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The incidence and prognosis of clonal hematopoiesis in patients with isolated neutropenia among patients with idiopathic cytopenia of undetermined significance (ICUS), known as ICUS-N or chronic idiopathic neutropenia (CIN) patients, is poorly defined. The current study sought to investigate the frequency and clinical significance of mutations of genes implicated in myeloid malignancies using next-generation sequencing in patients with CIN (n = 185) with a long follow-up. We found that 21 (11.35%) of 185 patients carried a total of 25 somatic mutations in 6 genes with a median variant allele frequency of 12.75%. The most frequently mutated genes were DNMT3A and TET2 involving >80% of patients, followed by IDH1/2, SRSF2, and ZRSR2. The frequency of transformation to a myeloid malignancy was low in the total group of patients (5 of 185 patients [2.70%]). However, from the transformed patients, 4 belonged to the clonal group (4 of 21 [19.05%]) and 1 to the nonclonal group (1 of 164 [0.61%]), indicating that the presence of mutation(s) confers a relative risk for transformation of 31.24 (P = .0017). The variant allele frequency of the mutant clones in the transformed patients was >10% in all cases, and the genes most frequently associated with malignant transformation were SRSF2 and IDH1. No significant differences were identified between the clonal and nonclonal groups in the severity of neutropenia. Patients with clonal disease were older compared with nonclonal patients. These data contribute to the better understanding of the heterogeneous entities underlying ICUS and highlight the importance of mutation analysis for the diagnosis and prognosis of patients with unexplained neutropenias.

Metabolic alterations in cancer represent convergent effects of oncogenic mutations. We hypothesized that a metabolism-restricted genetic screen, comparing normal primary mouse hematopoietic cells and their malignant counterparts in an ex vivo system mimicking the bone marrow microenvironment, would define distinctive vulnerabilities in acute myeloid leukemia (AML). Leukemic cells, but not their normal myeloid counterparts, depended on the aldehyde dehydrogenase 3a2 (Aldh3a2) enzyme that oxidizes long-chain aliphatic aldehydes to prevent cellular oxidative damage. Aldehydes are by-products of increased oxidative phosphorylation and nucleotide synthesis in cancer and are generated from lipid peroxides underlying the non–caspase-dependent form of cell death, ferroptosis. Leukemic cell dependence on Aldh3a2 was seen across multiple mouse and human myeloid leukemias. Aldh3a2 inhibition was synthetically lethal with glutathione peroxidase-4 (GPX4) inhibition; GPX4 inhibition is a known trigger of ferroptosis that by itself minimally affects AML cells. Inhibiting Aldh3a2 provides a therapeutic opportunity and a unique synthetic lethality to exploit the distinctive metabolic state of malignant cells.

Clonal cytopenia of undetermined significance (CCUS) is associated with an increased risk of developing a myeloid neoplasm with myelodysplasia (MN). To identify the features of the mutant clone(s) that is associated with clinical phenotype and progression, we studied the following cohorts of individuals: 311 patients with idiopathic cytopenia of undetermined significance (ICUS), 532 community-dwelling individuals without hematologic phenotype (n = 355) or with unexplained anemia (n = 177), and 592 patients with overt MN. Ninety-two of 311 (30%) patients with ICUS carried a somatic genetic lesion that signaled CCUS. Clonal hematopoiesis (CH) was detected in 19.7% and 27.7% of nonanemic and anemic community-dwelling individuals, respectively. Different mutation patterns and variant allele frequencies (VAFs) (clone metrics parameters) were observed in the conditions studied. Recurrent mutation patterns exhibited different VAFs associated with marrow dysplasia (0.17-0.48), indicating variable clinical expressivity of mutant clones. Unsupervised clustering analysis based on mutation profiles identified 2 major clusters, characterized by isolated DNMT3A mutations (CH-like cluster) or combinatorial mutation patterns (MN-like cluster), and showing different overall survival (HR, 1.8). In patients with CCUS, the 2 clusters had different risk of progression to MN (HR, 2.7). Within the MN-like cluster, distinct subsets with different risk of progression to MN were identified based on clone metrics. These findings unveil marked variability in the clinical expressivity of myeloid driver genes and underline the limitations of morphologic dysplasia for clinical staging of mutant hematopoietic clones. Clone metrics appears to be critical for informing clinical decision-making in patients with clonal cytopenia.

Background: The treatment for relapsed or refractory acute myeloid leukemia (R/R AML) has minimal chances and a low impact on improving survival. One of the most important goal is to treat unfit patients who are often intolerant to intensive chemotherapy and are not eligible for allogeneic stem cell transplantation. Most patients with AML, including nearly all patients older than 60 years, present multiple, sequentially acquired, somatic mutations. Isocitrate dehydrogenase 2 (IDH2) mutations are present in approximately 8-19% of cases (Buege MJ, Cancers 2018). IDH2 mutations occur early in the leukemogenesis and accumulate an oncogenic product (R-2-hydroxyglutarate) that arrests the histone demethylation pathway, thereby stopping haematopoietic differentiation (Rakheja D, Hum Pathol. 2012). Enasidenib (ENA) is a selective, powerful oral inhibitor of the oncogenic activity of the IDH2 mutant enzyme, that decreases R-2-hydroxyglutarate levels in vitro and in vivo. Interestingly, phase I/II trials showed an overall response rate (ORR) of 40.3% in R/R disease, with 19.3% of complete remission (CR) and with 6.8 % of CR with incomplete haematological recovery (CRi). Moreover, the reported median overall survival was 9.3 months, with 19.7 months (mo) for patients who achieved CR (Stein E, Blood 2017). Aims: To study retrospectively the efficacy and safety of ENA, as single agent, in improving overall survival (OS) and progression-free survival (PFS) in IDH2 mutated R/R AML patients (pts), unfit for intensive chemotherapy. Furthermore, to compare outcomes with a cohort of patients with R/R AML IDH2 wild-type (wt). Methods: Since 2018 we have retrospectively collected and analyzed data of unfit IDH2 mutated R/R AML patients, treated with ENA, thanks to the expanded access program of this drug. The dose was 100 mg/day for all pts. PFS and OS were estimated using the Kaplan-Meier product limit method. Therefore, we considered, as historical comparison, a sample of 28 pts with R/R IDH2 wt AML, treated with the best available therapy at our Institution in the same time frame and matched for clinical features. OS and PFS were compared using the log-rank test. Results: Nine IDH2 mutated pts were considered for analysis: 4 (44%) cases were de novo AML, while 5 (56%) were secondary (1 myelodysplasia and 4 myeloproliferative neoplasms). Median age at relapse was 71 years (range 47-79). Median number of previous therapies was 2 (range 1-3). All pts completed at least one cycle of ENA with a median number of 5 cycles (range 1-16). Median OS from AML diagnosis and from the beginning of ENA was 28 mo (range 3-65), and 15 mo (range 1-27) respectively; median PFS was 13 mo (range 1-14). Among the 28 patients of the control group, with a median age at relapse of 74 years (range 65-86) we recorded a median OS of 14 mo (range 7-62) and an OS from the last relapse of 2 mo (range 0,5-26). The ENA pts group showed a significantly better OS than the control population (p = 0,0419) (Figure 1). The most prominent toxicities were hyperbilirubinemia in 2 pts (22,2%) and IDH-differentiation syndrome (IDH-DS) in 3 (33,3%); though the drug was generally well tolerated. Therefore, patients were treated as outpatients in most cases. Conclusions: In the era of precision medicine, molecular target therapy is the most promising strategy to increase the probability of treatment success with limited side effects. Our experience confirms the efficacy of the IDH2 inhibitor ENA to treat unfit patients with R/R AML in the real life, showing significantly better outcome in terms of survival for the pts treated with target therapy, compared to pts treated with standard therapy. Disclosures Veronese: Janssen Cilag:Honoraria;Bayer:Honoraria;Novartis:Other: Travel Expenses;AstraZeneca:Other: Travel Expenses.

Background Low risk Myelodysplastic syndromes (LR MDS) are a heterogeneous group of clonal disorders of the hematopoietic stem cell characterized by ineffective hematopoiesis, peripheral cytopenias and relative increase of bone marrow blasts [List 2004]. The most common cytopenia is anemia, which occurs in 85-90% of cases (isolated in 35% of cases) [Fenaux 2013], and ranges from mild/asymptomatic to transfusion dependent. The standard of care for anemia remains supportive care and about 70% of cases benefits from erythropoiesis-stimulating agents (ESAs). According to the FAB classification, a low-risk group of MDS characterized by the presence of ring sideroblasts (RS) was recognized. In the 2017 WHO classification, the nosologic entities of MDS uni-linear and multi-linear dysplasia with RS (MDS-UD-RS, MDS-MD-RS) were established, to emphasize the importance of identifying forms with a potential therapeutic target [Arber 2016]. Luspatercept is a recombinant fusion protein consisting of the modified extracellular domain of human activin receptor type IIB (ActRIIB) linked to a domain of human immunoglobulin Fc G1. The drug showed efficacy in re-establishing erythropoiesis and was recently approved for the treatment of adult patients with very low- to intermediate-risk MDS-RS failing ESAs[Platzbecker 2017; Fenaux 2020]. Aims To retrospectively assess the efficacy and/or clinical benefit (defined as a reduction in red blood cells transfusions [RBCT] or increase in hemoglobin levels) of luspatercept in patients with LR MDS with RS in a real-life setting. Safety issues were also addressed and clinical and hematological predictors of outcome analyzed. Methods We considered all IPSS-R lower-risk MDS with RS patients with unsatisfactory response or unsuitable for ESAs, treated with luspatercept as monotherapy through an expanded access program since November 2020, in 2 tertiary hematologic centers in Milan, Italy. Luspatercept was administered according to the published schedule: starting dose 1,0 mg/kg every three weeks, with the possibility to increase up to 1,33 mg/kg and 1,75 mg/kg if patients did not reach transfusion independence or decreased transfusion burden after two consecutive infusions. Response to luspatercept was evaluated according to IWG 2018 criteria: Hb increase by > 1.5 g/dL and/or relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 wk compared with the pretreatment transfusion number in the previous 8 wk. Results We included a total of 17 pts (70% males, 30% females), with a median age of 68 years (range 45-89). The median follow-up from the start of the Luspatercept was 4 months (range 3-6).According to WHO 2017 we included 13 MLD (76%) and 4 ULD (24%); in all of them SF3B1 mutations was confirmed. Moreover, According to IPSS-R classification: 5 (27%)cases were intermediate and 12 (73%) low risk. All patients received at least three doses of luspatercept. Nine patients (53%) needed a dose escalation to 1,33 mg/kg, and 7 (41%) required the maximal dose of 1,75 mg/kg. Interestingly, not all patients received a dose escalation, and 8 (47%) obtained prolonged efficacy with 1 mg/kg dose. Hemoglobin levels increased in 9 pts (53%): 4 (24%), 3 (18%) and 2 (12%) cases at 1 mg/Kg, 1,33 mg/kg and 1,75 mg/dl, respectively. Medina increase was 1,5 g/dl (range 0,2 - 2,2) and these levels were maintained for a median of 4 months (range 3-6). In addition, considering transfusion burden, the independence was reached in 3 pts (18%), after a median time of 6 weeks from treatment start. Importantly, off the 14 patients remaining transfusion-dependent, 6 (35%) reduced the transfusion burden. The most prominent toxicity was increased blood pressure (grade 2) occurring in 3 pts (18%), and dizziness (grade 2) in 2 pts (12%); though the drug was generally well tolerated. No serious adverse events (SAEs) were reported. Therefore, patients were treated as outpatients in all cases. At the last follow up, all patients are alive and free from leukemic evolution. Conclusions: Our real-world experience confirms the efficacy of luspatercept in improving erythropoiesis and decreasing transfusion dependency in very low, low or intermediate risk MDS with RS, with an acceptable toxicity profile. Disclosures Fattizzo: Amgen: Honoraria, Speakers Bureau; Apellis: Speakers Bureau; Annexon: Consultancy; Momenta: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Alexion: Speakers Bureau; Kira: Speakers Bureau. Barcellini: Agios: Honoraria, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria; Novartis: Honoraria.

Introduction: One third of Chronic Lymphocytic Leukemia (CLL) patients harbor stereotyped B-Cell receptor (BCR). This is in contrast with the 1012 potential different BCRs that can be produced by the immune system. Some stereotyped BCR are also highly associated with prognosis. For example, the stereotyped subset #2 identifies aggressive CLLs with frequent SF3B1 and ATM alterations. This underlies an important role of BCR selection for emergence of CLL clones. Aim and methods: We raised the question of the existence and quantification of B-cells with stereotyped BCR of the CLL-type in a series of 69 healthy subjects (HS) from 18 to 78 years old, without any past of hematological history nor any detectable monotypic B-cells by flow cytometry. HS were divided in age three groups, adults (18 - 55 years, n= 31), senior-1 (55 - 65 years, n = 14) and senior-2 (> 65 years, n = 24). The variable region of the immunoglobulin heavy chain gene (IGHV) was amplified from genomic DNA of purified B-cells sequenced on an Illumina MiSeq and annotated with the online IMGT HighV-Quest tool. Clonotypes were defined as IGHV genes with the same rearranged V and J segment and with the same CDR3 amino acid sequence with one mismatch tolerance, and if a minimal threshold read number was reached (ranging 5 to 15 according to the DNA input and sequencing depth).Public clonotypes were those shared in between at least 4 (5%) HS. Detection of the 19 major stereotyped CLL's BCRs was performed with an in house R script. And was confirmed with the ARResT/AssignSubsets online tool (V Bistry et al, Bioinformatics, 2015). Exploration of the IGHV repertoire of the different B-cell subpopulations was done from public data (Mitsunaga, Mol Cell Proteomics, 2020). Results: To be independent of the number of reads and to compare HS to each other, clonotypic frequencies were ranked in 150 increasing intervals. In each case, the mean rank of clonotypic frequency ranged 3 to 7 with an SD in between 2 and 6 and was independent of the age category. A Z-score was calculated for each clonotype. Less than 1% of private clonotypes had a Z-score>1.96, while 10% to 30% of public clonotypes had a significant Z-score>1.96 (figure 1). This indicates that public clonotypes are often accumulated when compared to their private counterpart. A stereotyped CLL's BCR was found in 90% HS all stereotypes together. Subsets #2 and #5 were found in more than 50% of cases (figure 2). Frequencies of subsets #3, #59, #7C, #202, #14, #64B, decreased from 23% to 6% cases. Subsets #1, #4, #6, #8, #12, #16, #99 and #201 were never found. Frequencies of stereotyped BCRs ranged 5.2x10 -5 to 1.2x10 -4, being similar in the different HS age categories. Ranks of stereotyped BCR frequencies were almost always below the mean rank of private clonotypes, that indicates a very low abundance (figure 3). Junction analyses suggest that B-cells with stereotyped BCRs were polyclonal since they were very likely to derive from different B-cell precursors. Exploring the longitudinal repertoires of Mitsunaga and Snyder(Mol Cell Proteomics 2020), showed that stereotyped BCRs were almost restricted to immature and naïve B-cells and were fugace while public clonotypes were recurrently and frequently found in memory B-cells and could be stable over time for many of them. Conclusion: B-cells with stereotyped CLL BCRs were easily detected in healthy people whatever their age category. Remarkably, subsets #2 and #5 that are associated with aggressive CLL were found in more than 50% healthy donors at any age. Comparison with private and public clonotypic repertoire reveals that abundance of stereotyped BCR was almost always very low and was restricted to immature and naïve B-cells. Therefore, B-cells with stereotyped BCRs are produced throughout life in almost everybody. But these B-cells do not accumulate and do not seem to undergo to B-cell maturation. This suggests that stereotyped BCRs are not intrinsically prone to transformation and that clonal selection of CLL cells would involve additional events such as antigenic encounter or oncogenic alterations. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Although gene editing by CRISPR/Cas9 is a promising curative strategy for inherited and acquired diseases, potential off-targets remain a major concern. Most computational and biochemical methods for off-target search have focused on single genomes, not considering the impact of genetic diversity among human populations. Previous studies showed that genetic variants might significantly impact on- and off-target specificity. However, none of them explored the most extensive worldwide human genetic diversity dataset to examine the impact of population genetic variation on therapeutically relevant guide RNAs (gRNAs). Objective: To evaluate how genetic variation among human populations affects the predicted off-targets for gRNAs that have been used in clinical trials or had consistent results in preclinical studies. Methods: We selected 13 gRNAs tested for sickle cell disease (SCD), severe combined immunodeficiency, chronic granulomatous disease, X-linked hyper IgM syndrome, acquired immunodeficiency syndrome, and Leber congenital amaurosis. Off-target prediction was performed against the reference genome (hg38) and against population-specific genomes using CRISPRitz (https://github.com/pinellolab/CRISPRitz). Genomic variants with allele frequencies ≥1 % were obtained from both the entire gnomAD v3.0 dataset (76,156 whole-genome sequences) and each ethnic group separately. Off-target sequences were filtered considering up to four mismatches and bulges, and a cutting frequency determination (CFD) score ≥0.2 for those harbouring only mismatch events. Sequences were annotated with Annovar (https://annovar.openbioinformatics.org/). Results: A total of 1,727 off-target events were found against the reference genome for the 13 selected gRNAs. 134 additional events were detected with the gnomad_all dataset. When variants from different ethnic groups were considered 234 additional off-targets were observed. The distribution of CFD values was comparable between the population-specific/additional and the reference genome off-targets, as well as the distribution of their genomic localization. Most events mapped to intergenic regions (~50%), followed by intronic regions (~35%). The proportion of additional events varied for the different gRNAs (ranging from 7.8% to 27.7% increase), and the number of events was also variable among the populations. Considering the different ethnic groups, the highest number of events was found in African-ancestry populations (164) and the lowest in the non Finish European population (87), implying that some off-target events were found exclusively in one of the populations (91 in total). Although 219 (75%) of the variants within the population-specific/ additional off-targets have a frequency between 1-10%, 20 (6.8%) have a frequency higher than 80% in at least one of the populations analysed. Considering only the gRNAs used in gene therapy for SCD (n=6), 100 additional predicted off-targets were found in the African population of which 29 are exclusive, while only 77 were found in gnomad_all and 43 in the non-Finish European population, being 2 exclusive. Discussion: Rigorous analysis regarding off-target events is a necessary step to address the safety of gene therapy strategies. Although in silico analysis against the reference genome captures most predicted off-target events, we and others have demonstrated that an important proportion of additional events are lost if population-specific variants are not considered. Herein, we showed that the number of additional events is particularly higher when variants with allele frequencies >=1% in African populations are considered. This might occur because the African population is more genetically diverse and the reference genome was assembled based on Caucasian individuals. In addition, several off-target events are exclusively found in non-African populations, showing the importance of considering the genetic background of patients who undergo gene therapy. Additional caution should be taken for diseases that are more frequent in specific populations, such as SCD and β-thalassemia, for which there are several ongoing gene therapy trials. Disclosures No relevant conflicts of interest to declare.

Introduction : Although gender disparities are continually improving within the medical field, these issues persist in academia and are evident in research authorship. The purpose of this study was to monitor the trend of such phenomena at the American Society of Hematology (ASH) Annual Meeting from 2016-2020. Methods: We extracted data from acute myeloid leukemia (AML) poster presentations that were presented at the American Society of Hematology (ASH) Annual Meeting from 2016-2020. All poster presentations (n=1599) that fell under the "Acute myeloid leukemia: Clinical studies","Acute myeloid leukemia: Commercially available therapy, excluding transplantation", "Acute myeloid leukemia: Novel therapy excluding transplantation" and "Acute myeloid leukemia: Biology, cytogenetic and molecular markers in diagnosis and prognosis" subgroups were included in the study. There was a particular focus on the number of authors per poster presentation, gender of the first author, gender of the last author and geographical location of the first and last authors. The Google search engine was used to access to authors' biographical data and confirm their gender. T-tests and chi-square tests were used to better understand the gender differences. Results: The average number of authors per poster presentation was 12.5. Of the 1599 posters reviewed, men represented the majority of all first authors (917/1599 (57%) vs 682/1599 (43%); p=0.014) (Figure 1). Men were more likely to be final authors compared to women (1186/1599 (74%) vs 413/1599 (26%); p Conclusion: The number of women as first and last authors has steadily been increasing over the course of the past several years. Nevertheless, women continue to represent less than 50% of all first and last authors. This gender inequality was observed across all continents. Women were also less likely to be senior authors. It is important to continue to promote gender diversity in the field of medicine as it allows for different perspectives, greater collaboration and an increase in the talent pool. Figure 1 Figure 1. Disclosures Anwer: Janssen pharmaceutical: Honoraria, Research Funding; Allogene Therapeutics: Research Funding; BMS / Celgene: Honoraria, Research Funding; GlaxoSmithKline: Research Funding.

Background: Coronavirus disease-2019 (COVID-19) is an inflammatory, multisystem infectious disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-COV-2) and is associated with increased risk of thrombosis, particularly among critically ill patients. The myeloproliferative neoplasms (MPNs) include Philadelphia chromosome-negative (Ph-negative) MPNs polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), and Philadelphia-chromosome positive chronic myeloid leukemia (CML). Patients with MPNs, especially PH-negative, have increased risk of thrombotic complications. Given the increased propensity of thrombosis and prognostic significance of thrombosis in both COVID and MPNs, defining the risk of thrombotic complications in this patient population compared to the general population is important. Methods: Using an institutional database within the Mass General Brigham integrated health network, we retrospectively analyzed 63 consecutive patients with MPN who were ≥ 18 years old and tested positive for SARS-COV-2 infection based on polymerase chain reaction (PCR) testing from March 1, 2020 to January 1, 2021. We compared patients admitted to the hospital in our "MPN cohort" with patients admitted to the hospital from a separate COVID-19 (non-MPN cohort) Mass General Brigham registry of 1114 consecutive patients who tested positive for SARS-COV-2 infection based on PCR testing from March 13, 2020 to April 3, 2020. Care was taken to ensure the cohorts were mutually exclusive. The 90-day primary outcome for MPN cohort was a composite of all-cause death, any thrombosis (composite of arterial and venous thromboembolism [VTE]), International Society on Thrombosis and Haemostasis (ISTH) defined major and clinically relevant non-major bleeding. To identify risk factors for primary outcome in MPN cohort we used a multivariable logistic regression using age, sex, hospital admission status, MPN type, cytoreduction for MPN, hypertension, smoking status, baseline anticoagulation (AC), prior thrombosis (stroke, myocardial infarction or VTE) as co-variables. The 90-day outcomes of interest in our MPN vs non-MPN cohort analysis were any thrombosis, death, ISTH major and clinically relevant non-major bleeding and readmission for any reason. To assess impact of MPN status in hospitalized patients in our MPN vs non-MPN comparison, we used a multivariable logistic regression using age, sex, race, Hispanic ethnicity, ICU admission, treatment with steroids and/or Remdesivir, baseline AC and aspirin use, prior thrombosis (stroke, myocardial infarction or VTE), diabetes, heart failure, admission hematocrit, platelet count and D-dimer as co-variables. Continuous variables were compared using student t-test and categorical variables were compared using Fischer's Exact Test with a p value of < 0.05 considered significant. Results: Of the 63 patients with MPN (23 with PV, 17 ET, 4 PMF, 15 CML, 4 other), 27 (43%) were admitted to the hospital for COVID-19 and 5 (8%) required ICU admission. The mean age of all MPN patients was 66, 84% were White, 8% Black and 10% Hispanic. Primary 90-day outcome occurred in 12 (19%) of MPN patients. In multivariable analysis, only admission to hospital was associated with increased odds of composite (aOR 21.11, 95% CI 2.38 - 546.40), Figure 1A. In patients with (n = 27) and without MPN (n = 399) who were admitted to the hospital, patients with MPN were older (mean age 70 vs 61, p = 0.0076), more likely to be White (89% vs 54%, p = 0.0004) and less likely to be Hispanic (7% vs 29%, p = 0.0158), less likely to be admitted to the ICU (19% vs 43%, p = 0.0138), and more likely to be treated with corticosteroids (30% vs 14%, p = 0.025) or remdesivir (41% vs 13%, p < 0.0001). After multivariable logistic regression, diagnosis of MPN was significantly associated with increased odds of thrombosis (aOR 5.38, 95% CI 1.15-25.38) and readmission (aOR 6.28, 95% CI 1.60-24.88), but not bleeding (aOR 3.51, 95% CI 0.62-18.87) or death (aOR 4.29, 95% CI 0.95-18.99), Figure 1B. Conclusions: Thrombotic complications are common in patients with MPN and COVID-19, particularly if hospitalized for COVID-19. After multivariable analysis, MPN patients admitted for COVID-19 had a significantly increased risk of thrombotic complications compared with non-MPN patients. Figure 1 Figure 1. Disclosures Al-Samkari: Dova/Sobi: Consultancy, Research Funding; Novartis: Consultancy; Argenx: Consultancy; Rigel: Consultancy; Amgen: Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. Rosovsky: Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees. Fathi: Agios/Servier: Consultancy, Other: Clinical Trial Support; BMS: Consultancy, Other: Clinical Trial Support; AbbVie: Consultancy, Other: Clinical Trial Support; Pfizer: Consultancy; Trillium: Consultancy; Kura: Consultancy; Blueprint Medicines Corporation: Consultancy; Genentech: Consultancy; Novartis: Consultancy; Trovagene: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Morphosys: Consultancy; Kite: Consultancy; Foghorn: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; NewLink Genetics: Consultancy; Forty Seven: Consultancy; Ipsen: Consultancy. Goldhaber: Bayer: Consultancy, Research Funding; Boehringer-Ingelheim: Consultancy, Research Funding; BMS: Research Funding; Boston Scientific BTG EKOS: Research Funding; Daiichi: Research Funding; Janssen: Research Funding; Pfizer: Consultancy, Research Funding; Agile: Consultancy. Piazza: Portola: Research Funding; Bayer: Research Funding; Amgen: Research Funding; BMS: Research Funding; Janssen: Research Funding; BSC: Research Funding. Hobbs: Celgene/Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Merck: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Bayer: Research Funding; Incyte Corporation: Research Funding; AbbVie.: Consultancy.