Cluzeau, Thomas

Abstract Myelodysplastic syndromes (MDS) are clinically and biologically diverse disorders, emphasizing the need for personalized treatment approaches. The International Working Group for Prognostication of MDS (IWG_PM) recently introduced a molecular classification, referred to as the MDS taxonomy, that categorizes patients into 16 subgroups based on 21 gene mutations, 6 cytogenetic abnormalities, and loss of heterozygosity (LOH) at TP53 and TET2 loci. This study sought to validate and enhance the clinical relevance of the MDS taxonomy by analyzing a large retrospective cohort ( n = 5136) and transcriptomic data from a prospective cohort ( n = 477). The taxonomy successfully identified subgroups with distinct clinical characteristics and disease progression patterns. However, incorporating gene interactions from taxonomy subgroups did not improve the prognostic performance of the Molecular International Prognostic Scoring System (IPSS‐M). We further assessed whether the taxonomy could guide management in patients receiving disease‐modifying therapies. Except for the “ TP53 ‐complex” subgroup, taxonomy classifications were not predictive of hypomethylating agent response or transplant outcomes. Nonetheless, they correlated with overall survival, suggesting that while both IPSS‐M and the taxonomy capture disease biology, other non‐genetic factors may influence treatment response. RNA sequencing confirmed the biological distinctiveness of the taxonomy groups. Transcriptomic profiling of CD34+ bone marrow cells revealed unique, homogeneous gene expression patterns, particularly within the AML‐like, bi TET2 , SF3B1 , and TP53 ‐complex subgroups. Further integration of multi‐omics data may refine MDS classification, improving clinical decision‐making and guiding the development of targeted therapies.

Abstract Introduction: Standardized reporting of clinical trials results for MDS is essential to improve clinical interpretation and cross-study comparison. However, reporting of patient characteristics, response criteria, and endpoints in publications is often inconsistent; there is no systemic analysis of MDS trial reporting available. We conducted a systematic review of published MDS trial manuscripts on behalf of the international consortium for MDS (icMDS) to assess variability in reporting practices. Methods We searched ClinicalTrials.gov to identify all clinical trials registered for adults (≥18 years) with MDS that reported results between 2015-2024. Clinical trials that included acute myeloid leukemia (AML) or MDS/myeloproliferative neoplasms (MPN) were included if they enrolled ≥5 MDS patients. We excluded trials without an MDS cohort; non-therapeutic trials; trials focused on transplant interventions; or those which enrolled solid malignancies or other hematologic malignancies (chronic myeloid leukemia or lymphoid diseases). Finally, trials were required to have a manuscript available on Larvol, PubMed, or Google Scholar. Trials were categorized by disease risk (lower-risk [LR] vs. higher-risk [HR]) and trial phase (early phase [EP] vs. late phase [LP]). Results We identified 502 MDS trials on ClinicalTrials.gov, of which 351 did not meet inclusion criteria and 79 lacked a manuscript. A total of 72 trials (32 EP, 40 LP) with 80 publications (34 EP, 46 LP) were analyzed. Frequently reported baseline characteristics included age (100% EP, 100% LP), disease risk (74% EP, 74% LP), Eastern Cooperative Oncology Group performance status (85% EP, 72% LP), prior treatments (71% EP, 67% LP), and RBC transfusion dependency (32% EP, 70% LP). Less frequently reported characteristics included blood counts (hemoglobin [Hb; 38% EP, 54% LP], platelet count [38% EP, 54% LP], neutrophil count [24% EP and LP]) and bone marrow blasts (29% EP, 43% LP). Although disease risk was widely reported, definitions varied: IPSS and IPSS-R were each reported in 54% of manuscripts, while IPSS-M appeared in only 3%. Cytogenetic risk was separately reported in 39% of manuscripts (38% EP, 39% LP), and mutational data in 45% (47% EP, 43% LP). Responses per IWG 2006 criteria were reported in 84% of manuscripts. The primary endpoint involved safety/tolerability in 85% of EP manuscripts, though definitions were variable; recommended phase 2 dose was the most common (26% of EP manuscripts). In LP trials, primary endpoints were risk-specific: transfusion independence (TI) in 77% of LR, overall response rate (ORR) in 28% of HR, and complete remission (CR) or overall survival (OS) in 22% of HR. In HR manuscripts, CR was reported in 100%, ORR in 73%, hematologic improvement (HI) in 48%, RBC-TI in 23%, and OS in 80%. However, seven different definitions were used for ORR: CR + marrow CR + partial remission + HI per IWG 2006 was most common (35%). Event-free survival was reported in 25%; progression-free survival and relapse-free survival in 13%; and leukemia-free survival in 5%. Early mortality rate was reported in 35% (18% EP, 56% LP) and transplant rate in 58% (50% EP, 67% LP). Only 47% of HR and 90% of LR manuscripts identified HI-eligible patients. In LR-MDS, RBC-TI was reported in 72% of manuscripts but used six definitions. The most common were RBC-TI ≥8 weeks at any time during treatment (24%), ≥8 weeks within 28 weeks of treatment (13%), ≥8 weeks with Hb increase ≥1.0 (4%), ≥12 weeks with Hb increase ≥1.5 (4%), and ≥16 weeks within 24 weeks of treatment (12%). The remainder did not report RBC-TI, did not define it, or used a custom definition not used in another trial. HI was reported in 80% of LR papers with most of those reporting HI using IWG 2006 criteria (90%). Conclusion Reporting of baseline characteristics, response criteria, and outcomes is inconsistent in MDS clinical trials, with wide variability in response definitions, including ORR and TI. This heterogeneity limits interpretability, hampers historical comparisons and may obscure efficacy signals. Our findings highlight the need for standardized reporting guidelines to ensure clarity and consistency in MDS trial publications. As a next phase of this effort, we will conduct a formal Delphi process among icMDS experts to establish consensus recommendations for minimal and optimal MDS clinical trial reporting in manuscripts by disease risk (LR/HR) and trial phase (EP/LP).

Background: Myelodysplastic/Myeloproliferative neoplasms (MDS/MPN) represent a group of rare hematologic malignancies, distinguished by their concurrent dysplastic and proliferative features. Patients with these neoplasms have an increased risk of acute leukemia transformation and often present with extramedullary and constitutional symptoms. The only approved therapies for MDS/MPNs are hydroxyurea, decitabine (oral decitabine/cedazuridine and parenteral decitabine) or azacitidine (parenteral) for pts with CMML. Given the rarity and the heterogeneity of MDS/MPNs, prospective studies focusing specifically on MDS/MPN have been uncommon, and refining treatment strategies has been difficult. ABNL-MARRO ( A Basket study of Nove l therapy for untreated MDS/MPN and Relapsed/ Refractory Overlap Syndromes) is an international cooperative effort that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides a framework for collaborative studies around the world to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response (Moyo TK et.al BMC Cancer. 2022). Methods: ABNL-MARRO 001 (AM-001) is an open-label, phase 1b/2 study testing the treatment combination of ASTX727 (days 1-5), a fixed dose oral combination pill containing 35 mg of the DNMTi decitabine (DEC) and 100 mg of the cytidine deaminase inhibitor cedazuridine (CED), together with a series of active agents in myeloid disease (see Figure 1a) for MDS/MPN. In arm A, ASTX727 is combined with itacitinib 300 mg (days 1-28), a selective JAK1 inhibitor in newly diagnosed and relapsed/refractory (R/R) pts. Here we report results from the 3+3 dose de-escalation phase 1b portion used to determine the recommended Phase 2 dose (RP2D) in arm A. Dose-limiting toxicities (DLTs) were assessed in cycle 1. Disease response was assessed by the MDS/MPN IWG response criteria (Savona et.al., Blood. 2015). Results: Seven patients were enrolled with a median age 75 (range 32-82) years with newly diagnosed (4 pts) or R/R (3 pts) MDS/MPN. Three patients had CMML, 2 had MDS/MPN-U, and 2 had refractory MDS/MPN RST. One patient was not DLT evaluable given severe disease-induced cytopenia, and was not included in the assessment (patient 4 in Figure 1b). The majority of pts experienced a treatment-emergent adverse event (TEAE) of any grade; the most common (≥30% of pts) were thrombocytopenia (50%), neutropenia (30%), and constipation (30%); 50% of pts experienced a Grade ≥3 TEAE; the most common was neutropenia (30%). No DLTs were reported, and these AEs were consistent with what has been reported in the use of ASTX727 (Savona et al. Blood. 2022). One patient achieved a CR, and two additional patients had the best overall response of optimal marrow response after receiving 6 cycles of treatment. All patients are alive with a median follow-up of 12 months (range 6-17 months). The clinical responses and time-on-treatment of all pts in phase 1b are summarized in Figure 1b. Summary/Conclusion: Based on the preliminary results of the phase 1b study, the dosing schedule of 35 mg DEC / 100 mg CED daily for 5 days in combination with itacitinib 300 mg daily for 28 days was selected as the RP2D as it balanced clinical efficacy with an acceptable and manageable safety profile. This regimen and dose are being utilized in a 28-day cycle in the ongoing global, multi-center phase 2 study (NCT04061421).

Background. The inclusion of gene mutations and chromosomal abnormalities in the 2022 WHO and ICC Classifications of MDS has enhanced diagnostic precision and is expected to improve clinical decision-making process. Although these two systems share similarities, clinically relevant discrepancies still exist and potentially cause inconsistency in their adoption in a clinical setting. In this study on behalf of the International Consortium for MDS (icMDS), we adopted a data-driven approach to provide a harmonization roadmap between the 2022 WHO and ICC classification for MDS. A modified Delphi Process consensus approach is currently ongoing among icMDS experts to finalize a harmonized MDS classification scheme. Methods. We analyzed retrospective international cohorts of patients with a diagnosis of MDS (n=7017) and AML (n=1002) according to WHO 2016 criteria. Hierarchical Dirichlet Processes were applied to define clusters capturing broad dependencies among all gene mutations and cytogenetic abnormalities. To investigate the features of importance and their impact on the clustering process, we employed the SHapley Additive exPlanations approach (SHAP). This allowed to define harmonized labels for each clinical entity. The clinical relevance of the unsupervised clustering was assessed through the analysis of phenotypic features and outcomes among each group. ( Blood 2022;140: 9828-9830) Results. Patients' characteristics are summarized in Table 1. We identified 9 clusters, defined by specific genomic features. The cluster of highest hierarchical importance was characterized by biallelic inactivation of TP53 (biTP53). According to SHAP analysis, bi TP53 was defined as 2 or more TP53 mutations, or 1 mutation with copy number loss or cnLOH. Most patients assigned to bi TP53 cluster had TP53 VAF>10% (77.9%) and complex karyotype (70.1%). Assignment to bi TP53 cluster was irrespective of blast count. Patients with monoallelic TP53 mutation segregated into other clusters. Hierarchically, the second cluster included patients with del(5q). SHAP analysis highlighted 5q deletion alone, or with one other chromosomal abnormality other than -7, and absence of bi TP53, as the most relevant features. Most of these patients had blast counts <5% (88.1%). The third distinct cluster included patients with SF3B1 mutations (in the absence of concurrent del(7q), abn3q26.2, complex karyotype or RUNX1 mutation). Most patients with MDS and SF3B1 mutation had <5% blasts (94.2%). Common co-mutated variants in the SF3B1 cluster included mutant DNMT3A (25.2%) and TET2 (38.3%). Morphologically defined MDS cases (i.e., not meeting criteria for bi TP53, del(5q) or SF3B1) were preferentially assigned to the following additional clusters: SF3B1 and concurrent higher-risk mutations (e.g., RUNX1 and ASXL1); SRSF2 and concomitant TET2 mutations; U2AF1 mutations with del(20q), del(7q) or -7; SRSF2 with TET2 mutations and co-mutational patterns including RUNX1 and ASXL1; and AML-like genomic signatures. Our analyses suggest that morphologically defined MDS is characterized by a large heterogeneity in terms of mutation profiles, not entirely captured by the presence of unilineage versus multilineage dysplasia, percentage of bone marrow blasts, and presence of hypocellularity and fibrosis. To better investigate the continuum between high risk MDS (i.e., patients with ≥10% blasts) and AML, an exploratory comparison was made using a cohort of AML (defined according to WHO 2016) patients analyzed using the same statistical methods. Only a partial overlap in genetic signatures was observed between MDS with ≥10% blasts and AML. However, similarities were observed between the AML-like MDS clusters (characterized by mutant NPM1, bZIP CEBPA, and Core Binding Factor abnormalities) and AML clusters defined by the same genetic signature, thus supporting the classification of these entities as AML, irrespective of blast count. Conclusion. Our study demonstrated the utility of a data-driven approach based on advanced statistical methods to generate a harmonized classification for MDS. Table 2 shows a provisional, hierarchical classification algorithm. Further refinement of entity labels and classification criteria is the subject of the ongoing modified Delphi Process consensus approach among icMDS experts.

Abstract Background: Pts with HR-MDS unfit for hematopoietic stem cell transplant (HSCT) have poor outcomes and limited survival with single-agent hypomethylating agent (HMA) therapy. Novel treatments that provide durable responses and clinically meaningful survival benefit for pts with HR-MDS are needed. TIM-3 is a promising target in myeloid malignancies as it regulates innate and adaptive immune cells and is expressed on leukemic stem cells (LSCs) and blasts but not normal hematopoietic stem cells. Sabatolimab (MBG453) is a novel immuno-myeloid therapy that binds to TIM-3 on immune cells, facilitating antileukemic immune activation and phagocytic killing of leukemic cells. Sabatolimab also binds to TIM-3 on leukemic cells, potentially impeding self-renewal of LSCs via inhibition of TIM3-galectin-9. In an early phase (ph) trial (NCT03066648) sabatolimab + HMA therapy showed a durable clinical benefit and was well tolerated in pts with HR-MDS (Wei, EHA 2021). Study Design and Methods: The STIMULUS immuno-myeloid clinical trial program is investigating the safety, efficacy, and durability of multiple sabatolimab-based combination therapies in pts with myeloid malignancies. Additional exploration of the mechanism of action of sabatolimab and identification of potential biomarkers predictive of response is planned. This abstract summarizes the design of the 4 ongoing STIMULUS trials in previously untreated adult pts with HR-MDS who are not eligible for intensive chemotherapy (IC) or HSCT. STIMULUS-MDS1 (NCT03946670) is an international, randomized, double-blind, placebo-controlled Ph II trial evaluating sabatolimab + HMA therapy in pts with very-high, high-, or intermediate-risk (vH/H/IR)-MDS which has completed enrollment (N=127). The primary endpoints of STIMULUS-MDS1 are complete response (CR) and progression-free survival (PFS). STIMULUS-MDS2 (NCT04266301) is an ongoing, international, randomized, double-blind, placebo-controlled, Ph III trial of sabatolimab + azacitidine (AZA) in pts with vH/H/IR-MDS or chronic myelomonocytic leukemia-2. Target enrollment is ~500 pts. The primary endpoint in this trial is overall survival (OS). Key secondary endpoints are time to definitive deterioration of fatigue; duration of RBC transfusion-free interval; and improvement of fatigue, physical functioning, and emotional functioning. Other endpoints include CR, marrow CR (mCR), partial remission (PR), PFS, and leukemia-free survival (LFS). STIMULUS-MDS2 is a trial that aims to determine if sabatolimab + HMA has a statistically significant and clinically meaningful benefit in OS and quality of life vs HMA alone. STIMULUS MDS-US (NCT04878432) is a US-based, open-label, single-arm, Ph II trial investigating sabatolimab + HMAs of investigators' choice (AZA intravenous [IV] or subcutaneous, decitabine IV or oral decitabine) in pts with vH/H/IR-MDS. Target enrollment is 90 pts. Primary endpoint is safety, which will be evaluated via incidence and severity of adverse events (AEs) and serious AEs. Secondary endpoints include CR, PFS, LFS, and OS. This trial will provide further understanding of sabatolimab + HMA therapy with additional insight into the safety and efficacy of sabatolimab + oral HMA. STIMULUS-MDS3 (NCT04812548) is an international, open-label, single-arm, Ph II trial that explores triplet therapy of sabatolimab combined with AZA and the BCL-2 inhibitor venetoclax (VEN) in pts with vH/HR-MDS. Part 1 of this trial is a safety run-in comprising 2 safety cohorts with ~6 pts receiving sabatolimab 400 mg + AZA + VEN and ~12 pts receiving sabatolimab 800 mg + AZA + VEN. Primary endpoint of part 1 is safety (dose-limiting toxicities between cycle 1 day 8 and end of cycle 2). If (both 400 and 800 mg) sabatolimab + AZA and VEN are safe, the trial will progress to an expansion cohort (~58 pts) of sabatolimab 800 mg Q4W + AZA + VEN. The primary endpoint is CR. Secondary endpoints include CR + mCR rate, overall response rate (CR + mCR + PR + hematologic improvement), OS, PFS, LFS, and event-free survival. The STIMULUS immuno-myeloid clinical trial program is investigating the efficacy, safety, and improved quality of life of multiple sabatolimab-based combination therapies in pts with myeloid malignancies. The goal of ongoing STIMULUS-MDS trials is to gain insight into the promising durable benefit of sabatolimab combination therapies in pts with HR-MDS. Figure 1 Figure 1. Disclosures Zeidan: Jazz: Consultancy; Jasper: Consultancy; Pfizer: Other: Travel support, Research Funding; AstraZeneca: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Genentech: Consultancy; Epizyme: Consultancy; Daiichi Sankyo: Consultancy; Geron: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; BeyondSpring: Consultancy; Astex: Research Funding; Astellas: Consultancy; Aprea: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Agios: Consultancy; ADC Therapeutics: Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Borate: Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Cluzeau: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Agios: Honoraria; Amgen: Speakers Bureau; Jazz Pharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Astellas: Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Other: travel, accommodations, expenses; Takeda: Other: travel, accommodations, expenses. DeZern: Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Esteve: Jazz: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Giagounidis: Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Platzbecker: Celgene/BMS: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Geron: Honoraria; AbbVie: Honoraria; Takeda: Honoraria. Sallman: Kite: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Syndax: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Magenta: Consultancy. Santini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees. Sanz: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Other: Travel, accommodations, and expenses. Sekeres: Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Wei: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Van Hoef: Novartis Pharma: Current Employment. Nourry-Boulot: Novartis: Current Employment. Sadek: Novartis: Current Employment. Bengoudifa: Novartis Pharma AG: Current Employment. Sachs: Novartis Pharma AG: Current Employment. Sabo: Novartis: Current Employment, Current holder of stock options in a privately-held company. OffLabel Disclosure: Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3 and is under investigation for the treatment of patients with myeloid malignancies

Abstract Introduction: Patients with RR-AML, particularly older adults, have dismal outcomes and limited therapy options. Given low response rates and high toxicity with salvage intensive chemotherapy, and frequent ineligibility for allogeneic stem cell transplantation (alloSCT), many patients are treated with HMAs. Robust data regarding use of HMAs in AML predominates in the frontline setting, while their use in RR-AML has limited supportive data. Here wesought to analyze theoutcomes and their predictors in patients with RR-AML treated with HMAs. Methods:We collected data, spanning a period from 2006 to 2016, from 7 centers in the United States and 4 centers in Europe regarding patients treated with HMAs for RR-AML. Responses were defined by International Working Group criteria. Kaplan-Meier methods estimated overall survival (OS) from initiation of HMAs to death or end of follow-up. Multivariable logistic regression models estimated odds for response, and multivariable Cox Proportional Hazard (CPH) models estimated hazards ratios (HR) for OS. Covariates considered included HMA received, age at diagnosis (in years), AML classification at diagnosis (AML with myelodysplasia-related changes [AML-MRC], therapy-related [t]-AML), disease status (relapsed vs. refractory), number of therapy lines prior to HMA (1 vs. 2 vs. >=3), duration of first complete remission (CR1), white blood cell count, peripheral blood blast percentage, bone marrow (BM) cellularity (<=20% vs. > 20%), BM blast percentage (<=20% vs. >20%), cytogenetic risk group, and the presence of complex or chromosome 7 abnormalities. Results: Of 514 patients, 217 patients (42.2%) had refractory and 297 (58%) had relapsed AML. By end of study, 415 patients (88.5%) had died. Median follow-up for living patients was 11.6 months.Median age at diagnosis was 64 years (range [R], 16-92). AML-MRC was diagnosed in 29.0% while 8.2% had t-AML. Median number of prior therapies was 2 (R, 1-7), with 48.3% receiving 1 prior line, 30.2% receiving 2 prior lines, and 21.5% receiving >=3 prior lines. Prior alloSCT was performed in 21.2%. Only 1.9% had good risk (core binding factor) karyotype, while 56.2% had intermediate risk karyotype, and 41.9% had poor risk karyotype. Azacitidine was used in 45.8% and decitabine in 54.2%; median number of azacitidine cycles was 4 (Interquartile range [IQR], 2-6) compared to 2 for decitabine (IQR, 1-4, p <0.001). Best response to HMAs was CR in 11.7% (95%CI, 9%-14%), CRi in 6.4% (95%CI, 4.3%-8.8%), hematologic improvement (HI) in 8% (95%CI, 5.7%-10.5%), stable disease (SD) in 9.8% (95%CI, 7.2%-12.5%), while 64.1% (95%CI, 57.7%-66.2%) had progressive disease (PD). Median OS from HMA initiation for all patients was 6.9 months (IQR, 3.0-13.3). There was a significant difference in OS based on best response achieved [Figure 1]. Unadjusted OS showed an insignificant trend for worsening with increasing number of prior lines of therapy [Figure 2A]. In unadjusted analyses, there was no difference in OS based on HMA received in all patients [Figure 2B] or the subset who received only 1 prior line of therapy (median OS: Azacitidine vs. decitabine 8.4 vs 7.3 months, p=0.88). Following HMA therapy, the median number of subsequent therapies was 0 (R, 0-6), and only 12.8% underwent alloSCT. In multivariate CPH models, HMA used was not significantly associated with OS (HR=0.80, 95%CI, 0.42-1.51, p=0.49), while increasing age, and presence of complex cytogenetics and chromosome 7 abnormalities were significantly associated with risk of death [Table 1]. In multivariable logistic regression models, HMA used was not associated with achieving CR+CRi (Odds ratio=0.56, p=0.32). Conclusions: In this largest reported cohort of patients with RR-AML treated with HMAs, we found that HMAs are often used as alast line of therapy, with a minority of patients receiving subsequent treatment. Nonetheless, the minority of patients who achieve CR (11.7%) with HMA therapy had a median OS of 25.6 months. Therefore, use of HMAs for management of RR-AML is a reasonable intervention in the absence of clinical trial options. There appears to be no difference in OS or probability of achieving CR+CRi based on HMA used. Ongoing analyses in this dataset include further evaluations of predictors, including genetic mutations, and the development of prediction tools for clinical outcomes with HMA therapy. Figure 1. Figure 1. Disclosures Podoltsev: Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Ritchie:Novartis: Honoraria; Incyte: Speakers Bureau; Arian: Speakers Bureau; Pfizer: Honoraria; Celgene: Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Al-Kali:Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Santini:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Onconova: Consultancy; Amgen: Consultancy; Astex: Consultancy. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gore:celgene: Consultancy, Honoraria. Zeidan:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Key Points In the largest study of HMAs in RR-AML to date, 16% of patients achieved CR/CRi and experienced a median OS of 21 months. Low proliferative disease (peripheral blood blasts <5%) was associated with improved response and OS.