A sex-informed approach to improve the personalised decision making process in myelodysplastic syndromes: a multicentre, observational cohort study

Background Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. Methods In this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Dusseldorf MDS registry (n=1185). Recruitment periods for these cohorts were between 1990 and 2016. The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort. The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts. Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R). This study is registered with ClinicalTrials.gov, NCT04889729. Findings The study included 7792 (58middot7%) men and 5492 (41middot3%) women. 10 906 (82middot1%) patients were White, and race was not reported for 2378 (17middot9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p<0middot0001 in both cohorts; DDX41 not available in the EuroMDS cohort vs p=0middot0062 in the IWG-PM cohort; IDH2 p<0middot0001 in EuroMDS vs p=0middot042 in IWG-PM; TET2 p=0middot031 vs p=0middot035; U2AF1 p=0middot033 vs p<0middot0001) and mutations in two genes were enriched in women (DNMT3A p<0middot0001 in EuroMDS vs p=0middot011 in IWG-PM; TP53 p=0middot030 vs p=0middot037). Additionally, sex biases were observed in co-mutational pathways of founding genomic lesions (splicing-related genes, predominantly in men, p<0middot0001 in both the EuroMDS and IWG-PM cohorts), in DNA methylation (predominantly in men, p=0middot046 in EuroMDS vs p<0middot0001 in IWG-PM), and TP53 mutational pathways (predominantly in women, p=0middot0073 in EuroMDS vs p<0middot0001 in IWG-PM). In the retrospective EuroMDS cohort, men had worse median overall survival (81middot3 months, 95% CI 70middot4-95middot0 in men vs 123middot5 months, 104middot5-127middot5 in women; hazard ratio [HR] 1middot40, 95% CI 1middot26-1middot52; p<0middot0001). This result was confirmed in the prospective validation cohorts (median overall survival was 54middot7 months, 95% CI 52middot4-59middot1 in men vs 74middot4 months, 69middot3-81middot2 in women; HR 1middot30, 95% CI 1middot23-1middot35; p<0middot0001 in the GEMSD MDS registry; 40middot0 months, 95% CI 33middot4-43middot7 in men vs 54middot2 months, 38middot6-63middot8 in women; HR 1middot23, 95% CI 1middot08-1middot36; p<0middot0001 in the Dusseldorf MDS registry). We developed new personalised prognostic tools that included sex information (the sex-informed prognostic scoring system and the sex-informed genomic scoring system). Sex maintained independent prognostic power in all prognostic systems; the highest performance was observed in the model that included both sex and genomic information. A five-to-five mapping between the IPSS-R and new score categories resulted in the re-stratification of 871 (43middot0%) of 2025 patients from the EuroMDS cohort and 1003 (42middot0%) of 2387 patients from the IWG-PM cohort by using the sex-informed prognostic scoring system, and of 1134 (56middot0%) patients from the EuroMDS cohort and 1265 (53middot0%) patients from the IWG-PM cohort by using the sex-informed genomic scoring system. We created a web portal that enables outcome predictions based on a sex-informed personalised approach. Interpretation Our results suggest that a sex-informed approach can improve the personalised decision making process in patients with myelodysplastic syndromes and should be considered in the design of clinical trials including low-risk patients. Copyright (c) 2022 Published by Elsevier Ltd. All rights reserved

MDS-336: Phase 2 Study of Pevonedistat + Azacitidine versus Azacitidine in Patients with Higher-Risk Myelodysplastic Syndromes (MDS)/Chronic Myelomonocytic Leukemia (CMML) or Low-Blast Acute Myelogenous Leukemia (LB-AML) (NCT02610777): Subset Analysis in Higher-Risk MDS

Pevonedistat, the first small-molecule inhibitor of NEDD8-activating enzyme, disrupts proteasomal degradation of select proteins. Patients with higher-risk MDS/CMML (IPSS-R >3, including intermediate [≥5% blasts], high, or very high risk) or LB-AML naïve to hypomethylating agents were randomized 1:1 to receive intravenous pevonedistat 20 mg/m2 on days 1, 3, and 5 plus intravenous/subcutaneous azacitidine 75 mg/m2 on days 1–5, 8, and 9 (n=58), or azacitidine alone (n=62), in 28-day cycles. This abstract focuses on the higher-risk MDS subgroup. The study was powered on an endpoint of event-free survival (EFS). Overall survival (OS), overall response rate (ORR) and safety were also assessed. Patient-reported health-related quality of life (HRQoL) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) QoL Questionnaire-C30. Mutational profiling was performed on screening bone marrow aspirate samples. In the intent-to-treat (ITT) population (n=120), EFS trended longer (median, 21.0 vs 16.6 months; hazard ratio [HR]=0.67; 95% CI, 0.42–1.05; P=.076) and median OS was 21.8 vs 19.0 months (HR=0.80; 95% CI, 0.51–1.26; P=.334) with pevonedistat+azacitidine vs azacitidine. In patients with higher-risk MDS (n=67), EFS was longer (median, 20.2 vs 14.8 months; HR=0.54; 95% CI, 0.29–1.00; P=0.045) and median OS was 23.9 vs 19.1 months (HR=0.70; 95% CI, 0.39–1.27; P=0.240) with pevonedistat+azacitidine vs azacitidine. In response-evaluable patients with higher-risk MDS (n=59), ORR was 79% (pevonedistat+azacitidine) vs 57% (azacitidine); median duration of response was 34.6 vs 13.1 months, respectively. Median azacitidine dose intensity was 98% (both arms) in patients with higher-risk MDS. With pevonedistat+azacitidine vs azacitidine, 94% vs 83% of patients with higher-risk MDS had grade ≥3 adverse events (most common: neutropenia [38% vs 37%], febrile neutropenia [22% vs 31%]). No difference was observed in patient-reported HRQoL between arms, with similar mean scores maintained from study entry to end of treatment. Clinical activity was observed with pevonedistat+azacitidine in patients with higher-risk MDS harboring poor prognostic mutations. Pevonedistat+azacitidine led to longer EFS vs azacitidine in higher-risk MDS, had a comparable safety profile to azacitidine alone, and azacitidine dose intensity was maintained. A randomized phase 3 trial (NCT03268954) is ongoing

FT-2102, an IDH1m Inhibitor, in Combination with Azacitidine in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Ayndrome (MDS): Results from a Phase 1 Study

Abstract Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients and 3% of MDS patients. Mutated IDH1 metabolizes alpha-ketoglutarate into 2-hydroxyglutarate (2-HG), an oncometabolite that impairs differentiation. FT-2102 is an oral, highly potent, selective small molecule inhibitor of mutated IDH1, with the therapeutic potential to restore normal cellular differentiation. Azacitidine (AZA), a hypomethylating agent (HMA), is a standard of care for MDS and for AML patients unfit for intensive therapy. We present Phase 1 clinical data from the ongoing Phase 1/2 study of FT-2102 in combination with azacitidine (FT-2102+AZA) in patients with IDH1m AML and MDS (CT.gov: NCT02719574). Methods: A Phase 1 study was initiated to evaluate the safety, PK/PD, and antileukemic activity of FT-2102 in patients with IDH1m AML or MDS and included both dose escalation and expansion. FT-2102 was administered daily (150 QD or 150 BID) until disease progression or unacceptable toxicity; AZA was administered at 75 mg/m2 IV or SC daily for 7 days of each 28-day cycle. Eligible patients had IDH1m AML/MDS that was relapsed/refractory (R/R) or treatment-naïve (TN), were eligible for AZA therapy and had adequate liver and renal function. Prior IDH1 inhibitors and hypomethylating agents were allowed, and there were no restrictions for concomitant non-anticancer medications. Investigator-assessed responses were per modified IWG 2003/2006 criteria. Efficacy was assessed at Cycle 2 Day 1 and as clinically indicated thereafter. Adverse events (AEs) were assessed throughout the study per NCI CTCAE version 4.03. Results: At the time of the data cutoff, 07 April 2018, 27 patients had been enrolled and 26 had been treated with FT-2102+AZA, with a median of 3 months on treatment (range: 0.2 to 12 months). Of the 27 enrolled patients, 24 had AML (20 R/R; 4 TN) and 3 patients had MDS (all TN). The median number of prior antileukemia therapies was 3 (range: 0-5) in the AML patients. Doses of FT-2102 were 150 mg QD (n=7) and 150 mg BID (n=20). Thirteen (50%) patients discontinued treatment, with the most common reasons for treatment discontinuation were hematopoietic stem cell transplant (n=4), death (n=2), and progressive disease (n=2). No patients discontinued due to an AE. Severe (≥ Grade 3) AEs occurring in ≥ 5% of patients included febrile neutropenia (27%), anemia, thrombocytopenia, leukocytosis (19% each), fatigue, hypertension, neutropenia (15% each), nausea, pneumonia, hypokalemia (12% each) and abdominal pain (8%). Three patients had differentiation syndrome (IDH-DS), which resolved with FT-2102 temporary interruption, and treatment with dexamethasone, hydroxyurea, and supportive care in all three. Five patients died within 28-days of the last dose of study drug, none of which were considered related to FT-2102+AZA. No DLTs were observed during dose escalation. PK analysis demonstrated no impact of AZA on steady-state exposure of FT-2102. 2-HG levels to normal levels by C2D1. Table 1 shows the Investigator-assessed ORR per IWG. Responses have been seen as early as 1 month on treatment, and stable disease for greater than 6 months; 50% of patients remain on treatment. Conclusions: FT-2102+AZA is well tolerated in AML and MDS, with 150 mg BID selected as the RP2D based on safety, PK and PD (2-HG) response. Clinical activity has been observed, with an ORR of 42%. Durable CRs (>12 months) have been observed. The current data support the continued evaluation of FT-2102 150 mg BID+AZA in the Phase 2 study. Three Phase 2 combination therapy cohorts are currently open for enrollment in patients < 60 years with R/R AML or MDS naïve to HMA and IDH1m inhibitors; R/R AML or MDS with inadequate response/PD on HMA, and R/R AML or MDS who have progressed on a prior IDH1m inhibitor. Updated clinical data will be available at the time of presentation. Disclosures Cortes: Pfizer: Consultancy, Research Funding; Arog: Research Funding; Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Wang:Amgen: Consultancy; Jazz: Speakers Bureau; Amgen: Consultancy; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ferrell:Incyte: Research Funding. Jonas:LP Therapeutics: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding; Daiichi Sankyo: Research Funding; Kalobios: Research Funding; Glycomimetics: Research Funding; AbbVie: Consultancy, Research Funding; Forma: Research Funding; Accelerated Medical Diagnostics: Research Funding; Tolero: Consultancy; Esanex: Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy; Pharmacyclics: Research Funding. Wei:Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Pfizer: Honoraria, Other: Advisory committee; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Amgen: Honoraria, Other: Advisory committee, Research Funding; Celgene: Honoraria, Other: Advisory committee, Research Funding. Montesinos:Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau. Kelly:Forma Therapeutics Inc.: Employment. Li:Forma Therapeutics Inc.: Employment. Sweeney:Forma Therapeutics Inc.: Employment. Watson:Forma Therapeutics Inc.: Employment. Mohamed:Forma Therapeutics Inc.: Employment

Olutasidenib (FT-2102) in Combination with Azacitidine Induces Durable Complete Remissions in Patients with mIDH1 Acute Myeloid Leukemia

Abstract Background: Olutasidenib, a potent, selective, oral, small molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), has been previously shown, as a single agent, to be well tolerated and induce durable complete remissions in a subset of patients (pts) with high-risk relapsed/refractory (R/R) mIDH1 acute myeloid leukemia (AML), with an overall response rate (ORR) of 46% and a CR/CRh rate of 33% (de Botton et al., ASCO/EHA 2021). Azacitidine (AZA) has shown synergistic effects with mIDH1 inhibitors on releasing differentiation block in mIDH leukemia models in vitro. Here, we present results of an ongoing phase 2 trial (NCT02719574) in pts receiving olutasidenib (150 mg twice daily) in combination with AZA (75 mg/m 2) (Olu-AZA). Methods: Pts were enrolled into 1 of 4 Olu-AZA cohorts: (1) pts with R/R AML/MDS who were naïve to prior hypomethylating agent [HMA] and IDH1 inhibitor therapy, (2) pts with R/R AML/MDS who had inadequately responded to or had progressed on prior HMA, (3) pts with R/R AML/MDS who were previously treated with an IDH1 inhibitor as their last therapy prior to enrollment (including pts who received single-agent olutasidenib), and (4) treatment naïve [TN] mIDH1 AML pts who were candidates for AZA first line treatment. The primary endpoint was CR/CRh (complete remission [CR] according to modified IWG 2003 criteria plus CR with partial hematologic recovery [CRh]) response rate. CRh was defined as bone marrow blasts 0.5×10 9/L, and platelet count > 50×10 9/L. ORR, a secondary endpoint, comprised CR+CRh+CR with incomplete recovery (CRi) + morphologic leukemia-free state (MLFS) + partial remission (PR). Duration of treatment (DOT) time to response, and duration of response were estimated using Kaplan-Meier methodology. Due to the low number of MDS pts, response parameters are presented for AML pts only. Results: As of 16-June-2021, a total of 72 pts with AML/MDS (n=63/9) received Olu-AZA (R/R w/o prior HMA/IDH1 therapy, n=20; R/R with prior HMA therapy, n=21; R/R with prior IDH1 therapy, n=20; TN AML, n=11) with a median DOT of 4.7 mo (95% CI: 3.6, 5.7). The median age was 72 y (range: 28‒84) with a median number of prior therapies for R/R pts of 2 (1‒5). At the cut-off, 11 (15%) pts remained on treatment and 61 (85%) had discontinued, most commonly (≥10%) due to: disease progression (32%), transplant (11%), and AEs (10%). For pts with AML, the ORR across Olu-AZA cohorts was 40-68% with a median duration of ORR of 3.7-8.5 mo (not reached [NR] for TN AML) and a median time to first response (PR or better) of 1.6-2.8 mo (Table 1). Notably, the CR/CRh rate ranged from 30-47% including 23-45% of pts in CR, with a median duration of CR/CRh of 4.7-16.0 mo (NR for TN AML) and a median time to CR/CRh of 2.8-4.0 mo. For pts who were transfusion-dependent at baseline, 56-day transfusion independence was achieved by 40-100% of pts for platelets and 25-57% of pts for red blood cells (Table 1). Treatment-emergent adverse events (TEAEs) in ≥25% of pts were nausea (49%), constipation (40%), vomiting (35%), thrombocytopenia (32%), diarrhea (28%), and neutropenia (26%). Grade 3/4 all-causality TEAEs in >10% of pts were neutropenia (26%), thrombocytopenia (25%), anemia (19%), and febrile neutropenia (14%). TEAEs of QTc prolongation (all grades) were reported in 5 (7%) pts with grade 3 events in 2 (3%) pts. All pts were receiving concomitant medications associated with QTc prolongation. No events led to olutasidenib dose reduction or discontinuation. Hepatobiliary TEAEs associated with liver enzyme abnormalities (all grades) were reported in 15 (21%) pts, with grade ≥3 events in 6 (8%) pts. Most pts (n=11) required no dose modification or were successfully rechallenged, 3 pts with grade ≥3 events discontinued treatment, two after recurrence of abnormalities with rechallenge, and one pt died with liver function tests abnormal in the setting of AML progression and sepsis. There were no cases of Hy's law. Investigator-assessed IDH1 differentiation syndrome (any grade) was observed in 6 (8%) pts; most cases resolved with treatment interruption, dexamethasone, and/or supportive treatment; 2 pts had concomitant leukocytosis. Conclusions: Olutasidenib in combination with AZA was well tolerated and induced durable CR/CRh in a subset of high-risk pts with mIDH1 AML. Transfusion independence was achieved in a subset of pts in all cohorts. Additional analyses of safety and efficacy will be presented. Figure 1 Figure 1. Disclosures Cortes: Sun Pharma: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Esteve: Novartis: Research Funding; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Pfizer: Consultancy; Jazz: Consultancy; Abbvie: Consultancy. Bajel: Amgen: Speakers Bureau; Abbvie, Amgen, Novartis, Pfizer: Honoraria. Yee: Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Genentech: Research Funding; Geron: Research Funding; Tolero: Research Funding; Paladin: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Onconova: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Braun: Servier: Research Funding; Daiichi-Sankyo, Celgene: Consultancy, Honoraria. De Botton: Celgene, Agios, Forma Therapeutics, Astella, Daiichi Sankyo, Syros, Abbvie, Bayer, Seattle Genetics, Janssen: Honoraria; Celgene, Agios, Astellas, Daiichi Sankyo, Syros, Abbvie, Bayer, Janssen, Pierre Fabre, Novartis, Pfizer, Servier: Consultancy; Celgene: Speakers Bureau; Agios, Forma Therapeutics: Research Funding. Recher: Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, 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; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Janssen: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Watts: Takeda: Consultancy, Research Funding; Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding. Curti: Jazz Pharma: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees. Grove: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jonas: 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy; AbbVie: Other: Travel reimbursement. Montesinos: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Forma Therapeutics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Teva: M

Olutasidenib (FT-2102), an IDH1m Inhibitor As a Single Agent or in Combination with Azacitidine, Induces Deep Clinical Responses with Mutation Clearance in Patients with Acute Myeloid Leukemia Treated in a Phase 1 Dose Escalation and Expansion Study

Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients (pts) and approximately 3-4% of MDS pts. Olutasidenib is a highly potent, selective small molecule inhibitor of IDH1m with the therapeutic potential to restore normal cellular differentiation. Azacitidine (AZA) has shown synergistic effects with IDHm inhibitors on releasing differentiation block in IDHm leukemia models in vitro. Methods: The Phase 1 study (NCT02719574) assessed the safety, PK/PD, and clinical activity of olutasidenib in patients with IDH1m AML or MDS. Eligibility criteria included: IDH1m AML or MDS [relapsed/refractory (R/R) or treatment naïve (TN) pts not eligible for or refusing standard therapy], adequate liver and renal function. There were no restrictions for concomitant non-anticancer medications. IDH1m variant allele frequency (VAF) and co-mutations were measured at baseline and during treatment. Available safety data are presented for all pts (AML/MDS); efficacy data are presented for AML pts only. Results: As of April 12, 2019, 32 pts had been treated with single agent (SA) olutasidenib and 46 pts with olutasidenib in combination (COMBO) with AZA; median time on treatment was 4.2 mo for SA (range: 10% of pts, including thrombocytopenia (28% vs 33%), febrile neutropenia (22% vs 28%), anemia (22% vs 20%), pneumonia (16% vs 11%), and leukocytosis (13% vs 15%); COMBO-treated pts had more Gr 3/4 neutropenia (6% vs 28%), fatigue (6% vs 15%), and nausea (0% vs 9%). No QTcF prolongation was reported in SA while 3 (7%) pts treated with COMBO reported prolonged QTcF (1 Gr 3). Ten (13%) pts had differentiation syndrome (4 SA; 6 COMBO), which resolved with temporary interruption of olutasidenib and treatment with dexamethasone, hydroxyurea, and/or supportive care. None led to treatment discontinuation. Nineteen (24%) pts died on treatment or within 28 days of the last dose, no deaths were considered treatment-related. For AML pts, clinical responses occurred in 39% SA and 54% COMBO (CR 15% and 23%, respectively; Table 1). CRs were durable (up to >27 mo); disease control (SD >13 mo) was observed in pts without an IWG-defined response. Of the 59 AML pts (23 SA; 36 COMBO) who were transfusion-dependent at baseline, 26 (11 [48%] SA; 15 [42%] COMBO) and 21 (9 [39%] SA; 12 [33%] COMBO) became transfusion-independent (seen in all response categories) during 28 and 56 days on treatment, respectively. For R/R AML pts, median survival was 8.7 mo for SA and 12.1 mo for COMBO; for TN AML pts, median survival was 8.8 mo for SA (n=4) and not reached for COMBO. For R/R and TN AML patients with available pre- and on-treatment samples, IDH1m clearance or significant reduction (VAF <1%) was observed in 10/25 pts (40%) achieving an objective response and in 3/6 pts (50%) with stable disease. Mutation and 2-HG analyses suggest that pts who progressed on olutasidenib had a non-IDH1m-driven mechanism; updated analyses will be presented. Conclusions: SA and COMBO olutasidenib has shown favorable safety and clinical activity in IDH1m R/R AML with a SA ORR of 41% (95% CI: 21, 64) and a COMBO ORR of 46% (27, 67), and durable disease control. Olutasidenib induces deep responses with IDH1 mutation clearance in a subset of treated pts. Phase 2 investigations of SA and COMBO olutasidenib at the RP2D are ongoing in multiple IDH1m AML populations. Additional combinations are also being explored. Disclosures Watts: Jazz Pharmaceuticals: 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; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Baer:Forma: Research Funding; Kite: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Al Therapeutics: Research Funding. Yang:Agios: Consultancy; AstraZeneca: Research Funding. Prebet:pfizer: Honoraria; novartis: Honoraria; pfizer: Honoraria; Boehringer Ingelheim: Research Funding; novartis: Honoraria. Lee:Helsinn: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Roche Molecular Systems: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Ai Therapeutics: Research Funding. Schiller:Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Astellas: Research Funding; Agios: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Amgen: Other, Research Funding. Dinner:Agios: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy. Pigneux:Roche: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Amgen: Honoraria; Daichi: Honoraria; Astellas: Honoraria; Novartis: Honoraria. Montesinos:Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. Wang:Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; 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; Agios: Other: Advisory role. Seiter:Novartis, Incyte, Celgene, Astellas, Sanofi: Speakers Bureau; Novartis, Astellas,: Consultancy; Novartis, Forma, Sun Pharma, Celgene, Jazz, Roche: Research Funding. Wei:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. De Botton:Agios: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Pierre Fabre: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Janssen: Consultancy; FORMA: Consultancy, Research Funding; Syros: Consultancy; Bayer: Consultancy; Abbvie: Consultancy; Daiichi: Consultancy; Astellas: Consultancy. Jonas:AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ferrell:Astex Pharmaceuticals: Re

Molecular Characteristics of Response to Olutasidenib (FT-2102) in Patients with Relapsed/Refractory mIDH1 Acute Myeloid Leukemia

Abstract Background: Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1). Olutasidenib has previously shown clinical activity in high-risk AML patients (pts) in a Phase 1 clinical trial (Watts, Blood 2019). The planned interim analysis of an ongoing Phase 2 clinical trial (NCT02719574) in R/R mIDH1 AML pts receiving single-agent olutasidenib 150 mg twice-daily showed an overall response rate (ORR) of 46%, including 33% of pts with CR/CRh (de Botton et al., ASCO/EHA 2021). Here we present data analysis on the mutational characteristics of these pts and the relationship between mutations and clinical response. Methods: The Efficacy Evaluable (EE) set comprised mIDH1R132X pts whose first dose was ≥180 days before the data cut-off (18-JUN-20). The primary endpoint was CR/CRh (complete remission [CR] according to modified IWG 2003 criteria plus CR with partial hematologic recovery [CRh]) response rate. CRh was defined as bone marrow blasts 0.5×10 9/L, and platelet count >50×10 9/L. ORR, a secondary endpoint, comprised CR+CRh+CR with incomplete recovery (CRi) + morphologic leukemia-free state (MLFS) + partial remission (PR). IDH1 mutation subtypes were determined by central analysis, co-mutations were reported by investigators. Baseline characteristics and mutation subtypes were tabulated for the safety population and analysis of response rate by mutation type was performed on the EE set. Results: There were 153 R/R AML pts treated with olutasidenib 150 mg BID (safety set). Of those, 123 were in the efficacy evaluable (EE) set (centrally confirmed IDH1R132 mutation and received first dose at least 180 days prior to the data cut off). For the safety population, cytogenetic risk classification was favorable in 6 (4%) pts, intermediate in 109 (71%) pts, and poor in 25 (16%) pts (unknown, 13 [8%] pts). Eighty-five (56%) pts had IDH1R132C mutation subtype, followed by IDH1R132H (n=35 [23%]), IDH1R132G (n=12 [8%]), IDH1R132S (n=11 [7%]), and IDH1R132L (n=4 [3%]). Ninety-four (61%) pts had 1-3 co-mutations reported by the investigator at baseline, with 4-7 co-mutations in 20 (13%) pts, none in 6 (4%) pts, and not done/unknown in 33 (22%) pts. The most common co-mutations at baseline were: NPM1 (n=40 [26%]), DNMT3A (n=36 [24%]), and ASXL1 (n=21 [14%]. Receptor tyrosine kinase (RTK) mutations were reported in 32 (21%) pts (FLT3, n=18 [12%]; NRAS, n=10 [7%]; KRAS, n=3 [2%]; PTPN11, n=3 [2%]; KIT, n=2 [1%]; NF1, n=2 [1%]), with multiple mutations reported in some pts. For the EE population, responses were achieved in all IDH1R132 mutation subtypes, with ORR and CR/CRh response rates ranging from 27%-54% and 17%-50%, respectively (Table 1). The CR/CRh response rate was lower for pts with IDH1R132H mutations; notably, these pts tended to have a higher percentage of co-mutations, particularly mutations in NPM1 and RTK genes, including FLT3. For EE pts with available co-mutation data (n=96), the mean (SD) number of co-mutations was lower (p<0.05) in pts achieving CR/CRh (1.8 [1.1]; n=29) compared to pts with non-CR/CRh responses or non-responders (2.5 [1.7]; n=67). The ORR was 32%, 48%, and 53% for pts with NPM1, DNMT3A, and ASXL1 mutations, respectively, with corresponding CR/CRh rates of 24%, 34%, and 24% (Figure 1). Pts with RTK mutations at baseline had an ORR of 33% as compared to 46% for pts without any RTK mutation (p=0.26), with fewer pts with RTK mutations achieving CR/CRh than those without any RTK mutation (15% vs. 36%, respectively [p<0.05]). Conclusions: Responses were observed across IDH1R132 mutation subtypes, with a relatively lower CR/CRh response rate for pts with a R132H mutation as compared to other subtypes. Pts with a best response of CR/CRh had fewer co-mutations than pts who did not achieve CR/CRh. While the ORR was not significantly reduced for pts with RTK mutations, these pts had a lower CR/CRh response rate compared to pts without any RTK mutations. Additional genetic analyses using ddPCR for IDH1 mutations and NGS on a targeted panel of genes at baseline, best response, and end of study will be presented to further explore primary and secondary resistance mechanisms. Figure 1 Figure 1. Disclosures De Botton: Celgene, Agios, Forma Therapeutics, Astella, Daiichi Sankyo, Syros, Abbvie, Bayer, Seattle Genetics, Janssen: Honoraria; Celgene, Agios, Astellas, Daiichi Sankyo, Syros, Abbvie, Bayer, Janssen, Pierre Fabre, Novartis, Pfizer, Servier: Consultancy; Celgene: Speakers Bureau; Agios, Forma Therapeutics: Research Funding. Yee: Forma Therapeutics: Research Funding; Onconova: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Jazz: Research Funding; Tolero: Research Funding; AbbVie: Honoraria; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Geron: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher: BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Janssen: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wei: Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; 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. Montesinos: Forma Therapeutics: Consultancy; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Stemline/Menarini: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Braun: Servier: Research Funding; Daiichi-Sankyo, Celgene: Consultancy, Honoraria. Curti: Jaz

A sex-informed approach to improve the personalised decision making process in myelodysplastic syndromes : a multicentre, observational cohort study

Altres ajuts: the AIRC Foundation (Associazione Italiana per la Ricerca contro il Cancro; Milan, Italy; projects #22053 to MGDP, #26216 to GC, and #21267 to MTV), PRIN 2017 (Ministry of University and Research, Italy; project 2017WXR7ZT to MGDP), Ricerca Finalizzata 2016 and 2018 (Italian Ministry of Health, Italy; projects RF2016-02364918 to MGDP and NET-2018-12365935 to MGDP, FP, and MTV), the Cariplo Foundation (Milan, Italy; project #2016-0860 to MGDP), and the Beat Leukemia Foundation (Milan, Italy; to MGDP).Background: Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. Methods: In this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Düsseldorf MDS registry (n=1185). Recruitment periods for these cohorts were between 1990 and 2016. The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort. The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts. Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R). This study is registered with ClinicalTrials.gov, NCT04889729. Findings: The study included 7792 (58·7%) men and 5492 (41·3%) women. 10 906 (82·1%) patients were White, and race was not reported for 2378 (17·9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p<0·0001 in both cohorts; DDX41 not available in the EuroMDS cohort vs p=0·0062 in the IWG-PM cohort; IDH2 p<0·0001 in EuroMDS vs p=0·042 in IWG-PM; TET2 p=0·031 vs p=0·035; U2AF1 p=0·033 vs p<0·0001) and mutations in two genes were enriched in women (DNMT3A p<0·0001 in EuroMDS vs p=0·011 in IWG-PM; TP53 p=0·030 vs p=0·037). Additionally, sex biases were observed in co-mutational pathways of founding genomic lesions (splicing-related genes, predominantly in men, p<0·0001 in both the EuroMDS and IWG-PM cohorts), in DNA methylation (predominantly in men, p=0·046 in EuroMDS vs p<0·0001 in IWG-PM), and TP53 mutational pathways (predominantly in women, p=0·0073 in EuroMDS vs p<0·0001 in IWG-PM). In the retrospective EuroMDS cohort, men had worse median overall survival (81·3 months, 95% CI 70·4-95·0 in men vs 123·5 months, 104·5-127·5 in women; hazard ratio [HR] 1·40, 95% CI 1·26-1·52; p<0·0001). This result was confirmed in the prospective validation cohorts (median overall survival was 54·7 months, 95% CI 52·4-59·1 in men vs 74·4 months, 69·3-81·2 in women; HR 1·30, 95% CI 1·23-1·35; p<0·0001 in the GEMSD MDS registry; 40·0 months, 95% CI 33·4-43·7 in men vs 54·2 months, 38·6-63·8 in women; HR 1·23, 95% CI 1·08-1·36; p<0·0001 in the Dusseldorf MDS registry). We developed new personalised prognostic tools that included sex information (the sex-informed prognostic scoring system and the sex-informed genomic scoring system). Sex maintained independent prognostic power in all prognostic systems; the highest performance was observed in the model that included both sex and genomic information. A five-to-five mapping between the IPSS-R and new score categories resulted in the re-stratification of 871 (43·0%) of 2025 patients from the EuroMDS cohort and 1003 (42·0%) of 2387 patients from the IWG-PM cohort by using the sex-informed prognostic scoring system, and of 1134 (56·0%) patients from the EuroMDS cohort and 1265 (53·0%) patients from the IWG-PM cohort by using the sex-informed genomic scoring system. We created a web portal that enables outcome predictions based on a sex-informed personalised approach. Interpretation: Our results suggest that a sex-informed approach can improve the personalised decision making process in patients with myelodysplastic syndromes and should be considered in the design of clinical trials including low-risk patients. Funding: European Union (Horizon 2020 and Transcan programs), Italian Association for Cancer Research, Italian Ministry of Health, and Italian Ministry of University and Research

Effects of the Therapeutic Armamentarium on Survival and Time to Next Treatment in CMML Subtypes: An International Analysis of 950 Cases Coordinated By the AGMT Study Group

Background Chronic myelomonocytic leukemia (CMML) is an ultrarare stem cell disorder defined by the presence of monocytosis (≥1.0 G/l, ≥10%). Depending on white blood cell (WBC) count, CMML can be divided into a myelodysplastic (MD) (WBC ≤13 G/l) and a myeloproliferative (MP) variant (WBC >13 G/l). Although hypomethylating agents (HMA) have been shown to prolong overall survival (OS) in MDS patients (pts) in prospective, randomized phase III trials, only 6-14 MD-CMML pts were included, and MP-CMML pts were excluded [Silverman 2002; Kantarjian 2006; Fenaux 2009]. EMA approval of azacitidine (AZA) in CMML is thus based on limited experience and restricted to MD-CMML with 10-29% bone marrow blasts (BMB), whereas decitabine (DAC) is not approved for treatment (trt) of CMML in the EU. Smaller analyses and single-arm trials of HMA in CMML exist [Wijermans 2008; Ades 2013; Pleyer 2014; Zeidan 2017; Duchmann 2018; Santini 2018; Coston 2019; Diamantopoulos 2019], but it is still unclear whether HMA provide a benefit in CMML (subgroups) compared with other trts. Aim Evaluate the impact of HMA and hydroxyurea (HU) trt on OS and time to next trt (TTNT). Methods Data were collected from 7 European study groups and 2 US MDS Centers of Excellence; database lock 27.05.19; Assign Data Management and Biostatistics GmbH performed statistical analyses with SAS® 9.3. Of 1657 CMML pts, only those who received trt (n=950), with documented WBC and BMB at 1st line, were included in these analyses (n=845, cohort 1). Pts were stratified according to the EMA approved AZA indication, and inclusion/exclusion criteria of the GFM-DAC-CMML trial assessing DAC +/- HU vs HU (NCT02214407) (diagnosis of CMML, no prior trt [except supportive care, erythropoietin or ≤6 weeks HU], WBC ≥13 G/l and ≥2 of the following: BMB ≥5%, clonal cytogenetic abnormality [other than -Y], hemoglobin 16 G/l, platelet count 2 excluded) (n=486; cohort 2). Results In cohort 1, pts receiving HMA 1st line (n=375) had longer OS (19.8 vs 16.3 months [mo], P=0.0102) and TTNT (13.2 vs 6.7 mo, P=0.0001) than pts treated with non-HMA 1st line (n=470). Survival benefit was longer when comparing pts who received HMA (any time) (AZA [n=442], DAC [n=37], both [n=27]) with those that never received HMA (never HMA; n=339) (23.0 vs 13.0 mo, P<0.0001). Median OS was longer for MD-CMML (n=294) vs MP-CMML pts (n=551) (25.5 vs 15.0 mo, P<0.0001). OS was shorter for all pts with 1st line HU preceding any 2nd line trt (9.4 vs 19.6 mo; P<0.0001; Fig A), for MP-CMML pts separately (8.7 vs 15.6 mo, P=0.0001), and for the subset with HU preceding 2nd line HMA (11.6 vs 19.8 mo; P=0.0016; Fig B). The following were significantly less common in pts treated with HMA vs those that were not: diagnosis in the pre-HMA era (8 vs 43%), MP-CMML (48 vs 66%), splenomegaly (27 vs 36%), ECOG≥2 (12 vs 24%), 1 trt line (43 vs 74%). WHO subtype, karyotype, transfusion dependence, LDH, CPSS score, AML transformation and therapy-related CMML were comparable between cohorts. HMA are not approved in the EU for CMML pts with <10% BMB. In this subgroup (n=588), median OS was longer for MD-CMML vs MP-CMML (28.1 vs 17.0 mo, P<0.0001) and for pts who received HMA vs never HMA (26.5 vs 14.8 mo, P=0.0003). Pts with <10% BMB and MD-CMML (n=206) did not seem to benefit from HMA vs non-HMA trt (median OS 28.4 vs 25.3 mo, P=0.9908; Fig C), whereas the MP-CMML subgroup (n=382) did (24.4 vs 13.0 mo, P<0.0001; Fig D). HMA are also unapproved in the EU for MP-CMML pts with ≥10% BMB. In pts with ≥10% BMB (n=257), median OS was longer for MD-CMML vs MP-CMML (19.4 vs 11.2 mo, P=0.0023) and for pts who received HMA vs never HMA (18.3 vs 7.0 mo, P<0.0001). Both MD-CMML (OS 21.7 vs 10.9 mo, p=0.0134; Fig E) and MP-CMML pts (15.6 vs 6.3 mo, P<0.0001; Fig F) benefited from HMA trt vs never HMA. In cohort 2, 1st line trts were HU (n=214), HMA (n=187) and others (n=85). Comparing HMA vs HU 1st line, median OS was 15.6 vs 14.5 mo (P=0.0307) and median TTNT was 8.8 vs 6.5 mo (P=0.0452; Fig G). OS and TTNT were comparable for HU vs other trts (Fig G). Similar observations were made in the larger cohort 1 (Fig H). Conclusions HMA show promising results with survival benefits of +11.4, +10.8 and +9.3 mo in pts with MP-CMML <10%, and MD- or MP-CMML ≥10% BMB. In MP-CMML pts fulfilling GFM-DAC-CMML trial inclusion criteria, survival and TTNT were longest in pts receiving HMA 1st line as compared to HU or other trts. Preceding HU portends poor prognosis (-10.2 mo). Disclosures Pleyer: Abbvie: Other: Advisory board; Novartis: Other: Advisory board; Inflection Point Biomedical Advisors: Other: Advisory board; Celgene: Other: Advisory board; Agios: Other: Advisory board. Leisch:Novartis: Honoraria, Other: Travel support; Bristol-Myers-Squibb: Honoraria; Celgene: Other: Travel support. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Kaivers:Jazz Pharmaceuticals: Other: Travel Support. Heibl:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Roche: Honoraria; Daiichi Sankyo: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Geissler:Novartis: Honoraria; Roche: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria; AOP: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Ratiopharm: Honoraria. Valent:Blueprint: Research Funding; Pfizer: Honoraria; Deciphera: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Medina de Almeida:Novartis: Speakers Bureau; Celgene: Speakers Bureau. Jerez:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Germing:Novartis: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Symeonidis:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sanz:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman - La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen - Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Membership on an entity's Board of Directors or advisory committees, Research Funding. Greil:Boehringer Ingelheim: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Janssen-Cilag: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding. OffLabel Disclosure: Azacitidine is not approved for the treatment of MP-CMML or CMML with <10% BM blasts, decitabine is not approved for treatment of CMML in the EU, hydroxyurea is not approved for the treatment of CMML in the EU