Padron, Eric

Introduction: Patient-reported outcomes (PROs) such as quality of life (QOL) are variably affected in patients with myelodysplastic syndromes (MDS), but the heterogeneous composition of disease states grouped together as "MDS" increases the difficulty of assessing and understanding these outcomes. Moreover, little is known about the potential relationship between QOL and frailty in this population. Methods: The NHLBI MDS Natural History Study (NCT02775383) is a prospective cohort enrolling patients undergoing diagnostic work up for suspected MDS or MDS/myeloproliferative neoplasms (MPNs) in the setting of cytopenias. Untreated participants undergo bone marrow assessment with centralized histopathology review at enrollment for assignment into subcategories for longitudinal follow-up: MDS, MDS/MPN, ICUS, AML (<30% blasts), and "At-Risk" (cases with sub-threshold dysplasia or select karyotypic or genetic mutations). PRO and frailty data are collected at enrollment and every six months thereafter. PRO instruments include MDS-specific (QUALMS) and general (FACT-G, PROMIS Fatigue Short Form 7a, EQ-5D-5L) instruments, and a measure of frailty (VES-13). While no frailty instrument alone has been shown to be a substitute for comprehensive geriatric assessment, VES-13 has been successfully used in cancer-related studies for basic screening, where a score of 3 or more is considered frail (vulnerable). An analysis of variance (ANOVA) was used for the overall comparisons of mean baseline scores between diagnostic categories. Pairwise comparisons of scores between diagnostic categories and vulnerability subgroups were performed via two-sample t-tests. Results : Of 835 participants assessed for eligibility, 369 (44%) were classified as MDS, MDS/MPN, AML, ICUS or At-Risk, and further evaluated. Mean age was 72 years (standard deviation (SD)=10.7) and 68% were male. Mean baseline scores on the PRO measures are compared between diagnostic categories in the Table; scores did not differ significantly across categories. In particular, no significant differences were found between MDS and the other diagnostic categories. ICUS had similar QOL scores to MDS and MDS/MPN (e.g., means (SD) on EQ-5D-5L of 74.1 (17.8) in ICUS and 70.8 (19.4) in MDS, p=0.348) but had significantly higher scores than those for AML on EQ-5D-5L (60.7 (28.4), p=0.031). For the 216 participants with diagnostically-confirmed MDS, QOL impairment was similar to that routinely seen in other cancers; for example, the mean total FACT-G was 81.8 (SD=15.9), similar to localized breast cancer (82.4, SD=16.2), localized colorectal cancer (79.6, SD=16.1), and lung cancer with no current evidence of disease (82.6, SD=15.5; comparison means from Pearlman, Cancer, 2014). For frail/vulnerable participants with MDS or MDS/MPN (N=87), the most common reasons for vulnerability were age ≥75 years (68%), overall rating of health as poor or fair (62%), and difficulty with prolonged physical activity (90%) such as walking a quarter mile (75%) or doing heavy housework (70%). A minority also were vulnerable due to requiring help with instrumental activities of daily living (iADLS) such as shopping (28%) or managing money (16%). Mean QOL scores were compared between vulnerability subgroups (Figure). Vulnerable participants pooled over all diagnostic categories had significantly worse PROs than non-vulnerable participants for all measures (p<0.001). In particular, vulnerable MDS participants scored significantly worse on the QUALMS (mean 64.4, SD=13.4) vs. non-vulnerable MDS participants (mean 72.7, SD=13.3), p<0.001. Conclusions: Participants in our cohort with histologically-confirmed MDS-even low-grade MDS-had similar impairments in PROs as those with other cancers. Among those with histologically-confirmed MDS, vulnerable participants had significantly worse QOL on many measures compared to non-vulnerable participants, suggesting that this domain of function be specifically assessed in clinic. Moreover, while a "gestalt" of frailty may be inferred by observing how patients present and move in the office, these data suggest that other contributing domains, such as difficulty with prolonged physical activity and iADLs, should be evaluated explicitly. Disclosures Foran: H3Biosciences: Research Funding; Aptose: Research Funding; Kura Oncology: Research Funding; Takeda: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Xencor: Research Funding; Agios: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Actinium: Research Funding; Aprea: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Trillium: Research Funding; Revolution Medicine: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Padron:Incyte: Research Funding; Kura: Research Funding; Novartis: Honoraria; BMS: Research Funding. Sekeres:BMS: 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; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction: The NHLBI National MDS Study (NCT02775383) is a prospective cohort study conducted at 92 community hospitals and 29 academic centers. It enrolls patients undergoing work up for suspected MDS to understand the genetic, epigenetic, and biological factors associated with the initiation and progression of the disease. Previously untreated, cytopenic participants undergo both local and centralized pathology review and are assigned a diagnosis, including MDS, MDS/MPN, AML with blasts < 30%, and "Other". Emerging data suggests that Next Generation Sequencing (NGS), along with cytogenetics and clinical variables, may improve MDS diagnostic precision. Given that our study relies on central review (with additional tertiary pathology review used to adjudicate disagreements), we examined whether targeted gene sequencing data could be used to increase the agreement between local and central pathologic diagnosis of MDS vs. Other. Methods: Peripheral blood and bone marrow (BM) biopsy specimens from cytopenic patients, along with clinical history, CBC, and other results including karyotyping, FISH and pathology reports from local pathologists were reviewed by central pathologists. The updated 2016 WHO classifications were used to diagnose MDS. Targeted exon sequencing of 96 genes was performed using BM specimens. A subset of 648 individuals that were classified as MDS (n=212) or Other (n=436, including 90 CCUS and 89 individuals with other cancers) by pathology assessments were selected. A mean coverage of 1,317X was achieved and variants had a minimum variant allele frequency (VAF) of 2% (except FLT3). Variants for 596 subjects were manually reviewed to retain likely disease-causing variants to build a binary classifier (MDS vs. Other) using the maximum VAF per gene as input (Figure 1). Subjects diagnosed with MDS or Other by both central and local pathology were used for training, validation, and testing, and were considered "gold standard" (GS) cases (n=546). These subjects were split into 4 random groups with equal proportions of MDS cases. 75% of the GS cases were used to train and validate lasso-regularized logistic regression models using 3-fold cross validation. ROC curve analysis was carried out using the remaining 25% of GS cases (Test Set 1) on the best model to identify an optimal probability cut off point for classifying subjects as MDS. Model performance was then tested on 50 subjects for which the central and local pathology diagnosis disagreed (Test Set 2), as well as on 52 additional subjects irrespective of agreement (Test Set 3). Results : The best performing logistic regression model retained 7 genes as most informative in a discriminating diagnosis of MDS from Other based on their VAFs, in order of impact: TP53, SF3B1, U2AF1, ASXL1, TET2,STAG2, and SRSF2. We used this model to assign probabilities for each of the subjects in Test Set 1 and to estimate the performance using ROC analysis (Figure 1), resulting in a high area under the curve (AUC) of 0.89. We chose a probability cut-off of ≥0.17, being associated with a high percentage of correct classification of MDS with a sensitivity and specificity of 0.90 and 0.81, respectively. Among the cohort of 50 subjects with a discordant local and central pathology diagnosis (Test Set 2), the classifier accurately reassigned 37 subjects (accuracy = 74%) from the local to the central pathology. The blinded tertiary pathology reviewer agreed with central in all Test Set 2 cases. This included 24/34 MDS cases that had been labeled as Other by local pathology (positive predictive value [PPV]=0.89). 3/16 final pathology-classified Other cases were mis-classified as MDS by the local pathologist (negative predictive value [NPV] = 0.57). Next, we assessed the ability of the model to predict MDS vs. Other for 52 additional independent subjects using the third pathologist's diagnosis to break any ties (Test Set 3). The classifier correctly predicted 15/21 MDS cases (PPV=0.83) and misclassified 6/31 Others as MDS (NPV=0.82). The overall accuracy was 83%. Conclusions: We identified that VAFs for 7 genes can correctly re-classify subjects as either MDS or Other in 74% of cases that were misclassified between local and central pathology review. Further assessment on an independent cohort showed an accuracy of 83% of the model. Taken together, these data suggest that complementing pathology reviews with targeted sequencing of 7 genes could improve MDS diagnosis. Disclosures Lindsley: MedImmune: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Bluebird Bio: Consultancy; Takeda Pharmaceuticals: Consultancy. Bejar:Aptose Biosciences: Current Employment; AbbVie/Genentech: Honoraria; Astex/Otsuka: Honoraria; Takeda: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Forty-Seven/Gilead: Honoraria; Genoptix/NeoGenomics: Honoraria. DeZern:MEI: Consultancy; Astex: Research Funding; Abbvie: Consultancy; Celgene: Consultancy, Honoraria. Foran:H3Biosciences: Research Funding; Aptose: Research Funding; Kura Oncology: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Revolution Medicine: Consultancy; Xencor: Research Funding; Agios: Honoraria, Research Funding; Aprea: Research Funding; Actinium: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Komrokji:Acceleron: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Agios: Speakers Bureau; BMS: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Geron: Honoraria; Novartis: Honoraria. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Padron:Novartis: Honoraria; BMS: Research Funding; Incyte: Research Funding; Kura: Research Funding. Starczynowski:Captor Therapeutics: Consultancy; Tolero Therapeutics: Research Funding; Kurome Therapeutics: Consultancy, Current equity holder in private company, Research Funding. Sekeres:BMS: Consultancy; Takeda/Millenium: Consultancy; Pfizer: Consultancy.

In this phase 1 trial, inhibition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was associated with clinically meaningful responses in 5 of 15 patients with relapsed or refractory chronic myelomonocytic leukemia (CMML). Preliminary data suggest that this approach may be tractable in CMML bearing activating NRAS mutations.

Introduction: Myelodysplastic syndromes (MDS) are a heterogenous group of blood disorders defined by peripheral cytopenia(s), bone marrow failure, morphological dysplasia, and risk of progression. To understand the genetic, epigenetic and biological factors associated with the initiation and progression of MDS, NHLBI created the National MDS Study (NCT02775383). This is a prospective cohort study conducted at 92 community hospitals and 29 academic centers enrolling patients undergoing diagnostic work up for suspected MDS or MDS/myeloproliferative neoplasm (MPN) overlap syndrome. Eligible patients have yet to receive any therapy directed at their cytopenias. Previously untreated cytopenic participants underwent centralized histopathology and data review at the time of enrollment for assignment into distinct subcategories: MDS, MDS/MPN overlap, AML, and Other. Targeted exon sequencing of 96 genes was performed using marrow specimens from the first 300 consecutive individuals in the study. Here we report the genetic mutations for this cohort. Methods: NovaSeq 6000 was used for deep sequencing at a mean coverage of 1,286X and mean breadth (bases covered at ≥100X) of 99.8%. Reads were aligned against build GRCh38 using BWA-MEM, and VarScan2 was used to detect SNVs and INDELS. Variants were filtered for those with an allele base quality of >25 in combination with rule-based and manual review criteria. Subjects in the Other category without an identified malignancy were considered clonal cytopenias of undetermined significance (CCUS) when a mutation or a clonal cytogenetic change was present. Fisher's exact and Wilcoxon rank sum tests in combination with Bonferroni correction were applied to compare groups. Results : A total of 350 putative nonsynonymous pathogenic variants in 36 genes with an allele frequency of >.05 were identified across 150 patients (50%). At least one variant was noted in the following proportion of individuals: 61/72 (85%) with MDS, 13/13 (100%) with MDS/MPN, 15/17 (88%) with AML, and 61/198 (31%) in the Other category, of which 48 were CCUS and 13 were other cancers. Two CCUS patients only had a cytogenetic abnormality. Table 1 shows the distribution of variants in each subcategory of patients for the most commonly mutated genes in our cohort of 300 subjects. Mutations in these genes were enriched in specific groups: SF3B1, STAG2,TP53, and ASXL1 in MDS; TET2 in MDS/MPN; and IDH2 and TP53 in AML (one-sided p<0.0012). None were enriched in the Other group. Within the CCUS subset, 21 genes were mutated, with 37 of 50 (74%) patients having a mutation in TET2, ASXL1, SRSF2, SF3B1, or DNMT3A. The heatmap presented in Figure 1 summarizes variants by subject and allele frequency. Pair-wise comparisons of baseline characteristics of subjects between MDS, MDS/MPN, AML, or CCUS groups revealed no significant differences for age or sex. The CCUS group had significantly higher hemoglobins than the MDS group with median hemoglobin levels of 11.35 and 9.40 g/dL, respectively (p<0.0084). AML had significantly lower platelets compared to all other groups (median of 53 vs. > 110x109/L , respectively, p<0.0084). All groups significantly differed in their median ANC with AML having the lowest (0.8x109/L), followed by MDS (1.5x109/L), CCUS (2.45x109/L), and MDS/MPN overlap (5.95x109/L) (p<0.0084). There was no difference in the median number of variants per patient between groups or correlation with age (rs=0.11, p=0.18). The maximum variant allele frequency (maxVAF) per patient was highest in the MDS/MPN group (median = 0.42, range = 0.38-0.91) and lowest in the CCUS group (median = 0.37, range =0.06-0.98) with the MDS/MPN group having a significantly higher maxVAF compared to the MDS and the CCUS groups (p<0.0084). The proportions of subjects with mutations was similar for those who had abnormal (92% [34/37]) and normal (91% [80/88]) cytogenetics. Conclusions: Incorporation of gene-panel sequencing in the comprehensive evaluation of 300 adult cytopenic patients identified half of the cohort with potentially pathogenic variants. Ultimately, a diagnosis of CCUS was possible in 48 of 183 subjects (26%) not diagnosed with MDS, MDS/MPN overlap syndrome, AML, other cancers or clonal cytogenetics. This study continues to serially bank samples from patients with CCUS, in addition to MDS, MDS/MPN, and ICUS, with the goal to better understand the natural history of these diseases and their progression. Disclosures Lindsley: Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding. Bejar:Celgene: Consultancy; Takeda Pharmaceuticals: Research Funding; AbbVie/Genentech: Consultancy, Honoraria; Astex/Otsuka: Consultancy; Modus Outcomes: Consultancy; Daiichi-Sankyo: Consultancy. Al Baghdadi:Celgene: Consultancy, Honoraria; Heron: Consultancy, Honoraria; Tracon: Equity Ownership; Epizyme: Equity Ownership; Bristol Myer Squibb: Consultancy, Honoraria; Sunesis: Equity Ownership; Portola: Equity Ownership; Heron therapeutics: Equity Ownership; Cardinal health: Consultancy, Honoraria; Bristol Myer Squibb: Equity Ownership; Celgene: Equity Ownership; Spectrum pharmaceutical: Equity Ownership; Astrazeneca: Equity Ownership; Seattle genetics: Equity Ownership; Roche: Consultancy, Honoraria. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Foran:Agios: Honoraria, Research Funding. Gore:Celgene Corporation: Consultancy, Research Funding. Komrokji:DSI: Consultancy; Agios: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; pfizer: Consultancy; celgene: Consultancy; Incyte: Consultancy; JAZZ: Consultancy. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Starczynowski:Kurome Therapeutics: Consultancy. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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

Background: CMML is a heterogeneous disease with overlapping features of MDS and MPN. Several risk scores have been proposed in CMML, including CPSS (Such Blood 2013) that identifies 4 risk groups (low, intermediate-1 [int-1], int-2 and high risk) with median overall survival (OS) ranging from 12 months to > 5 years. HSCT is the only curative treatment in CMML, with an expected 20-40% post-transplantation OS. Current guidelines, common to MDS and CMML recommend rapidly transplanting higher-risk CMML and delaying transplant in lower-risk disease (de Witte Blood 2017). Retrospective transplant studies have shown better outcome in lower-risk CMML (Liu et al BBMT 2017). Whether this translates into a survival benefit compared to a delayed transplant strategy requires prospective studies. Multistate models based on retrospective data from transplant and non-transplant patients (pts) have addressed similar issues in MDS (Koreth JCO 2013, Della Porta Leukemia 2017). Through a large collaborative study, we address the question of optimal timing for HSCT in CMML patients through a similar large international collaborative study. Method: We retrospectively selected pts from 2 registries: International MDS/MPN Working Group (IWG cohort, Padron Blood Cancer J 2015) and EBMT with the following criteria: WHO-defined CMML, age ≤ 70y, ECOG 0-2, diagnosis after 2000, available CPSS at the time of diagnosis. Different states were considered in higher- (CPSS int-2 and high) and lower- risk (CPSS low/int-1) pts: diagnosis, AML transformation, transplantation and death. IWG data was used to estimate transition probabilities from diagnosis to AML, transplantation and death and from AML to transplantation and death. EBMT data was used for transplantation to death transitions (Figure 1). Results: 719 and 403 pts were identified in the IWG and EMBT registry, respectively (resp). Median age was 64 (range 16-70) in IWG and 58 (19-70) years in EBMT cohort. Patients were male in 69% and 67% of IWG and EBMT cohorts, respectively (resp). CPSS was low in 22% and 13%, int-1 in 31% and 31%, int-2 in 40% and 45% and high in 8% and 11% of the IWG and EBMT pts, resp. In the IWG cohort, the 1 year cumulative incidence of transformation into AML were 7.3% and 18.2% in lower and higher risk patients, resp. Among the 719 pts from IWG, 102 received HSCT. At the time of diagnosis the expected life time of higher risk (int-2 and high) patients was 25.2 months while it was 44.1 months in lower risk (int-1 and low) patients. Table 1 reports gain or loss in expected life time (until 60 months after diagnosis) for transplantation at different intervals from diagnosis (within 6, 12, 18 and 24 months) for patients who have survived and not transformed to AML until the prediction time point, taking into account CPSS at diagnosis. Expected life time is also given separately for higher risk pts after transformation into AML. There was a modest gain of life expectancy with transplantation in higher risk patients (CPSS int-2 and high) while it was not the case in lower risk patients. The survival gain in higher risk pts with HSCT rose from 1.11 at 6 months to 3.4 months at 24 months. There was also a survival benefit of HSCT in higher risk pts who were transformed to AML during their follow-up which was even higher in terms of gain of months: from 9.89 month if HSCT performed within 6 months to 14.25 months if performed within 18 months. Of note, the loss of survival in lower risk patients who underwent HSCT decreased over time: 11.1 months if HSCT is performed within 6 months and 3.7 months if HSCT is performed within 24 months, probably owing to transition to higher-risk CMML at this stage in some pts, a transition that could not be captured in the present dataset. Conclusion: For the first time, using a multistate model, we could provide evidence that the transplant benefit in CMML is restricted to higher-risk pts, in line with findings in MDS and current guidelines. More analyses will be performed to analyze other subgroups of patients, especially regarding their risk (other classification than CPSS, the role of somatic mutation…). More studies are needed to analyze the role of pre HSCT treatment and its potential impact on post-transplant outcome. Disclosures Robin: Novartis Neovii: Research Funding. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. Kroeger:Riemser: Research Funding; Novartis: Honoraria, Research Funding; Medac: Honoraria; DKMS: Research Funding; Neovii: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; JAZZ: Honoraria; Sanofi-Aventis: Honoraria. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Rampal:Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Finke:Riemser: Honoraria, Other: research support, Speakers Bureau; Neovii: Honoraria, Other: research support, Speakers Bureau; Medac: Honoraria, Other: research support, Speakers Bureau. Komrokji:Agios: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; Incyte: Consultancy. Killick:JAZZ: Honoraria; Celgene: Honoraria; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; ALEXION: Honoraria. Blaise:Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

BACKGROUND: CMML is a myelodysplastic/myeloproliferative neoplasm with a median survival of 32 months and no therapies that improve its natural history. We have previously demonstrated that CMML bone marrow mononuclear cells (BMNCs) are hypersensitive to GM-CSF and that the GM-CSF axis is a viable therapeutic target (Padron et al., Blood 2013). Lenzilumab is a novel, humaneered IgG1κ monoclonal antibody, with high affinity for human GM-CSF that has activity in preclinical models of CMML. We report a Phase 1 clinical trial testing the safety and preliminary efficacy of this agent in CMML. METHODS: The study was approved by scientific and ethical review boards. This was a multicenter Phase 1 study designed to evaluate the safety and determine the recommended phase 2 dose of lenzilumab in subjects with CMML. Dose escalation proceeded using a standard 3+3 study design to determine the maximum tolerated dose (MTD). Three dose cohorts included 200 mg, 400 mg, and 600 mg, were given IV on day 1 and 15 of cycle 1 and then only on day 1 of subsequent 28-day cycles. Key inclusion criteria included a WHO-defined diagnosis of CMML and a platelet count greater than 20 x103 cells/dL. Response was evaluated utilizing the MDS/MPN International Working Group Criteria (Savona Blood 2015). Pharmacokinetic analysis and pharmacodynamics were evaluated by pSTAT5 by flow cytometry. RESULTS: Between July 2016 and June 2018, a total of 15 patients were enrolled. The median age at study entry was 74 years (range 52-85) and 80% were male. Nine patients were classified as CMML-0, 3 as CMML-1, and 3 as CMML-2. Seventy three percent of patients had normal cytogenetics or -Y. The most commonly mutated genes at screening included TET2 60%, ASXL1 53%, SRSF2 47%, and RAS pathway (i.e. NRAS or CBL) mutations 40%. Nine patients were previously treated with hypomethylating agents and/or experimental therapies, 3 were treated with hydroxyurea only, and 3 were untreated. The mean Hgb was 9.7g/dL (7.6-14g/dL), the mean platelet count was 147 x103 cells/dL (16-942 x103 cells/dL), and 66% of cases were MPN-CMML by the French-American-British classification at study entry. Three patients were enrolled at each dose level and an additional 6 patients were enrolled at 600mg as planned. Consistent with prior studies of lenzilumab, no dose limiting toxicities were identified and no treatment emergent grade 3 or 4 toxicities were reported. The mean duration on therapy was 221.8 days (14-787 days) and the majority of patients discontinued study drug because of disease progression or lack of response (69%). Five of 15 (33%) patients enrolled achieved clinical benefit by MDS/MPN IWG criteria with 3 platelet responses, 1 neutrophil response, and 1 spleen response. An additional patient had bone marrow myeloblast reduction from 6% to 1% which allowed that patient to undergo allogeneic stem cell transplantation. Clinical response was not statistically associated with somatic mutations or changes in pSTAT5 between screening and cycle 3. However, 3 of 4 patients with NRAS mutation achieved clinical benefit or had clinical meaningful bone marrow myeloblast reductions. CONCLUSION: Lenzilumab is well tolerated in patients with CMML, with no grade 3 or 4 treatment emergent adverse events or DLTs reported. Durable clinical benefit was achieved in 33% of patients and one patient was bridged to allogenic transplant, providing proof of concept that GM-CSF inhibition has activity in CMML. The favorable safety and activity profile of lenzilumab warrants future evaluation as part of a combination regimen targeted to specific subtypes more likely to respond, including patients with NRAS mutations. Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sallman:Celgene: Research Funding, Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Komrokji:celgene: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; pfizer: Consultancy; DSI: Consultancy; Incyte: Consultancy. Lo:Humanigen: Employment. Durrant:Humanigen: Employment. Chappell:Humanigen: Employment. Ahmed:Humanigen: Employment. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

CMML is a lethal myeloid neoplasm with no therapies that improve its dismal prognosis. Inhibition of BET family members has been proposed as a therapeutic strategy based on preclinical data identifying BRD4 as a therapeutic target in acute myeloid leukemia. However, despite potent on-target transcriptional remodeling, early phase clinical trials have demonstrated only modest activity secondary to a variety of resistance mechanisms. In ovarian cancer BET inhibitor (BETi) treated cells, compensatory upregulation and addiction to pro-survival kinase networks have been observed. Given that over 50% of CMML cases have mutations upregulating kinase signaling, we hypothesized that BETi resistance is mediated by these networks in CMML and can be targeted therapeutically. We tested this hypothesis by performing a limited screen of kinase inhibitors alone and in combination with the IC20 of the BETi INCB54329 in 8 human leukemia cell lines. This screen revealed that the IC50 of the PIM inhibitor (PIMi) INCB53914 decreased after co-treatment with BETi in a majority of the leukemia cell lines tested. Synergy was validated chemically in U937, TF1 and SKM1 leukemia cells using other selective inhibitors of BET and PIM. We next assessed the activity of the BET-PIM combination in 14-day colony formation assays with 10 unique CMML bone marrow mononuclear cell (BM-MNCs) patient samples(Fig. 1A). These studies revealed that combination therapy significantly suppressed clonogenicity versus BMNCs treated with vehicle or single drug alone. Finally, this synergy was validated in vivo in 36 patient derived xenografts (PDX) from 3 CMML patients, as manifest by reduced leukemic burden/engraftment in CMML PDX treated with combination therapy(Fig. 1B). To explore the mechanism by which BETi and PIMi therapeutically synergize we treated U937 and SKM1 leukemia cells with INCB54329 and measured mRNA and protein levels for all PIM isoforms. Surprisingly, we identified that PIM1 was increased following treatment with INCB54329, other BETi, or a JQ1-derived PROTAC (Fig. 1C). PIM1 upregulation was also manifest in INCB54329 persistor U937 leukemia cells generated by daily BETi treatment for 6 weeks. Testing across a broader panel of leukemia cell lines revealed an inverse correlation between PIM1 induction and decrease in the IC50 of PIMi following BETi treatment, suggesting PIM1 upregulation confers sensitivity to combination therapy. Consistent with this, isogenic SKM1 leukemia cells engineered to overexpress PIM1 were resistant to INCB54329 and were more sensitive to INCB53914 versus controls cells. Recent studies have demonstrated that inhibitory miRNAs, especially those located near super-enhancers, are suppressed by BET inhibition. Given that several miRNAs are known to control PIM1 expression, we hypothesized that paradoxical PIM1 upregulation following BETi treatment was due to down-regulation of select miRNAs. To test this, we treated our leukemia cell models with broad inhibitors of miRNA activity (i.e., AGO and Dicer inhibitors) and observed a dose dependent increase in PIM1 levels similar to that seen with BET inhibition(Fig. 1Di). Further, integrating public H3K27 CHIP-seq and miRNA super enhancer datasets and using computational prediction algorithms, we identified 6 candidate miRNAs that could regulate PIM1 and were predicted to be controlled by BET inhibitors. Of these, only miR-33a levels were reduced in a dose dependent manner in SKM1 cells by BETi treatment(Fig. 1Dii). This was confirmed by genetically silencing all BET proteins, which suppressed miR-33a levels in SKM1 leukemia cells. Finally, miR-33a mimics (but not control miRNAs) abolished BETi-induced upregulation of PIM1(Fig. 1Diii). Collectively, these studies established BET and PIM inhibition as a novel and potent combination therapy for CMML that is mediated by miR-33a-dependent upregulation of PIM1(Fig. 1E). Disclosures Liu: Incyte Corporation: Employment. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding. Komrokji:Novartis: Speakers Bureau; JAZZ: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy. Epling-Burnette:Incyte Corporation: Research Funding. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Haura:Incyte Corporation: Research Funding. Reuther:Incyte Corporation: Research Funding. Koblish:Incyte Corporation: Employment.