Tefferi, Ayalew

Abstract Primary myelofibrosis (PMF) is one of three myeloproliferative neoplasms (MPN) that are morphologically and molecularly inter-related, the other two being polycythemia vera (PV) and essential thrombocythemia (ET). MPNs are characterized by JAK-STAT–activating JAK2, CALR, or MPL mutations that give rise to stem cell–derived clonal myeloproliferation, which is prone to leukemic and, in case of PV and ET, fibrotic transformation. Abnormal megakaryocyte proliferation is accompanied by bone marrow fibrosis and characterizes PMF, while the clinical phenotype is pathogenetically linked to ineffective hematopoiesis and aberrant cytokine expression. Among MPN-associated driver mutations, type 1–like CALR mutation has been associated with favorable prognosis in PMF, while ASXL1, SRSF2, U2AF1-Q157, EZH2, CBL, and K/NRAS mutations have been shown to be prognostically detrimental. Such information has enabled development of exclusively genetic (GIPSS) and clinically integrated (MIPSSv2) prognostic models that facilitate individualized treatment decisions. Allogeneic stem cell transplantation remains the only treatment modality in MF with the potential to prolong survival, whereas drug therapy, including JAK2 inhibitors, is directed mostly at the inflammatory component of the disease and is therefore palliative in nature. Similarly, disease-modifying activity remains elusive for currently available investigational drugs, while their additional value in symptom management awaits controlled confirmation. There is a need for genetic characterization of clinical observations followed by in vitro and in vivo preclinical studies that will hopefully identify therapies that target the malignant clone in MF to improve patient outcomes.

Abstract Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis, and a propensity toward transformation to acute myeloid leukemia. Type I JAK inhibitors (JAKi) are the only approved therapy and can provide symptom control and reduction of splenomegaly in eligible patients. However, JAKi do not significantly impact disease progression, and many patients are not eligible due to coexisting cytopenias. Patients with MF who have relapsed and/or are refractory (R/R) to JAKi have poor survival. Therefore, novel agents, moving beyond JAKi-based treatments, are urgently needed. CD123, also known as the interleukin-3 receptor alpha chain, is expressed on maturing myeloid cells and progenitors in MF, making it an attractive therapeutic target. Tagraxofusp (TAG, SL-401) is a CD123-targeted therapy which is FDA and EMA approved for the treatment of blastic plasmacytoid dendritic cell neoplasm. A phase 1/2 study of TAG monotherapy in patients with MF who were R/R to approved JAKi (NCT02268253) was initiated. Herein, we present updated safety and efficacy data. Methods: A 2-stage multicenter, phase 1/2 study enrolled patients with R/R MF. Patients in Stage 1 (dose escalation) received 7, 9, or 12 mcg/kg/day TAG intravenously on days 1-3, every 21 days (cycles 1-4), every 28 days (cycles 5-7), and every 42 days (for cycles 8 and beyond); 12 mcg/kg/day was given every 21 days (cycles 1-4), and every 28 days (cycles 5+) in Stage 2. Enrollment in Stage 2 (expansion) was restricted to patients who met the DIPSS-plus intermediate-2 or high-risk disease criteria, those who were R/R or intolerant to JAKi therapy, and those who were not eligible for immediate stem cell transplantation. Responses were assessed on the basis of the International Working Group MPN Research and Treatment/European LeukemiaNet (IWG-MRT/ELN) criteria (Tefferi et al. Blood 2013;122:1395-1398). Results: As of July 1, 2021, 39 patients with MF were treated. Median age was 70 years (range 54-87) and 46% were female. The baseline characteristics comprised thrombocytopenia (<100 × 10 9/L; 64%), including 36% with platelets <50 × 10 9/L; monocytosis (≥1.0 × 10 9/L; 21%), and splenomegaly (74%). Genomic assessments at study entry demonstrated molecular mutations in JAK2, CALR, MPL, and ASXL1 in 62%, 8%, 5%, and 23%, respectively; cytogenetic abnormalities were observed in 10 patients (4 patients: 20q-, 3 patients: 7/7q-, 2 patients: -5/5q-, 2 patients: 12p-, and 1 patient: 17q). Treatment-related adverse events are depicted in Table 1. The most common treatment-related adverse events (incidence ≥10%) included hypoalbuminemia (21%), headache, pyrexia, thrombocytopenia, and elevated alanine aminotransferase (15% each). Capillary leak syndrome (CLS) was reported in 3 patients, including 1 patient with grade 4; there was no grade 5 CLS. Stable disease was achieved in 21 patients (60%). In total, 12/24 patients (50%) with baseline splenomegaly achieved a spleen response (Table 2), 3/4 (75%) with concomitant monocytosis, and 13/24 (54%) with concomitant thrombocytopenia. Spleen responses were confirmed objectively by imaging, with the spleen volume reduction (SVR) thresholds for response set at 35%. Updated information on SVR will be reported at the time of presentation. Total Symptom Score (TSS) was reduced in 20/39 patients (51%), and 10/39 (26%) had reductions from baseline in both TSS and spleen size. Median overall survival was 29.2 months (95% CI 12.0-49.5; range 1-51 months). Conclusions: TAG monotherapy demonstrated clinical efficacy and a predictable and manageable safety profile in patients with MF characterized as high-risk, including those who are refractory to JAKi and those with associated monocytosis, thrombocytopenia, advanced disease, and high-risk genetic features. This phase 1/2 study confirms the safety and clinical efficacy of TAG administered as a monotherapy in a cohort of poor-prognosis patients with MF. Given the genomic and epigenomic complexity of MF, with the clonal heterogeneity and additional subclones, TAG is planned to be tested as part of a combination strategy in high-risk patients with MF who are either R/R, intolerant to, or who have had a prior suboptimal response to JAKi. Figure 1 Figure 1. Disclosures Yacoub: Agios: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Wang: Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Gupta: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding; Roche: Consultancy; Constellation Pharma: Consultancy, Honoraria; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Lee: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schiller: FujiFilm: Research Funding; Deciphera: Research Funding; Daiichi-Sankyo: Research Funding; Constellation Pharmaceuticals: Research Funding; Celator: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Actinium Pharmaceuticals, Inc: Research Funding; Samus: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Geron: Research Funding; Bluebird Bio: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Onconova: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; PrECOG: Research Funding; Regimmune: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; Forma: Research Funding; Delta-Fly: Research Funding; Sangamo: Research Funding; Elevate: Research Funding; Biomed Valley Discoveries: Research Funding; Bio: Research Funding; Actuate: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Leukemia & Lymphoma Society: Research Funding; Ono-UK: Consultancy, Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Arog: Research Funding; Trovagene: Research Funding; Tolero: Research Funding; Takeda: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Pharma: Consultancy; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Taparia: Novartis: Consultancy. Verstovsek: Protagonist Therapeutics: Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; PharmaEssentia: Research Funding; CTI BioPharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Ital Pharma: Research Funding; Blueprint Medicines Corp: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Khoury: Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Brooks: Stemline Therapeutics: Current Employment. Mughal: Stemline: Current Employment, Current holder of stock options in a privately-held company; Oxford University Press, Informa: Other: financial benefit and/or patents . Pemmaraju: LFB Biotechnologies: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Springer Science + Business Media: Other; MustangBio: Consultancy, Other; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; DAVA Oncology: Consultancy; Aptitude Health: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; CareDx, Inc.: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Sager Strong Foundation: Other; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy.

Abstract Background The detrimental effect of leukocytosis on survival in myeloproliferative neoplasms (MPN) has been well established for primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET ) (JCO. 2018;36:310; BJH. 2020;189:291) Previous studies have also implicated leukocytosis as a risk factor for leukemic transformation (Mayo Clin Proc. 2017;92:1118) and thrombosis in MPN (Blood Adv. 2019;3:1729). However, it is currently not clear as to which component(s) of white blood cells is responsible for these observations. In the current study, we sought to examine the individual prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC) and monocyte (AMC) counts, on overall (OS), leukemia-free (LFS), and myelofibrosis-free (MFFS) survival and in ET. Methods Study patients (n=349) were retrospectively recruited from the Mayo Clinic MPN database of 1,249 WHO-defined ET patients, evaluated over five decades (1967-2021), based on availability of information on ANC, ALC and AMC. Conventional criteria were used for diagnosis and definitions of major complications, including leukemic or fibrotic transformation (Blood 2016;127:2391). Conventional statistical methods were applied using JMP Pro 14.0.0 software package, SAS Institute, Cary, NC. Multivariable analyses included previously established risk factors for survival. Results 349 patients (median age 57 years, range 18-89; females 61%) with ET were included in the study: 46% JAK2, 34% CALR, 16% triple-negative and 4% MPL mutated; IPSET risk category high 24%, intermediate 41%, and low 35%; presenting median (range) values were 13.8 g/dL (11.1-16.4) for hemoglobin, 8.2 x 10(9)/L (3.2-52) for leukocyte count, and 859 x 10(9)/L (451-3460) for platelet count; palpable splenomegaly was present in 48 (14%); median followup was 10 years (range 0-47), during which time 118 deaths, 52 fibrotic progressions, and 14 leukemic transformations were documented. Multivariable analysis identified older age (p<0.001), increased ANC (p<0.001), decreased ALC (p=0.03), and male sex (p=0.04), but not AMC (p=0.8), venous thrombosis (p=0.4), or arterial thrombosis (p=0.4), as independent risk factors for OS. ANC of ≥8 x 10(9)/L and ALC of <1.8 x 10(9)/L were determined as appropriate cut-off values by ROC analysis. Subsequent multivariable analysis using these cut-off values resulted in HR (95% CI) of 5.2 (3.4-7.9; p<0.001) for age >60 years, 3.1 (2.1-4.6; p<0.001) for ANC, and 2.0 (1.4-3.0; p<0.001) for ALC; male sex was no longer significant in this analysis (p=0.14). An operational HR-based risk score assigned 3 adverse risk points for older age (>60 years), 2 for increased ANC (≥8 x 10(9)/L) and 1 for ALC (<1.8 x 10(9)/L), resulting in an new Age Anc Alc (AAA; triple A) risk model for survival in ET with estimates of median survival ranging from 9.7 to 36.6 years (Figure 1). In addition, ALC <1.8 x 10(9)/L was associated with inferior LFS (p=0.06) and MFFS (p=0.07) while AMC as a continuous variable showed borderline significance for MFFS (p=0.18). In univariate analysis, JAK2V617F allele burden showed significant association with OS (p=0.02), LFS (p=0.05) and MFFS (p=0.001); however significance for OS was lost in mutivariable analysis that included ANC and ALC. An external validation cohort from the University of Florence (n=485) confirmed the independent survival risk contribution from age >60 years (p<0.001; HR 9.9, 95% CI 5.4-18.0), ANC ≥8 x 10(9)/L (p=0.02; 1.9, 1.1-3.5) and ALC <1.8 x 10(9)/L (p<0.001; 2.0, 1.3-3.0). The Triple A risk model was also effectively applied on the Florence validation cohort (Figure 1): median follow-up 8.4 years; 87 deaths; 43 fibrotic progression; 12 leukemic transformations. The association of ALC <1.8 x 10(9)/L (p=0.04) and AMC (p=0.002) with fibrotic transformation was also validated in the Florence cohort. Conclusions: The current study identifies increased ANC and decreased ALC as age-independent risk factors for survival in ET, thus allowing the development of a globally applicable simple to use "Triple A" risk model that is based on Age, ANC and ALC. Decreased ALC also predicted fibrotic and leukemic progression. Our observations suggest potential value for immune profiling as an additional prognostic tool in MPN. Figure 1 Figure 1. Disclosures Szuber: Novartis: Honoraria. Vannucchi: BMS: 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; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Thrombosis is the main cause of morbidity and mortality in pts with Polycythemia Vera (PV). Current risk stratification is based on 2 variables: age >60y and history of thrombosis. Additional thrombotic risk factors in PV are generic cardiovascular risk factors and leukocytosis. JAK2V617F (JAK2VF) variant allele frequency (VAF) at diagnosis is highly heterogeneous. A VAF>75% was associated with higher rate of all thrombosis after diagnosis (Vannucchi AM et al, Leukemia 2007), and a VAF ≥ 60% correlated with increased rate of venous thrombosis (VT) in high-risk pts (Guglielmelli P et al, ASH 2018); however, predictive role of JAK2VF VAF is still debated. Aim: To evaluate the impact of JAK2VF VAF on rate of arterial and venous thrombosis in PV pts. Patients and methods: A cohort of 576 strictly 2016 WHO-defined PV pts followed at Univ. of Florence (1981-2020) were included. All pts were annotated for JAK2VF VAF, determined <3 years from diagnosis, and thrombosis at diagnosis and follow-up (FU). Arterial thromboses (AT) included stroke, transient ischemic attacks, retinal artery occlusion, coronary artery disease, and peripheral arterial disease; VT included cerebral venous thrombosis, deep vein thrombosis, pulmonary embolism. Splanchnic vein thromboses (SVT) were excluded. Only first occurring event was considered. Cox proportional hazard regression model was used for univariate and multivariable analysis. Kaplan-Meier (KM) analysis was used for time-to-event assessment, compared by log-rank test. Results: Median age was 61.4 y (range, 16.2-91.8), 58.2% were male; 62% were high-risk based on current classification. Median JAK2VF VAF was 41.5% (range, 0.3-100). A total of 76 (13.2%) pts had an AT event before/at PV diagnosis and 49 (8.5%) pts had an AT during FU. As regards VT, 64 (11.1%) and 39 (6.8%) pts had a VT before/at or after PV diagnosis, respectively. We found that JAK2 VAF as a continue variable was correlated with the risk of VT in FU (p=0.003) but not with AT (p=0.8). ROC analysis to determine the best cut-off level for JAK2 VAF predicting VT had an AUC of 0.72 and a best cut-off value of VAF=50%. VT at FU were significantly enriched in pts with VAF >50%: 14.5% versus 2.4%, p=<0.0001. VT -free survival (VT-FS) by KM was significantly shorter in the presence of a JAK2 VAF >50% (HR 4, CI 1.9-8.6, p<0.0001) (Figure 1A), whereas no difference was found for AT (HR 0.9). In addition to JAK2VF VAF>50%, univariate analysis for VT-FS identified history of VT (HR 2.9; CI 1.4-6.1, p=0.006), leukocytosis ≥11x10 9/L (HR 1.9; CI 1.1-3.4, p=0.02) and palpable splenomegaly (HR 1.9, CI 1-3.6; p=0.04) as risk factors. Multivariable analysis confirmed VAF>50% (HR 3.8, CI 1.8-8.1, p=0.0006) and previous VT (HR 2.4, CI 1.1-5.1; p=0.02) as independent risk factors for future VT. In contrast, univariate analysis for AT-free survival (AT-FS) identified history of AT (HR 2.5; CI 1.3-4.9, p=0.007), diabetes (HR 3.3; CI 1.6-6.5, p=0.0007), hyperlipidemia (HR 3.1; CI 1.7-5.6, p=0.0003) and hypertension (HR 2, CI 1.1-3.8; p=0.03) as predictors of future AT; age >60y showed only a trend (p=0.08). Multivariable analysis for AT-FS identified diabetes (HR 2.4, CI 1.2-5; p=0.02), hyperlipidemia (HR 2.3; CI 1.2-4.3, p=0.01) and previous AT (HR 2.1, CI 1-4.2; p=0.04) as independent predictors of future AT. Validation: Our findings were validated in an independent cohort of 315 2016-WHO defined PV pts from Policlinico Gemelli, Catholic Univ., Rome. After exclusion of 26 pts with SVT, analysis was conducted on 289 pts, 38 of them with thrombosis as heralding event (21 AT and 17 VT). Multivariable analysis confirmed JAK2VF VAF >50% (HR 2.3, CI 1.03-5.0, p=0.04) and previous VT (HR 4.5, CI 2.0-10.1; p=0.0003) as independent risk factors for future VT. In pts with VAF >50%, the rate of VT at FU was 19.9% vs 7.7%, P=0.005. KM curve showed that VT-FS was significantly shorter in pts with a JAK2VF VAF >50% (HR 2.2, CI 1.2-4.2; p=0.01) (Figure 1B). Of note, impact of JAK2 VAF>50% on VT at FU was statistically significant particularly in conventionally low-risk pts, accounting for an HR of 9.4 (CI 1.2-72) and HR 3.6 (CI 1.3-10) in Florence and Rome cohorts, respectively. Conclusions: These data support JAK2VF VAF as a strong independent predictor for future venous thrombosis in PV, in association with history of prior venous events, reinforcing that AT and VT are associated with unique risk factors in pts with PV. Supported by AIRC, Project Mynerva n.21267 Figure 1 Figure 1. Disclosures Vannucchi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Venetoclax, a small-molecule inhibitor of B cell leukemia/lymphoma-2, in combination with hypomethylating agents (HMA) has shown improved efficacy and survival benefit compared to HMA alone (DiNardo et al, 2020) in elderly/unfit patients with acute myeloid leukemia (AML). Since FDA-approval of this regimen for elderly/unfit AML patients, it is frequently utilized both in the upfront and relapsed/refractory setting. Cardiac events with venetoclax are not well described. In the VIALE-E trial, which included patients ineligible for standard induction chemotherapy due to congestive heart failure or stable angina, 15% of patients receiving azacitidine plus venetoclax experienced atrial fibrillation as a serious adverse event, vs. 1% in the azacitidine plus placebo group (DiNardo et al, 2020). Our objective was to provide an estimate of the prevalence of and a description of all cardiac events that occurred in AML patients undergoing treatment with venetoclax + HMA. Methods: 170 consecutive patients with AML who received venetoclax +HMA (azacitidine or decitabine) outside the context of a clinical trial between 1/2017-11/2020 at the Mayo Clinic were included. Patients received venetoclax + HMA either as upfront treatment or for relapsed/refractory disease. Patients with relapse following allogeneic stem cell transplant were excluded. We evaluated all cardiac events that occurred while treatment with venetoclax + HMA was ongoing. Baseline patient and treatment characteristics were compared using the Mann-Whitney U-test and the Fisher's exact test. All statistics were computed using EZR (Version 1.53). Results: 1. Patient characteristics A total of 170 patients who received venetoclax + HMA (median age 69 years [range 17-91], 63% males) were included. ELN risk category was either adverse risk (48%, 82/170) or intermediate risk (48%, 82/170) in the majority of patients. 64% (109/170) of patients received venetoclax + HMA as upfront treatment. Characteristics including age, ELN cytogenetic risk, cardiovascular risk factors, and upfront vs relapsed therapy were similar among patients with or without cardiac events. The only exception was a higher incidence of CEBPA mutation amongst those with cardiac events (12% vs 2%, p=0.03). The majority (83%, 141/170) of patients underwent an echocardiogram prior to initiation of therapy. 2. Cardiac events Of 170 patients treated with venetoclax + HMA during the study period, 34 (20%) patients experienced a total of 48 cardiac events. Of patients experiencing cardiac events, 32% (11/34) had no pre-existing cardiac disease and 12% (4/34) had no cardiovascular risk factors (Table 1). The majority of events occurred early in treatment course: 41% during cycle 1, 26% during cycle 2 and 15% during cycle 3 (Table 1). The most frequently occurring cardiac event (21%, 10/48 events) was a decrease in left ventricular ejection fraction on echocardiography, which was associated with symptoms in all ten patients. Second most frequent was atrial fibrillation with rapid ventricular response at 17% (8/48 events), followed by troponin elevation without electrocardiogram changes at 15% (7/46 events). Of patients with troponin elevation, 57% (4/7 events) occurred in the setting of another inciting factor such as severe anemia, while 43% represented a troponin elevation without explanation (Table 1). Other cardiac events included heart failure with preserved ejection fraction (n=4), other symptomatic arrhythmia (n=4), and symptomatic pericardial effusion or pericarditis (n=3). In addition, 2 of 34 (6%) patients experienced fatal cardiopulmonary arrest. The majority (88%) of cardiac events required either inpatient admission (62%, 21/34 patients) or intensive care unit (ICU) care (26%, 9/34 patients). 77% of patients required new cardiac medications or procedural intervention (n=4). In 27% of cases (9/34 patients), the cardiac event directly contributed to death (Table 1). Conclusions: Cardiac complications were observed in one-fifth (20%) of AML patients treated with venetoclax + HMA, despite the absence of preexisting cardiac disease in a third of cases; moreover 27% of events were fatal. Further comparative studies are required to identify salient clinical features predictive of cardiac complications in these patients. Figure 1 Figure 1. Disclosures Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Litzow: Astellas: Research Funding; Amgen: Research Funding; Omeros: Other: Advisory Board; AbbVie: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Biosight: Other: Data monitoring committee. Patnaik: Kura Oncology: Research Funding; StemLine: Research Funding.

Abstract Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence and subsequent expansion of leukemia-associated driver mutations (MT). These MT predominantly involve epigenetic regulators such as DNMT3A, ASXL1, and TET2 (DAT, 75%). CHIP is a disease of aging and is associated with increased all-cause mortality. Clonal Hematopoiesis (CH), when present in the context of unexplained cytopenias and MT variant allele fractions (VAF) >20%, is termed as clonal cytopenias of undetermined significance (CCUS). Chronic myelomonocytic leukemia (CMML) is a hematological malignancy characterized by TET2, ASXL1, and SRSF2MT as well as sustained monocytosis. It usually arises in the setting of existing CH and clonal monocytosis. Here, we assessed the clonal compositions involving DAT genes in patients (pts) with CHIP, CCUS, and CMML. Methods: We included 1008 pts: 54 (5%) with CHIP, 334 (33%) with CCUS, and 620 (62%) with CMML. Demographics, laboratory parameters, and mutational spectrum at diagnosis were collected. We characterized and compared DAT MT in all three cohorts and assessed correlations with clinical parameters. MT locus and type along with protein sequences were analyzed using ProteinPaint. All statistical analyses were performed using R. Results: Of the 1008 pts, 427 (42%) had DAT MT; 36 had CHIP (67%); 96 had CCUS (29%), and 296 had CMML (48%). The median age was 71 years (IQR 65-76), and 68% were male. CMML pts had higher white blood cell counts, absolute neutrophil counts, absolute monocyte counts, and lower hemoglobin and platelet counts in comparison to CCUS and CHIP pts. The distribution of age and sex were similar among the three groups. After a median follow-up of 11 months (IQR 9.5-12.8), there were no myeloid progressions in the CHIP group and 17 (18%) in the CCUS group (8 of which developed CMML, Table 1). There were 738 protein-altering or splice-site DATMT in 495 unique MT hotspots. Pts with TET2MT were older (71 years, compared to DNMT3AMT: 69 years and ASXL1MT: 69 years , p<0.022). ASXL1MT were more common in males (75%, compared to DNMT3AMT: 52% and TET2MT: 66%, p=0.005). The mean VAF (mVAF) were 15.5% for DNMT3AMT, 35% for ASXL1MT and 39.2% TET2MT, respectively (p<0.001). We then compared DATMT characteristics in CHIP, CCUS, and CMML groups: DNMT3AMT were most common in CHIP, followed by CCUS, and were very rare in CMML (35% vs. 15% vs. 3%, p<0.001), with mVAF of DNMT3AMT increasing across this spectrum (CHIP: 6.5% vs. CCUS: 17.1% vs. CMML: 43.4%, p<0.0001). While DNMT3A missense MTs were most common (n=62, 67.4%), the AML-associated R882 hotspot MT was seen in 26 (28%) pts (CHIP: n=3, 5%, CCUS: n=10, 16%, and CMML n=13, 21%, Figure 1a). None of the DNMT3AMT CHIP and CCUS pts progressed to CMML.ASXL1MT were most frequently seen in CMML (n=178, 28.6%), followed by CHIP (n=4, 7.4%), and CCUS (n=17, 5%, p<0.001). The mVAF of ASXL1MT was significantly lower in CHIP, followed by CCUS, and CMML (11% vs. 34% vs. 36%, p<0.0001). Truncating ASXL1 MTs were most common (n=205, 53%). Mutational hotspots included G646W (n=81, CCUS: n=6, 3%, CMML: n=75, 37%) and E635 (n=27, CHIP: n=1, 0.5%, CCUS: n=1, 0.5%, CMML: n=27, 13%, Figure 1b). Four ASXL1MT CCUS pts transformed to CMML (R965, E635, G646W, Q910*, and Q925*); of which 2 co-mutated with TET2MT, one with SRSF2MT, and one with an additional ASXL1MT.TET2MT were frequently encountered in CMML, followed by CCUS and CHIP pts (CMML: n=205, 33% vs. CCUS: n=88, 26.3% vs. CHIP: n=15, 27.8%, p=0.02). The mVAF of TET2MT progressively increased across the 3 groups (CHIP: 14.1%, CCUS: 31.9%, CMML: 45.5%, p<0.001). TET2MT occurred across the span of the gene, with no clear hotspots identified, with nonsense MT being most frequent (n=150, 37.3%, Figure 1c). Among the nonsense and frameshift TET2MT (n=209), 131 (63%) involved the N terminal region, and 78 (37%) involved the catalytic domain. Among 8 CCUS pts that transformed to CMML, 6 had TET2MT, including 4 with spliceosome co-MT. Conclusion: While CMML, a disease of aging, arises in the background of CH, the most common CH MT, DNMT3AMT, plays a minor role in this process, and in fact, DNMT3AMT tend to occur at younger ages. While DNMT3A MT and ASXL1MT are preferentially observed in hotspots, TET2MT span the entire gene. Clonal compositions largely involving truncating TET2MT and frameshift ASXL1MT, in conjunction with splicing MT, shape the CMML genotype. Figure 1 Figure 1. Disclosures Komrokji: Geron: Honoraria; Novartis: Honoraria; Agios: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria. Zeidan: Genentech: Consultancy; BeyondSpring: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Amgen: Consultancy, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Astex: Research Funding; Epizyme: Consultancy; Geron: Other: Clinical Trial Committees; Boehringer Ingelheim: Consultancy, Research Funding; AstraZeneca: Consultancy; Acceleron: Consultancy, Research Funding; Astellas: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Agios: Consultancy; Aprea: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; ADC Therapeutics: Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Jazz: Consultancy; Incyte: Consultancy, Research Funding; Ionis: Consultancy; Jasper: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; BioCryst: Other: Clinical Trial Committees. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Madanat: Blue Print Pharmaceutical: Honoraria; Stem line pharmaceutical: Honoraria; Onc Live: Honoraria; Geron Pharmaceutical: Consultancy. Griffiths: Takeda Oncology: Consultancy, Honoraria; Novartis: Honoraria; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Boston Biomedical: Consultancy; Astex Pharmaceuticals: Honoraria, Research Funding; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Consultancy, Honoraria. Lai: Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau; Jazz Pharma: Speakers Bureau; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Savona: CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. Litzow: AbbVie: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Amgen: Research Funding; Astellas: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding.

Abstract Background: Splenomegaly is a marker of disease progression in MF; larger spleen size (SS) is correlated with poorer survival and debilitating MF symptoms. In a retrospective real-world study of 408 patients (pts) with MF treated with ruxolitinib (RUX), pts with SS ≥ 10 cm below the left costal margin (LCM) were significantly less likely to attain a spleen response than pts with SS < 10 cm (Palandri 2017); this finding has not been reported in clinical trials of RUX. FEDR is a JAK2-selective inhibitor approved in the US, EU, Canada, and elsewhere as first-line (1L) MF treatment (Tx) and in pts previously treated with RUX. FEDR was evaluated as 1L MF Tx in the phase 3, placebo (PBO)-controlled JAKARTA trial, and in the phase 2, single-arm JAKARTA2 trial in pts previously treated with RUX. Pts allocated to FEDR 400 mg/day (d) in these trials reported substantial reductions from baseline (BL) in spleen volume and MF symptom severity after 6 FEDR Tx cycles. It is important to determine whether spleen volume and symptom improvements during FEDR Tx are influenced by degree of pre-Tx splenomegaly. Objective: Investigate the clinical efficacy of FEDR 400 mg/d in pts in JAKARTA & JAKARTA2 with large spleens at BL. Methods: The JAKARTA trial assessed FEDR 400 mg/d, FEDR 500 mg/d, and placebo in pts with JAK-inhibitor-naïve MF, and the JAKARTA2 trial evaluated FEDR 400 mg/d (starting dose) in pts resistant/intolerant to prior RUX. Both studies enrolled pts with intermediate- or high-risk MF, SS > 5 cm from LCM by palpation, platelets ≥ 50 ×10 9/L, and ECOG PS ≤ 2. These analyses include pts in each trial allocated to receive FEDR 400 mg/d in continuous 28d Tx cycles. Too few pts had BL SS < 10 cm by palpation in JAKARTA (n = 21) and JAKARTA2 (n = 12) for meaningful comparison vs SS ≥ 10 cm. Thus, in these post hoc analyses we divided pts according to the median SS (mSS) at BL in each study , and assessed changes from BL in spleen volume and MFSAF total symptom score (TSS) at the end of cycle 6 (EOC6). Spleen volume was assessed by MRI/CT scan; MFSAF TSS was the sum of 6 MF symptom scores: night sweats, early satiety, pruritus, pain under ribs-left side, abdominal discomfort, and bone/muscle pain. Pts must have had spleen volume and/or TSS data at BL and EOC6. R esults: In JAKARTA, 96 pts were randomized to FEDR 400 mg/d; mSS at BL for all pts was 16 cm (range 5-40). Median (range) BL spleen volume was 1771 (316-3396) mL in the < mSS cohort and 3329 (983-6430) mL in the ≥ mSS cohort; median TSS was 13.0 and 17.6, respectively. Spleen volume data were available at BL and EOC6 for 37 (82%) and 38 (75%) pts in the < mSS and ≥ mSS cohorts, respectively. Median spleen volume reduction (SVR) at EOC6 was -38% [95%CI -43%, -31%] in the < mSS group and -40% [-40%, -28%] in the ≥ mSS group (Figure). Changes in MF symptom scores at EOC6 were similar in the < mSS (n = 37) and ≥ mSS (n = 34) cohorts, with median TSS reductions of -49% and -51%, respectively. For individual symptoms, median reductions in abdominal discomfort, bone/muscle pain, and early satiety were similar between BL SS cohorts, whereas changes were greater in the < mSS group for pruritus and pain under ribs-left side, and greater in the ≥ mSS group for night sweats. In JAKARTA2, 97 pts received FEDR 400 mg/d (starting dose); BL mSS for all pts was 18 cm (range 5-36). Median (range) BL spleen volumes were 1937 (737-4305) and 4002 (1821-7815) mL for pts with < mSS and ≥ mSS, respectively; and BL TSS was 17.2 (0.7-48.0) and 23.6 (1.0-44.0). Spleen volume and MFSAF TSS data were available at BL and EOC6 for 41 and 29 pts, respectively, in the < mSS cohort, and for 41 and 22 pts in the ≥ mSS group. At EOC6, median SVR from BL was -35% [95%CI -40%, -29%] for pts with < mSS at BL and -30% [-37%, -17%] for pts with ≥ mSS (Figure). Median TSS changes were -36% and -49% in the < mSS and ≥ mSS cohorts, respectively; pts with ≥ mSS at BL had similar or greater reductions from BL in 5/6 MFSAF symptoms (all except pruritus) vs those with < mSS. Conclusions: These analyses demonstrate that extent of splenomegaly at BL in JAKARTA and JAKARTA2 did not influence the likelihood of achieving improvements in spleen volume or MF symptom severity for pts receiving FEDR 400 mg/d as 1L MF Tx or as post-RUX salvage Tx. For pts who completed 6 FEDR Tx cycles, reductions in spleen volume and TSS at EOC6 in the ≥ mSS cohorts in both studies were similar to those in the < mSS cohorts, even though BL spleen volumes and TSS were higher in the ≥ mSS groups. Figure 1 Figure 1. Disclosures Kiladjian: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Passamonti: BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vannucchi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees. Talpaz: Imago: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Other: Grant/research support . Cervantes: Bristol Myers Squibb: Consultancy, Honoraria. Harrison: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Sierra Oncology: Honoraria; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mesa: AOP: Consultancy; La Jolla Pharma: Consultancy; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Genentech: Research Funding; Samus: Research Funding; CTI: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Gilead: Research Funding; CTI: Research Funding; Pharma: Consultancy; Promedior: Research Funding. Mascarenhas: Geron: Consultancy; Merus: Research Funding; Geron: Consultancy, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Consultancy; Galecto: Consultancy; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forbius: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Verstovsek: Promedior: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corp: Research Funding; Protagonist Therapeutics: Research Funding; Genentech: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; PharmaEssentia: Research Funding; Celgene: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Devos: Alexion, AstraZeneca Rare Disease Inc.: Consultancy; Incyte: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb - Celegene: Consultancy; Novartis: Consultancy. Rose: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zhang: Bristol Myers Squibb: Current Employment. Sy: Bristol Myers Squibb: Current Employment.

Abstract Background: Therapy-related acute myeloid leukemia (AML) is a well-described entity and known to carry a worse prognosis, compared to de novo AML. In the current study, we sought to describe the presenting features and outcome of patients with AML, in the setting of previous history of cancer with or without exposure to chemotherapy or radiotherapy. Methods: A Mayo Clinic database of patients with AML was queried to identify patients with a previous history of cancer, both hematologic and solid tumors. A comparative analysis of presenting features, treatment details and survival were performed between patients with therapy-related AML (Group A) and those with AML and a history of cancer that had been managed with surgery alone (Group B). Results: A total of 250 patients (median age 68 years, range 19-90; 60% males) with AML and a previous history of cancer (both hematologic and solid) were identified; 182 (73%) cases were determined to be therapy-related AML (Group A) while the remaining 68 (27%) did not receive chemotherapy or radiotherapy for their antecedent cancer (Group B) (Table). Among group A patients 106 (58%) were exposed to chemotherapy, 37 (20%) to radiotherapy and 39 (22%) to combination chemotherapy and radiotherapy for their cancer. At the time of AML diagnosis, adverse karyotype was noted in 91 (51%) group A and 12 (19%) group B patients (p<0.0001); the incidence of adverse karyotype in patients exposed to chemotherapy vs radiotherapy alone vs combined chemoradiotherapy was 54% (57/106), 30% (11/37), and 59% (23/39) respectively (p=0.04). Group A patients, compared to those in group B, included more females (46% vs 24%; p=0.001), and more preceding hematologic malignancies (p=<0.0001). Next generation sequencing was performed in 74 patients and the results showed no significant difference between groups A and B (Table). Treatment and outcome in Groups A and B: Intensive and less intensive AML-directed chemotherapy were given to 100 (55%) and 44 (24%) patients in group A and 38 (56%) and 14 (21%) patients in group B (P=0.8). 79 (65%) remissions (complete remission (CR) 42 (29%) and CR with incomplete count recovery (CRi) 37 (26%) were documented in Group A and 37 (71%) remissions (CR: 21 (40%) and CRi=16 (31%) in Group B (P=0.2). After a median follow-up of 8.4 months (range: 0.9-217), 184 deaths were documented: 132 (72.5%) in Group A and 52 (76.5%) in Group B (P=0.5). 52 (36%) patients from Group A and 25 (48%) from Group B relapsed (P=0.1). The median (range) overall survival (OS) rates of patients from Group A was 13 (9-17) months and that of Group B was 14 (10-35) months (P=0.6). The 1-, 3- and 5-year OS rates were 52%, 28%, and 24% in Group A; and 62%, 33%, and 24% in Group B patients (Fig 1). Multivariable analysis identified relapse (HR 2.8, 95% CI 1.7-4.7) and failure to achieve CR/CRi (HR 2.8 95% CI 1.9-4.7) as risk factors for inferior survival (Fig 2a and 2b). The median (range) relapse free survival of patients in Group A was 28 (17 -81) and that of Group B was 27 (14 - 76) months (P=0.9) (Fig 2c). 28 patients underwent allogenic stem-cell transplant (25 in CR1 and 3 in CR2), 23 in Group A and 5 in Group B; the 1-, 3-, and 5-year OS of patients who underwent allogenic stem cell transplant were 88%, 72%, and 72% regardless of the group (Fig 2d). Conclusion: The current study did not find significant differences between AML patients with previous history of cancer with or without exposure to chemo/radiotherapy, in terms of either response to AML-directed therapy or overall or relapse-free survival, despite a higher prevalence of adverse karyotype in therapy-related AML. Figure 1 Figure 1. Disclosures Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Litzow: Pluristem: Research Funding; Actinium: Research Funding; AbbVie: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee.

Abstract 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<0.05. 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<0.0001, Figure A). This difference persisted when stratified by no disease modifying therapies (BSC only) 2 vs. 17 months (P<0.0001, Figure B), as well as among those who received at least one line of chemotherapy (14 vs. 24.6 months, P<0.001). Finally, a higher proportion of patients with t-AML underwent SCT and there was a trend towards improved survival for t-AML patients (vs. t-MDS 52.9 vs. 20.7 months, P=0.07) from the time of transplant. 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.