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Pulmonary arterial hypertension (PAH) is a life-threatening complication of β-thalassemia, especially in untransfused patients with thalassemia intermedia. Pinto and colleagues analyzed the outcome of 24 patients with PAH documented by right heart catheterization, and they report that with a median follow-up of 4 years, 54% died, most of which deaths were attributable to PAH. Patients who receive treatment that reduce their pulmonary pressures have improved survival, suggesting that improvement in monitoring and treatment are critical imperatives for these patients.

Patients with hematological malignancies (HM) undergoing hematopoietic stem cell transplantation (HSCT) have an increased vulnerability to SARS-Cov-2 (Sharma et al, Lancet Haematology 2020; Ljungman et al, Leukemia 2021), the reason why international guidelines strongly support the need for a protective vaccination for these subjects. The most relevant data currently available on the response to a complete anti-SARS-Cov-2 vaccination cycle in HM patients after HSCT refer to 314 patients reported in a Lithuanian national survey (Maneikis et al, Lancet Haematol 2021). In this study, the median titers of antibodies against SARS-Cov-2, determined 7-21 days after the second vaccination, were comparable to that of healthy controls (HC) in both autologous and allogeneic groups, with no patient found below the protective threshold of 50 arbitrary units (AU)/ml. Notably, the large majority of patients had received the transplant more than 1 year before vaccination. In a prospective, cohort study, we compared 114 patients, who had received an autologous or allogeneic HSCT at least three months before the first dose of vaccination, to 107 HC, matched for age and sex. Study population and HC received two doses of BNT162b2 anti-SARS-Cov-2 mRNA vaccine on days 1 and 21, between April and May 2021. Serological tests were performed by a commercially available immunoassay for the quantitative determination of anti-spike IgG antibodies to SARS-Cov-2. The cut-off for defining responders was 50 or greater AU/ml. Patients and HC samples were collected four weeks after the second dose of the vaccine. Table 1 reports the main clinical characteristics of patients and HC. Eighteen of 114 patients (16%) did not respond (24% in the allogeneic group, 6% in autologous recipients). Overall, median antibodies titers did not differ between HC and the entire cohort of transplanted patients, recipients of allogeneic HSCT, all patients responding to the vaccine or responders in the autologous subgroup (Figure 1A). All autologous HSCT recipients had significantly lower titers of antibodies than HC, while higher levels were found in responders who had received allogeneic HSCT (Figure 1A). Responders in the allogeneic subgroup showed antibodies titers significantly higher than responders in the autologous subgroup (Figure 1B). We further stratified patients in three groups, according to the time elapsed from transplant to vaccination: G1:5 years. Higher antibodies titers were observed in HC compared to all transplanted patients in G1 (Figure 1C), including both allogeneic (Figure 1D) and autologous (Figure 1E) HSCT recipients. No differences emerged in G2 between HC and all patients (Figure 1C), allogeneic (Figure 1D) or autologous (Figure 1E) HSCT recipients. Finally, no differences were found in G3 when comparing HC with all patients (Figure 1C) or allogeneic recipients (Figure 1D), whereas patients in the autologous subgroup showed significantly lower titers than HC (Figure 1E). Myeloma patients with controlled disease showed higher titers than patients with active disease (Figure 1F). According to median age, autologous HSCT recipients older than 57 years had significantly lower antibody levels than younger patients (Figure 1G). Autologous vs allogeneic HSCT, age of all patients and of allogeneic HSCT recipients, sex, type of allogeneic HSCT, conditioning regimen, age and sex of donor, occurrence of GVHD, disease type and single vs double autologous HSCT did not significantly impact on antibody levels (data not shown). No relevant side effects were recorded after vaccination. With a median follow up of 12 weeks, no case of COVID19 occurred among vaccinated patients. In our single center study, patients with a previous history of HSCT tolerated well BNT162b2 vaccine and mounted a potentially protective immune response in the majority of cases one month after two doses of vaccine. However, lack of response was not rare, especially in the allogeneic setting. The main factor associated with the quality of response was the time from HSCT, with lower responses within the first year from transplant and differences between autologous and allogeneic groups transplanted more than five years before vaccination. Here, a consolidated, complete immune reconstitution in allogeneic HSCT recipients, as well as age and a still active disease in the autologous setting, could have played opposite pivotal roles. Figure 1 Figure 1. Disclosures Delia: Gilead: Consultancy; Amgen: Consultancy; abbvie: Consultancy; Jazz pharmaceuticals: Consultancy.

PV, NR and MMP contributed equally Introduction Patients with red blood cell disorders (RBCD), chronic life threating multisystemic disorders in their severe forms, are likely to be at increased risk of complications from SARS-Cov-2 (Covid-19), but evidence in this population is scarce due to its low frequency and heterogeneous distribution. ERN-EuroBloodNet, the European Reference Network in rare hematological disorders, established a European registry to determine the impact of COVID-19 on RBCD patients and identify risk factors predicting severe outcomes. Methods The ERN-EuroBloodNet registry was established in March 2020 by Vall d'Hebron Research Institute based on REDcap software in accordance with the Regulation (EU) 2016/679 on personal data. The local Research Ethics Committee confirmed that the exceptional case of the pandemic justifies the waiver of informed consent. The ERN-EuroBloodNet registry on RBCD and COVID-19 is endorsed by the European Hematology Association (EHA). Eligible patients had confirmed RBCD and COVID-19. Data collected included demographics, diagnosis, comorbidities, treatments, and COVID-19 (severity grade, clinical manifestations, acute events, treatments, hospitalization, intensive care unit, death). For analysis of COVID-19 severity, two groups were established 1) Mild: asymptomatic or mild symptoms without clinical pneumonia and 2) Severe: pneumonia requiring oxygen/respiratory support and/or admission to intensive care unit. Continuous variables were compared using the Wilcoxon rank-sum test or Kruskall Wallis test, while categorical variables were analyzed using the Chi-square test or Fisher's Exact test. Relevant factors influencing disease or severity were examined by the logistic regression adjusted for age. Results As of June 2021, 42 medical centers from 10 EU countries had registered 373 patients: 191 Sickle cell disease (SCD), 156 Thalassemia major and intermedia (THAL) and 26 other RBCD. 84% of the SCD patients were reported by Spain, Belgium, Italy and The Netherlands and 92% of the THAL patients by Italy and Greece. The mean age of SCD was lower (22.5y) than of THAL (39.6y) with pediatric population accounting for 50.5% in SCD and 9% in THAL (p Age and BMI correlated with COVID-19 severity, as described in the general population (p=0.002, p Potential risk factors such as elevated ferritin, current chelation or history of splenectomy did not confer additional risk for developing severe COVID-19 in any patient group. Only diabetes as a comorbidity correlated with severity grade in SCD (p=0.011) and hypertension in THAL (p=0.014). While severe COVID-19 infection in SCD was associated with both ACS (p Overall, 14.8% RBC patients needed oxygen/respiratory support, 4.4% were admitted to ICU with an overall mortality rate of 0.8% (no deaths were registered in pediatric age), much lower than reported in other similar cohorts. Discussion Results obtained so far show that severe COVID-19 occurs at younger ages in more aggressive forms of SCD and THAL. Current preventive approaches (shielding, vaccinations) focus on age over disease severity. Our data highlights the risk of severe COVID-19 infection in some young patients, particularly those with SS/SB0 SCD, suggesting that immunization should be considered in this pediatric group as well. Results between similar sized cohorts of RBCD patients vary between each other and those presented here, highlighting the importance of collecting all of these small cohorts together to ensure adequate statistical power so that definitive risk factors (eg. age, genotype, comorbidities) can be reliably identified and used to guide management of patients with these rare disorders in the light of the ongoing pandemic. Figure 1 Figure 1. Disclosures Longo: Bristol Myers Squibb: Honoraria; BlueBird Bio: Honoraria. Bardón-Cancho: Novartis Oncology Spain: Research Funding. Flevari: PROTAGONIST COMPANY: Research Funding; ADDMEDICA: Consultancy, Research Funding; BMS: Research Funding; IMARA COMPANY: Research Funding; NOVARTIS COMPANY: Research Funding. Voskaridou: BMS: Consultancy, Research Funding; IMARA: Research Funding; NOVARTIS: Research Funding; ADDMEDICA: Consultancy, Research Funding; GENESIS: Consultancy, Research Funding; PROTAGONIST: Research Funding. Biemond: GBT: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Honoraria; Celgene: Honoraria; Sanquin: Research Funding. Nur: Celgene: Speakers Bureau; Roche: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Beneitez-Pastor: Agios: Honoraria; Alexion: Honoraria; Novartis: Honoraria; Forma Therapeutics: Honoraria. Pepe: Chiesi Farmaceutici S.p.A: Other: no profit support; Bayer S.p.A.: Other: no profit support. de Montalembert: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees. Glenthøj: Agios: Consultancy; Novo Nordisk: Honoraria; Novartis: Consultancy; Alexion: Research Funding; Bluebird Bio: Consultancy; Bristol Myers Squibb: Consultancy; Saniona: Research Funding; Sanofi: Research Funding. Benghiat: Novartis: Consultancy; BMS: Consultancy. Labarque: Novartis: Consultancy; Bayer: Consultancy; Sobi: Consultancy; NovoNordisk: Consultancy; Octapharma: Consultancy. Diamantidis: Genesis Pharma: Honoraria; Uni-Pharma: Honoraria; Bristol Myers Squibb: Consultancy; IONIS Pharmaceuticals: Research Funding; NOVARTIS, Genesis Pharma SA: Research Funding. Kerkhoffs: Sanofi: Research Funding; Terumo BCT: Research Funding. Iolascon: Celgene: Other: Advisory Board; Bluebird Bio: Other: Advisory Board. Taher: Vifor Pharma: Consultancy, Research Funding; Agios Pharmaceuticals: Consultancy; Ionis Pharmaceuticals: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Colombatti: Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novonordisk: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding. Mañú Pereira: Novartis: Research Funding; Agios Pharmaceuticals: Research Funding.

Iron overload and chronic viral hepatitis underlie the increased incidence of hepatocellular carcinoma in patients with Beta thalassemia, as recently emerged due to the prolonged survival. Conversely, there are very few studies examining the relationship between thalassemia and other malignancies. Although some Authors have indicated an increase in incidence of hematologic and solid tumours such as thyroid cancer and renal cell carcinoma, there are not enough data to make a conclusion. Moreover, there is even less data on a possible relationship between other Hemoglobinopathies and tumors risk. Seven Italian Specialized Centres for the treatment of Hemoglobinopathies, with the patronage of the "Società Italiana Talassemie ed Emoglobinopatie" (SITE), evaluated the incidence of malignant neoplasms in Hemoglobinopathies, their site and features. Each Center considered all consecutive patients of its own historical series; the cohort included 4104 patients (48% males), followed between 1970 and 2021 (Figure 1A), for a total of 143255 person-years of observation. The most common diagnosis was Transfusion-Dependent Beta Thalassemia (TDT) with 2122 subjects (51.7%), followed by Non-Transfusion-Dependent Beta Thalassemia (NTDT, 789 subjects, 19.2%), Sickle Cell Disease (SCD, 787, 19.2%), Hemoglobin H Disease (HbH, 375, 9.1%) and Other (34, 0.8%). Two-hundred-sixty-two patients had undergone bone marrow transplantation (BMT). A total of 157 diagnoses of cancer (153 patients, 52% males) was reported during the period of observation, corresponding to a prevalence of 3.8%, with the mean age at the diagnosis of 47±13 years. Hepatocellular carcinoma (HCC) was the most frequent site (62 cases) in both sexes (males 50%, females 32%) contributing to 41% of total number of cases, excluding non-melanoma skin cancer, and in all type of hemoglobinopathies (except HbH). No significant differences were found in the age of diagnosis of HCC stratifying for gender (males 48±14 years, females 51±9 years) and types of Hemoglobinopathies (TD 48±9 years, NTDT 51±10 years, SCD 50±14 years). After HCC, hematologic tumours (11), kidney (6), and lung (6) were the most frequent sites in men, accounting for 29% of all male cancers. For women, the most common incident cancers were breast (9), thyroid (8) and kidney (7), these representing 33% of all female cancer cases (Figure 1B). The first diagnoses of cancer dated back to the 1980s and their number sharply increased after the 2000s with a peak in the five-year period 2008-2012 and a (not significant) reduction in recent years. A similar trend may be noted considering HCC alone but in this specific case, the reduction reaches the level of significance (Figure 1C). The overall age-adjusted incidence rate of cancer in Hemoglobinopathies was estimated to be 391 cases/100000 person-years (95% C.I. 290-650) which was not statistically different from that of the Italian general population (632 cases/100000 person-years), both considering Hemoglobinopathies in total and each subgroup of patients. However, age-adjusted incidence rate of HCC was more than 7 times lower in general population (22 cases/100000 person-years) than in patients with Hemoglobinopathies (153 cases/100000 person-years, 95% C.I. 96-222, p Although preliminary, these findings provide novel insights into the relationship between cancer and Hemoglobinopathies, suggesting that the overall cancer risk is not increased in these patients. HCC is confirmed as the most frequent tumor, especially in patients with Beta Thalassemia (TD and NTDT), but advances in chelation, with renewed attention to hepatic iron, and the new drugs that have led to the eradication of hepatitis C even in these patients, may explain the recent reduction in the number of diagnoses that we have reported in this study. Acknowledgment. We would like to thank ALT (Associazione per la Lotta alla Talassemia R.Vullo - Ferrara). Figure 1 Figure 1. Disclosures Origa: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Longo: Bristol Myers Squibb: Honoraria; BlueBird Bio: Honoraria. Pinto: BlueBird Bio: 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. Quarta: Sanofi - Genzyme: Membership on an entity's Board of Directors or advisory committees, Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Speaker at conferences; Blue Bird Bio: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Celgene: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; Speaker at conferences; Takeda: Other: collaboration relationships for Advisory boards, Webinar events, editorial projects; speaker at conferences; Bristol Meyer Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Speaker at conferences. Casale: Novartis Farma SpA: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maggio: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Perrotta: Novartis Farma SpA: 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; Blue Bird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees. Forni: Celgene: Membership on an entity's Board of Directors or advisory committees; Bluebirdbio: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Introduction: Ineffective erythropoiesis (IE) is a crucial hallmark of β-Thalassemia (β-Thal) and sets the goal for treatment of both Transfusion-Dependent (TDT) and Non Transfusion-Dependent Thalassemia (NTDT) patients. The Growth Differentiation Factor (GDF) group has a relevant role in the molecular regulation of IE. Specifically, GDF11 contributes to the inhibition of RBC maturation and it is targeted by activin traps, such as luspatercept. However, its role is still debated; i.e., in a mouse model of β-Thal, the absence of GDF11 alone is not sufficient to mitigate IE (Guerra A et al., Blood, 2019). GDF15 increases from early until late phases of erythroid differentiation and negatively regulates erythroid cell development in-vitro, modulating maturation and apoptosis. (Ranjbaran R et a.l, Exp Cell Res, 2020). A few clinical studies found elevated serum GDF15 levels in β-Thal (Tanno T et al., Nat Med, 2007; Huang Y et al., Int J Med Sci, 2019), but data are sparse and a clear correlation with the severity of the pathology is still missing. Methods: We run an observational study at our institution. At routine checks, patients were asked to consent to a specific blood sample for GDF15, whereas hemoglobin (Hb), serum erythropoietin (Epo), ferritin (Ftn), iron, and transferrin saturation (TSat) were measured as part of clinical practice. In a small subset of patients, a consent for serial sampling was added. Serum GDF15 was measured by ELISA (DuoSet DY957, R&D Systems). Demographics were collected from clinical records. Statistical analysis was performed using Statistica 10 (Statsoft). Results: GDF15 levels were measured in 458 individuals: 267 TDT, 77 NTDT, 45 β-Thal trait carriers (BTC), and 69 healthy (H) subjects. Median (IQR) levels of GDF15 were significantly different among diagnoses (P Discussion: GDF15 levels correlated with the severity of β-Thal phenotype, showing a 26-fold (TDT), a 6-fold (NTDT) and a 2-fold (BTC) increase compared to controls. In TDT patients, higher GDF15 levels correlated with lower Hb and higher Epo, which are typically observed as a result of IE in thalassemia. In addition, GDF15 correlated with markers of altered iron metabolism, such as TSat and serum iron. In individual patients, GDF15 showed strong and consistent variation with treatment. GDF15 was also associated with quantitative markers of disease in NTDT and BTC patients. This is to our knowledge the larger sample of patients carrying β-thal mutations in which GDF15 levels were measured and correlated with the severity of the disease. These results show that GDF15 may be a suitable and useful quantitative marker of IE. Figure 1 Figure 1. Disclosures Piga: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron: Research Funding. Longo: Bristol Myers Squibb: Honoraria; BlueBird Bio: Honoraria.

Despite recent advances, there is still a lack of treatment options for patients with high-risk multiple myeloma (MM), warranting the need for novel therapeutic targets. Monopolar spindle 1 (Mps1), also known as TTK protein kinase, is localized at the kinetochores and centromeres essential for the mitotic spindle checkpoint and centrosome duplication. In cancer cells, high levels of Mps1 help to support aneuploidy, a common malignant trait. In fact, high MPS1 expression correlates to unfavorable prognosis in colon and breast cancers. Here, we report the importance of Mps1 in MM and perform functional characterization of a novel Mps1 inhibitor, OSU-13. To assess the relevance of Mps1 in MM prognosis, we analyzed the CoMMpass database and examined the association of MPS1 expression with clinical outcome and genetic alterations in MM patients (n=769). Elevated MPS1 expression correlates with decreased overall survival (p-value = 0.0001) and decreased event-free survival (p-value < 0.0001). In addition, MPS1 expression is higher in high-risk MM with specific genetic alterations, such as deletion of 17p (p-value = 0.0003), Myc translocation t(8;14) (p-value = 0.02), and gain of 1q21 (p-value = 0.0001). We therefore compared MPS1 expression in eight different MM cell lines and primary CD138 - and CD138 + cells isolated from bone marrow (BM) of four recently diagnosed, untreated MM patients. Gene expression levels assessed by quantitative qPCR were normalized to 18S mRNA internal control, and relative quantification was performed using the ΔΔCt method. MPS1 expression was higher in all MM cell lines compared to the average expression level in primary CD138 + BM plasma cells, with a minimum of 3.2-fold increase in L363 and a maximum of 16.2-fold increase in MM1S. In addition, MPS1 expression was 2-fold higher in CD138 + MM cells compared to CD138 - counterparts from the BM of the same patient, suggesting its selectivity as a target. Next, we characterized the effects of OSU-13, a novel Mps1 inhibitor. In an Mps1 target engagement assay (NanoBRET™) in HEK293 cells, we measured the relative levels of OSU-13-mediated inhibition of Mps1-NanoLuc binding to a fluorescent tracer in comparison to MM clinical candidates. OSU-13 showed EC 50=10 nM, almost 10-fold lower than other agents tested. Endpoint measurement by MTT (3-[4,5- dimethylthiazol- 2-yl]-2,5-diphenyltetrazolium bromide) assay was used to evaluate cytotoxicity of OSU-13. MM cell lines were treated with increasing doses of OSU-13 for 72h and cell viability was measured. OPM-2 was the most sensitive cell line (IC 50 = 610 nM), followed by H929 (IC 50 = 1440 nM), RPMI-8226 (IC 50 = 4196 nM), and U266 (IC 50 = 5071 nM). To investigate the kinetics and the mechanisms used by OSU-13 to cause cell death, we treated H929 and OPM-2 cell lines with 500 nM of OSU-13 for 24h, 48h, 72h, 96h, and 120h and assessed both Annexin V-FITC and Zombie-Aqua staining by flow cytometry. Treatment with OSU-13 caused an increase in Annexin V staining as early as 24h in H929 (2.1-fold) and OPM-2 (1.6-fold). Maximum increase of apoptotic cells (Annexin V single positive) was observed after 72h, with a 5-fold increase in OPM-2 and 8.6-fold increase in H929 cell line. Cell death peaked at 120h, with Zombie staining 74% of OPM-2 and 60% of H929 cells. The activity of caspases 3/7 was further assessed in H929 myeloma cells at five time points after treatment with different concentrations of OSU-13. Caspases 3/7 activation started after 48h with 500nM OSU-13, and peaked after 72h post-treatment with the same dose, in agreement with the Annexin staining kinetics results. Finally, we evaluated the in vivo effect of OSU-13 in tumor growth in a H929 MM subcutaneous xenograft model in CB.17 SCID mice. Mice were treated with 5 mg/kg or 10 mg/kg daily dose of OSU-13 per oral gavage for 21 days. Treatment with 10 mg/kg daily dose of OSU-13 produced a 22% tumor growth delay (p Collectively, we show here that elevated MPS1/TTK expression correlates with poorer prognosis in MM, and OSU-13, a novel Mps1/TTK inhibitor, induces apoptosis and cell death in MM cell lines, and decreases tumor growth in mice containing H929 cell xenografts. Together, our findings reveal that targeting the mitotic checkpoint using OSU-13 is a potential novel strategy, particularly for high risk MM. Disclosures No relevant conflicts of interest to declare.

Background: Outcomes of patients with relapsed/refractory AML (RR-AML) have remained poor. Therapy with venetoclax based combinations in this setting leads to CR/CRi rates of 21-49% (DiNardo CD et al. Am J Hematol 2018, Aldoss I et al. Haematologica 2018, Stahl M et al. Blood Adv 2020). Preclinical studies with BCL-2 inhibitors indicate potential mechanisms of drug resistance including overexpression of the anti-apoptotic protein MCL-1 (Konopleva et al. Cancer Cell. 2006). Pevonedistat is a first in class inhibitor of Nedd8 activating enzyme that induces the pro-apoptotic protein NOXA leading to neutralization of MCL-1 and apoptosis. Preclinical studies evaluating the combination of pevonedistat and venetoclax against AML cell lines have demonstrated a synergistic effect (Knorr KL et al. Cell Death Differ. 2015). Hence, we designed a phase I study to assess the safety and tolerability of adding pevonedistat to the combination of azacitidine and venetoclax in patients with RR-AML. Study design and methods: We conducted a phase I study with the combination of pevonedistat, venetoclax and azacitidine in patients with RR-AML. Patients aged 18 years or above with morphologically documented RR-AML, ECOG performance status 0-2 and adequate organ function were eligible. Major exclusion criteria were isolated extramedullary relapse, hematopoietic cell transplantation (HCT) within 100 days of enrollment, and active acute GVHD. Previous therapy with hypomethylating agents (HMA) or venetoclax was not an exclusion criterion. The dose escalation phase was conducted using 3+3 design. Treatment included azacitidine (75 mg/m 2 daily x 7 days), venetoclax (400 mg daily x 28 days), and pevonedistat in escalating doses (10-20 mg/m 2 IV days 1,3,5 of each cycle) with a cycle length of 28 days. Pevonedistat was given at 10 mg/m 2 dose in cohort 1, 15 mg/m 2 dose in cohort 2 and 20 mg/m 2 dose in cohort 3. The primary endpoint is to determine the recommended phase 2 dose (RP2D) and toxicity profile of pevonedistat, azacitidine and venetoclax. Other endpoints included determination of response rates, duration of response, survival, pharmacokinetics, correlation of response rates with AML genomic profile, correlation of pretreatment levels of BCL2, BCLXL, MCL1, BAX or BAK with response, determination of changes in NOXA (PMAIP1) mRNA and protein expression pre-and post-pevonedistat treatment, evaluation of BH3 mimetic profiling on bone marrow samples by flow cytometry and assessing the sensitivity of leukemia and leukemic stem/progenitor cells to pevonedistat ex vivo. Results: Thirteen patients participated in the dose escalation phase, 12 of whom were evaluable. Median age was 69 years (61-91), 30.8% had secondary/therapy related AML, 69.2% with adverse risk disease, 53.8% previously received venetoclax/HMA and 23.1% had relapse after prior allogeneic hematopoietic cell transplantation (HCT) (Table 1). Seven patients were enrolled into cohort 1 (pevonedistat 10 mg/m 2 dose) of which one was not evaluable, three patients enrolled into cohort 2 (pevonedistat 15 mg/m 2 dose), and three patients enrolled into cohort 3 (pevonedistat 20 mg/m 2 dose). Grade 3 or higher AEs included febrile neutropenia (23%), infection (15%), anemia (38%), neutropenia (54%), thrombocytopenia (38%). There was 1 dose limiting toxicity (DLT) in cohort 1 (atrial fibrillation) that triggered cohort expansion. However, subsequent patients did not experience DLT despite planned dose escalation. Of the 12 evaluable total patients, CR/CRi was observed in 5 (41.6%) patients. Notably, patients with RR-AML who were venetoclax/HMA naïve had a CR/CRi 83.3% (5/6 patients). The response rates for each cohort are summarized in Table 2. Three of the five patients with CR/CRi (60%) achieved MRD negativity by flow cytometry. Four patients who achieved CR/CRi proceeded to allogeneic HCT after therapy. Median OS of the cohort was 5.4 months (1.8-14) and median OS was not reached in patients with CR/CRi. Conclusions: The addition of pevonedistat to venetoclax and azacitidine backbone is safe and well tolerated in patients with RR-AML. Dose escalation yielded encouraging efficacy in venetoclax/HMA naïve RR-AML patients. The study is currently in the dose expansion phase. Details on correlative studies examining mechanisms of therapeutic efficacy and resistance will be reported in the main meeting. Figure 1 Figure 1. Disclosures Guru Murthy: Cardinal health: Honoraria; TG Therapeutics: Other: Advisory board meeting; DAVA Oncology: Honoraria; CancerExpertNow: Honoraria; Qessential: Honoraria; Techspert: Consultancy; Curio Sciences: Honoraria; Guidepoint: Consultancy. Abedin: AltruBio: Research Funding; Helsinn: Research Funding; Amgen: Honoraria; Pfizer: Research Funding; Agios: Honoraria; Actinium: Research Funding; Astellas Pharma Inc.: Research Funding. Litzow: Jazz: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Atallah: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau; Amgen: Consultancy.