Forma Therapeutics Research Articles

The Impact of Smoking on Survival in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Treated with the Combination of Intensive Therapy with Tyrosine Kinase Inhibitor (TKI)

The Impact of Smoking on Survival in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Treated with the Combination of Intensive Therapy with Tyrosine Kinase Inhibitor (TKI)

Outcomes of Patients with Acute Myeloid Leukemia (AML) with Myelodysplasia Related Changes (AML-MRC) Are Dependent on Diagnostic Criteria and Therapy

Outcomes of Patients with Acute Myeloid Leukemia (AML) with Myelodysplasia Related Changes (AML-MRC) Are Dependent on Diagnostic Criteria and Therapy

Updated Preliminary Results from a Phase II Study Combining Azacitidine and Pembrolizumab in Patients with Higher-Risk Myelodysplastic Syndrome

Updated Preliminary Results from a Phase II Study Combining Azacitidine and Pembrolizumab in Patients with Higher-Risk Myelodysplastic Syndrome

Allogeneic Transplantation for Myelodysplastic Syndrome in Adults over 50 Years Old Using Reduced Intensity/Non-Myeloablative Conditioning: Haploidentical Relative Versus Matched Unrelated Donor

Background: Allogeneic hematopoietic cell transplantation (HCT) has been a successful strategy to treat myelodysplastic syndrome (MDS). With only approximately one-third of patients having an HLA matched sibling, most transplants use mismatched relative (haploidentical) or unrelated donors. In the current analysis we sought to study outcomes after haploidentical related compared to HLA-matched unrelated donor HCT for MDS (de novo or therapy-related). Methods: We retrospectively studied 176 recipients of haploidentical related donor and 427 recipients of 8/8 HLA-matched unrelated donor HCT in the United States between 2012 and 2017. The primary outcome was overall survival. The effect of donor type on survival and other transplant outcomes were studied using a Cox regression model. Results: Patient and disease characteristics are presented in Table 1. Most transplants (85%) were for de novo MDS in both donor groups. Although all patients received reduced intensity regimens, the predominant conditioning regimens were confounded by donor type. Total body irradiation (TBI) 200 cGy/cyclophosphamide/fludarabine (TBI/Cy/Flu; 82%) was the predominant regimen for haploidentical HCT and fludarabine with busulfan or melphalan (Flu/Bu or Flu/Mel; 79%) without in vivo T-cell depletion was the predominant regimen for unrelated donor HCT. Similarly, graft-versus-host disease (GVHD) prophylaxis was also confounded by donor type. Posttransplant cyclophosphamide/calcineurin inhibitor/mycophenolate (PT-Cy/CNI/MMF) was the prophylaxis regimen for all haploidentical transplants. CNI/MMF (31%) or CNI/methotrexate (69%) was used for unrelated donor transplants. Peripheral blood was the predominant graft for both donor types. The median follow-up was 24 months (range 3-77) after haploidentical and 36 months (range 3-74) after unrelated donor HCT. Results of multivariate analysis, adjusted for HCT-CI, prior treatment with hypomethylating agents (HMAs), and IPPS-R did not show differences in survival by donor type (HR 0.98, p=0.85; 40% vs. 37%), Figure 1. However, the relapse rate (adjusted for prior HMAs, IPSS-R, and recipient sex) was higher after haploidentical compared to unrelated donor HCT (HR 1.60, p=0.002, 53% vs. 34%), which led to lower disease-free survival after haploidentical HCT (HR 1.30, p=0.03; 21% vs. 32%), Figure 1. To further test the effect of regimen intensity, low dose TBI regimens were compared to Flu/Bu and Flu/Mel; we did not observe a difference in relapse risk (HR 0.95, p=0.76). Non-relapse mortality did not differ by donor type (HR 0.88, p=0.46). Interval between diagnosis and transplant was also not associated with outcomes. Acute grade II-IV acute GVHD (HR 0.46, p<0.001) and chronic GVHD (HR 0.34, p<0.001) was less common after haploidentical HCT. The 1-year graft failure rate was higher after haploidentical compared to unrelated donor HCT (15% and 8%, respectively, p=0.02). Conclusion: Although the current analysis did not show differences in survival between haploidentical related and matched unrelated donor HCT, the higher relapse and consequently lower disease-free survival associated with the haploidentical HCT approach in this analysis (primarily TBI/Cy/Flu with PT-Cy/CNI/MMF) warrants caution. A more definitive comparison of the two donor types can be accomplished only if more haploidentical transplants were to use Flu/Bu or Flu/Mel conditioning. Figure 1 Disclosures Grunwald: Celgene: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Merck: Consultancy; Abbvie: Consultancy; Medtronic: Equity Ownership; Incyte: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Amgen: Consultancy; Trovagene: Consultancy; Cardinal Health: Consultancy; Janssen: Research Funding; Genentech/Roche: Research Funding; Novartis: Research Funding; Forma Therapeutics: Research Funding. Bolanos-Meade:Incyte Corporation: Other: DSMB fees. Bredeson:Otsuka: Research Funding. Gupta:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Mussetti:Takeda: Honoraria; BMS: Honoraria; Novartis: Honoraria; Italfarmaco: Honoraria. Nakamura:Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Solh:Celgene: Speakers Bureau; Amgen: Speakers Bureau; ADC Therapeutics: Research Funding. Weisdorf:Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy; Incyte: Research Funding.

Multicentre, Open Label, Randomized Phase III Study of Cpi-613® (devimistat) in Combination with High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) in Older Patients (≥ 60 years) with Relapsed / Refractory Acute Myeloid Leukemia (AML) - Armada 2000 (AML003) Trial

Multicentre, Open Label, Randomized Phase III Study of Cpi-613® (devimistat) in Combination with High Dose Cytarabine and Mitoxantrone (CHAM) Compared to High Dose Cytarabine and Mitoxantrone (HAM) in Older Patients (≥ 60 years) with Relapsed / Refractory Acute Myeloid Leukemia (AML) - Armada 2000 (AML003) Trial

Comparison of Clinical Evolution of Children with Sickle Cell Disease before and after Treatment with Hydroxyurea at Saint Damien Hospital, Tabarre-Haiti,2013-2018

INTRODUCTION Sickle cell disease (SCD), an autosomal recessive hemoglobinopathy, is associated with a high morbidity and mortality rate, especially in low income countries. In Africa, 5% of deaths among children under five are attributable to SCD [59th World Health Assembly, WHO 2006]. This chronic disease greatly alters the quality of life of affected children. However, according to several published studies, SCD clinical course can be improved with the administration of hydroxyurea, an antimetabolite drug. [Nkashama, Pan African Medical Journal,2015] Saint-Damien, a pediatric hospital in Haiti, has a current cohort of 1248 sickle cell children. Forty of them (3 %) benefit from hydroxyurea administration since November 2015. In this hospital, data on how hydroxyurea modifies SCD clinical course are lacking, despite the advantage of this drug described in literature [Charache,New England Journal of Medicine,1995]. This study aims to compare the evolution of children treated at Saint Damien Hospital, before and after receiving hydroxyurea. METHODS A retrospective analytic study was conducted from November 2013 to June 2018 in the Sickle Cell Clinic at Saint-Damien Hospital. We included 40 children aged 2 to 15 years old treated with hydroxyurea. All of them benefit of the same treatment protocol: Initial dose of 10 mg per kg per day increase to maintenance dose of 25 mg per kg per day. Any child whose treatment has been permanently discontinued regardless of the cause was excluded. Epidemiological and clinical data were collected using Excel 2010. We compared children clinical evolution two years before and two years after hydroxyurea administration using these parameters: frequency and duration of hospitalizations, hospitalization frequency for specific complications (pain crisis, stroke and acute chest syndrome), and frequency of blood transfusions. We calculated frequencies, ratios and means using Epi Info. We realized statistical analysis to compare quantitative variables with a p value significant when less than 5%. RESULTS Gender ratio was 1:1. The mean age of children at enrollment on hydroxyurea was 8 years. Thirty-eight children of 40 (95 %) experienced at least one hospitalization before receiving the drug, compared with 17 (42.5%) after, p=0.025. The mean duration of hospitalization was 9 days before and 6 days after, p=0.0319. The average number of hospitalizations per child was decreased by 30 %. Seventy percent of children were hospitalized at least once due to painful crisis 2 years before receiving hydroxyurea, compare to 22.5 % after. Thirty-one children (77.5%) were transfused at least once before receiving the drug and 9 (22.5%) after receiving it. There was no cases of acute chest syndrome or stroke reported after hydroxyurea, unlike before the introduction of the drug. (Table 1) CONCLUSION The percentage of hospitalized children and the average length of hospitalization stay decreased significantly with hydroxyurea intake; as well as the frequency of painful crisis and blood transfusions. Hydroxyurea acts directly on the two main causes of hospitalization in the sickle cell, reducing the morbidity related to this pathology; and demonstrating the direct benefit of this drug at Saint Damien Hospital. Since our cohort is young, we have not been able to follow his evolution over a longer period of time. We plan to continue to observe this cohort. But these first results already allow us to recommend a broader use of hydroxyurea for pediatric patients with SCD in Haiti. Disclosures Alvarez: Forma Therapeutics: Consultancy; Novartis: Consultancy.

Transcranial Doppler Velocities Conversion Rate Based on Increasing Hemoglobin Concentration: Analysies from the SCCRIP Cohort Study

Transcranial Doppler Velocities Conversion Rate Based on Increasing Hemoglobin Concentration: Analysies from the SCCRIP Cohort Study

Disease Modeling and Phenotype Rescue Using Inducible Pluripotent Stem Cells from Patients with Diamond-Blackfan Anemia

Diamond-Blackfan anemia (DBA) is a congenital ribosomopathy and bone marrow failure syndrome manifesting typically in infancy with erythroid hypoplasia. Approximately half of affected individuals also have developmental anomalies. Over time, additional cytopenias can develop, including reduced hematopoietic stem and progenitor cells (HSPC). Heterozygous loss-of-function mutations in over 20 ribosomal protein (RP) genes cause approximately 70% of DBA cases, although only 7 genes (RPS19, RPL5, RPS26, RPL11, RPL35a, RPS24 and RPS7) account for over 90% of patients with a known DBA genotype. Medical therapies including steroids, chronic transfusions are partially effective but have considerable side effects. Hematopoietic stem cell transplantation (HSCT) from matched related or unrelated donors is curative with recently reported good outcomes, although many patients lack a suitable donor and/or have serious treatment-related comorbidities that increase HSCT-related toxicities. Case reports of spontaneous genetic reversion in DBA suggest that RP gene-corrected HSPC have competitive advantage over RP-deficient cells, thus providing the rationale for gene therapy as a feasible therapeutic approach. Induced pluripotent stem cell (iPSC) technology provides a robust model of human disease and can recapitulate hematopoietic defects encountered in bone marrow failure syndromes. The goals of this study was to establish a culture system from patient-derived iPSCs that can recapitulate key aspects of DBA pathophysiology and provide a preclinical model for gene manipulation to correct the abnormal phenotype (Figure 1). We developed iPSCs from individuals with DBA who were enrolled on INSIGHT (NCT02720679), an IRB-approved, prospective study that includes biobanking of peripheral blood mononuclear cells (PBMNC) from patients with bone marrow failure syndromes. We first reprogrammed these DBA PBMNC into iPSCs using non-integrating Sendai virus to establish lines with pathogenic mutations in RPS19 (c.191>T, p.Leu64Pro), RPS19 (c.184C>T, p.Arg62Trp), RPL11 (c.61dupT, p.Cys21Leufs*13), and a variant of uncertain significance (VUS) in RPS7 (c.277_279delGTC, pVal93del). Undifferentiated iPSC lines exhibited abnormal ribosomal biogenesis revealed by polysome profiling and pre-rRNA analysis. Upon in vitrodifferentiation to hematopoietic lineages, the mutant iPSCs recapitulated DBA phenotypes with reduced CD34+ HSPCs, near absence of erythroid colonies (BFU-E and CFU-E) colonies and failure to produce erythroid cells in liquid culture. We used two methods to correct single nucleotide RP mutations in DBA iPSCs (Figure 1): i) CRISPR/Cas9-mediated homology-directed repair, and ii) base-editing, which utilizes catalytically inactive Cas9 fused to a deaminase that interconverts nucleotides directly in the absence of double-stranded DNA breaks. Corrected "isogenic" lines showed phenotype similar to wild type controls, with restored erythroid differentiation, and normal polysome maturation and pre-rRNA ratios. Because some patients carry large intragenic or whole RP gene deletions that are not amenable to gene correction, we also explored the feasibility of gene rescue by inserting a wild type copy of the defective gene (Figure 1). Using zinc-finger nuclease (ZFN), we inserted wild type RP cDNA constructs into the "safe harbor" AAVS1 locus on chromosome 19, thereby rescuing abnormal phenotypes of patient-derived iPSC lines with RPS19(p.Arg62Trp) and RPL11(p.Cys21Leufs*34) mutations. Additionally, we explored lentiviral gene delivery as an alternative method for RP gene replacement. We compared different promoters including MND, PGK and EF1a and found that the latter was most effective at rescuing RP gene expression in iPSC cells. Transduction of lentiviral vectors with wild type RPS19or RPL11fused to the EF1a promoter into three iPSC lines with RPS19or RPL11mutations resulted in stable transgene expression of RPS19or RPL11genes and phenotypic rescue. This study supports the feasibility of establishing iPSCs from DBA subjects with different genotypes. These iPSC lines provide a useful resource for numerous studies of DBA including preclinical approaches to gene therapy, evaluating the pathogenicity of RP gene variants of unknown significance and examining the pathophysiology of RP haploinsufficiency. Disclosures Estepp: Esperion: Consultancy; Forma Therapeutics: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Eli Lilly and Co: Research Funding; Daiichi Sankyo: Consultancy. Weiss:GlaxoSmithKline: Consultancy; Rubius Inc.: Consultancy; Cellarity Inc.: Consultancy; Beam Therapeutics: Consultancy; Esperion: Consultancy.

A 20-Year Review of Imatinib in Chronic Phase Chronic Myeloid Leukemia Patients after Failure with Interferon Therapy

A 20-Year Review of Imatinib in Chronic Phase Chronic Myeloid Leukemia Patients after Failure with Interferon Therapy

Final Results of Phase 2 Clinical Trial of LCL161, a Novel Oral SMAC Mimetic/IAP Antagonist, for Patients with Intermediate to High Risk Myelofibrosis

Final Results of Phase 2 Clinical Trial of LCL161, a Novel Oral SMAC Mimetic/IAP Antagonist, for Patients with Intermediate to High Risk Myelofibrosis

Machine Learning Prediction for Complete Response to Hypomethylating Agents with or without Additional Agents in Patients with Newly Diagnosed Myelodysplastic Syndrome

Machine Learning Prediction for Complete Response to Hypomethylating Agents with or without Additional Agents in Patients with Newly Diagnosed Myelodysplastic Syndrome

The Early Achievement of Measurable Residual Disease Negativity in the Treatment of Adults with Philadelphia-Negative B-Cell Acute Lymphoblastic Leukemia Is a Strong Predictor for Survival

The minimal or measurable residual disease (MRD) status following induction/consolidation chemotherapy is an important prognostic endpoint in adult patients with newly diagnosed acute lymphoblastic leukemia (ALL). However, the optimal time-point (TP) of MRD assessment and its impact on outcome remains unclear. We analyzed 215 patients with newly diagnosed Philadelphia negative B-cell ALL who received intensive chemotherapy, and had available MRD assessment by multicolor flow cytometry at two separate TPs. The median time to first TP (1TP) and second TP (2TP) were 24 and 110 days, respectively. At 1TP, 148 patients (68%) were MRD negative and 67 (32%) were positive. Of the 148 patients with negative MRD at 1TP, 147 (99%) maintained it through 2TP. Patients who were MRD negative at both TPs, early MRD responders, had the 3-year event-free survival (EFS), and overall survival (OS) rates of 65% and 76%, respectively. Patients with improved MRD status from positive to negative, late MRD responders, had lower 3-year EFS and OS rates, 42% and 58%, respectively (P = .001). Multivariate analysis showed that KMT2A (MLL) rearrangement and MRD positivity at 1TP were the only factors correlated with worse OS. In conclusion, the earlier achievement of MRD negative remission is a stronger prognostic factor for survival.

The Impact of Treatment Recommendation By Leukemia Artificial Intelligence Program (LEAP) on Survival in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

The Impact of Treatment Recommendation By Leukemia Artificial Intelligence Program (LEAP) on Survival in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Combination Thioguanine and Decitabine Is Highly Active in Patients with Advanced Myeloid Malignancies: A Single Institution Experience

BACKGROUND: Despite recent advances, outcomes remain poor in secondary and relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We previously demonstrated that combination thioguanine (6TG) and decitabine restores therapeutic efficacy in vitro in R/R AML (O'Dwyer K et al. Blood 2010;114:2657). Based on these data, we completed a Phase I dose-escalation study of 6TG with decitabine in advanced myeloid malignancies with an overall response rate (ORR) of 67% and median progression-free survival (PFS) of 42 weeks in responding patients (Lee DJ, et al. Blood 2016;128:2816). Moreover, 5 of the 6 study participants who had previously received a hypomethylating agent (HMA) responded, suggesting that 6TG in combination with decitabine can overcome HMA resistance. Because of these results, a cohort of patients with high-risk and R/R AML and MDS were treated with combination 6TG and decitabine at Columbia University Irving Medical Center, and we now report our clinical experience with this regimen. METHODS: A retrospective chart review was performed of all adult patients at our institution with advanced myeloid malignancies who had received at least one cycle of 6TG and decitabine between 2013-2017. The treatment regimen utilized the maximum tolerated dose of 6TG identified in the phase I trial. Up to 2 cycles of induction with 6TG 80 mg/m2/day PO in 2 divided doses was given on Days 1-12. Decitabine 20 mg/m2 IV was given on Days 3-12. Following this, maintenance cycles consisted of 6TG on Days 1-7 and decitabine on Days 3-7 at the same doses. Treatment was continued until the time of hematopoietic stem cell transplant (HSCT), disease progression, or toxicity. The primary objective of this retrospective analysis was to determine the ORR. Secondary objectives were to evaluate PFS and overall survival (OS) in this population. RESULTS: Forty-two patients were identified, 55% of whom were female, with a median age of 68 years (range, 23-83 years). Thirty-three percent of the patients had secondary AML; 62% had R/R AML; 2% had R/R MDS; and 2% had chronic myelomonocytic leukemia. By ELN genetic risk stratification, 38% were adverse-risk, 43% were intermediate, and 17% were favorable, while 2% were unknown. However, 36 (86%) patients failed prior therapy, suggesting that nearly all of the treated patients were poor-risk. Nineteen (45%) patients had received prior HMA therapy, and 6 (14%) had undergone previous HSCT. Patients received a median of 2 cycles of therapy (range, 1-10). Five (12%) patients achieved complete remission (CR), 7 (16%) obtained a CR with incomplete count recovery (CRi/p), and 2 (5%) had morphologic leukemia-free state (MLFS), for an ORR of 33% (CR+CRi/p+MLFS). One notable patient who achieved CR was a 73-year-old with secondary AML, complex cytogenetics, and a TP53 mutation who subsequently went on to HSCT. Another 5 (36%) responders had complex karyotypes or poor-risk genetics. Ten of the 14 responders (71%) failed prior therapy. Of the 19 who had received prior HMA therapy, 6 (32%) responded. Six of 14 (43%) responders proceeded to HSCT. Two additional patients had significant blast reduction and underwent HSCT. Responses and maximum blast reduction were obtained after two cycles of therapy. For the responders, the median PFS was 38 weeks (range, 11-not reached), while the median OS was 43 weeks (range, 11-not reached). CONCLUSIONS: Combined 6TG and decitabine is a highly active regimen in advanced myeloid malignancies, with an ORR of 33% in this cohort, and median PFS and OS of 38 and 43 weeks, respectively, in responding patients. This compares favorably to the expected response rate of 10-20% with decitabine monotherapy in this poor-risk population consisting of mostly secondary and R/R AML. These data also confirm our prior phase I study findings that the addition of 6TG to decitabine can overcome prior HMA resistance, with 32% of those who had previously failed HMA therapy responding. This combination remains a viable therapeutic option for elderly and unfit patients with high-risk and R/R AML who cannot tolerate intensive chemotherapy. Disclosures Heaney: BMS: Research Funding; Partner Therapeutics: Consultancy; Roche: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; AbbVie: Consultancy; Deciphera: Research Funding; Constellation: Research Funding; Blueprint: Research Funding; CTI: Research Funding. Lamanna:Ming: Research Funding; Celgene: Consultancy; Oncternal: Research Funding; TG Therapeutics: Research Funding; Infinity/ Verastem: Research Funding. Jurcic:Syros Pharmaceuticals: Research Funding; Astellas: Research Funding; AbbVie Inc: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Incyte: Consultancy; Kura Oncology: Research Funding; Forma Therapeutics: Research Funding; Genentech: Research Funding; Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Frattini:Celgene: Employment, Equity Ownership; Lin Bioscience: Consultancy. Lee:Abbvie: Research Funding; Roche: Research Funding; Tolero: Research Funding; Forty Seven, Inc.: Research Funding; Bayer: Research Funding.

Social Vulnerability Is Associated with Emergency Department Dependency in Pediatric Sickle Cell Disease Patients

Background: Sickle cell disease (SCD) is a complex genetic disorder characterized by significant, largely unpredictable heterogeneity in disease severity and healthcare utilization. The contribution of socioeconomic status (SES) and other environmental factors to this heterogeneity is poorly understood. In other disorders, SES is a major influence on healthcare quality and access, which can be affected by financial status, social stability, transportation, household overcrowding, and other variables. The multiplicative nature of these factors limits the ability to incorporate them in a single measure. The Social Vulnerability Index (SVI) was created by CDC to assist disaster management officials in identifying the locations of their most socially vulnerable populations (https://svi.cdc.gov/). SVI combines many of the SES factors that may contribute to disease severity and healthcare utilization. SVI has previously been validated for use assessing chronic conditions such as asthma, youth inactivity, and BMI. Thus, we hypothesized that SVI is associated with SCD-related severity and utilization. This analysis explores the relationship between census tract level social vulnerability and healthcare utilization in pediatric SCD patients. Methods: The Children's Healthcare of Atlanta's (CHOA) SCD Clinical Database houses a large, population-based cohort of pediatric sickle cell patients. It includes laboratory-confirmed SCD genotype, treatment history, and healthcare utilization for over 3,500 patients from 2010-2018. The database was queried for patients who had ≥1 SCD-related healthcare encounter from 2016-2018 and whose most recent address was in a metro Atlanta county. Addresses were geocoded and matched to CDC's SVI at the census tract level. The SVI combines 15 measures from the US Census and groups them into four related themes - SES, Household Composition & Disability, Minority Status & Language, and Housing & Transportation , which are combined into a percentile ranking of overall social vulnerability ranging from 0 (lowest) to 1 (highest). Patients were categorized by sickle cell anemia (SCA) genotypes (SS or Sβ0 Thalassemia) vs. other. Healthcare utilization was used to calculate the emergency department dependency ratio (EDR, ratio of ED visits to sum of ED and SCD clinic visits) and total inpatient days for acute illness as a measure of disease severity. As reported in previous studies, EDR was classified as high (>=0.33) or low (<0.33). SVI, age, and annual inpatient days were included as continuous variables. A logistic regression model was used to assess the relationship between SVI and EDR. SCA vs. other SCD genotypes, age, and total inpatient days were included as covariates and a backwards selection was used to find the best model. Results: Of the 2,578 active patients from 2016 to 2018, 1,328 met inclusion criteria. Mean age at the end of each measurement year was 10.0 years (SD=5.6), 47.7% were female, and 62.0% had SCA genotypes. Average inpatient days was 3.2 (SD=8.3). Average SVI was 0.50 (SD=0.28) and average EDR was 0.29 (SD=0.29); 44.8% of which were classified as high. All covariates were significant in the multivariate model. In the crude model, SVI was significantly associated with high EDR (OR=2.08, 95% CI: 1.62, 2.66). After controlling for inpatient length of stay, age, and genotype, SVI remained positively associated with high EDR (OR=1.85, 95% CI: 1.41, 2.44). Of the covariates, total hospital days (OR=1.28, 95% CI: 1.25, 1.32) was associated with a higher EDR. Older age (OR=0.97, 95% CI (0.96, 0.99) and SCA genotype (OR=0.41, 95% CI: 0.35-0.48), were negatively associated with high EDR. After controlling for SCA genotype, age, and length of stay, a 1 unit increase in SVI was associated with 85% greater odds of having a high EDR. Conclusions: The analysis demonstrates a significant relationship between SVI and EDR. Further analyses will assess the effect of distance to emergency department, treatment with hydroxyurea or chronic transfusions, and individual themes within SVI to further elucidate this relationship. A limitation of this analysis is that encounters were limited to those occurring at a CHOA facility. Overall, the results support our hypothesis that high social vulnerability is associated with increased reliance on the emergency department for care and that SVI may be a predictor of disease severity and increased healthcare utilization. Disclosures Lane: NHLBI: Research Funding; CDC: Research Funding; GA Dept: Other: Contract for newborn screeninjg follow-up services services; Bio Products Laboratory: Other: Sickle Cell Advisory Board; FORMA Therapeutics: Other: Clinical Advisory Board.

Selective Targeting of Histone Deacetylase 11 Disables Metabolism of Myeloproliferative Neoplasms

Introduction: Acetylated histone and non-histone proteins are pharmacologic targets for both solid and hematological cancers including myeloproliferative neoplasms (MPNs), a group of clonal hematological malignancies driven by aberrant JAK2/STAT signaling. MPNs are characterized by epigenetic alterations, including aberrant acetylation, which makes this disease particularly interesting for targeting with HDAC inhibitors. Four classes of histone deacetylases (Class I-IV HDACs) regulate gene transcription and modulate cellular processes that drive the initiation and progression of cancer. Pan-HDAC and class I-selective HDAC inhibitors have gained traction in clinical settings, yet we reasoned that specific targeting of the 18 distinct HDAC proteins may establish roles for select HDACs as therapeutic vulnerabilities in MPNs. Methods: To explore the roles of individual HDACs in MPN, we first conducted an inhibitor screen of compounds having distinct HDAC selectivity based on electrophoretic mobility shift assays with full-length human HDAC proteins expressed in baculovirus and unique peptide substrates. Ultra-specific HDAC6 compounds were initially targeted for analysis based on its previously defined role in HSP90-mediated JAK2 stabilization and translation. Survival of MPN cell line models, MPN patient samples, leukemia cell lines, and MPN disease progression in mice transplanted with Hdac6-/-, and Hdac11-/- hematopoietic stem cells (HSCs) transduced with the MPLW515L oncogene, as well as Tg-Hdac11-eGfp mice were used to show the role of HDAC6 and HDAC11 in oncogene-driven and homeostatic hematopoiesis. As further proof of specificity, HDAC6 and HDAC11 were genetically ablated in MPN model cell lines using either RNA interference or inducible shRNA. For HDAC11 substrate identification, a combination of RNA-seq, acetylated proteome (SILAC), global metabolomics (LC-MS), Seahorse metabolic assays (Agilent Technologies), enzymatic assays, and acetylation-specific immunoblotting and mutation profiling were performed (Fig. 1). Results: Despite the established interplay between HDAC6, HSP90 and JAK2, neither a highly selective HDAC6 inhibitor, HDAC6 silencing, nor the Hdac6 deficiency suppressed MPN pathogenesis, although there were clear effects on the acetylation of α-tubulin, a well characterized HDAC6-selective substrate. Intriguingly, both inhibition of HDAC11 activity with highly-specific HDAC11 inhibitors and silencing HDAC11 using an inducible validated shRNA, identified HDAC11 as a therapeutic vulnerability for multiple human MPN cell lines. The Tg-Hdac11-eGFP reporter mice showed that HDAC11 is expressed in several hematopoietic cell types, including myeloid cells, erythroblasts, and megakaryocytes. Thus, Hdac11-/- and Hdac11+/+MPLWT bone marrow were examined for steady-state hematopoiesis and transplantation chimerism. These studies demonstrated that HDAC11 does not contribute to homeostatic or transplantated bone marrow reconstitution. However, in the oncogenic MPL model, recipient mice transplanted withoncogenic MPLW515L-expressing Hdac11-deficient HSCs displayed markedly impaired cytokine-independent colony-formation, had less fibrosis, and displayed improved survival in primary and secondary MPN hematopoietic stem cell transplantation; thus HDAC11 contributes to MPN pathogenesis (Fig. 1). Studies in additional leukemia cell lines, including THP-1, HL-60, and mantle lymphoma cell lines, but not in Ramos or K562 cells, established that HDAC11 contributes to oncogene-driven events in other cell types. Mechanistically, RNA-seq, SILAC proteomics, and metabolic profiling revealed that HDAC11 controls aerobic glycolysis by deacetylating Lys343 of the glycolytic enzyme enolase-1 (ENO1), functionally inactivating ENO1. Finally, the effects of targeting HDAC11 on metabolism were augmented by blocking compensatory pathways of oxidative phosphorylation that are induced via JAK2V617Fand MPLW515L oncogenic signaling. Conclusions: Our comprehensive screens of HDAC inhibitors, coupled with our biological, in vivo and molecular studies, indicate that HDAC11 is an attractive and potent target for disabling MPN metabolism and pathogenesis. These finding support the rationale for further development of clinical HDAC11 inhibitors for the treatment of metabolically-active cancers such as MPNs. Disclosures Pinilla Ibarz: Teva: Consultancy; TG Therapeutics: Consultancy; Sanofi: Speakers Bureau; Bayer: Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Reuther:Incyte Corporation: Research Funding. Levine:Loxo: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Research Funding; Lilly: Honoraria; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Gilead: Consultancy; Celgene: Consultancy, Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Amgen: Honoraria. Verma:BMS: Research Funding; Janssen: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria. Epling-Burnette:Incyte Corporation: Research Funding; Celgene Corporation: Patents & Royalties, Research Funding; Forma Therapeutics: Research Funding.

Prognostic Factors for Progression in Patients (pts) with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) in Complete Molecular Response (CMR) within 3 Months of Therapy with Tyrosine Kinase Inhibitors (TKIs)

Prognostic Factors for Progression in Patients (pts) with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) in Complete Molecular Response (CMR) within 3 Months of Therapy with Tyrosine Kinase Inhibitors (TKIs)

Risk of Hemorrhage in Patients with Polycythemia Vera Exposed to Aspirin in Combination with Anticoagulants: Results of a Prospective, Multicenter, Observational Cohort Study (REVEAL)

Background Polycythemia vera (PV) is associated with an increased risk of thrombosis and major hemorrhage. Aspirin (ASA) is recommended for primary thromboprophylaxis in PV, but is commonly discontinued at the time of initiation of an anticoagulant (AC) due to concern for an increased risk of hemorrhage. High rates of recurrent venous thromboembolism have been reported with ACs alone in patients (pts) with myeloproliferative neoplasms, but limited data exist on hemorrhagic outcomes for ACs combined with ASA in pts diagnosed with PV. To assess the safety of dual antiplatelet and AC therapy in pts with PV, we assessed the rates of hemorrhage among pts enrolled in a large, prospective, observational cohort study. Methods The REVEAL study is a prospective, non-interventional, observational study of pts with PV conducted at 204 sites in the United States. Retrospective data up to 6 months before enrollment and prospective data following enrollment were entered into an electronic data capture form. Retrospective and prospective data pertaining to bleeding events and use of ACs and/or ASA were extracted for this analysis. Post-enrollment hemorrhagic events were graded according to CTCAE by treating physicians. Pt subgroups (AC only, ASA only, AC + ASA, or neither) were defined by treatments received prior to enrollment. Exposure-adjusted hemorrhagic event rates and the probability of hemorrhage in the post-enrollment period were estimated by subgroups. The association between risk of hemorrhage and the use of AC in combination with ASA after enrollment was assessed with a Cox proportional hazards model, with AC and ASA use as a time-dependent covariate, adjusting for age, sex, disease duration, and history of bleeding prior to enrollment. Time to first post-enrollment hemorrhagic event was modeled with time censored at death, date of discontinuation, or last visit; analyses were conducted for all hemorrhagic events and severe (grade 3 or 4) events. Results A total of 2510 pts were enrolled in REVEAL and included in this analysis. At the time of enrollment, the median age was 67 (range 22 to 95) years, 54.2% were men, 56.0% were diagnosed with hypertension, and 19.9% reported a history of thrombotic events. The ASA only subgroup consisted of 1490 (59.4%) pts, AC only 183 (7.3%) pts, and AC + ASA 108 (4.3%) pts. The most frequently prescribed ACs were warfarin, rivaroxaban, and apixaban. With a median (range) follow-up of 2.3 (0 to 3.6) years, 110 (4.4%) pts developed a hemorrhagic event. The most common sites were gastrointestinal (n=51, 46.4%), cutaneous (n=27, 24.5%), and genitourinary (n=12, 10.9%). Forty-six pts (1.8%) developed ≥1 severe hemorrhage, most commonly gastrointestinal (23/46, 50%) and central nervous system (7/46, 15.2%). Of the 46 pts with severe events, 38 (82.6%) required hospitalization and 7 (15.2%) were fatal (2 gastrointestinal, 2 subdural hemorrhages, 1 subdural hematoma, 1 cerebral hemorrhage, and 1 hemorrhagic stroke). At the end of the study period, 8.4% of pts (n=211) were receiving warfarin, 3.9% (n=99) rivaroxaban, and 2.6% (n=65) apixaban. The exposure-adjusted rate (per 100 pt-years [95% CI]) for any hemorrhage in the overall cohort was 2.0 (1.64, 2.39); in the ASA only subgroup and in the AC + ASA subgroup, these rates were 1.5 (1.09, 1.93) and 7.9 (4.17, 11.56), respectively. The overall 3-year cumulative incidence was 22.1% (12.42%, 33.52%) for any hemorrhagic event (Figure) and 3.0% (0.80%, 7.81%) for severe hemorrhagic events. Overall, pts receiving AC in combination with ASA in the post-enrollment period were over 4-fold as likely to have a hemorrhage (HR [95% CI] = 4.22 [2.57, 6.94]; P <0.0001) compared with those who received either one of the treatments alone, or neither treatment. Notably, the risk of severe hemorrhage was significantly higher for pts receiving AC and ASA combination in the post-enrollment period (HR [95% CI] = 3.06 [1.35, 6.95]; P=0.0074). Conclusions In a large prospective cohort of pts with PV, the combination of ACs with ASA was associated with an increased risk of bleeding compared with ASA alone. Based on the observed 3-fold increased risk of severe hemorrhage associated with the combination of ACs and ASA, caution is required when prescribing antiplatelet agents with ACs for the treatment of thrombotic disorders in pts with PV. Disclosures Zwicker: Quercegen: Research Funding; Parexel: Consultancy; Portola: Consultancy; Daiichi: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy; Bayer: Consultancy. Lessen:Astellas: Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Colucci:Incyte: Employment, Equity Ownership. Paranagama:Incyte: Employment, Equity Ownership. Grunwald:Genentech/Roche: Research Funding; Amgen: Consultancy; Cardinal Health: Consultancy; Pfizer: Consultancy; Medtronic: Equity Ownership; Celgene: Consultancy; Daiichi Sankyo: Consultancy; Merck: Consultancy; Trovagene: Consultancy; Incyte: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Research Funding; Abbvie: Consultancy; Agios: Consultancy; Forma Therapeutics: Research Funding.

DYRK1A Is Regulated By Oncogenic KMT2A and Required for Survival of KMT2A-Rearranged Acute Lymphoblastic Leukemia

Background: Research efforts have focused upon uncovering critical leukemia-associated genetic alterations that may be amenable to therapeutic targeting with new drugs. Targeting the oncogenic BCR-ABL1 fusion protein in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (B-ALL) with tyrosine kinase inhibitors to shut down constitutive signaling activation and induce leukemia cell cytotoxicity has remarkably improved patients' survival and has established a precision medicine paradigm for kinase-driven leukemias. However, multiple subtypes of B-ALL are driven through non-tyrosine fusion proteins, including the high-risk KMT2A-rearranged (KMT2A-R) subtype common in infants with B-ALL, leaving many patients with insufficient treatment options. Objectives: KMT2A-R B-ALL is associated with chemoresistance, relapse, and poor survival with a frequency of 75% in infants and 10% in older children/adults with B-ALL. Current intensive multiagent chemotherapy regimens induce significant side effects yet fail to cure the majority of patients, demonstrating continued need for novel therapeutic approaches. The goals of our study were to i) identify signaling molecules required for KMT2A-R B-ALL cell survival, ii) select ALL-associated targets that are not essential in normal tissues, and iii) develop new treatment strategies that may benefit patients with KMT2A-R ALL. Results: We performed a genome-wide kinome CRISPR screen using the pediatric KMT2A-R cell line SEM and identified DYRK1A among other signaling molecules as required for leukemia cell survival. DYRK1A is a member of the dual-specificity tyrosine phosphorylation-regulated kinase family and has been reported as a critical oncogene in a murine Down syndrome (DS) model of megakaryoblastic leukemia. In normal hematopoiesis, DYRK1A controls the transition from proliferation to quiescence during lymphoid development. Deletion of DYRK1A results in increased numbers of B cells in S-G2-M phase, yet also significantly reduces cell proliferation. Meta-analysis of ChIP-Seq data from two KMT2A-AFF1 cell lines (SEM and RS4;11) and a human KMT2A-Aff1-FLAG-transduced ALL model demonstrates that both N-terminal (KMT2AN) and C-terminal (AFF1C) and the FLAG-tagged KMT2A-Aff1 fusion directly bind to the DYRK1A promoter. Gene expression and RT-PCR analyses of SEM cells treated with inhibitors against two important KMT2A fusion complex proteins, DOT1L (histone methyltransferase) and menin (tumor suppressor), demonstrate that only menin inhibition induced DYRK1A downregulation. Interestingly, deletion of germline KMT2A in murine B-cells did not decrease DYRK1A expression. Taken together, these results suggest direct transcriptional regulation through the KMT2A fusion complex. Surprisingly, RNA and protein expression of DYRK1A was reduced in KMT2A-R ALL compared to other B-ALL subtypes. We then identified MYC as a potential negative regulator of DYRK1A that could explain the lower RNA and protein expression levels observed. A gain-of-function experiment showed marked downregulation of DYRK1A when MYC was ectopically expressed in murine B-cells, while loss of MYC resulted in DYRK1A upregulation. Parallel analysis of publicly available gene expression data from children with high-risk B-ALL (NCI TARGET database) showed significantly higher MYC RNA expression levels in KMT2A-R ALL as compared to other ALL subtypes, further validating our findings that MYC acts as a negative regulator of DYRK1A. Finally, to assess pharmacologic inhibition, we treated multiple KMT2A-rearranged ALL cell lines with the novel DYRK1A inhibitor EHT 1610 and identified sensitivity to DYRK1A inhibition. We then queried the Achilles database and identified that DYRK1A is not a common essential gene in normal tissues, suggesting minimal potential for on-target/off-tumor effects of DYRK1A inhibition. Conclusions: We identified a novel mechanism in KMT2A-R ALL in which DYRK1A is positively regulated by the KMT2A fusion protein and negatively regulated by MYC. Genetic deletion and pharmacologic inhibition of DYRK1A resulted in significant growth disadvantage of KMT2A-R ALL cells. While further studies are needed, we predict that combining DYRK1A inhibitors with chemotherapy could decrease relapse risk and improve long-term survival of patients with KMT2A-R B-ALL. Disclosures Crispino: MPN Research Foundation: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy; Scholar Rock: Research Funding; Forma Therapeutics: Research Funding. Tasian:Incyte Corportation: Research Funding; Gilead Sciences: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy.

Genetic Characteristics and Outcomes By Mutation Status in a Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Newly Diagnosed, High-Risk/Secondary Acute Myeloid Leukemia (AML)

Lindsley: Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding. Stone:AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding. Cortes:Astellas Pharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; BiolineRx: Consultancy; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding. Uy:GlycoMimetics: Consultancy; Astellas: Consultancy; Curis: Consultancy; Pfizer: Consultancy. Lin:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria. Ritchie:Celgene, Incyte, Novartis, Pfizer: Consultancy; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Celgene, Novartis: Other: travel support; Jazz Pharmaceuticals: Research Funding; Genentech: Other: Advisory board; Celgene: Other: Advisory board; Pfizer: Other: Advisory board, travel support; agios: Other: Advisory board; Tolero: Other: Advisory board. Prebet:novartis: Honoraria; pfizer: Honoraria; pfizer: Honoraria; novartis: Honoraria; Boehringer Ingelheim: Research Funding. Ryan:Jazz Pharmaceuticals: Employment, Equity Ownership. Faderl:Jazz Pharmaceutics: Employment, Equity Ownership. Lancet:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy.