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There is increasing recognition that pathogenic germ line variants drive the development of hematopoietic cancers in many individuals. Currently, patients with hereditary hematologic malignancies (HHMs) receive similar standard therapies and hematopoietic stem cell transplant (HSCT) approaches as those with sporadic disease. We hypothesize that patients with myeloid malignancies and deleterious germ line predisposition variants have different posttransplant outcomes than those without such alleles. We studied 472 patients with myeloid neoplasms, of whom 26% had deleterious germ line variants and 34% underwent HSCT. Deleterious germ line variants in CHEK2 and DDX41 were most commonly seen in American and Australian cohorts, respectively. Patients with deleterious germ line DDX41 variants had a higher incidence of severe (stage 3-4) acute graft-versus-host disease (GVHD) (38%) than recipients with deleterious CHEK2 variants (0%), other HHM variants (12%), or patients without such germ line variants (9%) (P = .002). Importantly, the use of posttransplant cyclophosphamide reduced the risk of severe acute GVHD in patients receiving HSCT for deleterious germ line DDX41-associated myeloid neoplasms (0% vs 53%, P = .03). Based on these results, we advocate the use of posttransplant cyclophosphamide when individuals with deleterious germ line DDX41 variants undergo allogeneic HSCT for myeloid malignancies, even when transplantation has been performed using wild-type donors.

Background: The rapid global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains the international public health concern of the decade. Early clinical data suggest that patients (pts) with hematologic malignancies are vulnerable to severe forms of SARS-CoV-2 and have higher mortality rates than the general population. Greater understanding of risk factors and outcomes associated with SARS-CoV-2 in pts with hematologic malignancies is crucial in order to develop individualized risk-benefit analyses to guide care. Herein, we report a cohort study from a Comprehensive Cancer Center evaluating outcomes in pts with hematologic malignancies who developed SARS-CoV-2. Methods: Adult pts at Northwestern Memorial Hospital with a current/prior hematologic malignancy and laboratory-confirmed SARS-CoV-2 infection confirmed by quantitative RT-PCR from nasopharyngeal swabs between March-July, 2020 were identified using electronic health records. Data were collected and analyzed based on epidemiologic, laboratory, and clinical characteristics. Severity of illness was defined by level of care (ambulatory, inpatient), need for advanced respiratory support (high flow nasal cannula, BiPAP, mechanical ventilation), incidence of thrombotic events, incidence of acute kidney injury (AKI), and/or death. Statistical analyses of risk factors, severity, and outcomes were performed. Subgroup analyses based on antineoplastic treatment status and receipt of SARS-CoV-2 -directed therapy were made. Active cancer treatment was defined as antineoplastic therapy within 12 months of SARS-CoV-2 diagnosis. Results: Demographic (Table 1) and clinical (Table 2) data were recorded from 73 SARS-CoV-2 infected pts. Sixty (80%) pts had lymphoid and 15 (20%) had myeloid neoplasms, 2 with concurrent lymphoid and myeloid neoplasms. Thirty-seven (51%) pts were undergoing active treatment for their malignancy. Twenty-one pts (29%) were managed in the ambulatory setting while 52 (71%) required hospital admission. Twenty-five (34%) pts required advanced respiratory support including 14 (19%) who required mechanical ventilation. Four pts (6%) had thrombotic events and 31 (42%) received SARS-CoV-2-directed therapies. Sixteen pts (22%) died during the study period. Pts on active cancer treatment had higher rates of hospital admission (81% v 60%; p=0.05) and AKI (51% v 29%; p=0.04) but similar rates of death compared with pts not on active treatment (24% v 20%; p=0.66) (Table 3). Comparing pts who received SARS-CoV-2 -directed therapy versus no therapy: pts on therapy had longer median lengths of stay (11 v 7 days; p=0.04) and higher rates of hospital admission (94% v 55%; p=0.0003) but similar rates of death (23% v 21%; p=0.91); pts in the ICU on SARS-COV-2 -directed therapy had lower rates of death (38% v 88% p=0.02) than pts who did not receive such therapy (Table 4). Twenty-six pts (36%) were tested for viral clearance, defined as two serial negative swabs ≥24 hours apart. Of these, 17 (65%) achieved clearance with a median time of 51 days (range 15-119 days). Thirteen pts (18%) had antibody (Ab) testing. Ten (77%) had detectable Abs: 8 were positive for IgG, 1 for IgG and IgM, and 1 had unspecified positivity. Notably, all 3 pts with undetectable Abs were on active cancer treatment. Conclusion: We demonstrate that pts with hematologic malignancies are exceptionally vulnerable to severe forms of SARS-CoV-2 with high mortality rates. The incidence of thrombotic events was low, an unexpected finding in the setting of a hyperinflammatory syndrome. Prolonged time to viral clearance was observed, a finding which may cause potential delays in the resumption of cancer-directed therapies. Notably, the majority of pts who received antibody testing had detectable antibodies suggesting that pts with hematologic malignancies may be able to mount an immune response to early vaccination. Accordingly, close monitoring, aggressive therapy, and early vaccination, when available, may be warranted for this population. Larger studies are needed to confirm our findings and help guide management of pts with hematologic malignancies during the SARS-CoV-2 pandemic. Disclosures Altman: Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Immune Pharmaceuticals: Consultancy; Syros: Consultancy; Genentech: Research Funding; Novartis: Consultancy; Amphivena: Research Funding; Amgen: Research Funding; Aprea: Research Funding; ImmunoGen: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; Fujifilm: Research Funding; Kartos: Research Funding; AbbVie: Other: advisory board, Research Funding; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Agios: Other: advisory board, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Theradex: Other: Advisory Board; ASH: Consultancy; Cancer Expert Now: Consultancy; France Foundation: Consultancy; PeerView: Consultancy; PrIME Oncology: Consultancy. Winter:Delta Fly Pharma: Consultancy; Amgen: Consultancy; Epizyme: Other: DSMB; CVS/Caremark: Consultancy; Ariad/Takeda: Consultancy; Norvartis: Consultancy, Other: DSMB; Merck: Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: advisory board. Gordon:Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Pro:Verastem Oncology: Research Funding. Ma:TG Therapeutics: Research Funding; Juno: Research Funding; Novartis: Research Funding; Kite: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria, Research Funding, Speakers Bureau; Bioverativ: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Karmali:BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Takeda: Research Funding; Karyopharm: Honoraria; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau.

Introduction: Therapy-related myeloid neoplasm (t-MN) includes acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) that occur as a complication of DNA-damaging therapies. The World Health Organization recommends considering t-MN as a single entity. Whether t-MDS and t-AML have distinct characteristics and outcomes is not known. The aim of this study was to compare clinicopathological characteristics and outcomes of t-MDS and t-AML. Methods: All patients diagnosed with t-MN based on the World Health Organization criteria were identified. Bone marrow biopsies, cytogenetic, and next-generation sequencing (NGS) were obtained at the treating physician's discretion. Pathogenic/likely pathogenic variants (PV) were called based on the standard criteria. Overall survival (OS) was calculated from the time of t-MN diagnosis until the last follow up using Kaplan-Meier analysis using Wilcoxon test. For survival analysis comparing chemotherapy to best supportive care (BSC) only, patients were censored at the time of allogeneic stem cell transplant (SCT). Multivariate analysis was performed using Cox proportional hazard method and corrected using false discovery rate (FDR). Statistical analysis was performed using JMP (v14.1, SAS Institute) and significance was defined as P Results: We identified 554 patients, of which 180 (32.4%), 365 (65.8%), and 9 (1.6%) presented as t-AML, t-MDS, and t-MDS/MPN respectively. t-MDS/MPN patients were excluded from further analysis due to a small number. Clinical and laboratory characteristics of the t-AML and t-MDS cohorts is shown in Table 1. t-AML patients were significantly more anemic and thrombocytopenic at presentation. As expected, t-AML had a higher peripheral blood and BM blast count. There was no difference in proportion of patients with chromosomal abnormalities, though a statistically significantly higher proportion of t-MDS patients had chromosome 5 abnormality, 5q deletion, monosomy 5, chromosome 7 abnormality, monosomy 7 compared to t-AML patients. On other hand, 11q23 (mixed lineage leukemia, MLL) rearrangement was more common in t-AML compared to t-MDS (9.3% vs. 2.8%, P=0.005). A higher proportion of t-MDS patients had PV detected by NGS compared to t-AML (92.9% vs. 85.6%, P=0.038). A higher proportion of t-MDS patients had PV in TP53 (37.6% vs. 21.4%, P=0.004) and ASXL1 (23% vs. 11.7%, P=0.016) genes; whereas a higher proportion of t-AML patients had PV in RAS (18.9% vs. 9.1%, P=0.013) and WT1 (8.1% vs. 2.9%, P=0.05) genes. One hundred twenty-eight (35%) of 365 t-MDS patients progressed to t-AML. The presence of any chromosomal abnormality at t-MDS diagnosis predicted a higher risk of transformation to t-AML (χ 2 3.9, P=0.03). t-AML patients had a significantly shorter OS compared to t-MDS (9.2 vs. 19.7 months, P Multivariate analysis for OS performed to control for all the variables that were different at presentation (except for blast count), showed that t-MDS (as opposed to t-AML) phenotype at diagnosis, and undergoing SCT were independent predictors of improved survival (Table 2). Conclusion: t-MDS and t-AML have distinct clinical, cytogenetic, and genetic features at presentation. In the absence of disease modifying therapies, t-AML is a more aggressive phenotype, consistently associated with a shorter survival. Even after controlling adverse risk features, t-AML phenotype had a shorter survival compared to t-MDS. Figure 1 Figure 1. Disclosures Litzow: AbbVie: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Introduction: Therapy related myeloid neoplasm (t-MN) is a rare but devastating complication of cytotoxic therapy used for management of unrelated malignancy or autoimmune diseases. Therapeutic options for t-MN are limited and although hypomethylating agents (HMA) are frequently used, the benefit of it in t-MN is unclear. There are no prospective trials of HMA in t-MN and published experience is based on retrospective analysis of small number of cases (n=42 to 54). The aim of this study was to assess the efficacy of HMA therapy in t-MN patients and evaluate predictors for it. Methods: t-MN patients managed with first line HMA therapy were analyzed. This study was approved by the participating institutional review board. Criteria for inclusion were a pathologically confirmed diagnosis of t-MN based on WHO 2016 criteria, age >18 years, and ≥1 cycle of decitabine or azacitidine. Patient characteristics were summarized by frequency (percentage). Overall survival was calculated from the time of starting azacitidine to last follow up or death date using Kaplan-Meier analysis. Multivariable analysis was performed using Cox proportional hazard model. Statistical analysis was performed using R program and significance was defined as P Results: Of the 554 t-MN patients analyzed, 184 (33%) patients were treated with HMA as the first line therapy and were included in the study. Median age at t-MN diagnosis was 70 (IQR 64-75) years and 112 (60%) patients were male. At the time of diagnosis, 84% (n=154) and 16% (n=30) patients were classified as t-MDS and t-AML and 47% (87/184) and 46% (49/107) of the evaluable patients had complex karyotype and TP53 somatic mutations (TP53 Mut) respectively. Azacitidine (n=145, 79%) was most frequently used HMA followed by decitabine (n=39, 21%). Median survival of the whole cohort since t-MN diagnosis was 13.2 months. At the time of analysis further treatment details were available for 78 patients and outcome of these patients were compared with primary MDS (p-MDS) and oligoblastic AML managed at the same institute. Completion of six-cycles of HMA (50% vs. 62%; P=0.07) and overall response rate (47 vs. 50%, P=0.22) was not significantly different between t-MN and p-MDS. However, median OS of t-MN was significantly poor compared to p-MDS (10 vs. 20 months, P=0.0004; Figure 1A). In t-MN patients treated with HMA as the first-line agent, median OS was significantly shorter in t-AML compared to t-MDS (7 vs.10 months, P=0.04; Figure 1B). Median OS was significantly shorter in patients with TP53 Mut and complex karyotype (Figure 1C-D). In Cox proportional hazard analysis, t-AML and complex karyotype were independently associated with poor outcome. Conclusion: This study demonstrates significantly poor outcome of t-MN patients treated with HMA therapy as first line. The outcome is particularly poor in t-AML and patients with complex karyotype and TP53 Mut. Hence there is urgent need for clinical trials of novel therapies for t-MN. Figure 1 Figure 1. Disclosures Sharplin: Kite Gilead: Honoraria; Novartis: Other: Travel Support. Ross: Keros Therapeutics: Consultancy, Honoraria; Bristol Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Background: Germline predisposition is increasingly being recognised in myeloid neoplasms (MN) including primary myelodysplastic syndrome. An unequivocal diagnosis of germline predisposition carries actionable considerations for patient management including donor stem cell source for allogeneic transplantation, dose-reduction of conditioning regimes and screening for extra-hematological disease (such as pulmonary abnormalities in patients with telomere biology disorders). In addition, the identification of MDS predisposition syndromes can avoid misdiagnosis (for example, distinguishing idiopathic thrombocytopenic purpura from thrombocytopenia due to RUNX1 germline variant). However, the prevalence of pathogenic germline variants (PGVs) in unselected pMDS patients presenting at older age remains unknown. Aim: This study assesses frequency and type of pathogenic germline variants in MDS patients and compares with age matched healthy controls and patients with other cancers. Method: We analysed 68 known cancer predisposition genes in germline samples of 146 samples from myeloid neoplasms. Study included primary MDS (n=51) and MDS diagnosed in cancer survivors with (n=77) or without prior exposure to cytotoxic therapy (n=18). Using uniform American College of Medical Genetics and Genomics (ACMG) guidelines for annotating germline mutation, we also compared the frequency of pathogenic germline variants in the same genes with patients with single cancer and age-match healthy controls (>70 years). Results: Pathogenic germline variants (PGVs) were identified in 19% (28/146) patients compared to 4% and 3% patients with single cancer and age-matched controls respectively (P80 years of age (Fig. 1D). Phenotypic features such as monocytopenia and mycobacterium infections (MonoMAC; SA460) and personal and family history of pulmonary fibrosis (SA918) were present in only two cases with PGVs. Family history of MDS/AML was present in only in four cases with PGVs, in which PGVs were found in typical myeloid malignancy genes (DDX41, GATA2). Importantly, some patients with family history of solid cancers carried PGVs in genes traditionally associated with solid cancers (e.g. MSH6, NF1, TP53 and BRCA1). SA927 had a PGV in MSH6 and multiple first-degree relatives with solid cancers including colon, renal and brain cancers. Moreover, 41% of adults with hematological disorders and a personal and/or family history of interstitial lung disease had PGVs in telomere biology disorder genes. Hence, family history should not be restricted to hematological disorders, but also solid cancers and non-malignant phenotypes (e.g. hepatic and pulmonary fibrosis). The frequency of PGVs was not different in patients with and without family history of cancer (23% vs. 13%, P=0.32). Conclusion: The frequency of PGVs is significantly high in MN compared to age matched healthy control and other cancer patients. Our observation of a high frequency of PGVs in the older MDS population warrants standardization of germline testing at diagnosis to guide optimal management of patients and their families. Figure 1 Figure 1. Disclosures Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Introduction: Therapy-related myeloid neoplasms (t-MN) are associated with extremely poor clinical outcomes in otherwise long-term cancer survivors. t-MN accounts for ~20% of cases of myeloid neoplasms and is expected to rise due to the increased use of chemotherapy/radiotherapy (CT/RT) and improved cancer survivorship. Historically, t-MN was considered a direct consequence of DNA damage induced in normal hematopoietic stem cells (HSC) by DNA damaging cytotoxics. However, these studies have largely ignored the bone marrow (BM) microenvironment and the effects of age and concurrent/previous cancers. Aim: We performed an exhaustive functional study of mesenchymal stromal cells (MSC) obtained from a comparatively large cohort of t-MN patients and carefully selected control populations to evaluate the long-term damage induced by cytotoxic therapy to BM microenvironment and its impact on malignant and normal haematopoiesis. Methods: Four different cohorts were used: (1) t-MN, in which myeloid malignancy occurred after CT/RT for a previous cancer (n=18); (2) patients with multiple cancer and in which a myeloid neoplasm developed following an independent cancer which was not treated with CT/RT (MC-MN; n=10); (3) primary MN (p-MN; n=7) untreated and without any prior cancer or CT/RT; (4) age-matched controls (HC; n=17). Morphology, proliferation, cellular senescence, differentiation potential and γH2AX DNA damage response was performed. Stem/progenitor supportive capacity was assessed by co-culturing haematopoietic stem cells on MSC feeder-layer in long-term culture initiating assay (LTC-IC). Cytokine measurements were performed using 38-plex magnetic bead panel (Millipore) and RNA sequencing libraries were prepared with Illumina TruSeq Total RNA protocol for 150bp paired-end sequencing on a NextSeq500 instrument. Functional enrichment analysis was performed using EnrichR software. Results: MSC cultured from t-MN patients were significantly different from HC, p-MN and MC-MN MSC according to multiple parameters. They exhibited aberrant morphology consisting of large, rounded and less adhesive cells compared to typical spindle-shaped morphology observed with controls. MSC from myeloid neoplasm also showed impaired proliferation, senescence, osteo- and adipogenic differentiation with t-MN MSC showing the greatest differences. DNA repair was dramatically impaired compared to p-MN and HC (Fig.1A). Importantly, these aberrant t-MN MSC were not able to support normal or autologous in vitro long-term haematopoiesis (Fig.1B). The biological characteristic and poor haematopoietic supportive capacity of MSC could be "cell-intrinsic" or driven by an altered paracrine inflammatory microenvironment. Interestingly, several inflammatory cytokines were higher in t-MN compared with marrow interstitial fluid obtained from p-MN patients (Fig.1Ci) and many of these including Fractalkine, IFNα2, IL-7 and G-CSF were also significantly higher in t-MN MSC conditional media (Fig.1Cii). Together, this data suggest that t-MN microenvironment is distinct from p-MN with paracrine production of pro-inflammatory milieu that may contribute to poor HSC supportive capacity. Preliminary whole transcriptome analysis revealed differential gene expression between t-MN and HC (Fig.1Di) and p-MN MSC. Importantly, the deregulated genes play critical role in cell cycle, DNA damage repair, and cellular senescence pathways explaining phenotypical characteristic of t-MN MSC (Fig.1Dii). Moreover CXCL12 expression, a key regulator of haematopoiesis, was significantly lower in t-MN compared to HC (p=0.002) and p-MN MSC (p=0.009), thus explaining poor HSC supportive capacity. The key difference between the p-MN, MC-MN and t-MN is prior exposure to CT/RT. To study this we obtained MSC from two t-MN patients for whom we had samples at the time of their primary cancer, post high-dose chemotherapy and at the time of t-MN. MSC displayed aberrant proliferation and differentiation capacity after high-dose cytotoxic therapy (2 to 4 years prior to developing t-MN) and remained aberrant at t-MN diagnosis (Fig.1E). Conclusions: BM-MSC from t-MN patients are significantly abnormal compared with age-matched controls and typical myeloid neoplasm. Importantly, prior CT/RT leads to long-term irreversible damage to the BM microenvironment which potentially contributes to t-MN pathogenesis. Disclosures Hughes: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hiwase:Novartis Australia: Research Funding.

Background: Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) patients are older and suffer with cardiovascular (CV) diseases. Management of these patients with antiplatelet and anticoagulation therapy is challenging as thrombocytopenia can increase the risk of bleeding. Aim: To assess burden and CV disease related mortality, review of anticoagulant /antiplatelet therapy and bleeding complications in MDS and oligoblastic AML patients. Methods: Electronic medical records of 910 MDS and oligoblastic AML patients enrolled in the South Australian MDS (SA-MDS) registry were reviewed. CV risk factors, CV and bleeding events requiring or occurring during hospitalisation, anticoagulation and/or antiplatelet therapy information were collected. Platelet counts of Results: At the time of MDS diagnosis, 72% (658/910) and 42% (386/910) patients had ≥1 and ≥2 CV risk factors. Twenty-five percent patients required hospitalization for CV events prior to the MDS diagnosis and their median OS was significantly poor compared to patients who did not have CV events (Figure 1A). During median follow up of 28 months after MDS diagnosis, 27.5% (251/910) patients were admitted with or developed CV events during hospitalization. In a Cox-regression analysis age, absolute monocyte count, CV risk factors and prior CV events were independent predictors of CV events following MDS diagnosis (Figure 1B). The most frequent CV events were arrhythmia (137/399; 34%), congestive cardiac failure (129/399; 32%), and ischemic heart disease (94/399; 23%). Atrial fibrillation (AF) contributed towards 78% (108/137) of all arrhythmias. 39% of AF occurred in the setting of infections and 12% patients died during the same hospitalization or were palliated. 89% of AF patients had a CHADS2VASc2 score ≥2, however only 30% (20/65) and 24% (16/65) events with available information were treated with anticoagulation and antiplatelet therapy respectively. While 60% (39/65) AF events did not receive antiplatelet or anticoagulation therapies. Four AF patients developed ischemic stroke following MDS diagnosis and five patients had stroke before MDS diagnosis and were subsequently diagnosed with AF. Importantly, 36% (34/94) AF patients developed 45 bleeding events. The frequency of bleeding events was not significantly different between patients treated with anticoagulation/antiplatelet therapy versus who were not treated (13.8% vs. 13.6%). Although, cumulative incidence of bleeding and CV events was similar at 29% and 28% at five-years (Figure 1C-D), only some patients had both events. Of the 387 patients, 39% (n= 152) and 39% (n=153) patients required hospitalization only for CV or bleeding events, while only 21% (82/387) required hospitalization for both bleeding and CV events. Identifying these three groups early is crucial to optimize their outcome. Of the 387 bleeding events, 88 (24%) were major and 296 (76%) were clinically relevant minor bleeding. Notably, 127, 47 and 15 bleeding events were gastrointestinal, intracranial and intraocular respectively. While 50% bleeding events occurred in the setting of moderate to severe thrombocytopenia, 19% and 31% of bleeding events occurred at platelet counts of >50-100 and >100x109/L respectively (Figure 1E). Details of anticoagulation/antiplatelet therapy were available for 66% (161/243) of bleeding events. Importantly, 76% of bleeding events occurred without anticoagulation and antiplatelet therapy, while 10% and 13% bleeding occurred while on anticoagulation therapy and antiplatelet therapy respectively. Conclusions: Our analysis demonstrates a significant burden of CV and bleeding in MDS. Only 23% of all bleeding events occurred while on anticoagulation therapy and some patients with recurrent CV events did not require hospitalization for bleeding. However, large numbers of CV events are sub-optimally managed due to perceived excess risk of bleeding. Therefore, guidelines for anticoagulation and/or antiplatelet therapy are required for MDS patients. Disclosures Hiwase: Novartis Australia: Research Funding.

Approximately 8% of un-selected pediatric (Zhang et al, NEJM 2015) and adult (Huang et al, Cell 2018) cancer patients have a deleterious germline (GL) variant. However, the frequency in patients with >2 non-related cancers, a combination of different hematological malignancies (HM) or a HM and a non-hematological malignancy, is not known. We hypothesize that genetic predisposition is higher in patients with multiple cancers, compared to historical literature for patients with a single cancer. Method: Clinical and laboratory information on 213 cancer patients, enrolled in the South Australian MDS (SA-MDS) registry (n=90) and University of Chicago clinic (n=123) were analyzed. Germline variants were identified by sequencing paired bone marrow and germline samples for 217-300 cancer related genes and annotated using American College of Medical Genetics (ACMG) 2015 guidelines as pathogenic or likely pathogenic (i.e. deleterious). Additionally, somatic mutations in 240 genes were identified in the SA-MDS cohort (n=90). Results: The median age at diagnosis was 64 years (interquartile range, 61-76 years). One-hundred and five patients had therapy-related myeloid neoplasm (T-MN), following treatment with chemo- and/or radiotherapy for an unrelated prior malignancy. While 100 patients had non-related multiple cancers (MC) one of them being HM without prior exposure to chemotherapy or radiotherapy, and, 8 patients had only myelodysplastic syndrome or acute myeloid leukemia. Overall, 20.5% (42/205) patients harbored 46 deleterious GL variants, annotated according to ACMG guidelines (Fig 1A). Most GL variants were in DNA repair pathway (26/46, 57%) followed by TP53, telomere maintenance and drug transport pathways (4/46, 9% each; Fig 1B). Three DDX41 variants were also seen. The frequency of patients with deleterious GL variants was similar in T-MN (21/105; 20%) and MC (21/100, 21%; Fig 1C). Similarly, the frequency of patients with deleterious GL variants in DNA repair pathways was also similar in T-MN (13/105, 12%) and MC (11/100, 11%). Of the patients with available cytogenetic data, complex cytogenetics were more frequent in patients with a deleterious GL variant compared to those without (11/28, 39% vs 28/125, 22%; p=0.06). At the time of analysis, somatic and germline mutation data on 240 genes was available in the SA-MDS cohort only (n=90). Somatic TP53 mutations were frequent in patients with deleterious GL variant (8/15, 53%) compared to patients without deleterious GL variant (11/75, 15%; p=0.003) (Fig 1D). Interestingly, 80% (4/5) patients with deleterious GL variant in a DNA repair pathway had a somatic TP53 mutation compared to 40% (4/10) with deleterious GL variant in non-DNA repair pathways. Conclusions: Our results from a large cohort show that patients with >2 non-related cancers have a higher frequency of deleterious germline variants compared to previous reports from patients with single cancer (20.5% vs 8%). Variants in the DNA repair pathway are the most common. The presence of deleterious germline variants is associated with genetic instability as evidenced by high frequency of complex karyotypes and somatic TP53 mutations. Disclosures Scott: Celgene: Honoraria. Godley:UpToDate, Inc.: Patents & Royalties: receives royalties from a coauthored article on inherited hematopoietic malignancies ; Invitae, Inc.: Membership on an entity's Board of Directors or advisory committees.