Abaza, Yasmin

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.

Introduction The International Prognostic Scoring System (IPSS) and its revised version (IPSS-R) were developed using datasets from patients (pts) with untreated MDS. The cytogenetic risk groups used in IPSS-R were expanded to 5 groups from the 3 used in IPSS. Among the new groups introduced in IPSS-R is the “very complex” karyotype (VCK) where ≥4 karyotypic abnormalities are seen compared to “complex karyotype (CK)” with only 3 abnormalities. However, the prognostic impact of VCK vs CK, as well as individual cytogenetic abnormalities and TP53 mutation (TP53mut) status within the CK and VCK subgroups in pts with MDS treated with hypomethylating agents (HMAs) has not been well studied. Hence, we analyzed these questions in a large cohort of HMA-treated MDS pts in the icMDS VALIDATE database. Methods The icMDS VALIDATE database contains MDS pts treated with frontline HMA monotherapy or HMA-based combinations from 22 specialized international centers. Pts with unknown HMA type, date of HMA initiation, missing age, missing sex, missing cytogenetic data, bone marrow or peripheral blood blasts ≥20%, or missing survival status were excluded. We performed time-to-event analyses using the Kaplan-Meier method and compared groups by the log-rank test. We measured overall survival (OS) from time of HMA initiation. VALIDATE protocol was exempted, acknowledged, or approved by all centers' IRBs. VALIDATE is supported by an independent grant from Abbvie. Results A total of 1940 pts were included. Median age was 70 (range: 18-99) years and 66% were men. According to IPSS-R cytogenetic risk groups, 1.9% (37) were very good, 43.4% (841) good, 15.5% (301) intermediate, 11.6% (226) poor, and 27.6% (535) very poor. By HMA type, 71% of pts were treated with azacitidine, 14% with decitabine, 6% with HMA and venetoclax, and 9% with another HMA combination. Approximately 28% of pts underwent allogeneic hematopoietic stem cell transplant (alloHSCT). The IPSS-R cytogenetic risk groups had different OS (p<0.001)with median OS (mOS; months [mo], 95% CI) as follows: very good (43.4, 34.7-72.5), good (41.7, 36.4-46.8), intermediate (24.5, 23.1-32.4), poor (24.2, 19.2-28.5), and very poor (13.6, 12.5-14.5). The difference remained significant (p=0.001) after censoring at time of alloHSCT with mOS as follows: very good (40.4, 23.2-64.3), good (24.3, 22.2-26.3), intermediate (19.3, 15.1-22.2), poor (12.2, 10.3-14.8), and very poor (9.1, 8.2-19.7). Interestingly, the difference between mOS for intermediate and poor risk cytogenetics became more apparent after censoring at time of alloHSCT. Next, we compared the outcomes of pts with CK and VCK to non-complex karyotype (NCK) MDS. The mOS for pts with VCK MDS (13.6 mo, 12.5-14.5) was worse compared to pts with CK (19.9 mo, 19.9-16.8; p=0.004) and NCK (36.1 mo, 32.7-37.8; p<0.001) MDS. Among the 1458 pts with available molecular data, more pts with VCK (75%, 330) MDS had a concurrent TP53mut compared to pts with CK (40%, 21; p<0.001) and NCK (7%, 64 p<0.001) MDS. Considering only patients with TP53mut MDS, mOS for pts with VCK (12.2, 11.1-13.9) was worse compared with NCK (24.2, 16-1-53.1; p<0.001) but not with CK (19.9, 9.5-NR; p=0.9); the difference between CK and NCK was not significant (p=0.16). Among pts with TP53 wildtype (TP53WT) MDS, VCK (15.0, 13.2-18.2) had a similar mOS to TP53WT CK (18.8, 12.6-41.1; p=0.19) while both groups had worse mOS compared to TP53WT NCK (33.4, 30.1-37.0) (p=0.01). In a survival analysis of 616 pts with MDS with ≥3 cytogenetic abnormalities, -17/del(17p) (12.8 mo; p=0.009), inv(3)/t(3q)/del(3q) (10.9 mo; p=0.006), and del(7q) (12.1mo; p=0.024), though not -7 (12.6mo; p=0.23), were associated with lower mOS compared to the pts with MDS without these abnormalities (14.3mo). Conclusions Using one of the largest databases of HMA-treated MDS pts, we show that IPSS-R cytogenetic risk categories associate with significantly different survivals among HMA-treated MDS pts, even after censoring at time of alloHSCT. Importantly, VCK MDS was associated with worse mOS compared to CK and NCK MDS but not in pts with a concurrent TP53mut. Among pts with MDS with ≥3 chromosomal abnormalities, having -17/del(17p), inv(3)/t(3q)/del(3q), or del(7q) was associated with worse survival.

Background Acute myeloid leukemia (AML) with TP53 mutation (m) has poor outcomes even in the contemporary era with median overall survival (OS) of 6-9 months. The only factor that has been shown to improve outcomes is allogeneic hematopoietic cell transplantation (allo-HCT) (Badar et al AJH 2022; Leukemia 2023). However, the role of allo-HCT for TP53-m AML continues to be a matter of debate given high rates of relapse after allo-HCT particularly in TP53-m AML with complex cytogenetics (CG). We used the COMMAND consortium database to investigate the factors that influenced physician's decision for allo-HCT in TP53-m AML. Method We conducted a multicenter observational study in collaboration with 7 U.S. academic centers under COMMAND consortium. We reviewed electronic medical records of 369 TP53-m AML patients to analyze reasons for not pursuing allo-HCT including refractory disease, donor availability, advanced age/co-morbidities, physician perspective on ineffectiveness of allo-HCT in improving outcome and patient's decision. Diagnostic criteria for TP53 allelic state were according to the International Consensus Classification (ICC) (Blood 2022; 140:1200). Next-generation sequencing and cytogenetic studies were performed according to institutional standard protocols. Results The median age at diagnosis was 68 years, with 222 (60.5%) patients being male. The majority of patients were diagnosed with de novo AML 179 (48.8%), followed by secondary AML (sAML) in 103 (28%) patients, and therapy-related (t)AML in 85 (23.2%) patients. Ninety-four percent of evaluable patients had complex cytogenetics (CG) and 192 (52%) had multi-hit TP53-m. One-hundred forty-seven (42%) patients received intensive chemotherapy (CPX 351 [66 (44%)], 7+3 [78 (53%)]), while 205 (58%) patients received low-intensity regimens including hypomethylating agents (HMA) plus venetoclax (137 [66%]) and HMA +/- investigational agents (68 [33%]). The rate of complete remission (CR)/CR with incomplete count recovery (CRi) was 34.4% and overall response rate (CR/CRi + partial remission [PR] + morphologic leukemia free state [MLFS]) was 52%. Forty-seven (13%) patients received allo-HCT in CR1 and 17 (5%) patients received allo-HCT in CR2. Of the 294 patients for whom data on allo-HCT decision-making was available, the most common reason for not proceeding to allo-HCT was refractory disease in 126 (43%) patients. Other significant reasons included advanced age/comorbidities (n=78 [30.6%]), physician recommendation (n=7 [2%]), patient's decision (n=24 [9.4%]), and patient relocation or changing healthcare providers (n= 9 [3.5%]). Two (0.4%) patients had no suitable donor available for allo-HCT. Amongst the 7 patients for whom allo-HCT was not pursued due to physician's decision, the median age of the patients was 69 years (R, 59-70), 3 (25%) patients had sAML, and all of them had multi-hit TP53-m associated with complex CG. Six out of seven (86%) patients received HMA plus venetoclax and 1 (14%) patient received HMA-based induction. Six patients achieved CR/CRi after induction and 1 patient had partial remission. The median survival of these patients was 11 months (R, 10.7-11.3), eventually all patients died from progressive AML. Conclusion Our survey suggests that the primary reason for not proceeding with allo-HCT was refractory disease, underlying the difficulty in achieving the disease control needed for allo-HCT. There is an urgent need for better frontline therapies tailored specifically for TP53-m AML, along with refined patient selection criteria to better identify candidates who would benefit most from allo-HCT to potentially improve their long-term outcomes.

Introduction: MPAL is a rare and heterogenous subtype of acute leukemia characterized by a single blast population with phenotypic expression of both myeloid and lymphoid lineages (biphenotypic) or multiple co-existing lineages of blasts that satisfy criteria for both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). MPAL presents both a diagnostic and therapeutic challenge given its rarity and resistance to traditional therapies. Data suggest ALL-directed or hybrid therapies are most effective at inducing durable remissions as a bridge to allogeneic stem cell transplantation (Allo-SCT; Lazzarotto 2023, Rasekh 2021); however, many are single-institution with limited sample sizes. Methods: A retrospective analysis at 7 US academic centers was performed. Adult patients (pts) with a confirmed diagnosis of MPAL between 2003-2023 were included. Comparisons of categorical and continuous variables utilized the Fisher exact test and Wilcoxon rank-sum or Kruskal-Wallis test as appropriate. Time-to-event outcomes were calculated using the Kaplan-Meier method and compared using log-rank test. Results: A total of 79 pts with MPAL were included in this study. Median age at diagnosis was 61 years (range, 18-89); 52% were ≥ 60 years. Majority of pts were male (60%), non-Hispanic white (64%), and had an ECOG ≤ 1 (83%). Of the 50 pts with baseline CSF analysis, 5 (10%) had CNS disease. Phenotypically, the predominant blast population was biphenotypic in 68%, myeloid in 17%, and lymphoid in 15% of cases. KMT2A-rearrangement and BCR::ABL1 translocation constituted 4% and 14% of cases, respectively, and 30% of pts had complex cytogenetics. Most common mutations at baseline included RUNX1 (33%), DNMT3A (30%), FLT3-ITD (26%), TET2 (19%), WT1 (19%), NRAS (18%), TP53 (17%), and ASXL1 (14%) mutations. Of the 79 pts, 61 (77%) received intensive chemotherapy (IC), 12 (15%) received HMA-based regimens, 4 (5%) received other non-intensive regimens, and 2 (3%) transitioned to hospice prior to therapy. Among those receiving IC, 37 (61%) received ALL-directed therapies, 16 (26%) AML-directed, and 8 (13%) received hybrid regimens which included FLAG-VIPR (6/8), 7+3+vincristine (1/8), and cladrabine/low-dose cytarabine/vincristine/dexamethasone (1/8). Therapies were phenotype-discordant in 4/61 pts receiving IC; 3 myeloblast-predominant MPAL pts received ALL-directed therapy and one lymphoid-predominant pt received AML-directed therapy. Among 54 pts with predominant biphenotypic blasts, 52% received ALL-directed regimens. Of the 11 pts with BCR::ABL1 translocation, 8 (73%) received dasatinib, 2 (18%) ponatinib, and 1 (9%) received both. Only 30% of pts with FLT3-ITD mutated MPAL (5/17) received a FLT3 inhibitor. Overall, 56% of pts achieved complete remission (CR) or CR with incomplete count recovery (CRi), with a median duration of response of 16.7 months (IQR: 8.1-46.1). The rates of CR/CRi were 39%, 56%, and 75% for myeloid, biphenotypic, and lymphoid MPAL, respectively. All pts with CNS disease (5/5) cleared after induction. Thirty-seven percent of pts proceeded with Allo-SCT in first remission (23% of myeloid pts, 58% lymphoid, 35% biphenotypic). Thirty-two percent of responders (CR/CRi; 14/44) relapsed with a median time to relapse of 9.4 months (range, 0.5-42). Median overall survival (OS) for the entire cohort was 51 months (95% CI: 15-89). The 2-year OS rate was higher in pts with lymphoid-predominant phenotype (83%) compared to biphenotypic (55%) or myeloid-predominant phenotype (38%; p=0.16). Median OS was significantly longer in transplant versus non-SCT recipients (121 vs 14 months) with a 1-year OS rate of 97% vs. 59% (p<0.0001), respectively. Among pts who achieved CR/CRi, median OS significantly longer in transplant versus non-SCT recipients (121 vs 55 months, p=0.031), with a 2-year OS rate of 91% vs 75%. Conclusions In this large multi-center study, there were differences in survival based on predominant blast phenotype, with improved OS in lymphoid-predominant MPAL. Although most pts with biphenotypic-predominant MPAL received ALL-directed regimens, OS was worse in this subtype compared to lymphoid-predominant MPAL. There was significantly improved OS among Allo-SCT recipients underscoring the importance of Allo-SCT in this subtype of acute leukemia. Additional studies are needed to understand this rare and heterogenous disease.

Introduction: TP53 mutations are found in 18% of adult patients (pts) with acute lymphoblastic leukemias (ALL), and portends poor prognosis (Saygin, Blood Cancer Discov 2024). TP53 mutations are often associated with low hypodiploidy and Li Fraumeni syndrome (germline) in children. However, we and others have shown that TP53-mutant (TP53-m) ALL arises from pre-existing TP53-m clonal hematopoiesis in adults as opposed to germline origin. The impact of co-occurring mutations, TP53 allelic frequency (AF) and different types of treatment on outcomes of TP53-m ALL are not fully characterized. We set out to investigate the clinical and molecular predictors of outcomes in adults with TP53-mutant ALL. Methods: We retrospectively studied 107 patients with TP53-m ALL treated at seven different academic centers in North America. Genetic profiling of pre-treatment bone marrow samples was performed with a comprehensive panel covering 147 myeloid and lymphoid genes. We also performed RNA-sequencing to identify fusions that define ALL subtypes. Single nucleotide polymorphism (SNP) array was used to define low hypodiploidy. Results: The median age at diagnosis was 59 years (range, 10-80), 42% were female, 70% White. 89% of pts had B-ALL while 11% had T-lineage ALL. 24% of pts were classified to have therapy-related ALL based on their history of exposure to genotoxic therapy for another cancer. 45% of pts had hypodiploid karyotype, 79% of whom were low-hypodiploid. 7% had hyperdiploid karyotype and 5% had BCR::ABL1. 11 pts had two different TP53 variants. 90% of TP53 variants involved the DNA binding domain. Most frequently observed co-occurring mutations involved CDKN2A (20%), NOTCH1 (12%) and RB1 (10%) genes. 71% of pts were treated with standard cytotoxic chemotherapy, while the remaining pts received newer antibody-based therapies (i.e., inotuzumab, blinatumomab) or venetoclax in first-line setting. 11% of pts received allogeneic hematopoietic cell transplant (HCT) in first complete remission (CR1) while 3% received HCT after relapse (CR2 or CR3). When patients with vs without low hypodiploidy were compared, we did not observe a significant difference in overall survival (OS) as outcomes were poor in both groups (median, 17 vs 19 months, p= 0.89). However, pts who had TP53 AF >0.5 had significantly worse OS when compared to pts with TP53 VAF <0.5 (13 vs 25 months, p= 0.03). Conclusions: TP53-m ALL is a very high-risk disease subtype and its dismal outcome is independent from presence of co-existing low hypodiploidy. Loss of heterozygosity, characterized by TP53 AF >0.5 is associated with even worse survival. New therapies are urgently needed to improve outcomes in this subset.

Introduction: Acute myeloid leukemia (AML) has been considered by many to be an oncologic emergency often leading to hospital admission for expeditious evaluation and treatment. Previous studies reported that time from diagnosis to treatment (TDT) does not impact outcomes (Sekeres, Blood, 2009), (Bertoli, Blood, 2013), (Rollig, Blood, 2020), however these analyses were restricted to intensively treated and/or non-United States (US) patients (pts). We report on a multi-center, retrospective analysis of TDT in adults with newly diagnosed AML receiving Hypomethylating agent (HMA) + venetoclax (Ven) using real-world data from the COMMAND. Methods: Eight US academic medical centers with AML expertise performed a review of adult pts within their center treated with HMA+Ven for newly diagnosed AML. TDT was defined as days from diagnosis of AML to initiation of treatment with HMA+Ven. Cytoreduction with hydroxyurea or leukapheresis was included to control for the effects of severity of presentation on TDT. The primary outcome was impact of TDT on overall survival (OS) (defined as date of diagnosis to date of death). TDT was treated continuously for time-to-event analyses. Secondary outcomes included measurable residual disease (MRD) by flow cytometric analysis (sensitivity <0.1%), complete response (CR), complete response with incomplete count recovery (CRi), defined by European LeukemiaNet (ELN) 2022 Guidelines (Dohner, Blood,2022), and early mortality (death within 30 and 60 days of initiation of HMA+Ven). Pre-planned subgroup analyses included those based on disease biology (FLT3 ITD, IDH1/2, TP53 mutation, ELN 2022 risk), HMA used (azacitidine vs decitabine) and age (<75 vs ≥75 years). For those analyses where TDT was significant in univariable analysis (P=0.1), multivariable analysis was conducted controlling for the following: ECOG performance status (PS), age, receipt of cytoreduction, ELN 2022 risk, and presence of individual pathogenic variants detected on broad myeloid gene next generation sequencing panels used at each institution. All analyses were conducted by a central statistician using RStudio statistical package. Results: 488 pts were included in the analysis. Median age was 76 (interquartile range: 70-80) and the majority of pts had an ECOG PS of 0 or 1 (56%). Most pts (67.6%) had adverse risk with 9.4% and 18.6% of pts having favorable and intermediate risk disease by ELN 2022, respectfully. The most common mutations identified were TP53 (27.5%), IDH1/2 (19.3%), NPM1 (16.4%), DNMT3A (16.8%), ASXL1 (15.4%), and FLT3-ITD (13.7%). Twenty-eight percent of pts received cytoreduction prior to initiation of HMA+Ven. Azacitidine+Ven was the most common regimen utilized (53.9%). Median number of cycles of HMA+Ven was 3 (IQR: 1-6). MRD (-) CR, MRD (+) CR, and CRi was achieved in 21.5%, 10.5%, and 16.4% of pts after one cycle of HMA+Ven. Median OS for the cohort was 10.4 months (95% CI: 9.4-12.6). Median TDT for the cohort was 9 days (IQR: 5-17). In univariate Cox model, longer TDT was associated with improved OS (HR: 0.989, 95% CI: 0.981 to 0.998; p = 0.013). In multivariable analysis, longer TDT was still associated with improved OS (HR: 0.987; 95% CI: 0.973-0.999; p=0.049). TDT and presence of bZIP in-frame CEBPA mutations were the only factors associated with improved OS, while ECOG PS of 2 or 3-4, when compared to ECOG PS=0 (p=0.035 and 0.0002, respectively) and therapy-related AML (p=0.002), were associated with worse OS. Notably, ELN 2022 risk and IDH1/2 or NPM1 mutation status did not impact OS. Discussion: In this real-world, multi-center, US-based analysis of pts with newly diagnosed AML treated with HMA+Ven we show that longer TDT is associated with improved OS even when controlling for severity of presentation, ELN 2022 risk score, ECOG PS, and age. This finding is consistent with data in pts treated with 7+3. Similar to results published in an electronic medical record-based analysis out of Germany (Baden, Haemotologica, 2024) in pts treated with lower-intensity Ven regimens, our results show that pts with newly diagnosed AML eventually treated with HMA+Ven are best served with a complete appraisal of disease biology and treatment planning before initiation of induction therapy. Given the consistent negative impact of ECOG PS and the findings of our study, future consideration for potential patient optimization strategies to improve ECOG PS prior to therapy initiation are warranted.

Introduction: Response assessment is used to evaluate effectiveness of hypomethylating agent (HMA)-based therapy in myelodysplastic syndromes/neoplasms (MDS) in clinical practice and trials. Recently, the clinical response criteria (IWG 2023) and the clinical-molecular risk assessment (IPSS-M) in MDS were published. However, it remains unknown whether the IWG 2023 response criteria have an independent impact on overall survival (OS) when adjusting for baseline IPSS-M risk. Additionally, the association of IWG 2023 response criteria with OS in patients (pts) undergoing allogeneic stem cell transplantation (allo-HCT) versus those who do not is unknown. Lastly, it is unclear if optimal time-to-transplant impacts OS in MDS pts who achieve a IWG 2023 defined remission with HMA therapy. We examined these questions in a large population of MDS pts within the multi-institutional international consortium for MDS (icMDS) VALIDATE database. Methods: High-risk MDS pts with IPSS ≥1.5 or IPSS-R >3.5 treated with HMA-based therapy were included in the study. Baseline IPSS-M risk was stratified into very low/low/moderate low (VL+L+ML), moderate-high/high (MH+H), and very high (VH). Response to treatment was evaluated using the IWG 2023 criteria and grouped into: composite complete response (cCR) and no cCR. cCR included: complete response (CR), CR equivalent (CRequ), CR bilineage (CRbi), CR unilineage (CRuni), and CR with partial hematologic recovery (CRh). We analyzed the differential impact of achieving cCR on HMA-based therapy prior to transplant on OS in pts who either did or did not undergo allo-HCT, while adjusting for their baseline IPSS-M risk in Cox regression analysis. Optimal time-to-transplant was determined based on age and IPSS-M category as described by Tentori et al. (JCO 2024). Pts proceeding to allo-HCT were stratified on whether they underwent transplant within the optimal time-to-transplant timeframe after MDS diagnosis or not. VALIDATE protocol was exempted, acknowledged, or approved by all centers' IRBs. VALIDATE is supported by an independent grant from AbbVie. Results: We analyzed 762 MDS pts. The median age at MDS diagnosis was 68 years (range: 19-95 years) and 64% of pts were male. Distribution of the baseline IPSS-M risk was: VL+L+ML in 110 (14%) pts, MH+H in 347 (46%) pts, VH in 305 (40%) pts. Pts received azacitidine monotherapy, decitabine monotherapy, and HMA-based combination therapy (e.g. HMA + venetoclax) in 52%, 21%, and 28% of cases, respectively. A total of 282/762 (37%) pts achieved cCR as their best response to HMA-based therapy. The median OS for all pts was 18.7 months (95% CI: 16.6-21.3 months). Pts who did not undergo allo-HCT (n=436, 57%) had an improved median OS if they achieved cCR when compared to pts in the no cCR group in all IPSS-M risk groups (VL+L+ML: 23.5 months vs. 10.7 months; MH+H: 20.8 months vs. 11.6 months; VH: 13.8 months vs. 7.5 months). Cox analysis demonstrated an independent effect of cCR on OS in these pts when adjusted for baseline IPSS-M risk (cCR vs. no cCR: HR 0.60, 95% CI 0.48-0.76, p<0.001). In contrast, in pts who subsequently received an allo-HCT (n=326, 43%), achieving cCR with HMA prior to allo-HCT did not provide an additional OS benefit, when adjusted for baseline IPSS-M risk (cCR vs. no cCR: HR 1.00, 95% CI 0.73-1.38, p=0.986). The median time-to-transplant was 6.7 months and 34% of transplanted MDS pts received their allo-HCT during the optimal timeframe. Among pts who achieved cCR with HMA-based therapy prior to allo-HCT, optimal time-to-transplant was associated with significantly improved OS (optimal vs. non-optimal timing: HR 0.55; p=0.033). Conclusion: Baseline IPSS-M risk and allo-HCT had an independent impact on OS, while IWG 2023 defined cCR had an independent effect on OS only in non-transplanted MDS pts. While this retrospective analysis occurred at large academic centers with specific expertise in the management of MDS, our data may have an impact on clinical practice: (i) failure to achieve cCR on HMA therapy prior to transplant should not impact the decision to proceed to allo-HCT, (ii) upfront allo-HCT without prior HMA therapy might also be an option if the clinical situation and availability of donors allow, and (iii) allo-HCT should ideally be performed during the timeframe that is considered optimal as defined by pt age and baseline IPSS-M.

Background: Acute promyelocytic leukemia (APL) is one of the most treatable leukemias in the current era, with cure rates upwards of 90%. Early mortality due to coagulopathies often seen at diagnosis is a major driver of adverse outcomes. Prompt initiation of all-trans retinoic acid (ATRA) is crucial for suspected APL, as it is known to reverse these coagulopathies. Chemotherapy-free protocols consisting of arsenic trioxide (ATO) and ATRA have become the standard of care for low-risk APL with high cure rates and reduced hematologic toxicities. For high-risk disease, there are multiple treatment options that have not been compared. Since APL is rare, there is a lack of real-world data for this disease. This retrospective review aimed to assess the outcomes of APL patients (pts) across multiple institutions and to examine the most common induction regimens, characteristics linked to early (30-day) mortality, and supportive care strategies. Methods: This retrospective study involved 9 institutions in the US and was conducted through the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND). Data included pts admitted from 8/5/2006 through 2/3/2024 with a confirmed diagnosis of APL. Each institution received a data-collection form and contributed data on APL pts from presentation to last follow-up. Key data categories included patient demographics, presenting laboratory and molecular data, treatment regimen, supportive care, and patient outcomes. Results: Data for 412 pts were identified with a median age of 51 (range 17-90) and 49% were female. Cardiovascular comorbidities were present in 44% of pts and 16% had a known pulmonary comorbidity. At presentation 109 (27%) had high risk-disease, defined as a white blood cell count (WBC) greater than 10 x 109/L. A FLT3 mutation was seen in 50% of tested pts, WT1 (22%), KRAS (3.6%), and NRAS (6.5%). The median WBC at presentation was 2 x 109/L (range: 0-166 x 109/L) and the median platelet count was 27 x 109/L (range: 2.0-315 109/L). Twenty-six percent presented with grade 2+ thrombosis, bleeding, or both. A higher percentage of pts with high-risk vs. low-risk disease presented with grade 2+ thrombosis, bleeding, or both (43% vs. 20%), DIC (60% vs. 36%), and mutated FLT3 (81% vs. 37%). The majority of pts received a chemotherapy-free induction regimen consisting of ATRA plus ATO. It was determined that 36 (8.7%) pts received induction with intermittent ATO plus ATRA (Burnett AK, Lancet Oncol 2015), 276 (67%) received daily ATO plus ATRA (Ravandi F, J Clin Oncol 2009 and Lo Coco, NEJM 2013), and 70 (17%) received a regimen inclusive of an anthracycline plus ATRA. Eleven pts did not start an induction regimen other than single-agent ATRA due to early death, while 19 had their regimen classified as “other” because they did not follow a conventional induction path. In total, 295/358 (82%) received ATRA within 24 hours of admission. At least 1 dose of gemtuzumab ozogamicin was given to 58 (14%) pts, of which 35 (60%) were considered high risk. The incidence of differentiation syndrome (DS) was 37% (n=154). Among the 243 pts who received steroid prophylaxis, 30% developed DS, compared to 52% of those who did not receive prophylaxis. Among the 360 pts with at least 1 available PCR result after starting induction, 94% achieved PCR-negativity. The 30-day mortality rate was 6.6%. On univariate analysis, presenting variables associated with a higher 30-day mortality include older age, diabetes, cardiovascular comorbidities, thrombosis or bleeding, DIC, eGFR < 60, elevated total bilirubin and D-dimer levels, and high-risk disease. The median overall survival (OS) of the cohort was not reached, and the 5- and 10-year OS was 88% (95% CI: 84-91%) and 79% (95% CI: 72-87%) respectively. The cumulative incidence of relapse at 3 years was 2.7% (95% CI: 1.4 - 5.1%), with no additional relapses observed. The incidence of CNS relapse at 3 years was 0.9% (95% CI: 0.3% - 2.8%), with 2 of the 4 pts classified as high-risk. Conclusion: This is the largest real-world evidence data collection in the US evaluating the outcome of pts with APL in the current era, inclusive of ATO as front-line induction. Outcomes for this disease remain extremely positive, with low 30-day mortality rates noted in this study along with durable OS rates and low incidence of relapse. Additional information on outcomes, safety, and supportive care will be presented at the meeting.

Background: Randomized studies in newly diagnosed (ND) AML patients with a FLT3 mutation show that adding 14 days of a FLT3 inhibitor to each intensive chemotherapy cycle improves overall survival. For patients unsuitable for intensive chemotherapy due to older age or comorbidities, the presence of a FLT3-ITD mutation is associated with high rates of early relapse and short remission duration. There is a limited survival benefit of venetoclax (ven) plus azacitidine (aza) compared to aza alone among patients with AML with a FLT3-ITD mutation. Accordingly, there is significant interest in adding FLT3-targeted therapy to lower intensity chemotherapy for patients with ND AML and FLT3 mutations, but to date no randomized data have demonstrated a survival benefit for this approach.Gilteritinib (gilt) is a highly potent and FLT3-selective oral tyrosine kinase inhibitor that is the standard therapy of relapsed/refractory FLT3-mutated AML, based upon superior survival in randomized studies. Gilt can also be combined safely with ven and/or aza, though myelosuppression remains a concern. Despite this, single institution studies of ven, aza, and gilt therapy of ND AML patients with FLT3-mutations show that this three-drug regimen is associated with near-universal complete remission rates (CR 90%, CRi 6%) and a majority of studied patients eliminate detectable FLT3-ITD (<1 x10-5) within four cycles by an ultrasensitive, amplicon-based NGS assay (Short, et al. JCO 2024). Rates of CR with full count recovery and survival appear superior to historical comparisons, but myelosuppression is potentially increased with the triplet regimen. These data demonstrate a need for multi-institutional comparative trials, not only to determine whether adding FLT3-inhibitors to ven and aza improve deep remission rates, but also to refine schedules of the triplet combination that improve tolerability for widespread use.Methods: This tier 1 MyeloMATCH substudy is an open-label, randomized phase 2 trial that will enroll ND AML patients older than age 60 or individuals judged by their treating physician to be best served by azanucleoside + ven-based therapy due to comorbidity. Subjects provide samples to the central MyeloMATCH Master Screening and Reassessment Protocol (MSRP, NCT05564390 ) and are assigned to the MM1OA-EA02 substudy (NCT06317649) based upon the presence of a FLT3-ITD or FLT3-TKD (D835) mutation by NGS. Subjects are randomized to one of three arms (regimens 1, 2, or 3), stratified by age (<70 years vs. older) and FLT3-ITD burden (ITD VAF>33% vs. lower VAF or D835). All study arms contain aza and ven administered in 28-day cycles with two study arms also including gilt. Regimen 1 is ven and aza administered as per the pivotal VIALE-A study. Regimen 2 adds gilt 80 mg once daily on days 1-28 and regimen 3 adds gilt on days 8-21 only. A marrow biopsy is performed during the first cycle (day 14-21, depending on study arm) and all chemotherapy is held until count recovery if a morphologic leukemia-free state or aplasia is seen. Patients receive up to two induction cycles to achieve remission and then receive ongoing consolidation cycles of therapy with a similar pattern of gilt administration up to 2 years. To minimize risk of cumulative myelosuppression, during consolidation azacitidine administration is reduced to days 1-5 on regimens 2 and 3 and ven limited to days 1-7 on regimen 2 and days 1-14 on regimen 3. For all arms, treatment-related adverse events prompt further reduction in ven, aza, or gilt dose or duration. Response will be measured after cycles 2 and 4, including centrally-performed MRD by flow cytometry. The primary endpoint is the rate of MRD(-) CR (<1 x 10-3) after up to 4 cycles. Key secondary endpoints include safety data, response rate, EFS, and OS. The study is powered to detect a 25% absolute improvement in MRD(-) CR rate in either triplet arm from a target accrual of 147 patients. A safety run-in for regimens 2 and 3 to confirm tolerability and feasibility will be performed after 20 subjects enroll to these arms; an interim futility analysis will be performed once response assessment of 50% of all planned accrual occurs. Study was activated on June 6, 2024 and is expected to continue until December 2025.

Introduction Patients with lower-risk (LR) myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) experience shortened survival and significant unmet medical need due to limited disease-modifying treatments. The NLRP3 pathway is activated in hematopoietic stem and progenitor cells and in the marrow microenvironment in myeloid neoplasms, contributing to ineffective hematopoiesis and clonal progression. DFV890, a small molecule NLRP3 inhibitor, blocks IL-1β and IL-18 secretion and pyroptotic cell death. Thus, DFV890 may disrupt the smoldering inflammation and provide disease-modifying benefits to patients by restoring normal hematopoiesis and suppressing clonal myeloproliferation. Methods This open-label, phase 1b, multicenter study evaluates DFV890 in patients with very low, low, or intermediate risk MDS per revised International Prognostic Scoring System (IPSS-R) criteria and low or intermediate-1 risk CMML per CMML-specific Prognostic Scoring System (CPSS) criteria (NCT05552469). The study comprises 2 parts: dose optimization and dose expansion. Eligible patients ≥18 years, with ECOG performance status ≤2, carrying a diagnosis of (a) IPSS-R-defined LR-MDS or (b) CPSS-defined LR-CMML, and have failed to respond to or not tolerated established first-line therapies as defined in the protocol. Key exclusion criteria include previous treatment with agents targeting the NLRP3 inflammasome and IL-1 pathway. DFV890 is administered orally twice daily (BID) for a minimum of 24 weeks (6 cycles of treatment) until treatment discontinuation. In the dose-optimization part, patients are randomized to receive either low- or high-dose, stratified by indication. Primary objectives are to assess safety and tolerability and determine the optimal for DFV890. Secondary objectives include assessment of pharmacokinetics, and evaluation of preliminary efficacy of DFV890 based on hematologic improvement (Garcia-Manero, Blood 2023). Exploratory objectives include assessment of peripheral cytokines and genetic alterations in blood and bone marrow, and patient-reported symptoms. Results As of April 15, 2024, 39 patients (median age, 74 years) with a median of 2 prior lines of therapy (range: 1-5) were treated with DFV890 in the dose-optimization part. Based on an 8-week screening period, 8 patients (20.5%) were RBC transfusion independent at baseline. Eighteen patients received low dose (17 with LR-MDS; 1 with LR-CMML), and 21 patients received high dose (18 with LR-MDS; 3 with LR-CMML). At data cutoff, 10 (25.6%) patients had discontinued treatment. Median duration of exposure was 10.7 weeks (range, 0.6-42.0 weeks). Adverse events (AEs) leading to study drug discontinuation were only reported in the high dose arm (2 patients, grade ≥3 neutropenia, n=1 and blood bilirubin increased, n=1). Treatment-related AEs (TRAEs) were reported in 10 patients (25.6%), with 4 (10.3%) experiencing grade ≥3 TRAEs (anemia [n=2], neutropenia, and rash [n=1 each]). No serious AEs related to DFV890 were reported. Peripheral cytokines were assessed as a marker of preliminary activity. Decrease in plasma IL-18 and IL-1RA levels observed in most patients, with a higher frequency in the low dose arm (IL-18 decreased in 8/8 patients in low dose arm vs. 4/7 in high dose arm; IL-1RA in 7/8 vs. 5/7), potentially due to less frequent dose interruptions. Changes in serum IL-6 levels were more heterogeneous; notably, among the patients with complete mutation and biomarker data, both patients with mutations in TET2 showed dramatic decreases in serum IL-6; IL-18 and IL-1RA also decreased in those patients. In addition, out of 8 patients who were transfusion-independent at baseline, 6 reported an increase in hemoglobin with treatment, 4 of whom with an increment >10% from baseline. Updated data including hematologic response assessment according to IWG will be presented at the meeting. Conclusions Preliminary findings from this ongoing study show a favorable safety profile in patients with LR-MDS and LR-CMML, in line with prior human studies with DFV890. Analysis of peripheral cytokines and hematologic parameters showed early indications of activity in a subset of patients, particularly those with mutations in TET2 and those transfusion independent at baseline. These findings will require confirmation with longer follow-up and in the dose expansion phase of the study.