High-risk Myelodysplastic Syndrome Research Articles

Anti-PD-1 Antibody (Sintilimab) Plus Decitabine As First Line Treatment for Patients with Higher-Risk Myelodysplastic Syndrome (MDS): Primary Results from a Single-Arm,Open-Label,Phase II Study

Background: Hypomethylating agents (HMAs) are the preferred treatment for untreated patients with higher-risk Myelodysplastic Syndrome (MDS). However, the survival rate of patients after HMA treatment remains poor. Studies have shown that HMAs upregulate the expression of PD-1/PD-L1 in MDS patients, making the combination of HMAs with PD-1 antibodies a compelling approach for MDS treatment. Consequently, we conducted this single-arm, open-label clinical trial (ChiCTR2100044393) to assess the safety and efficacy of sintilimab in combination with decitabine for patients with higher-risk MDS. Methods: Adult patients with higher-risk MDS, according to the IPSS-R, were eligible for enrollment in this study. The treatment regimen consisted of daily intravenous administration of decitabine at a dose of 20mg/m 2 for 5 consecutive days, along with intravenous administration of sintilimab at 200mg on the first and 22nd day of a 42-day treatment cycle. Treatment continued until disease progression, death, unacceptable toxicity, withdrawal of consent, or other protocol-defined reasons, with a maximum of 8 cycles allowed. The primary endpoint of this study was the overall response rate (ORR). To determine the sample size, we utilized Simon's optimal two-stage design. Secondary endpoints included the assessment of safety and various survival outcomes. Additionally, we investigated the relationship between the expression levels of immune checkpoints and the efficacy of the combination therapy and other potential biomarkers through genomic profiling. Results: As of the data cut-off on June 16, 2023, 53 patients were enrolled, with a median follow-up time of 14 months, and 52 patients were eligible for response evaluation. The median age of patients was 65 years (range 19-83), other characteristics were summarized in Table 1.The ORR was 76.9%, and 15 patients achieved complete response (CR), 13 marrow complete response(mCR),7 mCR+ hematologic improvement(HI), and 5 HI. Among the 40 responders, six patients (4 with CR and 2 with mCR) underwent allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) has not reached, and the median event-free survival (EFS) was 16 months. The 24-month OS and EFS rates were 54.8% (95%CI: 39.5-76.2) and 46.2% (95%CI: 31.2-68.3), respectively. The most common grade 3 or higher treatment-emergent adverse events (TEAEs) reported in 10% or more of the patients were febrile neutropenia (67.9%) and pulmonary infection (20.8%). A total of 17 patients (32.1%) experienced immune-related adverse events (irAEs), with the most common irAEs being rash (17.0%), thyroid dysfunction (9.4%), and pneumonia (7.5%), all resolved after glucocorticoid treatment. Regarding genetic mutations, the most frequently mutated genes were ASXL1 (34.0%), RUNX1 (30.2%), TET2 (17.0%), and U2AF1 (17.0%). Conclusion: To the best of our knowledge, this is the first study evaluating the efficacy and safety of the combination therapy with sintilimab and decitabine in previously untreated patients with higher-risk MDS. This regimen showed an encouraging anti-tumor activity with a manageable safety profile.

Results of a Phase 1/2 Study of Lower Dose CPX-351 for Patients with Int-2 or High Risk IPSS Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia after Failure to Hypomethylating Agents

INTRODUCTION: Hypomethylating agents (HMAs) are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) and chronic myelomonocytic leukemia (CMML). HMA failure (HMA-F) is associated with poor outcomes and median survival of 4 to 6 months. CPX-351 is a drug liposomal encapsulation of cytarabine (araC) and daunorubicin (dauno) at a synergistic 5:1 molar ratio approved for the treatment of pts with therapy-related acute myeloid leukemia (AML) or AML with MDS-related changes. Here we present the results of a phase I-II study of lower dose CPX-351 for HR-MDS and CMML after HMA-F. METHODS: We conducted a phase I/II clinical trial of CPX-351 for pts with MDS or CMML after HMA-F with Int-2 or High risk by IPSS, or Int-1 with >10% bone marrow (BM) blasts. The study included an initial phase I dose-escalation portion, following a 3+3 design, followed by a phase II dose expansion portion. Dose escalation included 4 dose levels of CPX-351: 10 units/m 2 (dauno 4.4mg/m 2 and araC 10mg/m 2), 25 units/m 2 (dauno 11mg/m 2 and araC 25mg/m 2), 50 units/m 2 (dauno 22mg/m 2 and araC 50mg/m 2) and 75 units/m 2 (dauni 33mg/m 2 and araC 75mg/m 2). Therapy was administered intravenously on days 1, 3 and 5 of 28-day cycles during induction and on days 1 and 3 of re-induction or consolidation. Re-induction was allowed in pts not achieving response after induction. The primary end point was to evaluate safety and determine the maximum tolerated dose of CPX-351. Responses were evaluated following 2006 IWG criteria. The Kaplan-Meir product-limit method was used to estimate median survival. RESULTS: Between June 2019 and September 2022, 23 pts have been treated: 15 in the phase I portion, and 8 in the phase II. A total of 17 pts had MDS, and 6 had CMML. Four (17%) pts had intermediate-1 risk IPSS and >10% blasts, 15 (65%) had intermediate-2 and 4 (17%) had high-risk IPSS. Median number of prior therapies was 1 (range 1-4) including 4 (17%) pts with failure to prior venetoclax therapy and 2 (9%) with prior HSCT. In the phase I portion, 3 pts received CPX-351 at dose level 1, 3 at dose level 2, 3 at dose level 3 and six at dose level 4. One pt treated at dose level 4 developed grade 2 congestive heart failure with grade 2 reduction in left-ventricular ejection fraction (LVEF). No additional DLTs were detected during the 28-day DLT evaluation window. The initial two pts treated at the P2RD of 75units/m 2 during phase II experienced cardiac complications: grade 3 congestive heart failure without reduction in LVEF and grade 3 right-sided heart failure, respectively. Study was amended to continue further treatment in phase II at dose level 3 (50units/m 2). Most common adverse events (AEs) were lower extremity edema (n=12, 52%), febrile neutropenia (n=11, 48%), dyspnea (n=10, 44%), mucositis (n=10, 44%), constipation (n=9, 39%), diarrhea (n=9, 39%), and generalized muscle weakness (n=9, 39%). Most common grade 3-4 AEs were febrile neutropenia (n=11, 48%), neutropenia (n=5, 22%), lung infection (n=4, 17%), diarrhea (n=4, 17%) and thrombocytopenia (n=3, 13%). The 4-week and 8-week cumulative incidences of mortality were 0% and 4%, respectively. Median number of days to cycle 2 was 47 days (range 30-83). Dose reductions of CPX-351 occurred in 4 (17%) pts. Median number of cycles was 3 (range 1-9). Median cycles to best response was 1 (range 1-3). Among pts with HR-MDS, the ORR was 71% (n=12): CR in 1 (6%), mCR with HI in 1 (6%) and mCR in 11 (59%) pts (Fig 1A). Among pts with BM blast reduction to <5% by the end of cycle 1, 11 (65%) and 9 (53%) had ANC recovery to >0.5x10 9/L and >1x10 9/L, respectively, and 8 (47%) and 6 (35%) had platelet recovery to >50x10 9/L and >100x10 9/L, respectively. Based on 2023 IWG response criteria, the ORR was 59% (n=10) including CR in 1 (6%), CR bilineage (CRbi) in 4 (24%) and CR unilineage in 5 (29%). Of 11 (65%) pts with baseline cytogenetic abnormalities, 2 (18%) and 2 (18%) achieved complete and partial cytogenetic responses, respectively. Three (13%) pts underwent HSCT at time of best response. Among pts with CMML (n=6), only one (17%) achieved response. Median response duration was 4.5 months (95% CI 0.7-8.2 months) and the median OS was 12.6 months (95% CI 3.6-21.7 months) (Fig 1B). CONCLUSIONS: Lower doses of CPX-351 in HR-MDS after HMA-F can induce clinically meaningful responses and be used as a bridge to allogeneic stem-cell transplant. Therapy is associated with median OS of 12.6 months in this population with expected survival of 4-6 months.

Update of a Phase II Trial of Guadecitabine in Higher-Risk Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia Under the International Working Group 2023 Criteria

Introduction: Guadecitabine is a dinucleotide of decitabine which has shown high response rates in higher-risk myelodysplastic syndrome. In this update we seek to evaluate the performance of the International Working Group (IWG) 2023 criteria in a prospective, systematically annotated clinical trial. Methods: Patients older than 18 years old with higher-risk MDS/CMML as defined by the International Prognostic Scoring System - Revised (IPSS-R), or those with more than 10% bone marrow blasts were eligible. Guadecitabine was administered at a dose of 60 mg/m2 subcutaneously daily for 5 days every 28 days. We re-classified patients by World Health Organization 2022, calculated IPSS-Molecular (IPSS-M) scores and clinical responses were reassessed under the IWG-2023 criteria and compared to IWG-2006. Results: From 2014 to 2018, 82 patients with MDS and 18 patients with CMML were enrolled and treated. Median age was 69 (IQR 62.5 - 75), 62% were male, 38.4% had complex karyotype, 86.6% were categorized as IPSS-M high or very-high risk. Additionally, 33.7% were TP53 mut, 21.4% were TP53 multi-hit. Forty percent of patients were classified as MDS-IB-2, 21.4% as MDS-biTP53, and 17.1% as MDS-IB1. Common mutations were TP53 (38.5%), ASXL1 (22%), DNMT3A (18%) in MDS. ASXL1 (61%), TET2 (61%), NRAS (28%), and SRSF2 (22 %) for CMML patients. Most common treatment-emergent adverse events were fatigue (79% G1-2, 6% G3), nausea (37% G1), injection site reaction (29% G1), and constipation (23% G1). Grade 3 events were febrile neutropenia (32%), infection (25%), and thrombocytopenia (16%). Eight-week mortality was 4%. Ninety-six patients were evaluable for response. The median number of cycles was 5 (IQR:3-8) number of cycles to best response was 3 (IQR:2-5). Median overall survival (mOS) was 16.8 months. Survival was response-dependent with mOS in months being 32, 23.3, 15.5 and 8 for complete remission (CR), mCR (marrow complete remission), HI (hematologic improvement) and NR (no response) by IWG 2006 criteria (Figure 1). By IWG-2023 overall response rate (ORR) was 52%, with a complete remission (CR) of 29%, 3% with complete remission with bilineage limited hematologic recovery (CRLbi), 11% with CRL with unilineage recovery (CRLuni), 5% complete remission with incomplete hematologic recovery (CRh), and 4% had hematologic improvement (HI). Patients classified as mCR by 2006 criteria (n=30) were reclassified as CR (6.6%), CRLbi (6.6%), CRLuni (33.3%), CRh (16.6%), HI (6.6%), NR (26.6%),and PR (3.3%). Patients in mCR who underwent allogeneic-stem cell transplant (allo-SCT) (n=9) had a mOS of 46 months, compared to 14.4 months to those who did not (log-rank, p < 0.005). Median OS in months was 32.8, 28.6, 17.5, 7.8, 16.8, and 9.2 for CR, CRLbi, CRLuni, CRh, HI, and NR, respectively (log-rank < 0.005). In a multivariate analysis TP53 multi-hitwas the only factor significant in prognosticating response (p = 0.023) and overall survival (p =0.03). Discussion: In this report we examine the performance of the IWG 2023 criteria in a prospective clinical trial. Patients classified as mCR had significantly heterogenous outcomes which were more precise when re-classified by IWG-2023. Patients in mCR may still benefit from allo-SCT. These criteria also demonstrate response-dependent overall survival outcomes. TP53 multi-hitwas predictive of response and overall survival. This analysis shows the improved accuracy of the IWG 2023 model in stratifying clinical responses and survival. These may serve as future benchmarks for drug development and trial design. Figure 1. Overall survival by A) IWG 2006 criteria and B) IWG 2023 criteria.

Alrizomadlin (APG-115) Alone or Combined with Azacitidine (AZA) in Patients (pts) with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) or Relapsed or Progressive Higher-Risk Myelodysplastic Syndrome (HR-MDS): Phase 1b Trial Results

*Drs. Yifan Zhai and Jianxiang Wang are co-corresponding authors. Background Pts with R/R AML and HR-MDS failing hypomethylating agents have limited therapeutic options and relatively dismal outcomes with available therapies. Investigational alrizomadlin is a novel, orally active, potent, small-molecule selective inhibitor that destabilizes the p53-MDM2 complex and activates p53-mediated apoptosis in tumor cells and has shown apoptotic activity in AML and MDS xenograft models, alone and combined with AZA. Here, we present safety and efficacy results of this therapy in these pts. Methods This open-label dose escalation and expansion trial included adults with R/R AML or relapsed/progressed HR-MDS (IPSS-R ≥ 4.5). MTD and RP2D of alrizomadlin ± AZA were determined by dose escalation. Alrizomadlin (100/150/200/250 mg) was administered orally on Days (D) 1-7 in 28-day cycles. In the combination dose escalation group, alrizomadlin (100/150/200 mg) + AZA (75 mg/m 2) was administered orally once daily on D 1-7 in 28-day cycles and at the combination RP2D during dose expansion. Responses were assessed per revised International Working Group (IWG) Response Criteria 2003, ELN 2017 classifications for AML, and IWG 2006 for MDS. Extensive pharmacokinetic (PK) analyses were performed. Results As of June 1, 2023, 29 pts were enrolled in China. In the monotherapy group, 21 pts (median [range] age, 65 [32-76] years; 76.2%, R/R AML) had a median (range) of 2 (1-10) prior lines of therapy. In the combination group, 8 pts (median [range] age of 69.5 [20-76] years; 50%, R/R AML) had a median (range) of 2 (1-4) prior lines of therapy. In both groups, common any-grade treatment-related adverse events (TRAEs; ≥ 20%) were hematologic- and gastrointestinal-related toxicities, hypokalemia, and dizziness, and most grade ≥ 3 TRAEs were hematologic toxicities. No grade ≥ 3 gastrointestinal toxicities were reported (Figure 1). One DLT, a pulmonary embolism (PE), was reported among 6 evaluable patients at the alrizomadlin 100 mg + AZA dose level: a 59-year-old pt with MDS had a prior COVID-19 infection and abnormal coagulation function before (and during) study treatment. The study investigator attributed the PE to the pt's COVID-19 infection, age, primary disease, and long-term bed rest. One pt in each arm discontinued treatment because of AEs. In pts with AML, the overall response rate (ORR) was defined as complete remission (CR) + CR with incomplete hematologic recovery (CRi) + partial response (PR) + morphologic leukemia-free state (MLFS). In pts with MDS, ORR was defined as CR + PR + marrow CR (mCR). In the monotherapy group, the ORR and CR/CRi rates among pts with R/R AML were 25% (4/16) and 18.75% (3/16), respectively. Three of 6 pts with MDS that progressed to R/R AML experienced responses, including 2 CRis and 1 MLFS. One of 10 pts with R/R AML treated with venetoclax + HMA experienced a CRi. In the monotherapy cohort, 4 pts with MDS refractory to HMAs were evaluated, of whom 2 experienced an mCR. The monotherapy RP2D was determined as 200 mg. In the combination group, 6 pts had an efficacy evaluation at least once. Among these pts, 3 of 3 with MDS experienced an mCR and 1 of 3 with R/R AML, MLFS. Among 4 pts with prior venetoclax + HMA treatment, 2 with MDS experienced an mCR and 2 with R/R AML showed a half marrow blast reduction at the end of C1 (Table 1). No PK drug-drug interaction between alrizomadlin and AZA was observed. Conclusions Alrizomadlin alone or combined with AZA demonstrated a manageable safety profile and preliminary efficacy in pts with R/R AML and HMA-refractory MDS. An antileukemic effect was observed in both monotherapy and combination settings, including a few pts whose disease failed on prior venetoclax treatment. Evaluation of the alrizomadlin + AZA cohort is ongoing. Internal study (CT.gov) identifiers: APG-115-AC101 (NCT04275518).

Psychometric Validation and Meaningful Change Threshold Determination of EORTC QLQ-C30 Physical Functioning and Promis SF v1.0-Fatigue 7a Functional Domain in Patients with High-Risk Myelodysplastic Syndromes Treated with Venetoclax and Azacitidine

Background : Patients with myelodysplastic syndromes (MDS) can experience fatigue, infection, anemia, bruising, and bleeding. Fatigue and physical functioning (PF) are often the most adversely impacted areas of patient health-related quality of life. The objective of this study was to generate quantitative evidence to determine whether the PF score from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Fatigue score from the Patient-Reported Outcome Measurement Information System - Fatigue Short Form 7a (PROMIS SF 7a) measures are suitable candidates for developing patient-reported endpoints for clinical trials in treatment-naïve patients with higher-risk MDS (HR-MDS). We also aimed to derive definitions for meaningful change for both PF and Fatigue scores to aid in interpretation of efficacy analyses using these scores. Methods : This analysis used aggregate data from the Phase 3 M15-954 study (NCT04401748), which is an ongoing, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of venetoclax in combination with azacitidine in treatment-naïve adult patients with HR-MDS. The EORTC QLQ-C30 and the PROMIS SF 7a questionnaires were administered on the first day of each 28-day cycle for the first 7 cycles and every 3 cycles thereafter, and at the treatment-completion visit. For both measures, the analyses evaluated item characteristics at baseline, whether the hypothesized structure was consistent with the scoring algorithms implemented in the trial, and the reliability and validity of scores; subsequently, definitions for meaningful improvement or deterioration were determined. Anchor-based analyses were used to generate definitions for meaningful deterioration or improvement from baseline to Cycle 4 Day 1 for EORTC QLQ-C30 PF domain, and Cycle 7 Day 1 for PROMIS SF 7a. Construct-aligned anchors were used for these analyses, with a change in Patient Global Impression of Severity (PGIS) - Physical Activities and in Patient Global Impression of Change (PGIC) - Physical Activities used as the anchor for the analyses of the EORTC QLQ-C30 PF scores and PGIS-Fatigue and PGIC-Fatigue used for the analyses of the PROMIS SF 7a scores. Results : Approximately 500 treatment-naïve higher-risk patients with MDS enrolled in the study were included in this analysis. Both EORTC QLQ-C30 PF and PROMIS SF 7a measures demonstrated adequate reliability and validity; both measures exceeded the cut-off for acceptable internal consistency reliability, test re-test reliability, and convergent validity with co-validators ( Table 1). The definition for deterioration for the EORTC QLQ-C30 PF domain was −13.33 (rounded to the nearest possible incremental change score), which was corroborated with the PGIC-Physical Activities ( Table 2). The correlation between the EORTC QLQ-C30 PF domain and PGIS-Physical Activities scores was −0.43, and the correlation between the EORTC QLQ-C30 PF domain and PGIC-Physical Activities scores was −0.34, indicating that these measures were sufficient to be used as anchors. For PROMIS SF 7a, the definition for deterioration and improvement was 3.90 and −3.50, respectively. Both results were also corroborated with the PGIC-Fatigue. The correlation between the PROMIS SF 7a and PGIS-Fatigue scores was 0.58, and the correlation between the PROMIS SF 7a and PGIC-Fatigue scores was 0.38, indicating that these measures were sufficient to be used as anchors. Conclusions : The psychometric evaluation of EORTC QLQ-C30 PF and PROMIS SF 7a Fatigue scores from M15-954 study's blinded data provides sufficient evidence of test re-test reliability, construct validity, responsiveness, and score interpretability and supports their use as endpoints for clinical trials in treatment-naïve HR-MDS patients for regulatory decision-making.

Venetoclax Plus Azacitidine Versus Azacitidine Alone As Post-Transplant Maintenance Treatment in High-Risk AML and MDS

Background: Disease recurrence is the main cause of transplantation failure for high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Exploring innovative approaches to prevent relapse in AML and MDS after Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is in urgent need. Both bcl-2 inhibitor venetoclax (VEN) and azacitidine (AZA) possess significant antitumor activity effects against myeloid neoplasms. The efficacy and safety of AZA alone as maintenance therapy in the posttransplant setting have been reported but the results are controversial. The combination of VEN and AZA has resulted in high response rates in treating AML patients. We conducted a prospective clinical trial to compare the utility and safety of the combination of VEN and AZA (VEN/AZA) and AZA alone as maintenance treatment in high-risk AML and MDS in the post-transplant setting. Methods: This is a prospective, multicenter, randomized clinical trial. Patients with AML or MDS who were evaluated as high risk of relapse and underwent allo-HSCT were randomly assigned into VEN/AZA group and AZA group by gender, age, and disease type based on the central randomization system. AZA was administered by subcutaneous injection for 5 days at a dose of 50 mg/m2. VEN was administrated at the dosage of 200 mg daily from day 1 to day 7. VEN/AZA maintenance therapy regimen comprised AZA and VEN used alternately every month. AZA alone group was administrated AZA every 2 months. Maintenance treatment lasted at least 1 year after transplantation unless relapse occurred. The primary endpoint of the study included overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR). The second endpoints included adverse events (AEs), nonrelapse mortality (NRM), incidence of acute graft versus host disease (aGVHD), and chronic GVHD (cGVHD). Results: From June 2022 to June 2023, 24 patients were given the study protocol. 9 patients (6 AML, 3 MDS) received VEN/AZA maintenance and 15 (7 AML, 8 MDS) patients received only AZA maintenance. The median initial time to receive maintenance treatment was 3.67 months after transplantation. The median follow-up time was 11.30 (95%CI, 8.18-14.42) months. Only 1 patient relapsed and died 3 months after relapse on the study. The overall survival (OS) and the cumulative incidence of relapse (CIR) at 500 days were 100% vs 75.0% (95% CI, 42.59%-100%, p=0.39) and 0% vs 12.5% (95% CI, 0.48%-44.48%, p=0.39) for VEN/AZA and AZA group, respectively. The most common adverse effects (AEs) were hematological toxicities. Grade 3 or 4 hematological toxicities were observed in 5/9 (55.5%) in the VEN/AZA and 7/15 (46.7%) in the AZA group. Conclusions: Our results suggested that both VEN/AZA and AZA maintenance therapy were tolerated and the combination of VEN and AZA as maintenance therapy may be feasible and safe in the posttransplant setting to prevent relapse for high-risk AML and MDS patients.

Phase 1/2a Trial of Bomedemstat with or without All- Trans Retinoic Acid (ATRA) in Advanced Myeloid Malignancies

Background: Acute myeloid leukemia (AML) is a devastating disease difficult to treat. Although > 60% of patients (pts) with AML treated with standard therapy achieve complete remission, at least 70% relapse. Overexpression of lysine-specific demethylase 1 (LSD1) mRNA and excess LSD1 protein have been observed in several cancer types, including progenitor populations of leukemic cells in AML. In preclinical studies, LSD1 inhibition impaired tumor growth and induced apoptosis of leukemic cells (Harris et al., 2012). In combination with ATRA, LSD1 inhibition enhanced survival in mouse models of AML (Shenck et al., 2014). In this first-in-human trial, we examine the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of bomedemstat with or without ATRA in pts with high-risk AML and myelodysplastic syndrome (MDS). Methods: In this multicenter, open-label phase 1/2a trial, eligible pts were aged ≥18 years old, with high-risk AML or MDS, ECOG PS ≤2 (AML), and International Prognostic Score (IPSS) of at least intermediate-2 or Revised International Prognostic Score (IPSS-R) of at least intermediate (MDS). Pts could not have received immunotherapy within <8 weeks, chemotherapy within <3 weeks (except hydroxyurea), and radiation to >30% of marrow within <2 weeks of treatment. In the dose-finding phase, pts received bomedemstat at a starting dose of 0.75, 1.5, 3.0, or 6.0 mg/kg once-daily in 14-day cycles (7 days on, 7 days off), either alone or in combination with 45 mg/m 2ATRA for up to 4 cycles. Treatment was allowed to continue upon evidence of clinical benefit. In the duration-finding phase, pts received 6.0 mg/kg bomedemstat with ATRA in 21-day (14 days on, 7 days off) or 28-day (21 days on, 7 days off) cycles. Treatment continued until progression, unacceptable toxicity, or withdrawal. Primary endpoint was safety and tolerability. Secondary endpoints included PK parameters and PD effect on hematopoiesis. Clinical responses were documented per revised/modified Cheson criteria. Data cut-off date was December 13, 2018. Results: A total of 45 pts enrolled with a median age 73 years (range, 42 to 88); 19 (42%) were female. A total of 39 pts had AML with 27 (69%) having an ECOG PS score ≤1. Six pts had MDS with 2 (33%) pts having an IPSS of Very High Risk and IPSS-R of High Risk. A total of 33 pts were enrolled in the dose-finding phase (0.75 mg/kg/d bomedemstat [n=3], 1.5 mg/kg/d [n=6], 3.0 mg/kg/d [n=4], 6.0 mg/kg [n=6], 3.0 mg/kg + ATRA [n=5], 6.0 mg/kg + ATRA [n=9]). Twelve pts enrolled in the duration finding phase, 4 received bomedemstat plus ATRA for 14/28 days, and 8 received bomedemstat plus ATRA for 21/28 days. A total of 21 (47%) pts discontinued, 8 (18%) due to death, 5 (11%) due to withdrawal and 4 (9%) due to physician decision. Any grade adverse events (AE) related to bomedemstat occurred in 42 (93%) pts. The most common were diarrhea (42%), nausea (42%), and thrombocytopenia (38%). Grade ≥3 bomedemstat-related AEs occurred in 30 (66.7%) pts. One pt receiving 6.0 m/kg plus ATRA had a grade 5 AE related to bomedemstat due to respiratory failure. No patient experienced dose-limiting toxicity and no maximum tolerated dose was determined. The table summarizes PK parameters in whole plasma for the dose-finding phase. Based on plasma exposures, the Data Safety Monitoring Committee designated 6.0 mg/kg bomedemstat as the PD dose. Mean percent change (standard deviation) in blast counts was 368% (400) for pts receiving 0.75 mg/kg bomedemstat, 2478% (3279) for 1.5 mg/kg, 10% (25) for 3 mg/kg, 2841% (6047) for 6 mg/kg/d. For pts with AML, overall median EFS was 0.97 months (mo) (95% CI, 0.93-1.46), and median OS was 18.8 mo (95% CI, 3.86 to NR). The 6-mo rate for EFS and OS were 9% (95% CI, 0-46%) and 64% (95% CI, 25%-86%), respectively. The overall response rate was 28.2% (95% CI, 15.0-44.9, [1 PR, 10 SD]). For pts with MDS, median EFS was 0.93 mo (95% CI, 0.57 to NR) and median OS was NR (95% CI, 0.57 to NR). One pt with MDS had SD as best response (95% CI, 0.4-64.1). Conclusions: Bomedemstat up to 6.0 mg/kg alone or in combination with ATRA was well-tolerated in pts with high-risk AML or MDS. Change in blast count seen in treated pts could be due to differentiation to monocytes induced by bomedemstat rather than blast count reduction per se. Objective responses were seen in a subset of pts with AML (28%). OS was numerically higher to historical data with standard of care. Bomedemstat is currently under investigation in myeloproliferative neoplasms.

Phase 1/2 Multicenter, Open-Label Study of CTX-712 in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes

Background and Significance Dysregulation of alternative splicing, caused by abnormal expression or mutation of splicing factors, has been identified as an important contributor to the genesis and progression of cancer, and suggested as a novel target for anticancer treatment. CDC2-like kinases (CLK) represent a family of dual-specificity tyrosine and serine-threonine kinases that are involved in the regulation of splicing by phosphorylation of serine/arginine-rich splicing factors (SRSFs) which play a central role in exon recognition. CTX-712 is an orally available, potent, selective, and a first-in-class pan-CLK inhibitor (CLK 1-4), that inhibits phosphorylation of SRSFs resulting in significant antitumor activity in vitro and multiple xenograft models in vivo. CTX-712 formulated in capsules is currently being evaluated in an ongoing first-in-man study in Japan, evaluating tolerability and early efficacy in patients with solid tumors or hematologic malignancies (JapicCTI-184188). Preliminary data from the Japanese study were presented during ASCO 2022 and ASH 2022, and showed an acceptable safety profile (doses up to 175 mg (MTD 140 mg) twice a week in 28-day cycles, observed DLTs included dehydration, decreased platelets, hypokalemia, and pneumonia) with early signs of clinical antitumor activity (2 partial responses / 26 treated solid tumor patients, 5 complete remissions and complete remission with incomplete hematologic recovery/ 8 treated patients with AML or MDS), warranting further clinical investigations.. (J Clin Oncol (2022) 40(16_suppl):3080. Blood (2022) 140(Supplement 1):6211-2.). This abstract details a second study with CTX-712 that has just been initiated. Study Design and Methods A new film-coated tablet formulation will be evaluated in this phase 1/2 multicenter, open-label study of CTX-712 in patients with (mutated or wild type spliceosomes genes) relapsed/refractory AML, higher risk MDS (IPSS-R intermediate, high, or very high), or high marrow blast (≥5 %) MDS/MPN (including CMML). The phase 1 part of the study will be conducted at 4 US sites, and all sites are currently open for enrolment. The study allows patients with performance status 0, 1, or 2, adequate organ function, and up to four prior lines of therapy. Due to potential risk of interactions (in vitro studies suggest CYP3A4 as main metabolic pathway for CTX-712), concomitant use of strong CYP3A4 inhibitors is prohibited. Use of azole antifungals that are not strong CYP3A4 inhibitors (e.g., isavuconazole) is permitted. The phase 1 part of the study consists of dose-escalation (sequential standard 3 + 3 design), where cohorts of 3 (or 6) patients will receive ascending doses of CTX-712 once weekly in a 28-day cycle with continuous monitoring of emerging clinical PK, PD, safety, and efficacy data, to determine the recommended phase 2 dose (RP2D) based on the suggestion by the Safety Review Committee (SRC). The protocol defines five different dose levels (20-140 mg, once weekly) but also authorizes the SRC to suggest up to two interim dose levels or alternate schedules (e.g., dosing two times a week) if supported by emerging data. The suggested RP2D will be used in a confirmatory phase 1 expansion cohort where an additional 10 patients (total n = 16; 8 patients with AML and 8 patients with MDS) will be treated to gain further confidence in the selected dose level. The phase 2 part of the study will commence after the RP2D has been identified and confirmed and aims at evaluating therapeutic activity in R/R AML (Cohort 2a) or R/R HR-MDS (Cohort 2b), in addition to confirmation of the safety profile. Clinical trial registry number: NCT05732103

Single-Cell Multiomics Analysis Reveals Potential Drivers of Response to the Anti-TIM3 Inhibitor Sabatolimab Combined with Azacitidine in MDS and CMML

Background The median survival for patients with newly diagnosed (ND) higher risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) remains poor. The potential curability of MDS and CMML with allogeneic hematopoietic stem cell transplantation supports the concept of anti-tumor immunity and has led to interest in evaluating immune-based therapeutic approaches in myeloid neoplasms. The immune checkpoint molecule TIM-3 (encoded by the gene HAVCR2) is a target of interest in myeloid neoplasms given its expression on leukemic stem cells as well as several subsets of immune cells including T cells, monocytes, dendritic cells and NK cells. Sabatolimab (MBG453) is an investigational IgG4 anti-TIM-3 antibody currently under evaluation for myeloid neoplasms. In this exploratory study, we sought to characterize the effects of sabatolimab combined with the hypomethylating agent (HMA), azacitidine, on the immune landscape using single cell sequencing of samples from subjects with MDS and CMML treated with the combination from a previously reported phase 1b study (NCT03066648; Brunner et al 2022). Methods Following IRB approval, single-cell RNA sequencing (scRNA-seq) and associated proteomic cellular indexing of transcriptomes and epitopes sequencing (CITE-seq) was performed on both blood (BLD) and bone-marrow (BM) derived samples from subjects with: 1) MDS (n=3) or CMML (n=2) treated with HMA therapy alone as part of standard care; 2) ND MDS (n=5) or CMML (n=3) treated with azacitidine combined with sabatolimab; and 3) relapsed/refractory MDS (n=3) treated with sabatolimab alone. Paired BLD and BM samples as well as samples from serial treatment time points were selected whenever feasible (Fig 1). A total of 206,183 cells from BM and 172,421 cells from BLD post-quality control filtering were analyzed. Further, scRNAseq data from normal BLD(200,000 cells) and BM(240,650 cells) generated as part of the human cell atlas (https://data.humancellatlas.org/explore/projects/cc95ff89-2e68-4a08-a234-480eca21ce79) were integrated with this dataset to assist with immune cell subset characterization, enable downstream comparisons to healthy hematopoietic cells, and to help define cell subsets associated with disease states. Results In baseline samples from subjects with MDS treated with azacitidine-sabatolimab, we found that an increased baseline abundance of interferon-responsive CD8 T cells in both the BM and BLD (FDR<0.1) was associated with response to therapy. An increased baseline abundance of plasmacytoid dendritic cells and a granulocyte population also suggested an association with response to therapy. Differential gene expression analysis of baseline samples from responding versus non-responding subjects with MDS treated with azacitidine-sabatolimab showed a higher baseline expression of TNF and IFNG in BM CD8 T cells and up-regulated expression of MHC-II machinery ( HLA-DRB1, HLA-DPA1, CD74) in myeloid cell subsets in responding subjects (FDR <0.1), suggesting that pre-treatment ability of these cells to be involved in antigen-presentation may play a role in response. In subjects with CMML treated with azacitidine-sabatolimab, we observed dynamic changes in cellular abundances and gene expression when comparing baseline to post-therapy timepoints. Specifically, BM CD8 T cell subsets showed an up-regulation of cytotoxicity genes ( GZMA), interferon response genes ( IFIT2, IFITM1, IFITM2) and IL32 cytokine post-therapy (FDR <0.1). When evaluating myelomonocytic cell populations, we observed an increase in CD16 monocytes post-treatment. Additionally, dendritic cells and monocytes showed an up-regulation of interferon response genes ( IFIT1, OAS1, IFI27). Conversely, we observed a down-regulation of metallothionein genes ( MT1E, MT1G, MT2A) as well as a collection of transcription factors ( NR4A1, FOSL2, JUN, CEBPB, CEBPD), NF-κB inhibitors ( NFKBIZ, NFKBIA) and CXCL8 in the post-treatment samples (FDR <0.1). Conclusions Our study provides one of the most comprehensive evaluations of the cellular dynamics of anti-TIM3 immunotherapy in patients to date, allowing for the nomination of novel putative predictive biomarkers of response and identification of potential immunomodulatory mechanisms induced by the combination of sabatolimab with azacitidine in MDS and CMML for further future analysis.

A Phase II Study of Single Agent Aspacytarabine (BST-236) in Adults Unfit for Intensive Chemotherapy with Relapsed or Refractory Acute Myeloid Leukemia (R/R AML) or Higher Risk Myelodysplastic Syndromes (R/R HR MDS)

Background-Common treatment approaches for R/R AML and to some extent HR MDS involve intensive chemotherapy regimens, typically combining high dose cytarabine with other drug(s), but these intensive regimens may not be suitable for unfit or elderly patients. To address this issue, a cytarabine prodrug called BST-236 has been developed, which delivers high doses of cytarabine while reducing systemic toxicity, making it a potential option for intensive chemotherapy in older and frail patients. This Phase II study aimed to assess the efficacy and tolerability of BST-236 in unfit patients with R/R AML or HR MDS previously treated with a non-intensive regimen. Methods-This ongoing Phase 2 trial (NCT 04827719) enrolled HR MDS and AML patients (pts) aged ≥ 75 years or with comorbidities incompatible with intensive chemotherapy. MDS pts were refractory or had relapsed to azacytidine (AZA), and AML pts to AZA, low-dose cytarabine (LDAC) or AZA -venetoclax (VEN), given as a first line regimen. Each BST-236 induction and maintenance course consisted of 6 daily 1-hour intravenous infusions at a dose of 4.5 g/m 2/d (containing 3 g/m 2/d of cytarabine). After completing 1 induction cycle, patients with stable disease (SD) or partial response could undergo a second similar cycle, and patients who achieved complete remission (CR) could receive 2 to 4 maintenance cycles at the same schedule. Inclusion of 20 AML and 20 MDS pts was planned. Results-From August 2021 to May 2023, 16 MDS and 20 AML pts from 9 centers were enrolled, with a median follow up of 3 months. MDS: Median age was 74.8 years [IQR, 71.2-76.4] and ECOG was 0- 1 in all but 1 patient . All pts were previously treated with AZA and 4 (29%) had adverse R-IPSS karyotype. 14/16 were evaluable for response after 1 induction: 1 (7%) CR, 2 (14%) marrow CR, 7 (50%) SD. Hematological improvement was observed in 6 (43%) patients. Two serious treatment related adverse events (SAE) - febrile neutropenia and sepsis - occurred in 2 pts. Median duration of hospitalization for the induction cycle was 29.5 days [IQR 25.5-32.5] and 30-day mortality rate was 0%. AML: Median age was 77.6 years [IQR, 73.8-79.4] and all pts had ECOG 0-1. Two pts were previously treated with AZA, 1 with LDAC, 17 with AZA-VEN and 8 (50%) had adverse ELN score. 17/ 20 pts were evaluable for response after 1 induction cycle : 2 (12%) CR including 1 CR with negative MRD, 1 (6%) CRi, 10 (59%) SD. Three SAE- infections and hepatobiliary disorders- occurred in 2 pts. Median duration of hospitalization for the induction cycle was 26 days [IQR 23.2-30.8] and 30-day mortality rate was 10%. Four MDS pts still need to be enrolled, and follow up is ongoing. An update will be presented at the meeting. Conclusion- Response rates with BST-236, in this pretreated older frail R/R AML and MDS population, were modest. Toxicity, including myelosuppression, however appears lower than with conventional intensive chemotherapy, suggesting this treatment could be interesting earlier in the disease course.

Ultra-Low-Dose of Decitabine with Venetoclax As Induction and Consolidation Therapy for Elderly or Frail Newly Diagnosed Acute Myeloid Leukemia and High Risk Myelodysplastic Syndrome Patients

Background: Venetoclax with hypomethylating agents is a new standard of care for newly diagnosed (ND) patients with acute myeloid leukemia (AML) who are 75 years or older, or unfit for intensive chemotherapy. Pharmacodynamic studies have suggested superiority of the longer 10-day regimen of decitabine which has shown promising results in high-risk AML in phase 2 trials. We hypothesized that venetoclax with 10-day decitabine may be effective in ND and secondly AML/MDS, particularly for high-risk subgroups. Methods: We retrospectively analyzed 45 patients with ND AML, secondary AML (sAML), or high-risk MDS who was older than 60 years or unfit for intensive chemotherapy due to frail / due to the COVID-19 pandemic. Patients were required adequate end-organ function. Patients received decitabine (6mg/m2 IV for 10-days) with oral venetoclax (400mg daily for 3 weeks (D10+VEN)) for induction, followed by the same chemo-free regimen for consolidation if patients responsed to induction therapy. The primary efficacy endpoint was overall response rate (ORR). The second endpoint was overall survival (OS) and progress free survival (PFS). Findings: Between January, 2020 and July , 2023, 45 patients were treated with this regimen, 31 (68.9%) had ND AML, 8 patients (17.8%) had untreated sAML, 6 patients (13.3%) had untreated high-risk MDS. The median age was 65 years (IQR, 59-69) and 26(57.8%) patients had ECOG performance status of 3 or higher. The ORR among all patients was 82.2% and in disease subgroups were: ND AML, 87.1% (27/31) (95% CI 79, 94); untreated sAML, 75% (6/8); untreated high-risk MDS, 66.7%(4/6). According 2022 ELN risk classification by genetics, the ORR in favorable risk patients was 87.5%(7/8), intermediate risk patients was 100%(12/12), adverse risk patients was 72%(18/25). The most common treatment-emergent adverse events included infections with grade 3/4 neutropenia (n=36, 80%) and febrile neutropenia (n=7, 15.6%). There were 2 grade 5 adverse events including one infections with Enterobacter cloacae Bacteremias combined with heart failure because of the shortage of Blood product transfusion during the COVID-19 pandemic, and one case of intracranial hemorrhage related to prolonged grade 3/4 thrombocytopenia. The one year OS of all patients was 71.9%(23/32), and in favorable risk patients was 83.3% (5/6), intermediate risk patients was 72.7%(8/11), adverse risk patients was 73.3%(11/15). The two-year OS of all patients was 58.3%(7/12). Conclusion: Ultra-low-dose of ten-day decitabine with venetoclax as induction and consolidation chemo-free therapy in elderly or frail newly diagnosed acute myeloid leukemia and high risk myelodysplastic syndrome result in high overall response rate and high 1-year overall survivial.

High Disease-Free Survival in Patients with High-Risk MDS Treated with Orca-T

BACKGROUND Allogeneic hematopoietic cell transplant (alloHCT) may be a curative treatment option for patients with myelodysplastic syndrome (MDS). The use of investigational therapies that potentially reduce transplant toxicity could improve outcomes in this patient population with difficult to treat disease. Per CIBMTR, survival after alloHCT for MDS using matched donors is approximately 65% at 1 year and relapse-free survival at 1 year was ~69% in MDS patients in the RICMAC trial who received myeloablative conditioning (MAC). Orca-T is a high-precision cell therapy biologic that includes stem and immune cells, derived from allogeneic donors, that leverages highly purified, polyclonal donor regulatory T cells to control alloreactive immune responses. In this phase 1b study, Orca-T was evaluated in MDS patients who were eligible for transplant per 2017 International Expert Panel recommendations. METHODS As of 03/31/23, 16 patients with intermediate to very high risk (HR) MDS with ≤10% blasts in the bone marrow at the time of transplant had received Orca-T in the phase 1b study. IPSS-M prognostic scores were Low (6%), Moderate Low (6%), Moderate High (19%), High (44%), and Very High (25%). Baseline HCT-CI scores were 0 (n=6), 1 (n=3), 2 (n=2), 3 (n=3), and 4 (n=2). The median f/u was 19.1 months (range 6.3 - 32.2). Patients were aged 43 - 65 (median 59) and 56% female. Donors were 8/8 HLA-matched related (n=7) or unrelated (n=9). Patients received a busulfan-based myeloablative chemotherapy regimen prior to Orca-T, followed by single-agent GvHD prophylaxis with tacrolimus. RESULTS Orca-T was successfully manufactured in a single, centralized GMP manufacturing facility for all patients enrolled, distributed, and infused throughout the U.S. Orca-T was delivered within < 72 hours vein-to-vein (i.e. time between end of donor apheresis to start of recipient's Orca-T infusion). Disease-free survival (RFS) at 12 months was 94% (Figure). At 1 year, no patients had experienced grade ≥ 3 acute GvHD and moderate to severe chronic GvHD had occurred in 2 patients. Modified GRFS (survival free of Grade 3-4 aGvHD, moderate-to-severe cGvHD and relapse) at 12 months was 75%. Non-relapse mortality (NRM) and overall survival (OS) were 0% and 94%, respectively, at 12 months. Additionally, one MDS patient with very poor prognosis, characterized by mutated TP53 and complex karyotype, remains in CR without active signs of acute or cGvHD at 500 days post-alloHCT. CONCLUSIONS Orca-T demonstrated promising results in this HR-MDS patient population, including high RFS, low incidence of GvHD, and very high OS at 1 year. A randomized controlled phase 3 multi-center trial comparing Orca-T to SOC in patients with MDS, AML, and ALL is currently enrolling across the US (NCT05316701).

Real-World Impact of Luspatercept on Patients with Myelodysplastic Syndromes Requiring Red Blood Cell Transfusions and with Prior Exposure to Erythropoietin-Stimulating Agents: A United States Healthcare Claims Database Study

Background: Myelodysplastic syndromes (MDS) are among the most common hematologic cancers in older US adults. MDS are characterized by abnormal bone marrow function leading to impaired production of blood cells, persistent cytopenia, and variable risk of progression to acute myeloid leukemia (AML). Since anemia is a common complication of MDS, many patients (pts) become dependent on red blood cell transfusions (RBCTs) and erythropoiesis-stimulating agents (ESAs) are the standard of care for patients with lower-risk MDS. In a randomized, double-blind, placebo-controlled phase 3 MEDALIST clinical trial, luspatercept, a first-in-class erythroid maturation agent, was shown to reduce the severity of anemia among transfusion-dependent (TD) pts with lower-risk MDS with ring sideroblasts (RS) status and who were refractory to prior ESA treatment (Fenaux P, et al. N Engl J Med 2020; 382:140-151). However, real-world evidence regarding the effect of luspatercept on transfusion burden among pts with MDS requiring RBCTs and with prior ESA exposure is currently limited. Aim: To describe clinical outcomes and MDS-related treatment patterns before and after the initiation of luspatercept among real-world pts with lower-risk MDS in the USA who required RBCTs before luspatercept initiation and were previously exposed to ESAs. Methods:In this retrospective claims-based cohort study, data from Symphony Health, a nationally representative database, (Jan 1, 2010 to June 30, 2022) were used to identify adults with ≥1 claim with a diagnosis of MDS (initial diagnosis on or after Jan 1, 2015) before the first claim for luspatercept (index date). Pts were considered TD at luspatercept initiation if they had ≥1 claim for RBCT in the 8 weeks before index date, and ESA-exposed if they had ≥1 ESA claim at any point before or at luspatercept initiation. Pts with chemotherapy treatments, with a diagnosis for refractory anemia with excess blasts, or with AML during the study period were excluded as they were presumed to have higher-risk MDS. Pts were also excluded if they had prior use of hypomethylating agents (HMAs) or a diagnosis for β-thalassemia, myelofibrosis, aplastic anemia, or breast cancer in the 6 months prior to index date (baseline period). Pt demographics and clinical characteristics were assessed during the baseline period. Pts' RBCT status (transfusion independent [TI] or TD) was measured in the 6 months after index date. A pt was considered 8-week TI if they had 0 RBCT in ≥1 rolling 8-week period in the 6 months after index date. 12-week, 16-week, and 24-week TI pts were defined similarly, using increasingly longer periods without RBCT. Pts' use of MDS-related treatment classes (ie, chemotherapy, ESAs, granulocyte-colony stimulating factor [G-CSF], HMA, and immunomodulatory imide drug [IMiD] agent) was measured before and after index date until end of data availability or clinical activity (follow-up). Results:The population comprisedof240 pts with MDS who were TD and had ESA exposure before luspatercept initiation. The mean (standard deviation [SD]) age was 75.4 (5.4) years and 56.7% were male. About one fifth of pts received ≥2 treatment classes before luspatercept initiation (2: 17.5%; 3+: 1.7%). Most pts (64.2%) achieved 8-week TI in the 6 months after luspatercept initiation. Similarly, 53.8%, 43.3%, and 29.6% of pts achieved 12-, 16-, and 24-week TI in the 6 months after luspatercept initiation, respectively (Figure 1). The percentage of pts achieving 8-, 12-, 16-, and 24-week TI was numerically higher among pts with positive RS status than those with negative/unknown RS status (Figure 1). Most pts (64.2%) did not require any additional MDS-related treatments during the study follow-up period (mean (SD) 15.6 (7.3) months). The most common treatment classes used after luspatercept initiation were ESA (22.5%) and HMA (16.3%; Figure 2). Conclusions:The findings of this real-world study strongly corroborate clinical trial results, showing that luspatercept is highly effective in reducing transfusion dependence among ESA-exposed pts with lower-risk MDS who were TD before luspatercept initiation. In this study, over half of pts achieved 8-week and 12-week TI status during the follow-up period, and more than a quarter did not require any RBCT over a 24-week period. Further, most pts treated with luspatercept did not require any additional MDS-related treatments during the follow-up period.

Hematological Response to Frontline Treatment in Lower Risk Myelodysplastic Syndromes (LRMDS) Is Associated with Better Overall Survival

Background The majority of LRMDS patients (pts) (70%) do not progress but unfortunately succumb to complications related to cytopenia, namely anemia and red blood cell transfusion dependency (RBC-TD) or their interplay with co-morbidities. RBC-TD is associated with worse outcome reflecting bone marrow failure and long-term sequela of RBC-TD. There is growing evidence that response to treatment and RBC transfusion independence (TI) are associated with favorable outcome. In lieu of 2 recent randomized clinical trials demonstrating efficacy of luspatercept & imetelstat in LRMDS, we assessed the impact of response to sequential lines of treatment in LR-MDS on overall survival (OS) to guide our treatment choices and to determine whether erythroid stimulating agents (ESA) should still be our 1 st line of therapy. Methods We included LRMDS pts (IPSS-R very low & low) from Moffitt Database who received ESA as frontline therapy (FL) and assessed subsequently outcomes with second line (SL) therapy (SOC or clinical trial). We excluded MDS/MPN and del5q pts. We also excluded all pts who eventually progressed to either higher risk MDS or AML to better reflect the majority LRMDS in that disease state. We assessed details of FL and SL. Pts who received FL & SL were then divided into 4 groups based on response to FL and SL therapy: group 1 (no/no), group 2 (no/yes) with response only to SL, group 3 (yes/no) response to FL only, and group 4 (yes/yes) with response to both lines of therapy. Response was defined as hematological improvement (HI) with ≥1.5 g/dl Hgb increase in non-TD pts and RBC-TI in TD pts at baseline for at least for 8 weeks. We compared median OS (mOS) among those groups. Results There were 603 LRMDS pts who met eligibility criteria and received ESA as FL (Table-1); 43% were RBC-TD, mean serum EPO was 132 (n=211 pts), 69% received epoetin, 17% darbepoetin and 14% with G-CSF. HI was observed in 42% of pts with no difference among ring sideroblasts (RS) +/- (46% vs 40%, p =.12). Response was higher among non-RBC-TD (52% vs 31%, p< .001). The median time to start ESA was 1.2 mo (0-249). The median time on ESA therapy was 11 mo (.4-213). 331 pts (55%) received SL which included HMA 43% (n= 142), lenalidomide 39% (n=130), luspatercept 7% (n=24), ATG 2% (n=8), investigational agent 4% (n=14), and other 4% (n=13) . The HI rate was 27% (91/331). No difference in HI based on RS nor RBC-TD was observed. The median duration on SL treatment was 6 mo (.1-93). 170 pts (28%) received 3 rd line of therapy with 7% HI, 88 pts (15%) received 4 th line of therapy with 3% HI and 39 pts (7%) had 5 th line of therapy with 2% HI. Among the 331 pts who received at least FL and SL, pts were divided into 4 groups based on response to (methods, table-2), the mOS was 114 mo among Yes/Yes response group, 103 mo among yes/no group, 97 mo no/yes and 64 mo among no/no ( P=.007; Figure-1). Response to FL was significantly associated with better OS after adjusting for RS (HR .74 ,95% CI .55-.99, p=.043). Conclusions Only half of patients who receive ESA as FL therapy for LRMDS received any subsequent therapies. Response rates were highest with ESA as FL than any SL therapy. HI with FL and/or SL is associated with improved OS. Lack of response to first line of therapy is associated with worse OS. Responses beyond SL were rarely observed. Identifying and moving agents with high HI rate as FL therapy and or selecting option based on predictors of best chance of response to a specific treatment as FL may lead to better overall survival.

Safety and Efficacy of Lisaftoclax (APG-2575), a Novel BCL-2 Inhibitor (BCL-2i), in Relapsed or Refractory (R/R) or Treatment-Naïve (TN) Patients (Pts) with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), or Other Myeloid Neoplasms

Drs. Yifan Zhai and Jie Jin are co-corresponding authors. Introduction Investigational lisaftoclax, a novel BCL-2 inhibitor, has shown antileukemic activities in pts with CLL. For the first time, we present the safety, pharmacokinetics (PK), and efficacy of lisaftoclax alone or combined with azacitidine (AZA) or homoharringtonine (HHT), in adults with AML, MDS, or other myeloid neoplasms. Methods In part one, lisaftoclax was administered orally once daily at an assigned dose (200, 400, 600, or 800 mg) to pts with R/R AML using a “3+3” dose escalation design. In part two, pts with R/R AML, mixed-phenotype acute leukemia (MPAL), blastic plasmacytoid dendritic cell neoplasm (BPDCN), or chronic myelomonocytic leukemia (CMML) were enrolled in Cohorts A, B, and C; pts with higher-risk MDS (blast cells > 5%; IPSS-R > 3.5) were enrolled in Cohort D; and older (≥ 75 yrs)/unfit pts with TN AML were enrolled in Cohort E. Lisaftoclax was administered orally once daily in either 28- or 14-day cycles (MDS only), depending on the assigned dose level. A daily ramp-up schedule was used to prevent tumor lysis syndrome (TLS).In part two, select lisaftoclax doses were combined with low-dose HHT (1 mg daily on days [d] 1-14; Cohort A) or standard-dose HHT (2 mg/m 2 daily on d1-7; Cohort B) or AZA (75 mg/m 2 daily on d1-7; Cohorts C, D, and E). Dose-limiting toxicity (DLT) was assessed during the first cycle. Results As of July 19, 2023, 115 pts were enrolled, including 89 with AML (64 R/R; 25 TN older/unfit), 22 MDS (7 R/R; 15 TN), 2 MPAL, 1 CMML, and 1 BPDCN. The median (range) age was 62.0 (18-81) years, and 66 (57.4%) were male. A total of 13 pts received lisaftoclax monotherapy, and 102 received combination regimens. DLTs (pneumonia, respiratory failure, and heart failure) were observed in 1 pt in Cohort C, and no TLS was reported. Treatment-emergent adverse events (TEAEs) were observed in all 13 (100%) pts who received lisaftoclax monotherapy, of whom all experienced grade (Gr) 3/4 AEs and 4 (30.8%) experienced serious AEs (SAEs). Common TEAEs (> 30%) included leukopenia, neutropenia, lymphopenia, thrombocytopenia, anemia, diarrhea, hypokalemia, hypocalcemia, and hypomagnesemia. Similarly, TEAEs were reported in 12 (85.7%) pts treated with lisaftoclax combined with HHT, with Gr 3/4 AEs occurring in 12 (85.7%) and SAEs in 2 (14.3%). Common TEAEs (> 30%) included leukopenia, neutropenia, thrombocytopenia, hypokalemia, hypocalcemia, and pneumonia. TEAEs were also observed in 75 (100%) evaluable pts treated with lisaftoclax combined with AZA, with Gr 3/4 AEs occurring in 55 (73.3%) and SAEs in 18 (24.0%). Common TEAEs (> 30%) included leukopenia, neutropenia, thrombocytopenia, anemia, and diarrhea. A total of 40.0% (46/115) of pts discontinued the study because of progressive disease (45.7% [21/46]), lack of clinical benefit (8.7% [4/46]), AEs (17.4% [8/46]), withdrawal (26.1% [12/46], including 4 for transplantation), and investigator's decision (2.2% [1/46]). Increased systemic exposure of lisaftoclax was discerned as the dosage escalated from 200 to 800 mg. Compared to lisaftoclax alone, no significant difference was observed in the PK profile of lisaftoclax when combined with AZA or HHT. In part one, the overall response rate (ORR) and composite remission rate (CRc [complete remission (CR) + CR with incomplete blood count recovery (CRi)]) were each 8.3% (1/12). Lisaftoclax 600 mg was administered for further optimization of the combination regimens, and 800 mg was also explored. In Cohort E (n = 21), among TN AML pts treated with lisaftoclax, ORR and CRc were 71.4% and 47.6%, respectively, and the median (range) time to CR/CRi/MLFS was 1.05 (95% CI, 0.99-NR) months. In Cohort C (n = 36), ORR and CRc were 75.0% and 44.4%, respectively, and the median (range) time to CR/CRi/MLFS was 1.25 (95% CI, 1.02-2.17) months; and median (range) progression-free survival was 10.22 (95% CI, 6.34-NR) months, with a median (range) follow-up time of 3.25 (95% CI, 0.79-14.29) months. In Cohort B, ORR or CRc was 75.0%. In Cohort D, ORR was 70.0% and CR/marrow CR was 60.0% (Table 1). Conclusions Lisaftoclax showed favorable tolerability as monotherapy and when combined with AZA or HHT, exhibiting encouraging clinical efficacy among pts with R/R AML or MDS and older/unfit pts with TN AML. This ongoing trial continues to enroll pts. Internal study (CT.gov) identifier: APG2575AC101 (NCT04501120).

Selinexor in Combination with Azacitidine (AZA) in Patients with Myelodysplastic Syndrome (MDS): A Real-World Retrospective Study

Background: Patients with higher-risk MDS face limited treatment options and poor outcomes. While HMAs are approved as frontline therapy for higher-risk MDS, primary failure occurs in 50% of HMA-treated patients, and most responders progress within 2 years. There is an unmet need to improve the efficacy of AZA frontline therapy while maintaining a tolerable safety profile. Preclinical studies have demonstrated that the combination of selinexor and azacitidine synergistically inhibits MDS cell proliferation and arrests the cell cycle at the G2/M phase (Yixuan Guo, 2022). The combination of selinexor and azacitidine may be a promising approach for treating MDS. Here, we present this single-center, real-world evidence supporting the use of selinexor in combination with AZA in MDS patients. Methods: Medical records of 19 patients with MDS receiving selinexor in combination with AZA at the First Affiliated Hospital of Soochow University between Jan 2022 and March 2023 were reviewed. Inclusion criteria were a pathologically confirmed diagnosis of MDS, and receipt of ≥1 cycle of azacitidine in combination with selinexor. HMA-naïve patients and those previously treated with HMAs were included. Patients with a diagnosis other than MDS or progression to AML before treatment with selinexor + AZA were excluded. Patients received selinexor 40-60 mg QW orally and AZA 75 mg/m 2 intravenously or subcutaneously on days 1-5 or 7 of each 28-day cycle. Responses were evaluated per the International Working Group criteria. Results: A total of 19 pts (median age, 54 y [range, 13-68 y]) were treated (Table 1). IPSS-R risk was high or very high in 15.8% and 68.4% of pts, respectively. IPSS-M risk was high or very high in 10.5% and 78.9% of pts, respectively. 57.9% of pts were previously treated with HMA. 63.2% had myelofibrosis, 42.1% had hepatosplenomegaly, 31.6% had a TP53 mutation, and 63.2% had poor or very poor-risk cytogenetics. As of Jun 10, 2023 at a median follow-up of 5.9 months (range 1.5-17.4 months), eight pts died (42.1%) due to disease progression. For the total cohort, the overall response rate (ORR) was 73%. In pts with worse survival prognosis, such as relapse and refractory, high and very high in IPSS-R, high and very high in IPSS-M, myelofibrosis and TP53 mut, the ORR was 64%, 81%, 76%, 75% and 83%, respectively (Figure 1). In seven pts with splenomegaly, six pts had reduced spleen volume, and one pt had no significant change by abdominal palpation or imaging examination. The 6-month overall survival (OS) was 74.7% in total pts, and 70.0% in pts previously exposed to HMA (Figure 2a, 2b). Selinexor + AZA therapy improved survival of patients with poor prognosis, such as TP53 mut (0.099), MF (+) (0.613), ≥high in IPSS-R (0.938) (Figure 2c, 2d, 2e). The survival of six pts who received transplantation after combination therapy was significantly prolonged, with 6-month OS was 83.3% (Figure 2f). Conclusion: Selinexor + AZA combination therapy was well tolerated with promising efficacy in patients with untreated or relapse/refractory MDS, including those with TP53 mutation, myelofibrosis, and higher risk in IPSS-R.

Bone Marrow Microenvironment As a Potential Key Regulator of Hematopoietic Cells Stemness in Myelodysplastic Syndromes (MDS)

Background and Rationale. Nuclear Phospholipase C (PLC) beta1 plays a pivotal role in Myelodysplastic Syndromes (MDS) and Azacytidine response [Cocco, L., et al. J Lipid Res. 2015; 56: 1853-60]. Hematopoietic Stem Cells (HSCs) primarily reside within the bone marrow (BM) microenvironment, where mesenchymal stromal cells (MSCs) regulate hematopoiesis through direct interactions with HSCs or cytokine secretion [Blau O, et al. Blood. 2011; 118:5583-92]. The aim of this study was to better elucidate the role of the BM microenvironment in interacting with MDS/AML cells, with particular emphasis on investigating the correlation between PLCbeta1 modulation and the distinctive BM microenvironment response after co-culture, in terms of PLCs gene expression, myeloid differentiation markers and cytokine secretion. Patients and Methods. As it is a very preliminary study, here we analyzed mononuclear cells obtained from 4 higher-risk MDS (RAEB-1, R-IPSS High or Very High, Complex Karyotype), who gave informed consent in accordance with the Declaration of Helsinki. Two patients were treated with Azacytidine (AZA, 75 mg/mq/die for 7 days every 28 days) and one of them reached the fifth cycle with a stable disease. All samples were obtained from the IRCCS-Institute of Hematology “L. e A. Seràgnoli”, Bologna, Italy, where clinical evaluations were also conducted. Co-cultures were established with HS-5 MSCs, while Real-Time PCR results were normalized using molecular data obtained from 10 healthy donors (HD). PLCbeta1 overexpression/silencing in vitro model was represented by THP-1 monocytic cells subjected to lentiviral transfection. Both wild-type and PLCbeta1 overexpressing/silencing cells (THP-1 OV/KD) were co-cultured with HS-5 cells for 96 hours. Results. Patients showed distinct basal expression patterns of PLCbeta1: higher in 1/4 MDS and lower in 3/4 MDS, as compared to HD. Irrespective of PLCbeta1 basal expression levels, or response to AZA, in 3/4 patients CD11b increased and CD14 decreased after co-culture. Only one patient, characterized by being a therapy-related MDS, displayed a reduced expression in all myeloid differentiation markers during co-culture. During AZA therapy and after co-culture, one patient showing a stable disease had a significant PLCbeta1 reduction, CD11b increase and CD14 decrease. In THP-1 OV cells co-cultured with HS-5 cells, we observed CD11b reduction, while no significant differences in both PLCs and other myeloid differentiation markers. In contrast, THP-1 KD cells, following co-culture, exhibited a notable increase in CD11b and a decreased CD14 expression. Moreover, THP-1 OV cells alone displayed inhibition of IL-8 secretion, that disappeared after co-culture, in favour of IL-1beta secretion. THP-1 KD cells exhibited suppressed secretion of IL-1alpha, IL-1beta, and IL-8. However, during co-culture, the production of both IL-1alpha and IL-1beta was restored. Conclusions. Our results, that must be confirmed in a larger group of patients, show that the impact of co-culture is not associated with the baseline levels of PLCbeta1, but co-culture recapitulates the PLCbeta1 KD in vitro model and the lack of response to AZA, showing an increase of CD11b and a CD14 reduction. Moreover, the presence of MSCs reversed cytokine secretion, as in co-cultured THP1 KD cells IL-1alpha and IL-1beta were highly secreted again. Considering their multiple roles in both physiological and pathological conditions, ongoing analyses are now further investigating their role in BM microenvironment, also using MDS-MSCs. In addition, we are now exploring the involvement of BM microenvironment in maintaining leukemic cells in a more undifferentiated state and the potential implications of these mechanisms on AZA response/resistance.

Real-World Treatment Patterns Among Patients with Myelodysplastic Syndromes Initiating Oral Decitabine and Cedazuridine or Intravenous/Subcutaneous Hypomethylating Agents

Introduction: Hypomethylating agents (HMAs) are recommended standard of care for patients with higher-risk myelodysplastic syndromes (HR-MDS). HMA therapies include intravenous (IV) or subcutaneous (SC) decitabine and azacitidine; however, parenteral administration of HMAs has been associated with increased patient burden. The oral HMA decitabine and cedazuridine (DEC-C) was FDA-approved in July 2020 for the treatment of MDS, and offers an alternative to IV/SC HMAs, with similar pharmacokinetic exposure and response rates compared to IV decitabine. This study examined treatment patterns among patients with MDS receiving oral DEC-C compared with IV/SC HMAs in real-world clinical practice. Methods: This was a retrospective analysis using the US Cerner Enviza claims database; medical and prescription claims data for patients were linked to mortality data from Datavant. Adults aged ≥18 years, who were diagnosed with MDS (ICD-10-CM code D46.x; all risk levels), and who had initiated a HMA (≥1 claim; August 1, 2020─August 31, 2022) were included; index date was defined as the first pharmacy or medical claim for DEC-C or IV/SC HMAs, respectively. Patients had variable follow-up after index and were followed until end of enrollment, death, or end of study. Propensity score matching (PSM; 1:1) was performed to balance for confounding factors (age, sex, acute myeloid leukemia [AML] diagnosis, Charlson Comorbidity Index [CCI] score, and red blood cell [RBC] transfusion); adjusted bivariate analysis was used to compare outcomes between treatment groups. Longitudinal persistence was assessed according to the number of cycles of therapy received during follow-up, where a cycle was defined as either 3-10 days of administration of index IV/SC HMA or 1 claim for oral DEC-C, within a 28-day cycle. Results: Of 1569 patients included, 160 (10.2%) received DEC-C and 1409 (89.8%) received IV/SC HMAs. In the DEC-C cohort, median age was 72.5 years and 66.9% were male; in the IV/SC cohort, median age was 69.0 years and 58.2% were male. Two-thirds of patients newly initiated HMAs during the study period (69.4% for DEC-C and 72.2% for IV/SC HMAs); 30.6% of the DEC-C cohort had switched from prior IV/SC HMA treatment. Both groups had high levels of comorbidity; 55.6% of patients in the DEC-C cohort and 58.4% in the IV/SC HMA cohort had CCI scores of ≥3, and 14.4% and 23.8%, respectively, had an AML diagnosis. During the 6-month pre-index period, half (55.3%) of patients in both groups received RBC transfusions, and one quarter (25.9%) received platelet transfusions. After matching, there were 158 patients in each treatment cohort and all covariates included in the PSM were balanced (standardized mean difference <0.2). Median age was 72.0 years and 74.0 years for the DEC-C and IV/SC HMAs matched cohorts, respectively, and 66.5% and 69.6%, respectively, were male. Mean CCI scores were 3.45 for DEC-C and 3.15 for IV/SC HMA groups and 14.6% and 15.8%, respectively, had an AML diagnosis pre index. Longitudinal persistence was comparable between the matched DEC-C and IV/SC cohorts during the first 6 months post-index, with similar proportions receiving the maximum number of treatment cycles (based on a 28-day cycle) at each month following index (73.8% vs 71.1%, 46.5% vs 48.7%, 28.6% vs 24.8%, for 2, 4, 6 months, respectively; Figure). However, a trend towards improved persistence with DEC-C versus IV/SC HMAs was observed in patients receiving treatment beyond 6 months (25.0% vs 17.0%, 18.5% vs 9.0%, 11.4% vs 7.6%, for 8, 10, 12 months, respectively). Mean time to discontinuation of treatment was also numerically higher for DEC-C compared with the IV/SC HMA group (87.7 vs 82.0 days); however, differences were not statistically significant. Conclusions: This study, which is to our knowledge the largest real-world report of oral DEC-C use to date, reveals similar but high levels of disease burden and comorbidities among patients with MDS receiving oral DEC-C and parenteral HMA therapy. Trends in treatment patterns suggest comparable persistence with oral DEC-C and IV/SC HMAs at early stages of therapy and improved persistence with oral DEC-C beyond 6 months. These data support the consideration of oral DEC-C as an alternative to chronic parenteral HMA therapy, with the potential for oral DEC-C to reduce the treatment burden associated with administration of IV/SC HMAs.

Targeting CDK8/CDK19 to Disrupt Leukemic Stem Cell-like Population in Acute Myeloid Leukemia: Exploring RVU120 As a Promising Frontline Therapy

Leukemic stem cells (LSCs) are implicated in the initiation, maintenance, and relapse of leukemia. The failure of current standard induction chemotherapy, which primarily targets dividing cells, has been linked to the quiescence of LSCs, leading to resistance to treatment. Consequently, there is an urgent need for novel therapies specifically aimed at eradicating LSCs to achieve more effective and durable treatment responses. CDK8 and its paralog CDK19 associate with the mediator complex and regulate gene expression programs linked to cancer and stem cell pluripotency. RVU120, a highly selective and potent CDK8/19 inhibitor, is currently undergoing clinical trials for AML and high-risk myelodysplastic syndrome (HR-MDS) (NCT04021368). Previous studies have demonstrated its potential mechanism of action on LSCs, wherein inhibition of CDK8/CDK19 led to the activation of lineage commitment genes in sensitive AML cells. Through recent gene expression analysis, it was discovered that inhibition of CDK8/CDK19 in transformed CD34+ cord blood cells resulted in the downregulation of stemness and quiescence-associated genes, while simultaneously upregulating genes associated with hematopoietic lineage-committed progenitors. Building on these findings, this study further investigates the potential of CDK8/CDK19 inhibition as a means to target LSCs, providing a rationale for RVU120 as a frontline treatment option in AML. The impact of RVU120 on LSCs has been investigated using an in vitro hierarchical AML-8227 model. This primary model maintains distinct populations in culture conditions, including CD34+CD38- cells with quiescent LSC potential, CD34+CD38+ cells enriched in progenitors, and CD34- more mature blasts (Lechman et al., 2016, Cancer Cell). The CD34+CD38- LSC population was further characterized by flow cytometry showing the expression of LSC surface markers, namely CD45RA, CD123, CD44, and negative expression for CD90, rendering it a suitable model for mechanistic studies. Next, AML-8227 cells were subjected to RVU120 treatment, resulting in a noticeable reduction in cell proliferation and viability. Flow cytometric analysis demonstrated a significant decrease in the percentage and total cell number of LSC-enriched/progenitor populations within the AML hierarchical model upon inhibition of CDK8/CDK19. Furthermore, RVU120 treatment induced the differentiation of cells, as evidenced by a sequential increase in the percentage of early myeloid differentiation marker, CD64, and late myeloid differentiation marker, CD14 (Fig. 1). In order to deconvolute the activity and mechanism of action of RVU120 in different cell populations, single-cell RNAseq analysis on AML-8227 cells has been performed at 24h and 3 days of treatment using technology from 10xGenomics. Additionally, analyzed AML-8227 cells have been enriched in the CD34+ population to evaluate the effect of RVU120 on stem and progenitor fraction at the single-cell level. The bioinformatic analysis of the performed experiment is ongoing and its results will be integrated into the data described above. CDK8 activity can be conveniently tracked by measuring specific phosphorylation of its target S726 on STAT5 protein. Dose and exposure-dependent inhibition of this marker has been established in cells exposed to RVU120. Levels of STAT5 S726 have been measured in different cell populations in patients from the first-in-human study of RVU120 in AML/HR-MDS. Consistent with established roles of CDK8 in LSCs, significantly elevated levels of pSTAT5 were observed in CD34+ stem/progenitor-enriched population when compared to CD34- blast cells measured at baseline before the start of the treatment (p<0.0001; ratio paired t-test; updated data from ASH 2022; Fig. 2). In summary, RVU120 displays cytotoxic and differentiating effects on well-characterized LSC populations in various models. Additionally, the CDK8 activity marker is directly associated with LSC-enriched bone marrow cells in AML patients, highlighting RVU120's potential as a promising therapeutic for targeting AML LSCs. Moreover, single-cell studies offer insights into its inhibitory effects on LSC-enriched populations and capacity for inducing differentiation. Overall, these results support RVU120 as a frontline candidate in AML therapy, countering therapeutic failure caused by persistent LSCs.

Safety and Tolerability of AZD0466 As Monotherapy for Patients with Advanced Hematologic Malignancies. Results from a Phase I/II Trial

Background: Overexpressionof B-cell lymphoma 2 (BCL-2)-related pro-survival proteins allows cancer cells to evade apoptosis, and targeting these proteins has become important in anticancer therapy. BCL-2 inhibition by venetoclax (VEN) is beneficial in many patients (pts) with acute myeloid leukemia (AML), but resistance is common due to upregulation of other pro-survival proteins such as BCL-extra-large (BCL-xL) and myeloid cell leukemia-1. Dual inhibition of BCL-2/xL has potential for broader activity than agents such as VEN. However, BCL-xL is critical for platelet survival and inhibition can cause dose-limiting thrombocytopenia (Konopleva and Letai. Blood 2018). To broaden therapeutic activity, we developed AZD0466, a drug-dendrimer conjugate in which the BCL-2/xL dual inhibitor AZD4320 is covalently conjugated to a pegylated poly-L-lysine dendrimer and gradually released by hydrolysis. Preclinically, AZD4320 showed greater inhibition of tumor growth than VEN and navitoclax in VEN-resistant xenograft models (Balachander et al. Clin Cancer Res 2020). A first-in-human study (NCT04214093) in pts with advanced solid tumors indicated that AZD0466 is well tolerated with no reported dose-limiting toxicities (DLTs). We present preliminary data from NIMBLE, a Phase I/II trial of AZD0466 in pts with advanced hematologic malignancies (NCT04865419). Methods: Module 1, Part A of NIMBLE is a dose-escalation study of AZD0466 monotherapy investigating its preliminary safety and tolerability, pharmacokinetics (PK), and preliminary efficacy. Dose escalation and de-escalation of AZD0466 follow a modified toxicity probability interval (mTPI-2) design. Eligible pts are ≥18 years old with relapsed/refractory (R/R) AML, acute lymphoblastic leukemia (ALL), or high-risk myelodysplastic syndrome. AZD0466 is administered IV with a dose ramp-up on Days (D) 1, 4, and 8, reaching the target dose on D8 of Cycle 1, with weekly administrations thereafter. Cycle duration is 35 days for Cycle 1 and 28 days for subsequent cycles. Pts remain on study until disease progression, unacceptable toxicity, or withdrawal of consent. Resul ts: As of May 31, 2023, 31 pts (n=25 AML, n=6 ALL; median age 69 years) had received ≥1 dose of AZD0466 at target doses of 300 mg (n=4), 600 mg (n=4), 1200 mg (n=7), 2400 mg (n=5), 3600 mg (n=9), and 5400 mg (n=2). Median treatment duration was 4.1 weeks (range 0.1−29.6). Twenty-two pts (71%) had prior VEN and 11 (35%) had prior hematopoietic stem cell transplantation. Treatment-emergent adverse events (TEAEs) of any grade reported in >10% of pts are displayed in Table 1. One Grade 5 intracranial hemorrhage unrelated to AZD0466 was reported. Four pts experienced a serious adverse event (SAE) possibly related to AZD0466 (alanine aminotransferase [ALT] increase, pneumonia, troponin T increase, and uncoded SAE). Grade ≥3 TEAEs possibly related to AZD0466, reported in 12 pts (39%), included febrile neutropenia (n=3), platelet count decrease (n=2), diarrhea, thrombocytopenia, ALT increase, blood creatinine phosphokinase increase, pneumonia, gamma-glutamyltransferase increase, lipase increased, and troponin T increase (n=1, each). DLTs of asymptomatic troponin increase were observed in two pts (3600 mg [n=1], 5400 mg [n=1]). Evaluation of maximum concentration and area under the concentration-time curve revealed dose-proportional exposure to AZD4320. Released AZD4320 represented 1-5% of total AZD4320 and had a longer half-life than total AZD4320. Preclinical modeling and PK data predicted that 5400 mg may be required to drive efficacy. As a surrogate of BCL-xL on-target activity, transient aggravation of thrombocytopenia post-dosing was observed across all dose cohorts followed by platelet recovery prior to the next dose. Platelet reduction was in line with preclinical models showing a substantial reduction at lower doses with a ceiling effect at higher doses. As of July 6, 2023, no complete responses have been observed. However, preliminary bone marrow (BM) blast reductions of >50% were observed in four pts (1200 mg [n=1], 2400 mg [n=2], 3600 mg [n=1]), indicating antileukemia activity of AZD0466. Conclusions: Given the observed DLTs of asymptomatic increase in troponin levels, and the lack of significant clinical benefit, the study was terminated.