Patel, Shyam A.

Acute myeloid leukemia (AML) pathogenesis is deeply rooted in the concept of clonal evolution, in which hematopoietic stem cells experience an initial genetic insult, followed by the sequential acquisition of mutations leading to various disease phenotypes. Through natural selection, a malignant clone can diversify and propagate with time. Aside from clonal evolution, a number of time-honored principles of molecular oncology account for the initiation and maintenance of AML. These principles include loss of heterozygosity, genomic instability, epigenomic disruption, deregulation of signaling pathways, anti-apoptotic mechanisms, and oncogene addiction. Such tenets of cancer biology not only explain AML cellular behavior but also may inform target validation in AML. Herein, we highlight the current state of targeted therapeutics, including the 14 novel agents (beyond 7+3 chemotherapy) approved by the Food and Drug Administration, in the context of these tenets and discuss future prospects by leveraging current knowledge of AML genomics. Such therapeutic concepts, including synthetic lethality, are especially relevant to TP53-mutant AML, as there are no unique therapies that have received regulatory approval for this subset to date. We emphasize the emerging role of single-cell genomics and multi-omics toward better understanding of AML biology and development of future successful AML therapies.

5045 Background: Radioligand therapy with radium-223 (Rad) and lutetium-177 (Plu) demonstrates notable hematologic toxicities in patients (pts) with prostate cancer (PC), including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Delivery of ionizing radiation to the bone microenvironment is a known risk factor for accelerating clonal hematopoiesis, although the incidence of clonal cytopenias with these agents is not well characterized. We hypothesized that pts treated with Rad and/or Plu would have higher risk of clonal cytopenia of undetermined significance (CCUS) vs matched controls in the “real-world”. Methods: We performed a retrospective study using de-identified aggregate data from the TriNetX US Research Collaborative Network from January 2010 to December 2025. Adult males with PC who received ≥1 administration of Plu and/or Rad were included; pts with prior myeloid malignancy were excluded. Primary outcomes were incidence of CCUS and MDS. Propensity score matching (PSM) was performed based on age, race, prior diagnosis of leukopenia, anemia, thrombocytopenia, or pancytopenia. Risk ratios (RR) with 95% confidence intervals (CI) were calculated. Results: We identified 2,569 pts treated with Plu alone and 2,007 treated with Rad alone and compared them with pts with advanced PC without exposure to either agent (unexposed control) (Table 1). After PSM, the incident risk of CCUS was greater in Rad-exposed pts (RR 2.62, 95% CI 1.45 – 4.73, p < 0.001) while Plu was not associated with a significant increase in CCUS or MDS. Direct comparison after PSM (n=1,433) demonstrated lower risk of pancytopenia (RR 0.46, 95% CI 0.37 – 0.56, p <0.001) and CCUS (RR 0.41, 95% CI 0.20 – 0.81, p =0.008) in Plu vs Rad. In unadjusted analysis, pts receiving both Plu and Rad had increased incidence of CCUS vs Plu alone (RR= 3.64, 95% CI 1.87 - 7.07, p <0.001) and higher risk of MDS vs either agent alone. Conclusions: This “real-world” analysis demonstrates that compared with unexposed controls, Rad – but not Plu – is associated with an increased risk of CCUS. Treatment with Plu and Rad portends a higher risk of CCUS than Plu alone, as well higher risk of MDS than either drug alone. Study limitations include its retrospective nature, missing/ unknown data (e.g. bone marrow and mutation analysis), and potential selection and confounding biases. As treatment sequencing evolves for pts with metastatic PC, further evaluation of clonal hematopoiesis, MDS/AML with adequate sample size and follow up in this population is warranted. ¹⁷⁷Lu-PSMA-617 Exposed(n = 2,569) Unexposed(n =2,569 ) Risk Ratio (95% CI) p -value CCUS 1.03% (26) 0.67% (17) 1.54 (0.84 – 2.82) 0.16 MDS 0.94% (24) 0.55% (14) 1.72 (0.89 – 3.32) 0.10 Radium-223 Exposed(n = 2,007) Unexposed(n = 2,007) Risk Ratio (95% CI) p -value CCUS 1.97% (39) 0.75 (15) 2.62 (1.45 – 4.73) <0.001 MDS 0.85% (17) 0.75% (15) 1.13 (0.57 – 2.26) 0.72

ABSTRACT Age‐related changes in human hematopoietic stem cells (HSCs) often form the basis for clonal hematopoiesis (CH), which presages the development of overt myeloid neoplasm with variable risk. CH can also arise after exposure to chemotherapy, radiotherapy, or immune interventions. In this study, we performed clinico‐genomic profiling of therapy‐related CH (t‐CH) ( n = 67) versus de novo CH ( n = 123) from a multidisciplinary CHIP Clinic. The most enriched mutations in t‐CH were TET2 (26.2%), DNMT3A (22.4%), and TP53 (8.4%). Median latency period from the time of initial exposure to the diagnosis of t‐CH was 6.96 ± 1.10 years. Patients with t‐CH had inferior event‐free survival compared to de novo CH (median 29.9 months versus 122.1 months, p = 0.0045). Overall survival was also shorter in t‐CH versus de novo CH (median 55.3 months vs. 129.2 months, p = 0.043). Genes that imparted significantly increased risk for progression from t‐CH to overt therapy‐related myeloid neoplasm (t‐MN) included JAK2 (relative risk (RR) 9.42, p = 0.0001), RUNX1 (RR 7.11, p = 0.001), EZH2 (RR 7.11, p = 0.001), and TET2 (RR 13.4, p = 0.01). Clonal dynamic modeling of patients with t‐CH who progressed to overt t‐MN showed an increase in the relative clonal fraction and new clonal outgrowth. In the t‐CH cohort, higher mean variant allele frequency was observed in progressors versus non‐progressors (77.1% vs. 30.6%, p = 0.017). This study sheds light onto outcomes for CH based on differing clinical ontogeny and has implications for previvorship for secondary malignancies.

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&lt;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&lt;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&lt;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&lt;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&lt;0.001, EFS: HR 1.43, 95% CI 1.23-1.65, p&lt;0.001), subsequent AHSCT (OS: HR 0.34, 95% CI 0.27-0.41, p&lt;0.001; EFS: HR 0.47, 95% CI 0.40-0.54, p&lt;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.

SummaryFrom a historical perspective, the treatment landscape of myelodysplastic syndromes/neoplasms (MDS) has experienced a standstill in terms of new approvals by the U.S. Food and Drug Administration up until the recent 5 years. The widespread availability of comprehensive genome sequencing has shed insight into human MDS biology toward the goal of rational therapeutic design. This new knowledge has inspired the development of investigational therapies that extend beyond the scope of traditional erythropoiesis‐stimulating agents and hypomethylating agents. We describe how these contemporary treatment options are changing the management paradigms for lower‐risk and higher‐risk MDS, based on the landmark trial data. We discuss investigational therapies in the MDS pipeline, such as venetoclax, emavusertib, canakinumab and olutasidenib. We highlight challenges and solutions to the successful translation of emerging therapies based on our improved understanding of the biology of MDS, including the genomics of MDS with mutated TP53. We discuss how the identification of biomarkers of response to therapeutics may help guide clinical trial design for certain subsets of patients. Finally, we discuss how multicentre randomized trials can help facilitate the clinical rollout of emerging MDS therapeutics.

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&lt;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&lt;.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&lt;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.