ALBERT

Description: Abstract 4031 Introduction: Because MDS are clinically heterogenous, classification and prognostic tools are essential to guide disease management decisions. The international, multicenter, phase 3 trial (AZA-001) enrolled 358 pts with higher-risk MDS as defined by French-American-British (FAB) criteria and International Prognostic Scoring System (IPSS) (Lancet Oncol 2009;10:223). The recent World Health Organization (WHO) classification of hematologic malignancies criteria (JCO 1999;17:3835) and the WHO Classification–Based Prognostic Scoring System (WPSS) (JCO 2007;25:3503) are increasingly being used in clinical practice. Aim: To evaluate whether overall survival (OS), hematologic improvement (HI), and transfusion independence (TI) in the subgroup of patients (pts) from AZA-001 who met WHO classification and WPSS criteria for higher-risk MDS are consistent with overall findings from AZA-001. Methods: According to protocol, AZA-001 enrolled pts with FAB-defined RAEB, RAEB-t, or CMML with more than 10% blasts, and IPSS Int-2 or High risk (Lancet Oncol 2009;10:223). Pts were randomized to AZA 75 mg/m2/d SC × 7d q 28d (n=179) or to a conventional care regimen (CCR; n=179), which included supportive care, low-dose ara-C, or intensive chemotherapy. This analysis included pts with WHO-defined RAEB-1 or RAEB-2 (pts with WHO-AML, CMML-1, CMML-2, or indeterminate classification were excluded) who had baseline WPSS risk of intermediate, high, or very high. Kaplan-Meier methods were used to estimate median OS and 95% CIs. HI and TI were defined by IWG-2000 criteria and results for AZA vs CCR were compared by Fisher's exact test. P values can only be used as a reference because these analyses were performed post hoc on a selected pt population that met WPSS criteria (40% of all AZA-001 pts did not meet these criteria and were excluded from analyses). Results: Overall, 215 pts in AZA-001 (106 AZA, 109 CCR) met a WHO classification for higher-risk MDS (RAEB-1: 13 AZA, 16 CCR; RAEB-2: 93 AZA, 93 CCR). Baseline WPSS risk was intermediate (1 AZA pt), high (66 AZA, 59 CCR), or very high (39 AZA, 50 CCR), with proportionately more CCR pts at very high risk than AZA pts (46% vs 37%, respectively). Median age was 68 years (range 42 – 83) in the AZA group and 70 years (range 38 – 88) in the CCR group. At baseline, 63% of both the AZA and CCR cohorts were RBC transfusion-dependent and 19% and 15%, respectively, were platelet transfusion dependent. Median OS was 26.3 months (95%CI: 17.2, not reached) with AZA vs 13.9 months (95%CI: 8.9, 18.8) with CCR, (log-rank p=0.016) (Figure). Rates of any HI and major erythroid and platelet lineage responses were better with AZA vs CCR (Table). RBC TI was also more frequent with AZA than with CCR (Table), but the platelet TI rate did not differ between treatment groups. Conclusion: These results are highly consistent with reported OS and hematological response outcomes for the entire AZA-001 population of higher-risk MDS pts classified by FAB and IPSS risk. The efficacy of AZA is consistently superior to CCR in pts with higher-risk MDS, irrespective of the classification and prognostic criteria used to describe them. Disclosures: Gattermann: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sanz:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Giagounidis:Celgene: Consultancy, Honoraria. Seymour:Celgene: Honoraria, Speakers Bureau. Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Merck: Honoraria; Cephalon: Honoraria; Novartis: Honoraria; J&J: Honoraria. Santini:Celgene: Honoraria. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Ramos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lucy:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment. Silverman:Celgene: Honoraria.

Description: Abstract 219 Chronic GvHD disease (cGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant. Unrelated cord blood transplant (UCBT) is associated with a reduced incidence of chronic GvHD when compared to other sources of stem cells, however risk factors analysis for incidence is scarce in the literature. We retrospectively analyzed 792 patients, 447 children (age6Gy in 30%), RIC in 21%. Busulphan-based conditioning was used in 50% and ATG was added in 81% of cases. CsA+steroid was the most common GvHD prophylaxis (49%); CsA+mycophenolate mofetil was used in combination in 46% of adults. Eleven percent of units were HLA-identical (antigen level for HLA-A and B, allelic for DRB1), while 39% and 50% had 1 or 2–3 mismatches, respectively. Median total nucleated cell (TNC) infused was 4.5−107/kg. Median follow-up was 39 months (3-158). Cumulative incidence (CI) of cGvHD at 2 years in the whole population was 31±2% (n=251). Chronic GvHD was extensive in 53% of children and adults. Regarding cGvHD organ involvement, skin and gastro-intestinal tract were the most frequent organ affected, 64% and 38% of cases respectively followed by liver (15%) and lung involvement (7%). Eighty-six percent of patients were treated with systemic therapy. Out of 251 patients who developed cGvHD, 137 had previously acute GvHD (77 out of 113 children and 60 out of 138 adults). Factors associated with a decreased incidence of cGvHD were: 0–1 HLA mismatched units (p

Description: Abstract 2933 Introduction: Survival analysis need of large period of time for getting results. Survival subrogates variables provide with earlier data for clinical decisions. The current treatment paradigm is nowadays how the quality of the different treatment responses impact in patient's survival with the new treatment options. Azacitidine (AZA) is a hypomethilating agent which was available for clinical trials or compassionate use in Spain before receiving it marketing authorization in May 2009. We present the final analysis from those patients diagnosed with mielodysplastic syndromes (MDS) or acute myeloid leukemia (AML) selected from a longitudinal, multicenter Spanish patient registry. Materials and Methods: This analysis retrospectively gathers clinical data about the treatment, disease progression and survival of patients with MDS or AML who had received AZA 75mg/m2 in compassionate use conditions, with a dosage regimen documented. Three different dosage regimens at the beginning of each 28-day cycle were used; group A: days 1–5 (M-F)/group B: days 1–5, 8–9 (M-F, M-Tu)/group C: days 1–7 (M-Su). Survival analysis was stratified by patients' basal conditions, dosage schedule and best response after 4th and 6th cycles. Results: Data were collected from 200 patients with MDS or AML according to the WHO diagnostic criteria. Basal data, effectiveness results and data from haematological tolerance are mainly summarized in table 1. Median survival time was 706 days (95% CI 588–1093) in those patients who achieved a response versus 225 days (95% CI 156–319) in those who did not. Survival analysis showed differences based on the best response achieved (p

Description: Abstract 1867 Background: The European LeukemiaNet MDS Registry programme is the largest and most comprehensive prospective population-based registry of ‘low-risk’ MDS patients followed from diagnosis. Objective: The primary objective of this study is to describe the demographics and the disease-management of newly diagnosed MDS patients within IPSS low and intermediate-1 categories. Methods: The project recruits patients from 107 sites in 11 countries, ranging from 2–25 sites per country and including a high proportion of non-University centres in small cities. Consecutive eligible adult patients are registered within 3 months of diagnosis. Local diagnosis is accepted and a large dataset is collected including laboratory data, clinical information (including co-morbidity and concomitant medication) plus health utility (EQ-5D). Data are entered via a web portal and are source verified by study monitoring visits to sites. Results: As of July 2010, 828 patients are registered; data are presented for the first 800 patients. Recruitment is highest from France (n=237) then UK (104), Greece (99), Spain (92), and Sweden (73). Median age is 74.2 yrs (range 18.7–95.3) and from the four largest recruiting countries is 74.6–77.1 yrs. Sixty one percent of patients are male. Twenty patients are non-Caucasian (n=763). Body mass index is overweight (WHO definition) in 43.4% pts and obese in 18.3%, comparable to WHO data for the general adult population (http://apps.who.int/bmi/index.jsp). RCMD is the largest WHO subgroup (34%), followed by RARS (19%), RA (18.4%), RAEB-1 (12.5%), del5q (5.4%), MDS-U (3.5%) and RAEB-2 (0.5%). All WHO subgroups have male predominance except del5q with a striking female excess (79%). IPSS score (n=743) is 0 (52.3%), 0.5 (33.2%), and 1 (14.4%). 84.5% patients have IPSS ‘good’ cytogenetics. 19% patients have 0 cytopenias, 53% 1 cytopenia, 20% 2 cytopenias and 8% 3 cytopenias. WPSS category (with transfusion dependence assessed at time of registration, n=727) is Very Low (35.5%), Low (39.5%), Intermediate (21%), High (4%). Bone marrow features: mean no. of dysplastic lineages = 1.9, bone marrow ring sideroblasts percent = 0 (60% pts),

Description: Background Therapy-related Myelodysplastic Syndromes (t-MDS) are those MDS occurring after cytotoxic and/or radiation therapy administered for a prior neoplastic or non-neoplastic disorder. Their prognosis is generally very poor. The commonly used risk prognostic models for MDS (IPSS and IPSS-R) are not validated in this entity as they were developed after the exclusion of therapy-related cases (Greenberg et al. Blood 1997; Greenberg et al. Blood 2012). Aims The main aims of this study are: a) to report clinical findings and overall survival on 233 patients with t-MDS, and to compare them with a large series of de novo cases; b) to test if IPSS-R is applicable to t-MDS patients. Patients and methods The study is based on the Spanish Registry for MDS, a retrospective database that includes more than 10000 cases. The investigators were asked to fill in a questionnaire regarding prior disease (PD) and prior therapy in those cases reported to be t-MDS. Herein are described the clinical features and overall survival of the first 233 cases with the required information, and compared with patients with de novo MDS from a single center series (n=725). Log Rank test was applied to asses IPSS-R in t-MDS group. Results The 233 reported patients were diagnosed between January 1993 and February 2014. The series includes 104 women (44,6%) and 129 men (55,4%). One hundred and two patients (43.9%) had a primary hematologic malignancy, 119 (51%) had a solid tumor, and 12 (5.1%) received cytotoxic therapy for autoimmune disorders. Ninety eight patients (42.6%) received only chemotherapy (CT), 45 (19.6%) received only radiotherapy (RT), 44 (19.1%) received combined modality treatment (CMT), and 43 (18.6%) received an autologous stem cell transplantation (ASCT). The median time of latency between PD and diagnosis in t-MDS group was 4.56 years (range: 0.03-29.63) in patients previously treated with CT or CMT, significantly lower than the observed after RT (8.54; range 0.83-23.02) or ASCT (8.64; range 2.87-28.32) groups (p=0.023 and p Disclosures No relevant conflicts of interest to declare.

Description: Monosomy 7 is the second commonest abnormality in myelodysplastic syndrome (MDS). Recent studies (Cordoba et al 2012, Schanz et al 2012) have shown partial loss [del(7q)] of the chromosome (chr) is associated with better prognosis than total loss (-7). However it is still unclear if the biogenesis of these 2 abnormalities are separate or step wise progression of del(7q) to -7. Moreover monosomy 7 (-7) often occurs in the presence of other cytogenetic abnormalities which further adversely impacts the prognosis. We designed a multicenter study to describe and compare clinical features, bone marrow characteristics, genetic profile and outcome of a large population of MDS patients with del(7q) or -7 as sole cytogenetic abnormality. We retrospectively analysed 224 MDS patients who presented at diagnosis with the loss of chr. 7 as isolated cytogenetic abnormality or acquired it during follow up. We also performed a deep targeted mutational screen of the 24 commonest mutated genes in MDS. Patients were included from the King’s College Hospital of London (n=75), the Spanish MDS group (n=107), the University of Medicine of Göttingen (n=35) and the "Città della Salute e della Scienza" hospital of Turin (n=11). Fifty-five patients presented with isolated del(7q) and 169 with isolated -7. Median age at diagnosis was 69 and 64 years old in the two groups, respectively (p n.s.). According to WHO classification 18 patients had refractory anemia (RA), 3 RA with ring sideroblasts (RARS), 61 refractory cytopenia with multilineage dysplasia (RCMD), 42 RA with exces of blasts type 1 (RAEB-1), 53 RAEB-2, 25 MDS/MPN (MDS/Myeloproliferative neoplasm) and 8 MDS unclassified. Fourteen patients with bone marrow blasts percentage between 20 and 30% were also included. MDS with excess of blasts type 1 or 2 were more frequent in the del(7q) group (56% vs. 42%) whereas MDS/MPN prevailed in the -7 group (14% vs. 4%), p=0.049. At diagnosis, del(7q) patients had a higher platelet count whereas there were no differences in neutrophils count and haemoglobin between the two groups; despite similar basal haemoglobin levels a higher number of patients with del(7q) was transfusion dependent (52% vs. 32%, p=0.015). Regarding the mutational status, we have so far analysed 55 patients, 45 with del(7q) and 10 with -7. Overall we found 118 different allele variants (37 previously described as somatic mutations in cancer) across 24 myeloid genes commonly mutated in MDS. Sixty-four percent of patients had 1 or more previously described mutations, with a range of 1 to 6 mutations per patient (median 1). The genes involved in epigenetic modification were the most commonly mutated (in 36% of patients). Genes encoding for spliceosome components, signalling factors, transcriptional factors and STAG2 were mutated in 29%, 22%, 16% and 2% of patients respectively. There were no differences in mutation distribution between patients with -7 and patients with del(7q). Median survival for the whole cohort was 23 months and was significantly affected by WHO diagnosis and, interestingly, by bone marrow cellularity: patients with hypocellular marrow at diagnosis had a better outcome with a median survival of 38 months, compared to 26 and 23 for normocellular and hypercellular marrow respectively (p= 0.031). Patients with isolated del(7q) had a trend towards longer survival than patients with -7 (32 vs. 23 months), but this difference was not statistically significant. Overall 30% of patients were treated with azacytidine, 20% with intensive chemotherapy, 5% with immunosuppressive drugs and 5% with other therapies, including lenalidomide; 46 patients (20.5%) underwent allogeneic transplantation and this significantly impacted on survival (median survival 35 months for transplanted patients vs. 22 for not-transplanted ones, p=0.002), regardless of induction treatment or cytogenetic status. In conclusion, although patients with del(7q) had worse disease characteristics (excess of blasts and transfusion dependence), they showed a trend towards a better survival than those with -7. Preliminary data on the genetic profile showed a prevalence of mutations in the genes involved in epigenetic regulation with no significant differences between the partial and total loss of chr.7. Disclosures No relevant conflicts of interest to declare.

Description: Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm characterized by a highly variable clinical course. Based on clinical, hematologic and cytogenetic parameters, we previously developed a CMML-specific Prognostic Scoring System (CPSS) that stratifies patients into 4 different risk groups [Blood 2013;121:3005-15]. Recently, recurrent somatic mutations have been identified in CMML, and preliminary evidence suggests that selected mutated genes may provide useful prognostic information. In this study, we performed a comprehensive mutation analysis of genes implicated in myeloid malignancies in a large and well characterized cohort of CMML patients with the aim to dissect relationships between genotype and disease phenotype and to integrate somatic mutations into a clinical/molecular prognostic model. Thirty-eight genes were analyzed by high throughput sequencing (Illumina MiSeq, San Diego, CA) in a cohort of 199 CMML patients (pts) diagnosed according to WHO classification, and in 12 pts with monocytosis not fulfilling WHO diagnostic criteria. Myelodysplastic and myeloproliferative subtypes (CMML-MD and CMML-MP, respectively) were defined according to FAB criteria. Least absolute shrinkage and selection operator (Lasso) and Cox proportional hazards methods were adopted to select and weight variables for prognostic scoring. Ninety-three percent of pts showed at least one somatic mutation (median number per patient: 2, range 0-6). The most frequently mutated genes were TET2 (44%), SRSF2 (43%), ASXL1 (34%), KRAS (11%), NRAS (10%), CUX1 (10%), CBL (9%), RUNX1 (7%), SETBP1 (7%), JAK2 (6%), SF3B1 (6%), and U2AF1 (5%). A significant association was found between mutations in TET2 and RNA splicing factors (P=.037), 42 of 199 CMML pts (21%) showing co-occurrence of TET2 and SRSF2 mutations. Mutations in genes involved in signaling were significantly associated with CMML-MP (P=.002), whereas SF3B1 mutations were associated with CMML-MD (P=.024). The number of mutations per patient inversely correlated with overall survival (OS) (HR=1.32, P=.021). In univariate analysis, mutations in ASXL1 (HR=2.31, P=.026) , RUNX1 (HR=3.53, P=.02) and SETBP1 (HR=3.85, P=.005) significantly affected OS. Focusing the analysis on disease subtype, ASXL1 mutations significantly affected survival in CMML-MD (HR=3.45, P=.025), whereas CUX1 and SETBP1 had a significant prognostic value in CMML-MP (HR=4.33, P=.013 and HR=4.4, P=.025, respectively). In order to investigate the additive value of somatic mutations to current prognostic assessment, we first fitted a Lasso Cox regression model for genetic variable selection. The selected variables were then included in an unpenalized Cox regression in order to obtain unbiased coefficients. The statistically significant variables were CPSS-specific cytogenetic risk groups (HR=2.49, P=.001), mutations in ASXL1 (HR=2.77, P=.018), RUNX1 (HR=5.39, P=.009) and SETBP1 (HR=3.96, P=.013). Based on regression coefficients, we defined a CMML-specific genetic risk score that was able to identify three different groups (Low risk: normal karyotype and –Y; Intermediate: other abnormalities, mutations in ASXL1; High: trisomy 8, complex karyotype, mutations in RUNX1 or SETBP1), with significantly different OS (HR=2.24, P

Description: Abstract 1856 Background: Sixty to 80% of patients (pts) with higher-risk myelodysplastic syndromes (MDS) require RBC transfusions to manage symptoms of anemia. Transfusion-associated complications include iron overload, transmitted infections, alloimmunization, and decreased overall survival (OS) (Cancer 2006;106:2087; JCO 2005;23:7594). The phase 3 AZA-001 study compared azacitidine (AZA) with conventional care regimens (CCR) in pts with higher-risk MDS (Lancet Oncol 2009;10:223). For all pts randomized to AZA, the reported median number of RBC transfusion events in the 56-day pre-randomization baseline (BL) period was relatively low (1.0, range 0 – 10), since 68/179 (38%) AZA-treated pts required no RBC transfusions (Haematologica 2009:Abstract 0813). However, pretreatment transfusion burden in the 111 RBC transfusion-dependent (TD) pts treated with AZA was substantial in many cases. It is unknown to what extent pts with higher RBC transfusion requirements at BL achieve transfusion independence (TI) and derive an OS benefit from AZA treatment. Aim: To assess OS in pts with higher-risk MDS treated with AZA in the AZA-001 study who were RBC TD at BL, based on pretreatment transfusion needs and posttreatment transfusion status. Methods: In AZA-001, 179 pts with higher-risk MDS (FAB-defined RAEB, RAEB-t, or CMML with 〉10% blasts, and IPSS risk Int-2 or High) were randomized to AZA (75 mg/m2/d SC × 7d q 28d). Of these pts, 111 (62%) were RBC TD at BL and 50 pts (45%) achieved TI during AZA treatment (Lancet Oncol, 2009;10:223). (Because so few pts who received CCR became TI on treatment [13/114, 11%], this analysis included only AZA-treated pts.) Erythropoietic stimulating agents were not permitted on study. BL RBC TD was defined as receiving ≥1 transfusion during the 56-day pre-randomization BL period, and per IWG 2000 criteria, TI on treatment required an RBC transfusion-free period ≥56 consecutive days. BL characteristics of pts who remained TD and of pts who achieved TI were evaluated and compared descriptively. Median OS was estimated using Kaplan-Meier (KM) methods for pts with pretreatment RBC transfusion burden of ≥1 (ie, all pts in the analysis), 1, or ≥2 transfusions (similar to IWG 2006 criteria for TD). The KM OS distributions for the on-treatment TI and TD groups were compared within in each cohort defined by pre-treatment RBC transfusion burden using the log-rank test. Results: Among the 111 AZA-treated pts who were RBC TD at BL, median age was 70 yrs (range 42 – 83), 77% were male, and 91% had ECOG performance scores of 0–1. Most pts (84/111, 76%) required ≥2 RBC transfusions in the 56-day pre-randomization BL period (Table). Median number of RBC transfusions at BL was 2 (range 1 – 10) in pts who achieved TI, and 3 (range 1 – 9) in pts who remained TD. Of pts who required ≥2 RBC transfusions at BL, 35 (42%) achieved TI. One-third (7/21) of pts with the highest RBC transfusion requirements at BL (≥5 transfusions) achieved TI during AZA treatment. Median OS was improved 3-fold for all cohorts of pts who achieved RBC TI with AZA, regardless of RBC transfusion burden at BL, compared with median OS in pts who remained TD (log-rank p

Description: Key Points Risk assessment is crucial in patients with CMML because survival may range from a few months to several years. Integrating clinical features, morphology, and genetic lesions significantly improves risk stratification in CMML.

Description: Background: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adult populations include several rare hematologic malignancies with similar clinicopathologic features that have a significant impact on patient QOL and lead to increased risk of infection, hemorrhage, anemia and transformation to AML (e.g. CMML, aCML, MDS/MPN-RST, and MDS/MPN-U). The only approved therapies for any of the MDS/MPNs are DNA methyltransferase inhibitors (DNMTis) for patients (pts) with CMML. Due to both the rarity and the heterogeneity of MDS/MPNs, it has been challenging to study in dedicated, prospective studies and thus refining treatment strategies has been difficult and optimal salvage treatments in pts who fail DNMTis have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation providing the framework for clinical trials for MDS/MPN, and explore clinical-pathologic biomarkers. Study Design and Methods: The first study within ABNL-MARRO, ABNL MARRO 001 (AM-001), is an open label, randomized phase 1-2 study that will test 3 novel oral treatment combinations in MDS/MPNs, with each of 3 treatment arms including a novel targeted agent and ASTX727, a fixed dose combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine oral bioavailability. The novel agents combined with ASTX727 are: a selective JAK1 inhibitor itacitinib, pan PIM inhibitor INCB053914 and LSD1 inhibitor, INCB059872. Each combination will be tested first in a safety run-in (Phase 1b) to determine the RP2D and schedule of each combination therapy using a 3+3 de-escalation design, and a maximum of four dose decrements will be allowed. After the RP2D and schedule has been determined for a given novel drug combination, efficacy of that combination therapy in MDS/MPN pts will then be evaluated in phase 2 using a Simon's Two-Stage design to allow early discontinuation of any futile treatment regimen and to pursue potentially beneficial combinations in larger cohorts of pts. While each of the targeted agents either has undergone or is currently undergoing safety testing in combination with the DNMTi in myeloid diseases, clear rates of expected responses in MDS/MPN are not known. Retrospective studies of DAC or AZA reveal overall response rates (ORR) from 10-56% in CMML (Helbig et al, 2019; Duchman et al, 2018; Coston et al, 2019). The ORR from the ASTX727 single agent phase I study was 30%, but this included only 14% CMML (remainder MDS pts) and 45% of pts with previous treatment with AZA or DAC (Savona et al, 2019). Finally, and importantly, there are insufficient clinical trial data available for pts non-CMML MDS/MPN syndromes. Thus, the criteria for the Simon's Two-Stage design for each arm are based on best estimation from results of above studies. Accordingly, the null hypothesis that the ORR, as per the MDS/MPN Proposed Response Criteria (Savona et al, 2015; combined CR+MR+PR+Clinical benefit - CB), is 35%, will be tested against a one-sided alternative. In the first stage, 14 DNMTI-treatment naïve (TN) pts will be accrued in each AM-001 Arm and will receive treatment at the RP2D and schedule of the novel targeted agent and of ASTX727, as determined in the phase 1. If there are 5 or fewer responses in these 14 pts before the 7th cycle of therapy, the Arm will be stopped for futility. Otherwise, 30 additional pts (including both TN subjects and subjects relapsed after/refractory to other DNMTI-containing therapies) will be accrued for a total of 44. The null hypothesis will be rejected if 21 or more responses are observed in 44 pts before the 7th cycle of therapy. This design yields a type I error rate of 0.05 and power of 80% when the true response rate is 55%. The probability of early termination and expected sample size of any arm is 64% and 25 pts, respectively, assuming low (35% RR) efficacy Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will establish the ABNL MARRO infrastructure that leverages the expertise of the MDS/MPN international working group (IWG) for future prospective studies; will forge innovative scientific research that will improve our understanding of pathogenetic etiologies; and will inform the clinical application of diagnosis, risk stratification tools, and response assessments in MDS/MPNs. Disclosures Savona: AbbVie: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties. Fenaux:Aprea: Research Funding; Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Padron:Incyte: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Sanz: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; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Santini:Menarini: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Acceleron: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: 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; Johnson & Johnson: Honoraria. OffLabel Disclosure: ASTX727, LSD1 inh, PIM inh, JAK1 inh in MDS/MPN