. The median duration of response was 6.7 months (mo) (R, 5.9-7.5). Amongst 56 (12%) pts who underwent allo-HCT, the median overall survival (mOS) from time of allo-HCT was 21.9 mo. The mOS among pts ≥ 70 yrs was 6.5 mo. The mOS in mo was better in HR-MDS (16.4), compared to de novo AML (6.5), MDS transformed AML (7.1) and MPN-BP (5.27), p= 0.003. We conducted multivariable analysis for OS using baseline variables that were significant/ showed trend towards significance, on univariate analysis ( p <0.1). HR-MDS (HR; 0.43, 95% CI: 0.23-0.82, p= 0.01), CR/CRi (HR; 0.55, 95% CI: 0.39-0.77, p= <0.001) and allo-HCT (HR; 0.28, 95% CI: 0.16-0.47, p= <0.001) positively impacted OS. Whereas age ≥ 70 yrs showed trends towards inferior OS (HR; 1.31, 95% CI: 0.95-1.80, p=0.09). Complex CG (HR; 1.63, 95% CI: 0.83-3.21, p =0.15) and MH TP53 mut (HR; 1.30, 95% CI: 0.67-2.52, p= 0.42) did not retain significance for OS. Conclusions: Our multi-center study suggests that disease directed treatment in older TP53 mt HR-MN leads to modest response rates with short durations of response in the absence of allo-HCT. 12% of pts were able to receive allo-HCT with improvement in OS close to 2 yrs. The decision to treat this poor risk gp of pts should be based on individual pt characteristics and desires.