Greenberg, Peter L.

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).

Abstract Background and Significance: CMML is a myeloid neoplasm characterized by hematopoietic stem and progenitor cell (HSPCs) monocytic bias, leading to downstream monocyte expansion that plays a key role in disease maintenance and progression. Monocytes in CMML express high surface expression of the homing C-C chemokine receptor 2 (CCR2), which promotes malignant monocyte survival. Expansion of CCR2+ monocytic progenitors drives acute transformation in CMML and contributes to venetoclax resistance in AML. For these reasons, CCR2 is a potential novel therapeutic target in CMML and monocytic AML. The CyTAC platform was designed to enable targeting of cell surface antigens that demonstrate limited or ineffective binding to conventional therapeutic antibodies. A CyTAC is a heterobivalent small molecule that binds to both a target of choice and to a fully humanized monoclonal antibody. STX-0712 comprises a CCR2 CyTAC which potently binds to CCR2 on malignant cells, and a CyTAC humanized ADCC-enabling monoclonal antibody, which when combined eliminates target cells via enhanced effector-mediated killing in the presence of NK cells. We have demonstrated that treatment with STX-0712 ex vivo results in human target engagement and pharmacodynamic activity, and in vivo leads to depletion of CCR2 MO1 monocytes in a potent and dose-dependent manner in CMML and AML (ASH 2024). Therapeutic depletion of CCR2+ malignant monocytes presents a novel opportunity to develop a potential disease-modifying targeted therapeutic agent. We have designed a first-in-human, phase 1 clinical trial to evaluate the effect of CCR2 CyTAC in patients with refractory/resistant CMML, and relapsed/refractory monocytic or monocytic predominant AML. Study Design and Methods This is a phase 1, first-in-human, open-label, multicenter clinical trial based in the USA to evaluate STX-0712 as a monotherapy in patients with CMML and AML who have no remaining treatment options known to confer clinical benefit. STX-0712 will be administered as a single intravenous (IV) infusion every 3 weeks (additional regimen schedules may be explored) until evidence of disease progression, death, intolerance to study medication, or withdrawal of consent. The study consists of a dose-escalation and dose-expansion part and includes two cohorts: Cohort 1 (refractory/resistant CMML) and Cohort 2 (relapsed/refractory monocytic or monocytic predominant AML). Dose escalation will begin in participants with CMML using the Bayesian Optimal Interval (BOIN) design, with a minimum of three patients enrolled at each dose level. Backfilling of up to two cleared dose levels will be initiated once efficacious exposure levels are reached and at least one CMML participant has achieved a complete remission (CR) or a partial remission (PR), marrow response, or clinical benefit as defined by the MDS/MPN IWG 2015 criteria. In the AML cohort, backfilling may begin once at least one participant has achieved a response defined by ELN 2022 criteria. Dose expansion will occur upon completion of dose escalation in each cohort, using a Simon 2-stage adaptive design. Approximately 47 CMML and 58 AML patients may be enrolled in this phase 1 study. The primary objectives of the study are to evaluate the safety and tolerability of STX-0712 and to determine the minimal safe and biologically effective dose, recommended phase 2 dose (RP2D), and/or maximum tolerated dose (MTD), and to characterize dose-limiting toxicities (DLTs). Secondary objectives include evaluation of preliminary antitumor activity, pharmacokinetic (PK) parameters, and pharmacodynamic effects of STX-0712 on CCR2+ malignant cells in blood and bone marrow. Key exploratory endpoints include: (1) assessment of changes in CCR2+ tumor cells following STX-0712 dosing, (2) evaluation of candidate biomarkers, (3) characterization of T cells, B cells and NK cells at baseline and over the course of treatment, and (4) to explore the effects of STX-0712 on patient-reported outcomes using the CMML Symptoms Assessment Tool (MPN-SAF-TSS scoring system) and the EuroQoL 5 Dimension 5 level (EQ-5D-5L) for AML. Enrollment for Cohort 1 (CMML) began in March 2025, and the study is ongoing. Clinical Trial Information: NCT06950034

Abstract Excessively restrictive inclusion and exclusion criteria in clinical trials are one of many barriers to clinical trial enrollment for patients with myelodysplastic syndromes/neoplasms (MDSs). Many organizations are developing efforts to increase clinical trial eligibility; yet, several recent publications focused on patients with MDS suggest that many patients with this disease may be excluded from clinical trials unnecessarily. Clinical trial eligibility should reflect the phase of the study and risks of the agent being studied. Phase 3 trials should be less restrictive than early-phase trials to represent the real-world population as closely as possible. We hypothesize that many clinical trials, particularly phase 3 trials, have unnecessarily restrictive eligibility criteria. This study aims to evaluate the most common eligibility criteria according to phase of trial and to determine whether criteria correspond with drug safety signals. We identified MDS clinical trials registered on ClinicalTrials.gov from 1 January 2000 to 1 September 2023 and analyzed the eligibility criteria of 191 therapeutic MDS trials. We found that categorical inclusion and exclusion criteria are remarkably similar in representation across trial phases. Additionally, only 13% of trials are concordant with drug safety signals, suggesting that the eligibility criteria are often arbitrary. On behalf of the icMDS (International Consortium for Myelodysplastic Syndromes), an association of international MDS experts, we provide a position statement on restrictive eligibility criteria for MDS clinical trials that should be avoided with the aim of removing barriers to clinical trial enrollment.

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

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.

Background: Heterozygous somatic mutations in the genes encoding RNA splicing factors SF3B1, U2AF1, SRSF2 or ZRSR2 induce aberrant splicing in cancer cells and are among the most common mutations in patients with MDS, AML or CMML. H3B-8800 is an orally available small molecule that binds to the SF3b complex and induces alternative splicing changes in cells. Because splicing factor mutant cells depend on residual wild-type function of splicing factors for survival, we hypothesized that H3B-8800 would induce preferential cell killing of mutant cells by further perturbing splicing to synthetic lethality. In pre-clinical models, H3B-8800 preferentially kills spliceosome mutant cells and induces antitumor activity in xenograft leukemia models with core spliceosome mutations (Seiler M et al Nature Medicine 2018). Therefore, we conducted a phase I clinical trial (NCT02841540) of H3B-8800 in patients with MDS, AML or CMML. Here we describe the safety profile and clinical outcomes of the dose escalation cohorts in this phase I trial. Methods: This phase I trial explored the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of H3B-8800 in patients with myeloid cancers. Dose escalation cohorts, employing a standard 3+3 design, examined 2 different once daily dosing regimens (schedule I: 5 days on/9 days off; schedule II: 21 days on/7 days off) in a 28-day cycle, with stratification based on lower-risk (LR) versus higher-risk (HR) myeloid neoplasms. Results: As of June 16th, 2019, 84 patients were enrolled at 24 centers in the US and Europe. Dose ranged from 1-40 mg among 65 patients on schedule I, while 19 patients were enrolled with dose ranging from 7-20 mg on schedule II. The patient population included AML (n=38), CMML (n=4), HR-MDS (n=20), LR-MDS (n=21) and 1 MDS with unknown risk level. Most patients (88%) had spliceosome mutations of interest. The most common mutations were in SRSF2 (p.P95H in 17, p.P95L in 9, p.P95_R102Del in 4), SF3B1 (p.K700E in 11, p.R625C in 4), and U2AF1 (p.Q157P in 6, p.S34F in 4). Patients remained on treatment from 7 to 819 days; 25 patients (30%) had time on treatment greater than 180 days, 20% more than 1 year and 2% over 2 years. The median therapy duration for LR-CMML/MDS, HR-CMML/MDS, and AML patients were 216, 62, and 47 days respectively. Most observed treatment related treatment-emergent adverse events (TEAEs) were Grade 1 or 2. The most common treatment-related (as judged by the investigator, >10% frequency) TEAEs in the patients treated on schedule I were diarrhea (75%), nausea (37%), fatigue (28%) and vomiting (27%). The most common treatment-related TEAEs in the patients treated on schedule II were diarrhea (68%), vomiting (42%), QTc prolongation (21%), nausea (16%), and fatigue (16%). The most common dose limiting toxicity was prolongation of the QTcF interval >500 msec (n=2, 40 mg on schedule I and n=1, 20 mg on schedule II, all ≥Grade 3) and bradycardia without other arrhythmias (n=1, 14 mg on schedule II, ≥Grade 3). No ophthalmic AEs were observed; 1 patient (LR-MDS) experienced durable marrow aplasia. The maximum tolerated dose (MTD) has not been confirmed for either Schedule I or Schedule II. PK analysis indicates that H3B-8800 is rapidly absorbed and exhibits dose-proportional increase in plasma exposure. Consistent dose-dependent target engagement (i.e., alteration in mature mRNA transcripts) was observed in blood mononuclear cells from patients enrolled in the 2 mg up to 40 mg dose cohorts on both schedules. Despite this splicing modulation, no objective complete responses (CR) or partial responses (PR) meeting International Working Group criteria were observed. One patient with CMML had a durable platelet response that began in Cycle 1 and persisted through Cycle 13. Nine red blood cell (RBC) transfusion-dependent patients with MDS or CMML and 2 patients with AML did not require RBC transfusions for ≥8 weeks (up to 28 weeks) while on study. One platelet transfusion-dependent patient with LR-MDS did not require platelet transfusions for ≥8 weeks. Conclusion: Results from this first-in-human multicenter prospective clinical trial of a splicing modulator in myeloid neoplasms demonstrate dose-dependent target engagement and predictable PK profile of H3B-8800, and safety even with prolonged dosing. Although no objective CR or PR were achieved, decreased RBC or platelet transfusion requirements were observed in 12 (14%) of enrolled patients. Disclosures Steensma: H3 Biosciences: Other: Research funding to institution, not investigator.; Pfizer: Consultancy; Aprea: Research Funding; Stemline: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Astex: Consultancy; Onconova: Consultancy. Wermke:Novartis: Honoraria, Research Funding. Greenberg:Notable Labs: Research Funding; Celgene: Research Funding; Genentech: Research Funding; H3 Biotech: Research Funding; Aprea: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Font:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Komrokji:Agios: Consultancy; JAZZ: Speakers Bureau; DSI: Consultancy; JAZZ: Consultancy; Incyte: Consultancy; Novartis: Speakers Bureau; celgene: Consultancy; pfizer: Consultancy. Yang:Agios: Consultancy; AstraZeneca: Research Funding. Brunner:Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Ades:Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Coombs:H3 Biomedicine: Research Funding. Foran:Agios: Honoraria, Research Funding. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Amphivena: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Micol:AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy. Perez De Oteyza:Celgene: Speakers Bureau. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Buonamici:H3 Biomedicine: Employment. Kim:H3 Biomedicine: Employment. Gourineni:H3 Biomedicine: Employment. Marino:H3 Biomedicine: Employment. Rioux:H3 Biomedicine: Employment. Schindler:H3 Biomedicine: Employment. Smith:H3 Biomedicine: Employment. Yao:H3 Biomedicine: Employment. Yuan:Eisai: Employment. Yu:H3 Biomedicine: Employment. Platzbecker:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: H3B-8800 (experimental, unapproved)

Abstract Background Therapy-related myeloid neoplasm (tMN) includes t-myelodysplasia (tMDS) and t-acute myeloid leukemia (tAML) and are serious late effects of the treatment of cancer. Prognosis of tMN is poor, related to the increased frequency of adverse cytogenetics and other clinical features which predict poor response to conventional treatment. Over the last years, azacitidine (AZA) has become the standard of treatment for high risk MDS (Silverman, JCO 2002; Fenaux, Lancet Oncol 2009) and has shown efficacy in AML. AZA represents an interesting option for patients with tMN considering its safety profile and its efficacy in poor prognosis subgroups of apparently de novo MDS patients including those with monosomy 7. Most prospective trials of AZA have excluded patients with tMN. Most tMN data are retrospective or registry studies (Bally, Leuk Res 2013). This abstract presents the results of 47 t-MN patients prospectively enrolled as a specific cohort in the E1905 study. Methods E1905 study is a randomized phase 2 study from the North American Leukemia Intergroup (NCT00313586, Prebet , ASH 2010) testing 10 days of AZA (50mg/m2/d s.c.) vs. 10 days of AZA + the histone deacetylase inhibitor entinostat (4 mg/m2/d PO days 3 and day 10). 6 cycles of treatment were planned; responding patients could receive up to 24 cycles. MDS, CMML, and AML with myelodysplasia-related changes were included. Patients with tMN were subsequently accrued as a separate cohort after amendment of the protocol. Response was assessed using IWG 2000 criteria (Cheson et al, Blood 2000); the primary endpoint of the overall trial was achievement of a normal hemogram in 25% of treated patients in either treatment arm. Results A total of 47 patients were included. Median age was 70 years (39y-83y), 45% male, and 94% of patients had ECOG PS 0-1. 29 patients could be subclassified as t-MDS and 18 as t-AML. At inclusion, median peripheral blood counts were: neutrophils 1.0 G/l, Platelets 35 G/L, Hemoglobin 9.2 g/l, peripheral blood blasts 0%, marrow blasts 14.0%. 68% of patients were RBC transfusion dependent and 40% platelet transfusion dependent. As expected, the cytogenetic evaluation showed a high frequency of unfavorable risk cytogenetics (74%) as compared to normal or intermediate risk cytogenetics (26%). Baseline characteristics were not statistically different between the 2 arms. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4 and was significantly higher in patients treated with AZA monotherapy (6 cycles vs.3 cycles, p=0.008). 8 patients in the combination arm and 1 patient in the AZA monotherapy arm died of infection or hemorrhage before cycle 3. In an intent to treat analysis, overall response rates (CR, PR, or trilineage Hematologic improvement) were 11/24 (46%) in AZA monotherapy (95% CI 26 – 67%) and 4/23 (17%) in the combination arm (95% CI 5 – 39%, p=0.06 comparing the two arms). Median overall survival in the two arms were 12.8 months and 5.7 months (p=0.008). Conclusions In this group of very high risk patients with therapy-related myeloid neoplasms, the use of the novel 50 * 10 schedule of azacitidine monotherapy appears effective, with response rates comparable to those for patients with de novo MDS/AML treated on the same protocol (74 pts, 40% with unfavorable cytogenetics, ORR=32%, median OS=18 months). Because there are no prospective data examining the approved dose schedule of AZA (75 mg/m2/day * 7 days), it is not clear if this surprisingly high response rate derives from the current extended schedule of lower dose AZA, or would be true with standard dose AZA as well. This high response may enable many of these patients to proceed to allogeneic stem cell transplant. Entinostat combined with azacitidine at the dose and schedule applied in E1905 does not appear to be effective and tolerable as compared to azacitidine alone. Disclosures: Prebet: CELGENE: Honoraria. Off Label Use: Use of azacitidine in acute myeloid leukemia. Gore:CELGENE: Equity Ownership, Research Funding.

Abstract Background. Gene mutation profiling is increasingly employed for diagnosis, risk stratification, and clinical management in patients with MDS. However, current World Health Organization MDS classification is still based on histologic findings (with the exception of SF3B1 for MDS-RS), and guidelines generally suggest that clinical decisions be guided by clinico-pathologic risk stratification tools such as Revised International Prognostic Scoring System (IPSS-R). We sought to study beliefs and patterns of practice with respect to gene mutation profiling among health care providers who manage patients with MDS. Methods. A link to a 23-question web-based survey was emailed to members of the Eastern Cooperative Oncology Group (ECOG)-ACRIN Cancer Research Group, Alliance for Clinical Trials in Oncology (Alliance), and the Southwest Oncology Group (SWOG), and the Cancer Trials Support Unit (CTSU) on 5/1/2018 with 6 subsequent weekly reminders. The Qualtrics survey platform was used to record anonymous responses. We used descriptive statistics to analyze the data. No incentive was provided for responses. Results. Of 371 received responses, 262 were received from providers who did not manage MDS patients or lacked analyzable data and therefore were excluded. Of 109 eligible responses, 108 responders were from institutions representing 31 US states (one respondent was from South America). Median age of respondents was 48 years (range, 33-75); 43 (39%) were women. A third of responders (32%) worked at a university hospital, while 25%, 17%, and 5% worked at a community hospital, private practice, or other settings, respectively. While 37% of participants worked at institutions with guidelines for clinical care of MDS patients, 28% reported that their institutional guidelines recommended MDS-specific gene mutation profiling. Such testing was performed at institutions of 13% participants; institutions of 26% of responders tested a general AML panel that included MDS-specific genes. The total number of respondents whose institutions sent out either an MDS-specific gene panel or a general AML gene panel with MDS-specific genes was similar, 25% and 12%, respectively (Fig. 1). Of those who routinely perform molecular testing, 94% do so at diagnosis, 56% at relapse, 33% during preparation for stem cell transplant, 31% after the failure of hypomethylating agents (HMA), 24% during screening for a clinical trial, and 15% at initial treatment (Fig. 2). MDS gene mutation profiling was felt to be most helpful in diagnosis (rarely 11%; sometimes 49%; often 30%; always 9%), risk stratification (sometimes 31%; often 51%; always 15%), and prognosis (sometimes 31%; often 51%; always 14%); its role was more limited in response assessment (never 12%; rarely 25%; sometimes 44%; often 14%) and to predict responses to HMAs (never 5%; rarely 28%; sometimes 52%, often 14%) (Fig. 3). Various types of evidence were used to stratify MDS risk and prognosis: genetic mutations were used by nearly everyone (95%); 70% relied on morphologic findings, while gene expression/transcriptome profiling was used by 40%. Eighty-four percent of responders reported relying on conventional prognostic models like IPSS-R to identify high-risk patients for whom they would consider intensive treatment options. For this purpose, 62% would also rely on mutation profiling, and 32% would also consider higher frequency of gene mutations. While mutations in the p53 pathway were felt to be helpful in terms of risk stratification and treatment decisions by 70% of responders, 43%, 39%, 31%, 26% 23%, 20%, and 3% considered mutations in spliceosome, DNA methylation, transcription factors, histone modification, signaling, RAS pathway, and cohesin genes, respectively, to be useful as well. Approximately 31% of responders were not certain as to which mutations would affect risk stratification and management choices and said they needed to review literature. The respondents also cited multiple limitations to wider clinical use of MDS gene mutation profiling (Fig. 4). Conclusions. Our survey demonstrates widespread use of gene mutation profiling in the management of patients with MDS, but also reveals substantial variability in beliefs, practices, testing logistics, and interpretation of molecular profiling. Our findings emphasize the need for high-quality data to develop consensus evidence-based guidelines for gene profiling of MDS patients. Disclosures Sekeres: Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Bejar:AbbVie/Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Foundation Medicine: Consultancy; Astex/Otsuka: Consultancy, Honoraria; Modus Outcomes: Consultancy; Takeda: Research Funding; Genoptix: Consultancy. Gore:Celgene: Consultancy, Research Funding. Zeidan:Ariad: Consultancy, Speakers Bureau; Gilead: Consultancy; Incyte: Employment; Celgene: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Novartis: Consultancy; Pfizer: Consultancy.