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Komrokji et al examined the proposed international working group proposal to designate SF3B1-mutant myelodysplastic syndrome (MDS) as a unique disease entity, using a single-institution validation cohort of 1779 MDS patients, of whom 320 harbored SF3B1 mutations. They confirmed the demographics of older age, low-risk disease, ring sideroblasts, and low blast percentage. They further confirmed better overall survival that is negatively impacted in those patients with concomitant mutations, high variant allele fraction, and increased blast percentage.

Purpose: Chronic myelomonocytic leukemia (CMML) is a rare leukemia characterized by peripheral monocytosis with no disease-modifying therapies. CMML cells are uniquely hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF) and robustly engraft in immunocompromised mice that secrete human cytokines. To leverage these unique biological features, we conducted an integrated human and murine study evaluating ruxolitinib, a JAK1/2 inhibitor that potently downregulates intracellular GM-CSF signaling. Patients and Methods: A total of 50 patients with WHO-defined CMML were enrolled in this open-label, multi-institution phase I/II clinical study, with a ruxolitinib dose of 20 mg twice daily studied in phase II. In parallel, 49 patient-derived xenografts (PDX) derived from 13 study participants were generated and randomized to receive ruxolitinib or vehicle control. Results: The most common grade 3/4 treatment-related toxicities observed were anemia (10%) and thrombocytopenia (6%). The clinical overall response rate was 38% by Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) International Working Group (IWG) criteria and 43% of patients with baseline splenomegaly achieved a spleen response. Profiling of cytokine levels and somatic mutations at baseline failed to identify predictive biomarkers. PDX models derived from screening samples of study participants recapitulated responses seen in humans, particularly spleen responses, and corroborated ruxolitinib's clinical efficacy in a randomized murine study not feasible in human trials. Conclusions: Ruxolitinib demonstrated clinical efficacy and an acceptable adverse event profile in patients with CMML, identifying a potential novel therapeutic in this rare malignancy. Furthermore, this study demonstrates proof of concept that PDX modeling can recapitulate responses of patients treated on clinical trial and represents a novel correlative study that corroborates clinical efficacy seen in humans. See related commentary by Shastri and Adrianzen-Herrera, p. 6069

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Median overall survival of this aggressive myeloid malignancy is only 2-3 years, with a 15-30% risk of acute leukemic transformation. The paucity of clinical trials specifically designed for CMML has made therapeutic management of CMML patients challenging. As a result, treatment paradigms for CMML patients are largely borrowed from MDS and MPN. The standard of care still relies on hydroxyurea, hypomethylating agents (HMA), and allogeneic stem cell transplantation, this latter option remaining the only potentially curative therapy. To date, approved drugs for CMML treatment are HMA, including azacitidine, decitabine, and more recently the oral combination of decitabine and cedazuridine. However, HMA treatment does not meaningfully alter the natural course of this disease. New treatment approaches for improving CMML-associated cytopenias or targeting the CMML malignant clone are emerging. More than 25 therapeutic agents are currently being evaluated in phase 1 or phase 2 clinical trials for CMML and other myeloid malignancies, often in combination with a HMA backbone. Several novel agents, such as sotatercept, ruxolitinib, lenzilumab, and tagraxofusp have shown promising clinical efficacy in CMML. Current evidence supports the idea that effective treatment in CMML will likely require combination therapy targeting multiple pathways, which emphasizes the need for additional new therapeutic options. This review focuses on recent therapeutic advances and innovative treatment strategies in CMML, including global and molecularly targeted approaches. We also discuss what may help to make progress in the design of rationally derived and disease-modifying therapies for CMML.

Transforming growth factor beta (TGF-β) signaling pathway is key to hematopoiesis regulation. Increased activation of this pathway contributes to ineffective terminal erythroid differentiation in myelodysplastic syndromes (MDS). Luspatercept is a novel fusion protein that traps TGF-β ligands preventing them from binding to Type II TGF-β receptors, thereby decreasing phosphorylated SMAD2/3 resulting in the downstream effect of promoting erythropoiesis. Seminal clinical trials using luspatercept, PACE-MD and MEDALIST, demonstrated impressive efficacy in the treatment of transfusion-dependent anemia in intermediate risk or lower MDS had led to the US FDA approval for this indication. This review summarizes luspatercept mechanisms of action, efficacy/safety data supporting its use and ongoing clinical trials in MDS.

Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is characterized by anemia, ring sideroblast erythroid precursors, and persistent thrombocytosis. Case reports suggest lenalidomide may be effective in treating MDS/MPN-RS-T. We evaluated a large series of patients with MDS/MPN-RS-T to compare hematological improvement (HI) response rates among different drug therapies including lenalidomide. We identified 167 patients with MDS/MPN-RS-T. Among the patients tested, 84% had SF3B1 mutations and 43% had JAK2 V617F mutations. The median OS for the cohort was 81 months. Overall, 76 patients (46%) received erythropoiesis-stimulating agents (ESAs), 47 patients (28%) received lenalidomide, and 45 patients (27%) received hypomethylating agents (HMAs). The HI rates were 58%, 53%, and 24%, respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMAs. Rates of HI improvement were higher in patients with MDS/MPN-RS-T treated with ESAs or lenalidomide, in comparison to those treated with HMAs.

Recent studies demonstrated that MYC epigenetically regulates AML cell survival and differentiation by suppressing IDH1/2-TET2-5hmC signaling and that MYC overexpression is associated with poor survival outcomes in multiple AML patient cohorts. However, the oncogenic roles of MYC in MDS remain to be explored. A total of 41 patients with de novo MDS were retrospectively identified using the Total Cancer Care database at the Moffitt Cancer Center. A total of 61 % of patients had low MYC expression and 39 % of patients had high MYC expression defined as MYC reactivity by immunohistochemical staining in ≥5% of bone marrow (BM) cells at the time of MDS diagnosis. The median MDS-to-AML progression free survival (PFS) was significantly shorter in the high MYC group (median PFS 9.3 vs. 17.7 months, HR = 2.328, p = 0.013). Further, overall survival (OS) was also shorter in the high MYC patients (median OS 19.7 vs. 51.7 months, HR = 2.299, p = 0.053). Multivariate analyses demonstrated that high MYC expression is an independent poor prognostic factor for the MDS-to-AML progression (HR = 2.275, p = 0.046). Our observations indicate that MYC may play a crucial role in MDS transformation to AML and the underlying mechanisms of MYC-driven MDS clonal expansion and leukemic transformation require further investigation.

Chronic myeloid leukemia (CML) has long been thought to be the model disease for immunotherapy with its characteristic BCR-ABL fusion protein. Although targeted therapy using tyrosine kinase inhibitors (TKIs) is highly effective at inducing remission, most patients require life-long TKI to decrease the risk of relapse. In recent years, much effort has been devoted to finding ways to eliminate CML stem cells (LSCs); the source of disease persistence. Areas covered: In this review, the authors present recent immunologic findings pertinent to CML, vaccinations targeting leukemia antigens, interferon combination therapies, and other emerging strategies aimed at increasing immunogenicity and improving outcomes in patients with CML. Recent publications and abstracts found in Pubmed and hematology/oncology meetings related to these topics were identified and incorporated into this review. Expert commentary: Further understanding of the immune system and antigenic composition of LSCs has allowed for novel therapeutic development. Immunotherapies are effective at the malignant stem cell level and combining these approaches with TKI is a promising option. Despite ongoing challenges, it is increasingly recognized that a cure may be achievable through immunotherapies.

ASXL1 and SRSF2 mutations in AML are frequently found in patients with preexisting myeloid malignancies and are individually associated with poor outcomes. In this multi-institutional retrospective analysis, we assessed the genetic features and clinical outcomes of 43 patients with ASXL1mut SRSF2mut AML and compared outcomes to patients with either ASXL1 (n=57) or SRSF2 (n=70) mutations. Twenty-six (60%) had secondary-AML (s-AML). Variant allele fractions suggested that SRSF2 mutations preceded ASXL1 mutational events. Median overall survival (OS) was 7.0 months (95% CI:3.8,15.3) and was significantly longer in patients with de novo versus s-AML (15.3 versus 6.4 months, respectively; p=0.04 on adjusted analysis). Compared to ASXL1mut SRSF2wt and ASXL1wt SRSF2mut , co-mutated patients had a 1.4 and 1.6 times increase in the probability of death, respectively (p=0.049), with a trend towards inferior OS (median OS = 7.0 vs. 11.5 vs. 10.9 months, respectively; p =0.10). Multivariable analysis suggests this difference in OS is attributable to the high proportion of s-AML patients in the co-mutated cohort (60% vs. 32% and 23%, respectively). Although this study is limited by the retrospective data collection and the relatively small sample size, these data suggest that ASXL1mut SRSF2mut AML is a distinct subgroup of AML frequently associated with s-AML and differs from ASXL1mut SRSF2wt /ASXL1wt SRSF2mut with respect to etiology and leukemogenesis. This article is protected by copyright. All rights reserved.

Background: NPM1 is commonly mutated in AML and represents a distinct entity under the WHO 2016 classification. It is one of the few mutations that can potentially support favorable risk by ELN 2017. Mutations that are highly specific for secondary AML (sMT) including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2 (Lindsley et al.) have been shown to confer poor prognosis. Objective: In this study, we explore the outcomes in patients with NPM1 mutated AML. Methods: This was a retrospective study of NPM1 AML mutated patients who were treated at the Moffitt Cancer Center from 2013-2020. Only those with NPM1 mutations and NGS performed at diagnosis were included in the study (n=115). Kaplan-Meier, univariate, and multivariate analyses were performed. Results: Of the 115 patients (54M/85F, median age 61 at diagnosis), majority had de novo AML (83.5%). Over half of them had favorable risk (55.7%), followed by intermediate risk (35.6%), and adverse risk (8.7%). Almost 80% had normal cytogenetics at the time of diagnosis. Common co-mutations included DNMT3A (47.8%), FLT3-ITD (39.1%), TET2 (20%), FLT3-TKD (18.3%), IDH1 (18.3%), and IDH2(16.5%). sMT occurred in 16.5% of the entire cohort and 17.2% among those with ELN favorable risk. Patients with sMT have a significantly lower rates of relapse freedom after CR/CRi (26.3% vs 52.1%, p=0.047). Numerically, higher rates of relapse after CR/CRi (47.4% vs 34.4%, p=0.301) and higher rates of never achieving CR/CRi (26.3% vs 13.5%, p=0.175). Among favorable risk, OS was 14. 7 months for sMT vs not reached for those without sMT (p Conclusions: Our findings suggest NPM1 mutated AML patients with sMT have significantly worse prognosis despite being classified as favorable risk by ELN 2017 at diagnosis. This may have treatment implications in the need for and/or timing of HCT. Further studies and larger datasets are needed to confirm these observations.

Chronic myelomonocytic leukemia (CMML) is a rare, heterogeneous myeloid malignancy classified as a myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) overlap syndrome by the World Health Organization (WHO). Its initial presentation can be incidental or associated with myelodysplastic or myeloproliferative symptoms and up to 20% of patients harbor a concurrent inflammatory or autoimmune condition. Persistent monocytosis is the hallmark of CMML but diagnosis can be challenging. Increased understanding of human monocyte subsets, chromosomal abnormalities, and somatic gene mutations have led to more accurate diagnosis and improved prognostication. A number of risk stratification systems have been developed and validated but using those that incorporate molecular information such as CMML Prognostic Scoring System (CPSS)-Mol, Mayo Molecular, and Groupe Francophone des Myelodysplasies (GFM) are preferred. Symptom-directed approaches forms the basis of CMML management. Outcomes vary substantially depending on risk ranging from observation for a number of years to rapidly progressive disease and acute myeloid leukemia (AML) transformation. Patients who are low risk but with symptoms from cytopenias or proliferative features such as splenomegaly may be treated with hypomethylating agents (HMAs) or cytoreductive therapy, respectively, with the goal of durable symptoms control. Allogeneic hematopoietic cell transplantation should be considered for intermediate to high risk patients. The lack of effective pharmaceutical options has generated interest in novel therapeutics for this disease, and early phase clinical trial results are promising.

Hypomethylating agents (HMAs) are widely used in the treatment of myelodysplastic syndromes (MDSs), yet identifying those patients unlikely to benefit remains challenging. We assessed response and overall survival (OS) in 247 patients molecularly profiled by next-generation sequencing (NGS) before first-line HMA therapy, and a subset of 108 patients were sequenced serially during treatment. The most common mutations included TP53 (33.1%), ASXL1 (19%), TET2 (16.5%), DNMT3A (14.1%), and SRSF2 (12.1%). The overall response rate was 42.1%, with the composite TET2-mutant/ASXL1 wild-type genotype representing the strongest predictor of response (overall response rate, 62.1%; complete remission rate, 34.5%). The median OS for the cohort was 15 months, and the number of mutations detected by NGS (hazard ratio [HR], 1.22; P = .02), as well as mutations in TP53 (HR, 2.33; P = .001) and EZH2 (HR, 2.41; P = .04) were identified as independent covariates associated with inferior OS in multivariable analysis. Serial molecular profiling revealed that clearance of TP53 mutations during HMA therapy was associated with superior OS (HR, 0.28; P = .001) and improved outcome in patients proceeding to allogeneic hematopoietic cell transplantation. These data support baseline molecular profiling by NGS in MDS patients treated with HMAs and provide novel observations of sequential profiling during therapy that provide particular value in TP53-mutated disease.

Background Cytogenetic profile is an essential parameter in myelodysplastic syndromes (MDS) risk stratification by both International Prognostic Symptom Score (IPSS) and Revised (R)-IPSS. Almost one-half of patients with MDS have normal cytogenetics by metaphase karyotype. Here we report the yield of MDS fluorescence in situ hybridization (FISH) panel detecting cytogenetic abnormalities in these patients and its impact on risk stratification. Patients and Methods Among patients with normal metaphase karyotype, we assessed those patients who had cytogenetic abnormalities detected by an MDS FISH panel, which included probes for del (5), del (7), del (20), trisomy 8, and del (17p). Risk stratification was calculated by both IPSS and R-IPSS. Results Of 1600 patients with MDS with normal metaphase karyotype, 53 (3%) patients had cytogenetic abnormality detected by MDS FISH panel. Integrating the MDS FISH panel cytogenetics (IPSS + FISH restaging) resulted in upstaging the score, where 53% of low-risk IPSS were upstaged to intermediate (int)-1, 56% of int-1 were upstaged to int-2, and 78% of int-2 were upstaged to high risk. Based on the R-IPSS, 61% of very low-risk patients, all low-risk patients, 92% of intermediate-risk patients, and 50% of high-risk patients with FISH abnormalities were upstaged, respectively. Conclusion The yield of MDS FISH panel detecting cytogenetic abnormalities in patients with normal karyotype by G-banding is low and may not warrant ordering the panel in all patients. Among the 3% of patients with normal karyotype who had cytogenetic abnormality detected by FISH, the risk score assignment by IPSS and R-IPSS was upstaged.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with dismal clinical outcomes. Conventional chemotherapies were previously shown to have some clinical efficacy, however, long-term outcomes of BPDCN patients remain poor. In a recent clinical trial, SL-401 demonstrated an overall response rate (ORR) of 90% in previously untreated BPDCN patients. Despite promising outcomes observed in SL-401 studies, there remains a lack of data regarding the optimal first-line therapy. In this single institution retrospective study, we explored the survival outcomes based on front-line treatment and allogeneic stem cell transplant (allo-SCT). A total of 49 patients with confirmed diagnosis of BPDCN were included in the study. Median age at diagnosis was 71.4 (32.0-91.4) years with a male predominance (82%). Among these, 11 (22%) patients had concurrent hematologic neoplasms at the time of BPDCN diagnosis. The most common site of disease involvement was skin (n=42, 86%) followed by bone marrow (BM) (n=32, 65%), lymph node (LN) (n=13, 27%), and nasopharynx (n=2, 4%) with 14 (29%) and 5 (10%) patients having skin and BM involvement only, respectively. Of note, 17 (35%) patients had both skin and BM disease and 8 (16%) had simultaneous skin, BM, and LN involvement. In the front-line setting, CHOP-based regimens, hyper-CVAD, and SL-401 were used in 10 (20%), 11 (22%), and 12 (24%) patients, respectively. The median cycle number of SL-401 treatment was 6 (1-73). Allo-SCT was performed in 10 (20%) patients and 4 (8%) patients received autologous stem cell transplant (auto-SCT). Transplant was performed following first-line therapy in 11 patients (CR, n=10; PR, n=1) and second-line therapy in 3 patients (CR, n=3). Among 21 vs. 12 patients who received chemotherapy vs. SL-401 as their first-line therapy, a total of 11 (52%) and 3 (25%) patients underwent transplant. A total of 23 (55%), 13 (31%), and 6 (14%) patients achieved a complete response (CR), partial response (PR), and progressive disease (PD), respectively. CR rate was higher in patients who were treated with hyper-CVAD compared to others, however, it was not statistically significant (50% in CHOP-based regimens vs. 91% in hyper-CVAD, P=0.064; 50% in SL-401 vs. 91% in hyper-CVAD, P=0.069). The median PFS was 9.9 months and the median OS was not reached when all patients were included for the analyses. In the subgroup analyses, patients who were treated with hyper-CVAD had longest PFS compared to patients treated with CHOP-based regimens (HR=0.217, 95%CI=0.050-0.933, P=0.003) or SL-401 (HR=0.385, 95%CI=0.126-1.179, P=0.075) although the PFS difference between hyper-CVAD and SL-401 did not reach the statistical significance. There was no PFS difference between SL-401 and CHOP-based regimen treated groups (HR=0.931, 95%CI=0.321-2.70, P=0.894). In the OS analysis based on first-line therapy, there was no difference between patients treated with SL-401 compared to patients treated with chemotherapy regimens (HR=1.597, 95%CI=0.460-5.548, P=0.431). Further, there was no OS difference between individual types of front-line therapies (P=0.678). In contrast, patients who received allo-SCT showed significantly longer OS outcomes compared to patients with no transplant (HR=0.160, 95%CI=0.0453-0.56, P=0.041). Additional OS analyses based on age ( In conclusion, our study supports current recommendations of using SL-401 or hyper-CVAD as the first-line treatments followed by consolidation with allo-SCT in the eligible responders to induction therapy to further improve survival outcomes in BPDCN patients. Disclosures Lancet: Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Sokol:Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Honoraria, Speakers Bureau; Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Ponatinib is associated with cardiovascular adverse events (CAEs), and its frequency in the real world is limited. In this retrospective study, we examined the survival outcomes and associated toxicities in 78 consecutive ponatinib-treated patients with chronic myeloid leukemia (CML) at the Moffitt Cancer Center from January 2011 through December 2017. The most common non-CAE was thrombocytopenia (39.7%), occurring in a dose-dependent fashion. Eighteen patients (23.1%) experienced some form of CAE, with the most common being arrhythmia (9%) and hypertension (7.7%), whereas 3 patients experienced myocardial infarction (3.8%). Before 2014, most patients were started on ponatinib 45 mg daily. There was an inverse correlation between cardio-oncology referral and the number of CAEs (P = .0440); however, a lower ponatinib starting dose, more frequent dose reduction, and increased cardio-oncology referral all were likely to have contributed to the observed decrease in CAEs after 2014. The response rate and 5-year overall survival (OS) were higher than those observed in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial (major molecular response, 58.7% vs 40% and OS, 76% vs 73%; median follow-up of 32.5 months). Ponatinib-treated patients with chronic phase–CML did not show a significant improvement with allogeneic stem cell transplantation, whereas those with accelerated phase/blast phase–CML had a much better outcome (median OS of 32.9 months vs 9.2 months; P = .01). These results demonstrate that ponatinib is highly effective. Dose adjustments and increased awareness of the cardiotoxicities associated with ponatinib may help maximize its benefits.

Introduction: Patients with myeloid malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), are at a high risk of severe SARS-CoV-2 infection. It is uncertain whether patients with AML and MDS, who frequently have quantitative or qualitative deficiencies of neutrophils and/or lymphocytes, will develop protective immunity from SARS-CoV-2 vaccines. The primary aim of this analysis was to describe the immune response and safety profile to the mRNA-1273 vaccine amongst a cohort of patients with AML and MDS. Methods: We enrolled AML and MDS patients to a large, single-site observational study of mRNA-1273 vaccination in cancer patients during the period January 12 to January 25, 2021. Blood specimens were collected from patients prior to the first and second vaccine doses (Days 1 and 29) and ~28 days after the second vaccine dose (Day 57) for antibody analyses. Retrospective chart review was done to collect information on baseline characteristics, cancer diagnoses, treatments received, and disease status. To evaluate serostatus, a two-step ELISA was performed, measuring IgG responses. SARS-CoV-2 antibody positivity rates were compared using the Fisher exact test or Chi-square test. The association of SARS-CoV-2 antibody titer and patient characteristics was examined by using Kruskal-Wallis test. Paired t-test was used to analyze the difference of SARS-CoV-2 antibody titers among day 1, after dose 1 and dose 2. Results: A total of 46 patients, 30 patients with AML and 16 patients with MDS, were included in this study. The median age at vaccination for the entire cohort was 68 yrs (range 37-85 yrs). The majority of patients were males (58.7%) and Caucasians (95.7%). Table 1 describes the baseline characteristics of the patients. The median time from diagnosis to the start of vaccination series was 24.3 months (range 4.5-105). One third of the patients (32.6%, n=15) were on active treatment for their disease during the course of vaccination with hypomethylating agents (n=6; 13%), erythroid maturation agent i.e. luspatercept (n=2, 4.3%), immunomodulatory drugs i.e. lenalidomide (n=1; 2.2%) and targeted therapy (6; 13%). Targeted therapy included patients on enasidenib (n=4), midostaurin (n=1) and gilteritinib (n=1). A total of 32 patients (69.6%) were post allogeneic stem cell transplantation for their disease. The median time since allo-SCT for the entire cohort was 17 months (4.9-75.8 mos). The majority of the patients (n=40, 87%) were in remission at the time of vaccination. We found that two patients with AML relapsed post vaccination. Overall, 69.6% patients were seropositive at day 29 (after first vaccine dose) and 95.7% patients were seropositive on day 57 (after 2 vaccine doses). Table 2 describes response to the vaccine in our cohort and the differences in seropositivity rate after one and two doses of vaccine, based upon disease characteristics. Age, gender, race, disease status, time to vaccination from disease diagnosis, number of prior lines of therapy, whether on active treatment, laboratory parameters (including ALC and ANC), whether the patient had undergone allo-SCT, and therapy at time of vaccination did not significantly affect the seropositivity rate. Antibody titer levels were significantly higher after the 2 nd vaccine dose than after 1 st dose (mean 3806.5 vs 315, p Conclusion: In this observational study, the largest reported to date amongst AML and MDS patients with serial serologic data following 2 vaccine doses, we found that the vast majority of patients with AML and MDS converted to seropositivity after two doses of the vaccine. Although the overall sample size was relatively small, most clinical and laboratory variables (including neutropenia and lymphopenia) did not affect the seropositivity rate. Antibody titer levels increased dramatically following the 2 nd vaccine dose, indicating the potential utility for serial vaccination (i.e. additional dosing) in poorly-responsive patients. While these findings should be substantiated in a larger cohort, mRNA-273 SARS-CoV-2 vaccine appears to induce a strong humoral response in this population of patients with AML and MDS. Figure 1 Figure 1. Disclosures Komrokji: PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sallman: Incyte: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Padron: Taiho: Honoraria; Kura: Research Funding; BMS: Research Funding; Blueprint: Honoraria; Incyte: Research Funding; Stemline: Honoraria. Kuykendall: BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; CTI Biopharma: Honoraria; Incyte: Consultancy; Novartis: Honoraria, Speakers Bureau; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; PharmaEssentia: Honoraria. Giuliano: Merck & CO: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet: Daiichi Sankyo: Consultancy; BerGenBio: Consultancy; Celgene/BMS: Consultancy; Millenium Pharma/Takeda: Consultancy; Agios: Consultancy; ElevateBio Management: Consultancy; AbbVie: Consultancy; Astellas: Consultancy; Jazz: Consultancy.

Background: Venetoclax plus hypomethylating agents (HMA) (HMA+VEN) is a standard of care treatment for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. In the phase 3 VIALE-A trial, azacididine (aza)+VEN compared to aza alone demonstrated an improved overall survival of 14.7 months versus 9.6 months, respectively. A common toxicity with HMA+VEN is myelosuppression. The prognostic implications of incomplete count recovery despite leukemia free state after HMA+VEN treatment in AML is unclear. We aimed to compare the outcomes of those who achieved complete remission (CR), complete remission with incomplete hematologic recovery (CRi), or morphologic leukemia-free state (MLFS) in AML patients treated frontline with HMA+VEN. Methods: Patients seen at Moffitt Cancer Center between 2019 and 2021 diagnosed with AML and treated with frontline HMA+VEN were retrospectively evaluated and included for analysis. Patients were stratified by best response; either CR, CRi, or MLFS. Baseline characteristics were compared by chi square (categorical variables) and t- test (continuous variables). Survival estimates were calculated using the Kaplan-Meier method from date of diagnosis and groups were compared using log-rank test. Results: Of the 102 patients treated with HMA+VEN in the frontline setting, 48% (n=49) had blast clearance with a best response of CR in 27/102 (26.4%), CRi in 16/102 (15.7%), or MLFS in 6/102 (5.9%). The remainder had residual disease. Baseline characteristics were similar among the three response groups (Table 1) as was mutational distribution (Table 2). There was no difference between AML WHO classification subtype (p= .148). Decitabine or aza was used at the discretion of the treating physician did not significantly impact responses (p= .225). In those who achieved CR, 14% had prior therapy related AML compared to 37.5% in CRi and 33.3% in MLFS (p= .314). Antecedent MDS or MPN with transformation to AML was seen in 22.2%, 18.8%, and 66.7% of CR, CRi, and MLFS respectively (p= .029). Of those, 3.7% in CR group had HMA use for prior MDS/MPN compared to 0% in CRi and 50% in MLFS (p= .000). The median relapse free survival was not reached for CR, CRi, and MLFS (Figure 1), it is important to note that 3 of the 6 MLFS patients died without relapse . At median follow up of 23 months, median overall survival (OS) in the CR group was significantly longer, 31 months, compared to 18 months in the CRi group and 8.5 months in the MLFS group (p=0.0415) (Figure 2). Transplant was achieved in 26% of CR and 6.3% of CRi and 0% of MLFS and was not significant among the groups (p = .124). Conclusion: Patients who received frontline HMA+VEN for AML directed therapy and achieved CR/CRi had better survival compared to those who achieved MLFS. Our data suggest that incomplete recovery of blood counts plays a significant role in overall survival regardless of leukemia free state. Further, the data demonstrate significantly higher secondary AML with antecedent MDS or MPN in the MLFS group compared to CR and CRi groups. Of those, prior HMA therapy was also identified as significantly higher in the MLFS group compared to CR and CRi groups which may contribute to the prolonged cytopenias and worse OS. While the limitation to this study is overall small number of patients, it suggests that a goal of CR over CRi or MLFS is desirable for superior OS. In the future, it would be of interest to incorporate the rates of responses and variables that may have an impact such as therapy dose adjustment, time to response, and delays in therapy due to cytopenia. Additional studies identifying dose adjustments or other ways to improve hematologic recovery would be valuable to potentially improve outcomes in this difficult to treat population. Figure 1 Figure 1. Disclosures Padron: Stemline: Honoraria; Taiho: Honoraria; BMS: Research Funding; Incyte: Research Funding; Blueprint: Honoraria; Kura: Research Funding. Sallman: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees. Komrokji: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau; Geron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; Astellas: Consultancy; Jazz: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy. Sweet: AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: CPX-351 is a liposomal encapsulation of cytarabine and daunorubicin maintained at a synergistic 5:1 molar ratio. It is approved for the treatment of patients with newly diagnosed therapy related myeloid leukemia (t-AML) or with AML with myelodysplasia-related changes (AML-MRC). Improved outcomes with CPX-351 compared to 7+3 have been reported irrespective of AML subtype (t-AML, AML-MRC), age subgroup (60 to 69 vs 70 to 75 years), prior hypomethylating agent (HMA) exposure and whether the patients undergo transplant. Here we compare outcomes of patients with de-novo AML vs those with secondary AML when treated with CPX-351. Methods: We retrospectively identified all previously untreated AML patients who received CPX-351 as first line therapy at Moffitt Cancer Center between August 2017 and July 2020. Charts were reviewed to collect demographic data, disease characteristics and outcomes. Overall survival was calculated from date of diagnosis. Results: A total of 118 patients were identified. The median age at diagnosis was 67 years (range 41-81 years). 66% patients were male (n=66). We reviewed prior history of antecedent hematologic malignancy (AHM) and divided patients into 5 cohorts: (A) No prior AHM (n=60), (B) Prior history of MDS (n=41), (C) prior history of chronic myelomonocytic leukemia (CMML) (n=8), (D) prior history of myeloproliferative neoplasm (MPN) including myelofibrosis, polycythemia vera and essential thrombocytosis (MF/PV/ET; n=4) and (E) prior myelodysplastic syndrome/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U) (n=5). Table 1 shows baseline disease characteristics of all cohorts. Complete remission plus complete remission with incomplete hematologic recovery (CR+CRi) rate for the entire cohort was 58.5% (n=69). Of all patients who achieved CR/CRi, 36.2% (n=25) ultimately relapsed. 50.7% (n=35) patients proceeded to an allogeneic stem cell transplant in CR1. Of the 49 non-responding patients (41.5%), 33 (67.3%) were re-induced with a high dose cytarabine based regimen. The CR/CRi rate after re-induction was 57.5% (n=19). At a median follow up of 15 months the median duration of remission for the entire cohort was 29 months (mos). The duration of remission was significantly different for the 5 cohorts (A: 29 mos, B: not reached, C: 8 mos, D: not reached, E: 2.5 mos, p=0.0061). The 30 day treatment related mortality for the entire group was 3.3% (n=4). At a median follow up of 18.1 mos for all 118 patients, the median overall survival is 17.3 mos. Median OS for cohort A is 20.4 mos, cohort B is 14.8 mos, cohort C 7.2 mos, cohort D is not reached and cohort E is 4.6 mos (p 0.002). Patients without an AHM had an improved OS compared to those with pre-existing CMML (20.4 vs 7.2 mos; p 0.0027) or MDS/MPN-U (20.4 vs 4.6 mos; p 0.004). However, absence of AHM was not associated with statistically significant longer OS compared to patients with prior MDS (20.4 vs 14.8 mos; p 0.1224). When looking at the impact of prior hypomethylating agent (HMA) therapy in cohort B, there was a significant OS advantage for patients who were not treated with HMA for prior MDS compared to those who were (25 vs 13 mos; p 0.0061). On the contrary, for patients with CMML (cohort C) treated with prior HMA, this had no impact on OS after CPX-351 induction (8 months vs 8 months; p=0.9506). We then looked at the pre and post next generation sequencing (NGS) data for the patients that achieved CR/CRi with CPX-351. From the 52 patients that had mutations on NGS at diagnosis, 19 (36.5%) patients cleared mutations and 33 (63.5%) did not clear mutations. From the 36 patients that had secondary MDS like mutations on diagnosis, 15 (41.7%) patients cleared the mutations while 21 (58.3%) did not. For both of these cohorts of patients the OS and rate of relapse was not different. However, RFS was better for patients that cleared mutations, but this did not reach statistical significance (27 vs 11 mos, p=0.2738). Conclusion: Overall survival of patients treated with CPX-351 for AML with no known AHM was significantly greater compared to patients with prior history of CMML or MDS/MPN-U. However, a prior history of MDS did not lead to statistically significant decrease in OS. Prior HMA exposure results in inferior outcomes in patients with prior MDS, but not CMML, likely because of the shorter OS for the entire CMML cohort overall. Pre and post NGS data showed that clearing mutations at remission did not affect OS and rate of relapse. Figure 1 Figure 1. Disclosures Sallman: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; AbbVie: 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, Speakers Bureau. Komrokji: Acceleron: Consultancy; Geron: Consultancy; Jazz: Consultancy, Speakers Bureau; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Padron: Taiho: Honoraria; Kura: Research Funding; Incyte: Research Funding; Blueprint: Honoraria; Stemline: Honoraria; BMS: Research Funding. Kuykendall: Protagonist: Consultancy, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria; Blueprint: Honoraria; Abbvie: Honoraria; Pharmaessentia: Honoraria; Incyte: Consultancy. Lancet: AbbVie: Consultancy; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy; Agios: Consultancy; Astellas: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy; Jazz: Consultancy. Sweet: Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction: Treatment-free remission (TFR) is an emerging treatment goal in chronic phase chronic myeloid leukemia (CP-CML). The NCCN guidelines suggest patients must meet the following criteria in order to be eligible for an attempt at TKI discontinuation: use of a TKI for at least 3 years with no history of TKI resistance who have maintained a deep molecular response (MR4 - BCR-ABL IS ≤0.01%) for at least 2 years. The aim of this study was to identify predictors of long-term TFR in CP-CML patients who discontinue TKI therapy at our institution. Methods: We retrospectively identified all CP-CML patients who had discontinued TKIs after meeting TKI discontinuation criteria at Moffitt Cancer Center. Patient charts were reviewed to collect data on demographics, disease characteristics, and outcomes. TFR was calculated from date of TKI discontinuation to date of molecular recurrence (defined as loss of MMR (BCR-ABL IS ≥0.1%) or date of last follow up). Statistical analysis was performed utilizing Kaplan-Meier curves and log rank (Mantel-Cox) test. Results: A total of 102 patients met TKI discontinuation criteria and stopped treatment to attempt TFR. The median age at diagnosis was 53.5 years (19-83 years). The median age at TKI discontinuation was 61 years (28-92 years). Fifty (49.5%) patients were male. Four patients (3.9%) had previously received interferon α. At a median follow up of 29 months, the TFR rate was 56.8%, with molecular recurrence occurring in 44 patients. 93 patients had a follow up of at least 6 months. Of the 44 patients with molecular recurrence, 37 (84%) recurred within 6 months and 41 (93%) within 12 months of TKI cessation. The rate of TFR at 12 months and 24 months was 58% (95% CI: 48-68%) and 53% (95% CI: 43-64%), respectively [Figure 1]. Baseline characteristics along with univariate analysis of the 102 patients included in the study are shown in Table 1. Age, BMI at discontinuation, gender, Sokol risk index, last TKI prior to discontinuation, lines of therapy, or duration on TKI prior to discontinuation did not significantly affect rates of TFR. Patients with sustained MR4.5 (BCR-ABL IS Conclusions: At our center, 102 CP-CML patients qualified for TKI cessation. The rate of TFR at 12 months was 58% which is consistent with published data from numerous TKI discontinuation clinical trials. We were unable to identify any factors that were predictive of successful TFR, however those patients with a deeper molecular response (MR 4.5) at the time of TKI cessation trended towards higher rates of TFR at 12 months, suggesting that the depth of response is important for achieving prolonged TFR. Identifying methods to further deepen molecular response in CP-CML patients may ultimately lead to higher rates of TFR in the future. Figure 1 Figure 1. Disclosures Nodzon: Takeda: Consultancy. Komrokji: Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy. Sallman: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Incyte: Speakers Bureau; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Padron: Blueprint: Honoraria; Incyte: Research Funding; Stemline: Honoraria; Taiho: Honoraria; Kura: Research Funding; BMS: Research Funding. Kuykendall: BluePrint Medicines: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria, Speakers Bureau; CTI Biopharma: Honoraria; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; PharmaEssentia: Honoraria. Lancet: Jazz: Consultancy; Astellas: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy; AbbVie: Consultancy. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; MEI, Sunesis: Research Funding. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background To recognize the growing list of recurrent genetically defined eosinophilia driven by constitutively active tyrosine kinase fusion genes, the World Health Organization (WHO) created a provisional entity of myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) with rearrangement of PFGFRA, PDGFRB or FGFR1, or with PCM1- JAK2. These eosinophilic disorders are clinically and genetically heterogeneous. Annotating additional somatic mutations and relevant clinical features may have an impact on treatment selection and refine prognostication. In this study, we aim to describe the clinicopathologic characteristics and outcome with upfront targeted tyrosine kinase inhibitor (TKI) therapy in patients (pts) with MLN-Eo. Methods We retrospectively reviewed clinical and molecular data on 39 pts with newly diagnosed MLN-Eo with PDGFRA, PDGFRB, FGFR1, JAK2 or FLT3 rearrangement at Moffitt Cancer Center, Duke Cancer Center, and the UCSF Comprehensive Cancer Center. Clinical data was abstracted in accordance with institutional review board approved protocol. Pts were divided to two categories based on morphologic classification of the disease at diagnosis or at transformation: chronic phase and blastic phase disease. Each category was then divided into two subgroups: Cohort A) upfront TKI +/- other systemic therapy and Cohort B) no upfront TKI arm. Median time from chronic phase disease to blastic phase and median overall survival (mOS) (in whole cohort) were calculated using Kaplan Meier method and compared with log-rank test. Cox proportional hazards (PH) model was used to calculate hazard ratio (HR) in univariate analyses. Result Among the 39 pts included in the analysis, 22 pts had PDGFRA fusion (20)/activating mutations (2), 4 had PDGFRB, 7 had FGFR1, 2 had JAK2 (PCM1-JAK2 and BCR-JAK2), and 4 had FLT3 (3 ETV6-FLT3 and 1 FLT-3-TRIP11). Median age at first diagnosis of myeloid/lymphoid neoplasm was 54.5 years (range 9-76). Seventy-seven percents (30/39) were male. Chronic eosinophilic leukemia (CEL) was the most common clinical diagnosis and occurred in 11 pts (28%). Seven (18%) pts had both myeloid and lymphoid neoplasms either concurrently or sequentially. Sixteen (41%) pts presented with de-novo blastic phase at time of initial diagnosis. Among 23 pts who presented with chronic phase disease at diagnosis, nine patients did not receive TKI upfront. Five out of the nine patients (55%) developed blastic phase disease with a median follow up of 73 months. The median time to blastic phase was 45 months. No patients in the upfront TKI arm (n=14) had blastic transformation during follow up (Figure 1a, p Among 21 pts who had blastic phase disease (16 pts with de-novo diagnosis and 5 pts with blastic transformations), 95% of them (20/21 pts) had treatment information and follow-up data available. At a median follow up of 37 months, 11 pts (55%) were deceased, and median OS was 44 months. Seven pts (35%) underwent allogeneic stem cell transplant (alloHSCT). Four patients received upfront TKI, and all of them achieved complete remission and were alive at the time of the study (Figure 1b). Among those pts, 2 had FLT3-ETV6 rearrangement, 1 with PDGFRA rearrangement and 1 with FGFR1 rearrangement. Two pts received single agent TKI only and two pts received TKIs followed by alloHSCT. In the univariate analysis, upfront TKI use was significantly associated with improved OS (HR 0.067, 95% CI [0.009-0.512], p=0.009). Complex cytogenetics at the time of initial diagnosis was associated with inferior OS, though statistical significance was not reached (table II). Conclusion Our data suggests that upfront TKI therapy is associated improved survival outcomes in pts with MLN-eo and is effective in preventing blastic transformation from chronic phase disease. As proposed, the driver oncogene most likely occurs in hematopoietic stem cells/progenitor cells in this entity. Upfront TKI can potentially suppress, even in some cases eradicate the malignant clone. The study is limited due to small sample size and retrospective nature, and larger study is needed to validate our observation. Figure 1 Figure 1. Disclosures Sokol: Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Membership on an entity's Board of Directors or advisory committees. Shah: Novartis: Consultancy, Other: Expenses; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy. Lancet: Agios: Consultancy; AbbVie: Consultancy; Celgene/BMS: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; BerGenBio: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Jazz: Consultancy. Kuykendall: Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BluePrint Medicines: Honoraria, Speakers Bureau; Prelude: Research Funding; Abbvie: Honoraria; Incyte: Consultancy; Novartis: Honoraria, Speakers Bureau; PharmaEssentia: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; CTI Biopharma: Honoraria. Padron: Stemline: Honoraria; BMS: Research Funding; Kura: Research Funding; Blueprint: Honoraria; Incyte: Research Funding; Taiho: Honoraria.

Background Hypomethylating agents (HMA) remain the backbone for treating higher risk myelodysplastic syndromes (MDS) patients (pts) with less than 20% of pts achieving complete response (CR) and median overall survival (OS) of 12-18 months. Ongoing studies in higher risk MDS are assessing the role of adding venetoclax (Ven) to HMA. Preliminary data have reported promising higher response rate as first line therapy (1L) HMA/Ven) as well as activity in relapsed/refractory MDS to HMA. (R/R MDS). Method We analyzed all higher risk MDS pts treated at Moffitt Cancer Center defined by revised international prognostic scoring system (R-IPSS) by ≥ intermediate risk who received HMA as first line therapy after diagnosis. We compared outcomes of those pts who received single agent IL HMA, 1L HMA/Ven combination and HMA with Ven add back strategy after HMA failure (R/R MDS HMA/Ven). OS was defined from time of diagnosis. Results We identified 1193 higher risk MDS pts who received HMA 1L, 1158 pts received single agent HMA (1L HMA) (1027 azacitidine (AZA) and 131 decitabine (DAC)), 35 pts received 1L HMA/Ven combination (26 AZA and 9 DAC backbone). Among pts treated with HMA alone as first line, 31 were treated subsequently with HMA/Ven combination for R/R MDS without transformation to AML. The median duration of follow up from diagnosis was 96 months (mo) for 1L HMA, 15 mo for 1L HMA/Ven and 36 mo for HMA/Ven R/R MDS. Focusing on first line therapy, 1127 received 1L HMA alone with no subsequent Ven add back and 35 pts 1L HMA/Ven. Table-1 summarizes baseline characteristics, 1L HMA/Ven pts were more likely to be MDS-EB2 and more pts harbored ASXL-1 somatic mutation (SM). The overall response rate (ORR) (HI+) was 77% for 1L HMA/Ven compared to 40% 1L HMA (p The rate of AML transformation was 23% and 37% for IL HMA/Ven and 1 L HMA alone respectively, p = .08. The overall survival was 21 mo (95% CI 11-32) and 20 mo (95%CI 19-22) for IL HMA/Ven and 1 L HMA alone respectively, p= .86. Among patients who proceeded to allogeneic stem transplantation (AHSCT) (n=269) 13 pts received 1L HMA/Ven, the median OS was not reached compared to 38 mo (95%CI 27-50) among who received 1L HMA alone (p=.2). The 2-year survival probability rate was 91% and 51% for IL HMA/Ven and 1 L HMA alone who proceeded to AHSCT respectively. (Figure 1 A) Among pts who received 1L HMA alone as first line, 31 pts later received HMA/Ven for R/R MDS. The median number of 1L HMA therapy alone was 6 cycles. The ORR was 61% (CR 13% and mCR 48%). The median OS from time of diagnosis for pts who received HMA/Ven for R/R MDS was 33 mo (95% CI 31-36) compared to 21 mo (95% CI 11-32) for those who had IL HMA/Ven and 20 mo (95%CI 19-22) for those who received 1L HMA alone with no subsequent Ven therapy. (p=.02). (Figure-1 B) Nine of 31 pts who received HMA/Ven R/R MDS underwent AHSCT compared to 22 who did not proceed to transplant with median OS 31 and 33 mo respectively, (p = .7). Conclusions Among higher risk MDS patients, 1L HMA/Ven combination yields significantly higher complete response rates including ASXL-1 mutant MDS compared to 1L HMA alone. The OS survival benefit for 1L HMA/Ven in higher risk MDS pts can only be addressed in randomized clinical trial but our data suggest promising activity among those who received 1L HMA/Ven and proceeded to AHSCT (2-year OS 91%). Ven add back strategy to HMA after 1L HMA failure has clinical activity and was associated with OS benefit. Figure 1 Figure 1. Disclosures Komrokji: Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria; Abbvie: Honoraria, Speakers Bureau; Agios: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Geron: Honoraria. Padron: Taiho: Honoraria; Stemline: Honoraria; BMS: Research Funding; Blueprint: Honoraria; Kura: Research Funding; Incyte: Research Funding. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kuykendall: Protagonist: Consultancy, Research Funding; Pharmaessentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Blueprint: Honoraria; Incyte: Consultancy; Celgene/BMS: Honoraria; Abbvie: Honoraria. Lancet: AbbVie: Consultancy; Celgene/BMS: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; BerGenBio: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; Astellas: Consultancy; Jazz: Consultancy. Sallman: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Venetoclax for treatment of myelodysplastic syndromes

Background The revised international prognostic scoring system (R-IPSS) incorporated severe neutropenia (SN) defined as absolute neutrophil count (ANC) < 0.8 x10 9 /L as a prognostic variable. Among MDS patients (pts), 18% had ANC < 0.8 x10 9 /L (Greenberg et al, Blood 2012). Current treatment guidelines recommend considering hypomethylating agents or immunosuppressive therapy for treating MDS patients (pts) with neutropenia with low neutrophil response reported in clinical studies ( Method We analyzed all MDS pts treated at Moffitt Cancer Center with known ANC values around time of diagnosis and who had next generation sequencing (NGS). We defined SN around time of diagnosis for the purpose of this study according to the R-IPSS cut off (ANC 0.8 x10 9 /L) and stratified pts into two groups based on this definition. Results We identified 1972 MDS pts with known ANC who underwent NGS testing among whom 466 pts (24%) had SN by R-IPSS definition. Table-1 summarizes baseline characteristics comparing SN and non-SN pts. Neutropenic pts were slightly younger, had higher myeloblasts percentage, lower platelets count, higher risk disease by R-IPSS and were more likely to be classified as MDS-EB subtypes based on WHO 2016 criteria. Ninety-three pts had isolated SN (Hgb > 10 g/dl and platelets > 100 x10 9 /L). IDH mutations (MT) (IDH-1/IDH-2) were the only MT observed at higher rate among neutropenic pts. Table-2 summarizes landscape of common MT observed comparing SN and non-SN pts in the whole group and stratified by R-IPSS (lower risk defined as very low to intermediate and higher risk as high and very high groups). There was no difference in other genes not included in the table (NRAS, SETBP1, ZRSR2, CBL, JAK-2, FLT-3, NPM-1 and PHF6). Among the whole cohort, 13% of MDS pts with SN harbored IDH MT compared to 6% in non-SN pts (p < .005). Both IDH-1 and IDH-2 MT were more common in neutropenic pts and among both lower and higher risk R-IPSS groups. The most common observed hot spot in IDH-2 was R140, although the R172 hotspot was observed more in SN pts. Among pts with isolated SN, 18% harbored IDH MT compared to 12% in non-isolated SN (p=.1); however, IDH-1 MT were more common in pts with isolated SN (11% vs 4%; p=.01) but no difference in IDH-2 MT (8% in both isolated SN and non-isolated SN groups, p=.8). TP53 was observed in 26% compared to 19% respectively for SN and non-SN pts, p The median overall survival (mOS) was shorter (25 months (mo) vs 42 mo; p Given lack of effective treatment options, two symptomatic IDH1 SN lower risk MDS pts have been treated with ivosidenib. Both pts achieved a complete hematologic response within 2 weeks of initiation of therapy (ANC 0.3 to 2.8 and ANC 0.21 to 2.4), which has been durable for 5 and 26 months, respectively. Conclusions Severe neutropenia is present in almost one fourth of MDS pts and it is associated with worse outcome. IDH mutations are enriched among SN MDS pts regardless of R-IPSS risk group. In pts with isolated SN, IDH-1 but not IDH-2 were more frequently observed compared to non-isolated SN. IDH mutations were associated with worse outcome among non-neutropenic pts. Notably, in 2 of 2 IDH-1 MT SN pts, treatment with ivosidenib resulted in ongoing, durable complete hematologic responses. The underlying biology of this observation (likely differentiation block or inhibition of dioxygenase enzymes) and the role of IDH inhibitors as potential targeted therapy for MDS pts with neutropenia should be further explored. Figure 1 Figure 1. Disclosures Komrokji: BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria; Geron: Honoraria; Novartis: Honoraria; Abbvie: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Agios: Honoraria, Speakers Bureau. Kuykendall: Prelude: Research Funding; Abbvie: Honoraria; BluePrint Medicines: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Honoraria; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau. Sweet: Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet: BerGenBio: Consultancy; AbbVie: Consultancy; ElevateBio Management: Consultancy; Celgene/BMS: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Millenium Pharma/Takeda: Consultancy; Agios: Consultancy; Jazz: Consultancy. Padron: Taiho: Honoraria; Blueprint: Honoraria; Kura: Research Funding; Incyte: Research Funding; BMS: Research Funding; Stemline: Honoraria. Sallman: Incyte: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: 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, Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Use of IDH inhibitors in MDS

Introduction: CPX-351 is a liposomal encapsulation of cytarabine and daunorubicin maintained at a synergistic 5:1 molar ratio. It is approved for the treatment of patients with newly diagnosed therapy related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Improved outcomes with CPX-351 vs 7+3 have been reported irrespective of AML subtype (t-AML, AML-MRC), age subgroup (60 to 69 vs 70 to 75 years), prior hypomethylating agent (HMA) exposure and whether the patients undergo transplant. The 2017 European Leukemia Net (ELN) classification stratifies AML into 3 risk groups based on genetic and mutational profile. Our aim was to compare outcomes of patients with AML treated with CPX-351 based on the 2017 ELN risk stratification and also compare outcomes post allogeneic stem cell transplantation (alloSCT) by ELN risk groups. Methods: We identified all AML patients who received CPX-351 as first line therapy at Moffitt Cancer Center between August 2017 and July 2020. A retrospective review of patient charts was conducted to collect demographics, disease characteristics and outcomes. Overall survival (OS) was calculated for the entire cohort from date of diagnosis. Relapse free survival (RFS) was calculated in those who achieved CR/CRi from the time of remission to the date of relapse or death from any cause. Results: A total of 118 patients with previously untreated AML who received first line CPX-351 were identified. Median age at diagnosis was 67 years (range, 41-81 years). 56% (n=66) patients were male. Based on the 2017 ELN risk stratification the study population was divided into 3 groups: (A) favorable risk (n=7), (B) intermediate risk (n=35), (C) adverse risk (n=76). The favorable risk patients included patients with NPM1 mutation (n=6) and one patient with t(16;16) but also had BM dysplasia. The CR/CRi rate for the entire study population was 58.5% (n=69). The CR/CRi rate for the favorable and intermediate risk group was significantly better compared to the adverse risk group (71.4% and 74.3% vs 50%, respectively, p=0.0421). The rate of relapse was not statistically different for the 3 risk groups (A- 40%, B- 30.8% and C-39.5%, p=0.76). 30-day mortality was 3.3% for the entire cohort. Of the 26 intermediate risk patients who achieved CR/CRi, 57.7% (n=15) proceeded to an alloSCT in first remission. OS was significantly longer in the transplanted patients than those who did not undergo transplant in CR1 (not reached vs 13 months, p=0.016). Only 1 (6.7%) of the 15 transplant patients relapsed while 7 (63.6%) of the non-transplant patients relapsed (RFS; not reached vs 5 months; p Of the 38 adverse risk patients who achieved CR/CRi, 52.6% (n=20) underwent allo transplant in CR1. No significant difference was noted in OS between the transplanted patients and the non-transplanted patients. (not reached vs 8 months; p=0.2679). However, transplant in CR1 resulted in a lower rate of relapse (15% vs 67% without transplant; p=0.0023) and improved RFS compared to those adverse risk patients who did not proceed to transplant (not reached vs 8 months; p=0.0007). At a median follow up of 22 months for the entire cohort, the median OS for the favorable, intermediate and adverse risk groups was not reached, 17 and 15 months, respectively (p=0.1967). At a median follow up of 13 months for patients who achieved CR/CRi, the RFS for the favorable and intermediate groups was not reached and for the adverse risk group was 26 months which lacks statistical significance (p=0.97). Conclusion: In patients who receive first line CPX-351 for previously untreated AML, ELN risk stratification is able to predict for CR/CRi rates but does not significantly impact OS. In the intermediate risk patients, allo transplant after a CPX-351-induced CR/CRi resulted in significantly improved RFS and OS suggesting that transplant should be considered in ELN intermediate risk patients in first CR after CPX-351. Figure 1 Figure 1. Disclosures Sallman: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees. Komrokji: AbbVie: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy. Kuykendall: Abbvie: Honoraria; BluePrint Medicines: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria, Speakers Bureau; CTI Biopharma: Honoraria; Incyte: Consultancy; Novartis: Honoraria, Speakers Bureau; PharmaEssentia: Honoraria; Prelude: Research Funding; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Padron: BMS: Research Funding; Incyte: Research Funding; Kura: Research Funding; Stemline: Honoraria; Blueprint: Honoraria; Taiho: Honoraria. Lancet: AbbVie: Consultancy; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; BerGenBio: Consultancy; Celgene/BMS: Consultancy; Millenium Pharma/Takeda: Consultancy; Agios: Consultancy; Astellas: Consultancy; Jazz: Consultancy. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction: Dasatinib is a second generation tyrosine kinase inhibitor (TKI) which is approved for treatment of chronic myeloid leukemia (CML). Pleural effusion (PE) is a unique toxicity associated with dasatinib use. The risk of development of PE with dasatinib was reported to be 6-9% per year in DASISION and 5-15% per year in CA180-034. At a 5 and 7 year follow up 28% and 33% of patients developed PE in DASISION and CA180-034, respectively (Cortes et. al. J Clin Onc 2016 and Shah et. al. Am J Hematol 2016). PE led to discontinuation of dasatinib in only 6% and 7% patients in DASISION and CA180-034, respectively. Alternative TKIs are required in these cases with the goal to avoid recurrence of PE. Recently, switching to bosutinib after development of a PE while on dasatinib has been shown to be associated with a 30% risk of developing a recurrent PE, higher than the reported rate in front line trials (Tribelli et. al. Ann Hematol 2019). Objective: The aim of this study was to identify the incidence of pleural effusions in a cohort of patients treated with dasatinib for chronic phase (CP)-CML, and the safety of switching therapy to bosutinib. Methods: A retrospective chart review of all patients who had received dasatinib for treatment of CP-CML between 1992 and 2020 at Moffitt Cancer Center was performed. Patient data including baseline characteristics, date of diagnosis, line of treatment, date of initiation and termination of treatment, reason for discontinuation and dose were collected. PE was graded according to the CTCAE v5.0 (common terminology criteria for adverse events). A descriptive analysis of the data collected is reported. Results: A total of 390 patients, 184 males and 206 females, were treated with dasatinib during their course of treatment for CP-CML. The median age of diagnosis of CML was 50 years. 79% of patients were Caucasian. Dasatinib was used as front line therapy in 150 (38.4%) patients, second line in 177 (45.3%) patients and third line or above in 63 (16.1%) patients. A total of 69 patients (17.6%) developed any grade of PE, with 33 (48%) patients considered to have CTCAE grade 2 PE, 34 (49%) patients grade 3, and only 1 patient developed grade 4 PE. The dose of dasatinib for the patients that developed PE was 140 mg (6%), 100 mg (71%), 70 mg BID (4.3%), 70 mg (3%), 20 mg (3%) and unknown (13%). Therapy was changed to another TKI without a dose modification in 43% patients, the dose was reduced in 46% patients and we do not have information about dose available for the other 11% patients. Recurrence of PE was observed in 34 (49%) patients. PE directed treatment included a combination of furosemide (49%), steroids (20%) and thoracentesis (49%). The median time from initiation of dasatinib to development of PE was 31 months. Only 12 patients (17.3%) continued dasatinib after development of PE, while the other 57 patients discontinued the drug. Median duration of therapy on dasatinib was 39 months in patients that developed PE. Therapy was switched to bosutinib in 13 patients out of whom 6 (46%) re-developed PE. The median time to re-accumulation of PE after switching to bosutinib was 9 months. While only 14.2% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE. Conclusion: A change in TKI to bosutinib was associated with a 46% risk of recurrence of pleural effusion in patients who develop pleural effusion on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib. Further prospective studies are needed to determine the safety of bosutinib in this setting. Disclosures Nodzon: Takeda: Consultancy. Komrokji: BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees. Sallman: Kite: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: 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, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; Takeda: Consultancy; Intellia: Membership on an entity's Board of Directors or advisory committees. Padron: Stemline: Honoraria; Blueprint: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding; Taiho: Honoraria. Kuykendall: Prelude: Research Funding; PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet: Jazz: Consultancy; Astellas: Consultancy; BerGenBio: Consultancy; Agios: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; Millenium Pharma/Takeda: Consultancy; AbbVie: Consultancy. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; MEI, Sunesis: Research Funding; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

BACKGROUND: Over the past 25 years research has shifted from predominantly focused on men to research that includes both men and women. In addition, myelodysplastic syndromes (MDS) have only been included in the SEER registry since 2001 and are largely understudied. This has resulted in a knowledge gap in the difference in clinical phenotype, genotype, and outcomes between men and women diagnosed with MDS. The aim of this abstract is to identify those gender-based differences. METHODS: This was a retrospective study using a large MDS database at Moffitt Cancer Center. We compared baseline clinical and molecular characteristics and outcomes based on gender. Chi-square tests were used for comparing categorical variables and t-test for continuous variables. Kaplan-Meier method was used to compare survival. RESULTS: The Moffitt Cancer Center MDS data base includes 4413 patients among whom 2922 (66%) were men and 1658 (34%) were women. Table-1 summarizes baseline characteristics based on gender. Women were slightly younger (mean age at diagnosis 66.5 versus 69 years for men, p < 0.001). There were more Hispanic/black women than men (9% versus 5%, p = There were gender differences in molecular profile. (Table-2). SRSF2 mutation, U2AF1 mutation, ZRSR2 mutation, ASXL1 mutation, and RUNX1 mutations were observed more frequently in men. ZRSR2 was expected. The median overall Survival (mOS) was longer for women in lower-risk MDS, but not in higher-risk MDS. (Figure- 1 and 2) The overall mOS was 37.5 months (mo) for females compared to 35 mo for males, p=0.002). The mOS for very/low R-IPSS was 81 and 62 mo, for intermediate risk R-IPSS 35 mo vs 33 mo, and for high/very high-risk R-IPSS 16.7 versus 17.4 mo respectively for females and males (p< 0.001). The rate of AML transformation was not different (32% and 34%, respectively for women and men, p =0.16). Women were more likely response to ATG/CSA than men (38% versus 19%, p= 0.04) There were no differences in response to erythroid stimulating agents, hypomethylating agents, lenalidomide treatment or rate of allogeneic hematopoietic stem cell transplant (AHSCT). CONCLUSION: This retrospective review of a large data base of MDS patients highlights important gender differences in clinical and molecular MDS disease features. We identified differences in rates of selected somatic mutations. Men had more splicing machinery mutations, ASXL-1, and RUNX-1 mutations. Women had better overall survival mainly in lower risk MDS and higher responses to immunosuppressive therapy. Acknowledgement of Funding: NINR Grant # 1K23NR018488-01A Figure 1 Figure 1. Disclosures Tinsley-Vance: Novartis: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Taiho: Consultancy; Fresenius Kabi: Consultancy; Abbvie: Honoraria; Astellas: Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Padron: Kura: Research Funding; Blueprint: Honoraria; Stemline: Honoraria; BMS: Research Funding; Taiho: Honoraria; Incyte: Research Funding. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet: Daiichi Sankyo: Consultancy; Agios: Consultancy; Astellas: Consultancy; AbbVie: Consultancy; ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy; BerGenBio: Consultancy; Celgene/BMS: Consultancy; Jazz: Consultancy. Kuykendall: BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Prelude: Research Funding; PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sallman: Syndax: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau. Komrokji: Geron: Consultancy; Acceleron: Consultancy; AbbVie: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees.

Introduction: Hypomethylating agents (HMA) are commonly used in treatment of high risk chronic myelomonocytic leukemia (CMML), although only 40% patients (pts) respond. Decitabine failed to improve overall survival (OS) in comparison with hydroxyurea in proliferative CMML (Itzykson et al. 2020). Preliminary results have suggested safety and clinical activity of HMA and venetoclax combination (HMA-Ven) in a small CMML cohort (n=9; Morita et al. 2020). However, real world evidence lacks on efficacy of HMA-Ven and its impact on outcome in pts with CMML and post-CMML secondary acute myeloid leukemia (sAML). Methods: In this single center retrospective study, clinical and genomic data were collected from medical records of CMML pts treated with HMA-Ven at Moffitt Cancer Center. Treatment response was assessed with International Working Group criteria for CMML and European Leukemia Network 2017 criteria for post-CMML sAML. Survival estimates using Kaplan-Meier statistics and multivariate analysis (MVA) with Cox regression were performed in SPSS. Results: Our study included 26 pts with CMML. At time of HMA-Ven initiation, 13 (50%) pts had CMML and rest 13 (50%) had sAML from antecedent CMML [Table 1]. Median age at HMA-Ven initiation was 74 years. Majority (84%) of pts were Caucasian, and gender distribution was even. There were no significant differences in cytopenias or monocytosis between groups. About half the pts (n=7) in CMML group had proliferative CMML at HMA-Ven initiation. Overall, 58% pts received HMA-Ven in relapsed/ refractory setting and 50% had prior HMA failure, with no significant difference in CMML and sAML cohorts. On assessment of recurrent mutations present at HMA-Ven initiation, ASXL1 was the most frequent (61%), followed by TET2 (35%) and SRSF2 (35%). There was no significant difference in incidence of mutations between CMML and post-CMML sAML. In pts receiving HMA-Ven for CMML, overall response rate (ORR) was 62%, with one (8%) pt experiencing complete remission (CR) [Table 2]. Marrow CR was noted in half the pts with CMML. In post-CMML sAML pts, ORR was 54%, including one (8%) CR and three (23%) CRi. Both pts achieving CR in our study were HMA-naïve. Treatment with HMA-Ven induced response in 5 out of 7 (71%) HMA refractory pts with CMML. A total of 5 sAML pts (19% overall; 38% of sAML) died within 60 days of HMA-Ven initiation, with one death within 30 days. Three pts with CMML and two with post-CMML sAML were bridged to allogeneic stem cell transplant (allo-SCT). Median duration of HMA-Ven treatment was 2.3 months (mo) overall (CMML- 5.5 mo, sAML-2 mo), 4.3 mo in responding pts, 2.7 mo in those bridged to allo-SCT, and 5.5 mo in responding pts not proceeding to allo-SCT. Median number of HMA-Ven cycles was 3 (1-16), with no difference between groups. Two (15%) CMML pts progressed to AML while on HMA-Ven treatment. Median event free survival (EFS) was 4.3 (95% CI: 1.6-7.0) mo (CMML vs. post-CMML sAML- 5.7 vs. 2.5 mo, p= 0.194). Most common reasons for treatment discontinuation were refractory cytopenias (n=8, 31%) and progressive disease (n=8, 31%). Median OS (mOS) of entire cohort was 8.1 mo (95% CI: 3.6-12.6) since HMA-Ven initiation, with a median duration of follow up of 17.4 mo. Patients receiving HMA-Ven for CMML had significantly prolonged mOS compared to post-CMML sAML (15.6 vs. 4.1 mo, p= 0.007) [Figure 1]. Disease status at HMA-Ven initiation remained an independent prognostic factor (p= 0.045) for OS after adjusting for ASXL1 mutation and allo-SCT status on MVA. Overall, no significant difference in mOS was observed between pts receiving HMA-Ven as 1 st line vs. later lines of therapy (9.7 vs. 8.1 mo, p= 0.586), and between HMA-naïve and refractory pts (9.7 mo vs. 8.1 mo, p= 0.707). Presence of RAS pathway mutations was not predictive of OS. In treatment-naïve pts (n=11), mOS was 9.7 mo (CMML vs. sAML- not reached vs. 2.5 mo, p= 0.280). Among pts with an objective response to HMA-Ven, mOS was 9.7 mo [CMML vs. s-AML- not reached vs. 4.9 mo (95% CI: 0-11.3); p= 0.96]. Median OS in pts bridged to allo-SCT (n=5) was similar (8.1 mo) to overall study population. Conclusions: Treatment with HMA-Ven led to an ORR of 58% (54% in HMA refractory cohort) in pts with CMML and post-CMML sAML. However, achievement of CR was rare, with a short duration of treatment. Notably, EFS and OS were poor, particularly in the setting of transformed CMML, supporting urgent need for novel therapeutic strategies in this rare patient population. Figure 1 Figure 1. Disclosures Kuykendall: Prelude: Research Funding; PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweet: Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet: Millenium Pharma/Takeda: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Agios: Consultancy; Astellas: Consultancy; Jazz: Consultancy; AbbVie: Consultancy. Padron: Stemline: Honoraria; Taiho: Honoraria; Blueprint: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding. Komrokji: Geron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; Acceleron: Consultancy; AbbVie: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees. Sallman: Bristol-Myers Squibb: 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; Takeda: Consultancy; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau.

Introduction: Patients (pts) with myelodysplastic syndrome (MDS) are divided into risk categories: very low (VL), low (LR), intermediate, high (HR) and very high, using the revised international prognostic scoring system (R-IPSS). The natural history of lower risk MDS is not well described. Some patients present with a rapidly progressive form of LR-MDS leading to worsening cytopenia and or increase bone marrow (BM) blasts with or without progression to acute myeloid leukemia (AML). The aim of this study was to evaluate the patterns of progression and factors that can predict progression to HR-MDS and/or AML. Methods: We studied a large cohort of lower risk MDS pts (n=1914) defined as VL and LR R-IPSS MDS at Moffitt Cancer Center. We divided our patients into 4 cohorts based on the natural history of their disease progression pattern: 1) Pts who remained low risk MDS throughout their period of follow up (LR-LR), 2) Pts who progressed from LR to HR MDS (LR-HR) without AML transformation, 3) Pts who progressed from LR to HR MDS and then AML (LR-HR-AML) and 4) Pts who progressed from LR MDS to AML directly (LR-AML). Results: Majority of pts 68% (1300) remained in LR-MDS, 16.5 % (317) progressed from low risk to high risk MDS (LR-HR) without AML transformation, 6.5% (124) progressed from low risk to high risk MDS and then AML (LR-HR-AML) and 9% pts (173) progressed from low risk MDS to AML directly (LR-AML). At a median follow up of 199 months (mo), the median OS for the LR-LR, LR-HR, LR-HR-AML and LR-AML groups was 80.7, 61.2, 48.3, 42.8 mo, respectively (Figure 1; p Table 1 shows baseline characteristics of the four cohorts. Clinical and laboratory risk factors for progression included male gender (p1000 mcg/L (p Gene mutations associated with an increased risk of direct or indirect AML progression included SRSF2 (p We divided the pts into 3 subgroups based on estimated median OS (5 years) and found that 398 patients (31%) in the LR-LR cohort fall in the Conclusion: To our knowledge this is one of the largest cohorts to describe natural history of LR-MDS pts and the first study to detail the different patterns of disease progression including progressing to HR-MDS without AML transformation (16.5%), HR-MDS to AML (6.5%) and directly to AML (9%). We identified the clinical and molecular factors associated with different patterns of disease progression. For pts who remained in LR-MDS, one-third had estimated median OS < 2 years and one-third of deaths within 2 years were MDS related. Identifying those LR-MDS pts with higher risk of disease progression or disease related death within 2 years will be crucial to tailor therapy accordingly. Figure 1 Figure 1. Disclosures Tinsley-Vance: AbbVie: Honoraria; Astellas: Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Fresenius Kabi: Consultancy; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy; Taiho: Consultancy. Kuykendall: Incyte: Consultancy; Celgene/BMS: Honoraria; Abbvie: Honoraria; Blueprint: Honoraria; Pharmaessentia: Honoraria; Protagonist: Consultancy, Research Funding; Novartis: Honoraria, Speakers Bureau. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet: Millenium Pharma/Takeda: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; ElevateBio Management: Consultancy; Astellas: Consultancy; BerGenBio: Consultancy; AbbVie: Consultancy; Agios: Consultancy; Jazz: Consultancy. Padron: Taiho: Honoraria; Kura: Research Funding; Incyte: Research Funding; Stemline: Honoraria; BMS: Research Funding; Blueprint: Honoraria. Sallman: Intellia: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, 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, Speakers Bureau; Incyte: Speakers Bureau; Magenta: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees. Komrokji: BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; AbbVie: Consultancy.

Introduction: Enhancer of zeste homolog (Ezh)-2 is a critical component of polycomb repressive complex, essential for self-renewal and differentiation of hematopoietic stem cells. EZH2 (chromosome 7q) mutations reported in myeloid disorders are loss of function type, with an incidence of 4-6% in published literature. Presence of EZH2 mutation has been linked to poor overall survival (OS) in patients (pts) with myelodysplastic syndromes (MDS) in studies (Bejar et al. 2015). However, potential clinical and genomic determinants of outcome in EZH2- mutant (MT) MDS is not well characterized. Methods: In this large retrospective study, all pts treated for MDS at Moffitt Cancer Center with available next generation sequencing (NGS) results at diagnosis were eligible for inclusion. Clinical, demographic, and genomic data were collected from the annotated institutional MDS database. Patients in whom the NGS panel did not include EZH2 and those with benign or variants of unknown significance were excluded from the analyses. Survival estimates using Kaplan-Meier statistics and multivariate analysis with Cox regression were performed in SPSS (v.26). Results: Our study included a total of 1,774 pts with MDS, with 83 (4.7%) harboring a pathogenic EZH2 mutation [Table 1]. Patients with EZH2-MT MDS were older than EZH2-wild type (EZH2-WT) group (median age at diagnosis- 72 vs. 69 years, p= 0.010). No gender difference was noted between groups. Both groups had similar baseline hemoglobin, white blood cell, platelet, and bone marrow blast counts. Complex karyotype was less frequent in EZH2-MT pts compared to their WT counterparts (7% vs. 18%, p= 0.013). Concurrent deletion (7q) or monosomy 7 was noted in 12% pts with EZH2-MT MDS. Myelodysplastic syndrome with excess blasts was the most common WHO 2016 classification subtype in both EZH2-MT and WT pts. Approximately 36% pts in EZH2-MT and 38% in EZH2- WT groups fell into high or very high prognostic risk categories by revised International Prognostic Scoring System (IPSS-R). The most common co-occurring somatic mutation in EZH2-MT pts was ASXL1, with a significantly higher frequency than EZH2-WT (54% vs. 19%, p = Treatment with erythropoiesis stimulating agents led to a hematologic improvement in 40% pts in both groups [Table 2]. Patients with EZH2-MT MDS showed a trend for lower rates of overall response (OR) and complete remission (CR) to hypomethylating agents (HMA) compared to those with EZH2-WT MDS (26% vs. 39%, and 6% vs. 12%, respectively; p= 0.050). Response to treatment with lenalidomide was similar in both groups. There was no significant difference in the rate of progression to AML or time to AML transformation between groups. Median overall survival (mOS) was 30.8 months in pts with EZH2-MT MDS, compared to 39.4 months in EZH2-WT group (p= 0.297) [Figure 1]. In pts with IPSS-R lower risk (LR- very low, low, and intermediate) MDS, presence of EZH2 mutation was associated with inferior survival (mOS- 35.5 vs. 61.2 months, p= 0.003) [Figure 2]; however, it was not an independent predictor of OS in LR pts after adjustment for age at diagnosis, ASXL1 and RUNX1 mutational status in MVA. In the EZH2-MT group, pts with EZH2-MT ASXL1-WT RUNX1-WT MDS (n=29) had a significantly prolonged mOS compared to EZH2-MT ASXL1-MT/ RUNX1-MT pts (48.7 vs. 26.8 months, p- 0.031). Concurrent chromosome 7 abnormalities were associated with significantly worse OS (mOS- 20.8 vs. 35.5 months, p= 0.002) among EZH2-MT pts. Conclusions: In our study, the incidence of pathogenic EZH2 mutation was 4.6%, comparable to prior reports. Patients with EZH2-MT MDS were significantly older, more commonly harbored deleterious ASXL1 and RUNX1 mutations, and showed a trend towards lower CR and OR rates to HMA. Median OS did not differ overall between EZH2-MT and WT groups. Presence of an EZH2 mutation was a predictor of OS in IPSS-R LR pts, although it was not independent on MVA adjusting for age, ASXL1, and RUNX1 mutational status. In the EZH2-MT group, concurrent del (7q) or monosomy 7 was associated with worse OS, indicating biallelic loss of function. Future clinical trials should explore potential role of novel targeted therapies in improving outcome in pts with EZH2-MT MDS. Figure 1 Figure 1. Disclosures Hussaini: Stemeline Therapeutics: Honoraria. Tinsley-Vance: Jazz: Consultancy, Speakers Bureau; Taiho: Consultancy; Abbvie: Honoraria; Astellas: Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy; Fresenius Kabi: Consultancy. Kuykendall: PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; Prelude: Research Funding; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweet: AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; Millenium Pharma/Takeda: Consultancy; Daiichi Sankyo: Consultancy; BerGenBio: Consultancy; ElevateBio Management: Consultancy; Astellas: Consultancy; Agios: Consultancy; Celgene/BMS: Consultancy; Jazz: Consultancy. Sallman: Takeda: Consultancy; Agios: 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, Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Magenta: Consultancy. Padron: Blueprint: Honoraria; Taiho: Honoraria; Incyte: Research Funding; BMS: Research Funding; Stemline: Honoraria; Kura: Research Funding. Komrokji: Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; AbbVie: Consultancy; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background: There is a paucity of research on racial and ethnic disparities in myelodysplastic syndromes (MDS). Research focused on racial and ethnic disparities for MDS is essential to improve knowledge and understanding to deliver racial and ethnic sensitive care. There are limited studies that delineate the incidence of cytogenetic and molecular features of MDS by race and ethnicity (Yan, et al. 2021, Ramadan, et al.,2016). The aim of this abstract is to report the difference in clinical phenotype, genotype and outcomes of White, Black and Hispanics from a large MDS data base. Methods: Adult patients were identified through the Moffitt Cancer Center MDS data base and divided into racial/ethnic categories. Fisher exact test and chi-square tests were used to compare categorical variables. Univariate survival analysis was estimated using the Kaplan-Meier method. Results: From analysis of 4414 patients with MDS, 4131 (93%) were White, 116 (3%) Black and 167 (4%) Hispanic. Table-1 summarizes baseline characteristics. There were more Black and Hispanic women diagnosed with MDS (p < .001). Black and Hispanic patients were younger at diagnosis (p Table-2 summarizes somatic mutations (SM) landscape among the different racial groups, IDH2 SM (p=0. 01) and NPM-1 SM (p=.004) were more common in Black MDS patients. MPL (p < 0.005) was observed more frequently among Hispanic patients. There was no difference in response to any modality of treatment based on race. Hispanic patients were more likely to undergo allogeneic hematopoietic stem cell transplant 50 (29.9%, p The median overall survival (mOS) was 35 months (mo), 31 mo, and 52.5 mo for White, Black and Hispanic patients respectively, p= .01 shown in Figure 1. For very low/low R-IPSS the mOS was 67.6, 52 and 93 mo respectively, p= .028, Figure 2a. For intermediate risk R-IPSS the mOS was 33, 30 and 51 mo respectively, p=0.2, and for high/very high-risk R-IPSS the mOS was 16.8, 21.7, and 25 mo respectively, p=.025. See Figures 2b and 2c. There was no difference in rate of AML transformation Conclusions: This large retrospective study revealed racial/ethnic differences in clinical and molecular features of MDS. Hispanic patients had better overall survival. Continued research in this area is recommended to better understand the phenotype and genotype of patients from diverse ethnic/racial backgrounds. Acknowledgement of Funding: NINR Grant # 1K23NR018488-01A Figure 1 Figure 1. Disclosures Tinsley-Vance: Novartis: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau; Taiho: Consultancy; Fresenius Kabi: Consultancy; Incyte: Consultancy, Speakers Bureau; Astellas: Speakers Bureau; Abbvie: Honoraria; Jazz: Consultancy, Speakers Bureau. Padron: Stemline: Honoraria; Blueprint: Honoraria; Kura: Research Funding; Taiho: Honoraria; Incyte: Research Funding; BMS: Research Funding. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Lancet: Celgene/BMS: Consultancy; BerGenBio: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy; Astellas: Consultancy; Agios: Consultancy; Jazz: Consultancy. Kuykendall: PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; Prelude: Research Funding; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sallman: Incyte: Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Syndax: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Intellia: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees. Komrokji: AbbVie: Consultancy; Geron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau.

Context: Myelofibrosis (MF) rarely presents in young patients. Young patients with MF enjoy a more indolent disease course and a lower incidence of adversely prognostic clinical and genomic variables. Analysis of this population may identify patient-specific variables that predict for early disease onset or progression, as well as keys to myeloproliferative neoplasm pathogenesis, specifically with regard to inflammation. Design: We analyzed MF patients ≤ 50 years at diagnosis. Comorbid conditions present at diagnosis were classified by etiology. DIPSS score (range 0–5) was calculated from clinical variables (except age) at initial presentation and 3 and/or 5 years later, when available. Change in DIPSS represented a surrogate for clinical disease progression. Results: Among 63 patients, the median age was 43.6 years. Twenty-four (38%) were men. Forty-six (73%) had primary MF, while 17 (27%) had secondary MF. At first presentation, 18 (29%), 28 (44%), 14 (22%), and 2 (3%) had low-, int-1-, int-2-, and high-risk disease by DIPSS, respectively. With a median follow-up of 55 and 95 months from presentation and diagnosis, respectively, median OS was not reached. Among 58 patients with a known reason for presentation, 36 (62%) presented due to incidental lab abnormalities, and 17 (29%) presented with symptomatic disease (symptomatic cytopenias, splenomegaly, constitutional symptoms, thrombosis), with symptomatic cytopenias being most common (n = 9; 16%). Among 31 (49%) with comorbidities accompanying/predating diagnosis, 5 (8%) were infectious, 10 (16%) autoimmune, 10 (16%) inflammatory, 12 (19%) cardiovascular/metabolic, and 1 (2%) malignant. Six had more than one class of comorbidity. Twenty-six patients had clinical data sufficient to calculate a DIPSS score at 3 and/or 5 years after presentation. Nine (35%), 8 (31%), and 9 (35%) had a decrease, no change, and increase in DIPSS, respectively. Increasing DIPSS correlated with a worse OS (p=0.05) and the presence of comorbidity (p=0.02). Conclusions: In young MF patients, comorbid conditions are common and correlate with an increased risk of disease progression, which, in turn, correlates with poor survival. This supports the role of inflammation in disease initiation and progression and identifies potential therapeutic avenues to delay disease progression and/or identify patients at high risk of progression. No grant funding was used for this study.

Context: Clinical trials of IDH1/2 inhibitors demonstrated promising outcomes in IDH1/2mut AML patients. However, a substantial fraction of patients fail to respond to IDH1/2 inhibitors in AML. Recent preclinical studies have shown MYC prevents the normal myeloid differentiation and cell death by suppressing IDH1/2-TET2-5hmC signaling. Objective: Evaluate if high MYC expression is associated with poor survival outcomes in IDH1/2mut AML patients treated with ivosidenib or enasidenib. Design: We retrospectively identified AML patients who had IDH1/2 somatic mutations based on NGS assessments. Clinical and demographic data were extracted from the medical records. Pre-treatment MYC protein levels were assessed by immunohistochemistry (IHC) staining using BM biopsy specimens. Results: A total of 28 (IDH1mut, n=11; IDH2mut, n=18; IDH1/2mut, n=1) patients were included in the study. Median age at AML diagnosis was 66 years, and 60% of patients were male. Twelve (42%) patients had secondary AML and 9 (32%), 11 (39%), and 6 (21%) patients had favorable, intermediate, and adverse risk, respectively, at AML diagnosis. A total of 17 (60.7%) and 6 (21.4%) patients received intensive chemotherapy and hypomethylating agents as their first-line therapy. Among 28 patients, 22 (78.5%) and 6 (21.4%) patients had low and high MYC expression (≥5% by IHC staining), respectively, prior to IDH1/2 inhibitor treatment. Median number of treatments prior to IDH1/2 inhibitors was 3 (1–6) and the median duration of IDH1/2 inhibitor treatment was 3.2 (0.3–30) months (IDH1mut, 3.3 [0.3–30] months; IDH2mut, 2.5 [0.7–14.5] months). Treatment response was assessed in 27 patients, and 11 (40.7%) had CR/CRi (high vs low MYC, 20 vs 45.5%, p=0.6185). The median PFS was shorter in high MYC patients (1.6 vs 4.4 months, HR=2.348, p=0.0515). The median OS was also significantly shorter in high MYC patients (2.5 vs 8.5 months, HR=5.971, p Conclusions: High MYC expression was associated with significantly shorter PFS and OS in IDH1/2mut AML patients. Consistent with our recent studies that showed MYC represses IDH1/2 and TET2 expression in AML, this study suggests that MYC may play an important role in the resistance mechanism of IDH1/2 inhibitors. Additional studies with larger cohorts are warranted to further confirm and validate these findings.

Context: Azacitidine (aza) remains the backbone of treating higher-risk MDS patients (pts), with less than 20% of pts achieving complete response (CR) and median overall survival of 14–18 months. Ongoing studies in higher-risk MDS are assessing the role of adding venetoclax (ven) to aza in higher-risk MDS. Objective: We report, here, single-institution experience of aza/ven combination in the upfront treatment of higher-risk MDS, comparing it to historical aza alone. Design: We identified 35 pts who received aza/ven for intermediate or higher-risk MDS by R-IPSS compared to 1175 similar-risk MDS pts who historically received aza upfront therapy alone. Results: The median follow-up for the aza/ven group was 15 months (mo) compared to 93 mo for aza alone. No differences were observed in baseline demographic or disease characteristics comparing aza/ven group to aza alone except for higher rates of ASXL-1 and N-RAS somatic mutations (SM) among aza/ven treated pts. There was no difference in median OS among the two groups: median OS was 20 mo for both groups. The CR/marrow CR (mCR) rate was higher with the aza/ven combination, 71% (31%/40%), compared to 25% for aza alone (13%/12%) (p Conclusion: Aza/ven combination is associated with higher responses overall and among ASXL-1 SM higher-risk MDS pts and encouraging early data support aza/ven as a bridge to AHSCT, with 90% 2-year OS.

Hodgkin lymphoma with symptomatic osseous involvement can have a similar presentation to osteomyelitis. Common findings in symptoms, laboratory workup, and imaging can make it very difficult to distinguish between the two diseases. Excisional biopsy should be pursued if fine-needle biopsy is equivocal and suspicion of lymphoma is high. We report a case of a 40-year-old man who presented with a history of marine animal sting on his neck and later developed erythema in the area, chest pain, constitutional symptoms, adenopathy, and imaging classic for sternal osteomyelitis. Fortunately, initial biopsy prompted the possibility of lymphoma, and further workup was initiated, which confirmed Hodgkin lymphoma. This case is a good reminder that malignancies and infections can share many common features, and keeping a broad differential diagnosis can be lifesaving. Proper staging and risk stratification of Hodgkin lymphoma help determine the optimal treatment.

Chemotherapy remains the first-line therapy for aggressive lymphomas. However, 20–30% of patients with non-Hodgkin lymphoma (NHL) and 15% with Hodgkin lymphoma (HL) recur after initial therapy. We want to explore the role of high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) for these patients. There is some utility of upfront consolidation for-high risk/high-grade B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma, but there is no role of similar intervention for HL. New conditioning regimens are being investigated which have demonstrated an improved safety profile without compromising the myeloablative efficiency for relapsed or refractory HL. Salvage chemotherapy followed by HDT and rescue autologous stem cell transplant remains the standard of care for relapsed/refractory lymphoma. The role of novel agents to improve disease-related parameters remains to be elucidated in frontline induction, disease salvage, and high-dose consolidation or in the maintenance setting.

Key Clinical Message Mixed phenotype acute leukemia with t(9;22) is a rare disease with poor prognosis, and information on optimal treatment is limited. We describe a case where our patient experienced positive outcome after nonacute myeloid leukemia‐type intensive induction therapy followed by postremission therapy with stem cell transplant.

Background: Therapy related myelodysplastic syndromes (t-MDS) account for 10-20% of all myelodysplastic syndromes (MDS). They are associated with poor outcome namely driven by high occurrence of poor risk cytogenetics and TP53 mutations. Acquired SF3B1 splicing mutation is the sole somatic mutation (SM) associated with favorable outcome in de novo MDS and is described among 80% of patients with ring sideroblasts (RS) subytpe. The prognostic value of SF3B1 SM in the context of t-MDS has not been reported. We aimed to compare the outcomes of patients with SF3B1 mutation (mut) between t-MDS and de novo MDS, and the outcome among t-MDS patients harboring SF3B1 mut to those with SF3B1 wild type t-MDS. Patients and Methods: Patients with myelodysplastic syndrome seen at Moffitt Cancer Center between 2013 and 2019 were evaluated and included for analysis. SF3B1 mutational status was assessed via next generation sequencing. We included patients with known SF3B1 status. These patients were further stratified into de novo MDS and those with t-MDS. Further, outcomes of t-MDS patients were evaluated based on SF3B1-mut vs SF3B1-WT. Baseline characteristics were compared by chi square (categorical variables) and t- test (continuous variables). Survival estimates were calculated using the Kaplan-Meier method from date of diagnosis and groups were compared using log-rank test. Multivariate survival analysis performed by means of Cox proportional hazards regression. Results: In a large cohort of patients with myelodysplastic syndrome, 320 patients were identified with SF3B1 SM who were classified as de novo MDS (n=289) and t-MDS (n=31). Baseline characteristics were similar among both groups with t-MDS patients being slightly older and harboring high risk cytogenetics. Mutational distribution was also similar except for CBL which was more observed in t-MDS compared to de novo (10% vs 1%, p-value =.002). AML, transformation rate was 12.5% vs 12.9% for de novo MDS and t-MDS respectively, p-value .943. Median overall survival (OS) in those with de novo MDS SF3B1-mut vs t-MDS SF3B1-mut was 103 months vs 59 months, p-value .001. t-MDS patients were then stratified by wild type SF3B1 (SF3B1-WT) and SF3B1-mut. Of the 272 t-MDS in our database with known SF3B1 status, 31 were SF3B1-mut (11%). Of those with SF3B1-mut, 60% were classified as MDS-RS compared to 4.1% of those SF3B1-wt with t-MDS. Complex cytogenetics were seen in 37.4% vs 10.3% of patients with SF3B1-WT vs SF3B1-mut, p-value .009. TP53 mutation was seen in 36.1% SF3B1-WT vs 10% SF3B1-mut, p-value .004. AML transformation rate was 34.4% in SF3B1-WT compared to 12.9% SF3B1-mut, p-value .016. Median overall survival was17 months in SF3B1-WT vs 43 months in SF3B1-mut, p-value .004. Conclusion: In our study, SF3B1 mutations are more commonly seen in de novo than in therapy related MDS. De novo MDS SF3B1-mut had better outcomes compared to t-MDS SF3B1-mut although rate of AML transformation was similar. In patients with therapy related MDS, those with SF3B1-mut had better outcomes than those with SF3B1-WT. Additionally complex cytogenetics, TP53 mutation, and transformation to AML occurred more with SF3B1-WT than with SF3B1-mut. In the absence of SF3B1 mut, t-MDS with ring sideroblasts has been reported to have higher rate of TP53 mut compared to de novo MDS-RS. To our knowledge, our data is first to suggest that among t-MDS patients, SF3B1-mut may portend a better prognosis. Disclosures Padron: BMS: Research Funding; Novartis: Honoraria; Kura: Research Funding; Incyte: Research Funding. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy. Komrokji:Acceleron: Honoraria; Geron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; JAZZ: Honoraria, Speakers Bureau; Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria, Speakers Bureau.

Background: Genetic alterations are increasingly being recognized to play an important role in both diagnosis and prognosis of MDS. In general, SF3B1 mutated MDS is known to have favorable outcomes whereas those with mutated TP53 have dismal survivals. However, it is unclear if the impact of these mutations applies to all subtypes of MDS including del(5q), a unique entity that is known for its sensitivity to lenalidomide and better prognosis. A prior study suggests TP53 mutations are associated with worse outcomes in del(5q) MDS (Jadersten et al. 2011), but a more recent study did not find this association and instead they showed SF3B1 mutants (MT) conferred shorter survival compared to wild-type (WT) (Meggendorfer et al. 2017). Herein, we describe our experience of del(5q) MDS patients and assess the prognostic impact of somatic mutations in this population. Methods: We retrospectively reviewed our database of 132 patients with del(5q) MDS who were treated at the Moffitt Cancer Center from 2001 to 2019. Sixty-three patients had molecular data available for analysis. Fisher's exact test of independence was used to determine significance for categorical variables. Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Kaplan-Meier analysis with log-rank test was used to estimate survival outcomes. Results: A total of 132 patients (47M/85F) with a median age of 70 at diagnosis were included in this analysis (Table 1). The majority had isolated del(5q) (86.3%) and the remaining with del(5q) plus other aberration(s) but not meeting criteria as complex cytogenetics. Among patients who received lenalidomide (n=98), 50%, 42.9%, and 7.1% achieved hematologic improvement (HI) or better, no response (NR), and disease progression (DP)/death with a median overall survival (OS) of 93.2, 72.4, and 25.6 months from the time of diagnosis, respectively (p Of the 63 patients with molecular data available, 23.8% were found to have TP53 mutations with a median variant allele frequency (VAF) of 20.4% and 10% SF3B1 MT (median VAF 38.9%). Other common mutations include TET2 (19%) and DNMT3A (17%) as shown in Figure 2. Interestingly, TP53 status did not impact OS (MT 86.4 vs. WT 73.3 months; p=0.72), but those with SF3B1 mutations had a significantly shorter median OS compared to WT (23.9 vs. 83.5 months; p=0.001) (Figure 3). When test for effects of multiple genes had on survival, no combinations were found to be predictive. Univariate analysis showed lenalidomide response significantly impacted OS (HI compared to NR: HR 0.19, 95% CI: 0.05-0.68, p=0.005). Multivariate regression confirmed lenalidomide response and SF3B1 status are independently associated with outcomes. Conclusions: SF3B1 mutations, typically correlate with favorable risk in MDS, are associated with significantly worse prognosis compared to WT in patients with del(5q) MDS. On the contrary, there was no significant difference in OS in patients with TP53 MT vs. TP53 WT. A substantial portion of patients benefited from lenalidomide; however, after lenalidomide failure survivals were limited. Despite the known overall associations between MDS and mutations such as SF3B1 and TP53, our data suggests the del(5q) subset behaves differently which adds to the heterogeneity of the disease. Further studies are needed to clarify the impact of treatments and somatic mutations on outcomes. Disclosures Sallman: Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy; Celgene, Jazz Pharma: Research Funding. Padron:Novartis: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding. Lancet:Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. Komrokji:BMS: Honoraria, Speakers Bureau; Agios: Speakers Bureau; Abbvie: Honoraria; Incyte: Honoraria; Acceleron: Honoraria; Novartis: Honoraria; Jazz: Honoraria, Speakers Bureau; Geron: Honoraria.

Many prognostic scoring systems have been developed for chronic myelomonocytic leukemia (CMML). Although these efforts have been informative, no single model has been considered the consensus for CMML prognostication and all models are only moderately prognostic. CMML clinical models utilize mainly hematology and morphology parameters to estimate risk. A better understanding of cytogenetics and the genomic landscape of CMML have resulted in integrated risk models such as CMML Prognostic Scoring System (CPSS)-Mol and Mayo Molecular that may provide better prognostic accuracy for an individual patient. For example, frameshift/nonsense ASXL1 mutations have been consistently shown to confer inferior outcomes leading to its incorporation into some of the major risk classification systems. Prognostication in the setting of therapeutic interventions such as hypomethylating agents and allogeneic hematopoietic cell transplantation have also garnered considerable interest. Despite having many validated risk models available, not a single system is universally adopted. Herein, we will provide an overview of how these systems evolved and progress toward a uniform system.

MYC is an oncoprotein that coordinates the expression of genes involved in metabolism, cell differentiation and survival in various types of malignancies. However, the underlying oncogenic mechanisms and the clinical significance of MYC expression in the acute myeloid leukemia with myelodysplasia related changes (AML-MRC) remain to be answered. A total of 135 patients were retrospectively identified using Total Cancer Care (TCC) Moffitt Cancer Center (MCC) databases. Diagnosis of AML-MRC was based on the 2016 WHO classification utilizing bone marrow (BM) evaluation. MYC protein expression level was assessed by immunohistochemistry (IHC) staining using paraffin-embedded BM trephine biopsy samples obtained at the time of diagnosis or relapse. Concurrent somatic mutations were assessed using targeted next generation sequencing that include 54 genes. A total of 38% (n = 51) and 62% (n = 84) patients had high and low MYC expression, respectively. The most common somatic mutation in our cohort was TP53 followed by DNMT3A, and ASXL1. The median OS was significantly longer in low MYC patients (median OS 42.3 vs. 17.05 months, p = 0.0109). Multivariate analysis including MYC expression level, transplantation status, gender and age demonstrated high MYC expression (HR 1.77, 95% CI 1.004–3.104, p = 0.045) to be an independent poor prognostic factor. Further studies are needed to identify the underlying mechanism of MYC driven oncogenesis in AML-MRC. Additionally, the prognostic impact of MYC on the AML survival in a larger cohort that include diverse somatic mutations and chromosomal abnormalities requires further investigation.

e19010 Background: Recent studies showed that IDH1/2 are frequently mutated in AML and that aberrant 2-HG elevation driven by the mutant IDH1/2 proteins plays a pivotal role in AML development. Subsequent clinical trials of IDH1/2 inhibitors demonstrated promising outcomes in IDH1/2mut AML patients. In this single institutional retrospective study, we explored the efficacy and safety outcomes of IDH1/2mut AML patients treated with Ivosidenib or Enasidenib. Methods: We retrospectively identified AML patients who had IDH1/2 somatic mutations based on NGS assessments. Clinical and demographic data were extracted from the medical records. Statistical analyses were performed using GraphPad Prism (v.7.03) and SPSS (v.24.0). Results: A total of 43 ( IDH1mut, n = 12; IDH2mut, n = 33; both IDH1/2mut, n = 2) patients were included in the study. Median age at AML diagnosis was 67.6 (24.2-83.3) years and 24 (55.8%) patients were male. Eighteen (42%) patients had secondary AML and 13 (34.2%), 17 (44.7%), and 8 (21.1%) patients had favorable, intermediate, and adverse risk, respectively. A total of 23 (53.5%) and 9 (20.9%) patients received intensive chemotherapy and hypomethylating agents as their 1st line therapy. One patient received Enasidenib as the 1st line therapy and the rest of the patients had relapsed/refractory disease prior to IDH1/2 inhibitor therapy. Median number of treatment prior to IDH1/2 inhibitors was 4 (0-8). The median duration of IDH1/2 inhibitor treatment was 3.2 (0.2-31.6) months ( IDH1 mut, 2.5 [0.7-13.5]; IDH2 mut, 3.4 [0.2-31.6]). Treatment response was assessed in 38 patients and 18 had overall response (CR, n = 7 [18.4%]; PR, n = 11 [28.9%]). Among these, 13 patients had concurrent somatic mutations in FLT3, KRAS, NRAS, or PTPN11. The overall response rate in these patients was not statistically different compared to patients who did not have these mutations (38.5% vs. 40%, p > 0.05). The median PFS was 3.9 (0.4-14.7) months ( IDH1 mut, 5.6 [1.7-11.5] vs. IDH2 mut, 3.7 [0.4-14.7], p > 0.05) and median OS was 7.6 (0.4-44.1) months. The most common reason for IDH1/2 inhibitor discontinuation was disease progression (n = 21) followed by adverse events (n = 3) and allogeneic transplant (n = 2). The adverse events were assessed in 41 patients and the most common adverse events were differentiation syndrome ( IDH1 mut, n = 3; IDH2 mut, n = 5) and leukocytosis ( IDH1 mut, n = 4; IDH2 mut, n = 4) followed by hepatic toxicity ( IDH2 mut n = 7), and QTc prolongation ( IDH1 mut, n = 3). Conclusions: Our study indicates that IDH1/2 inhibitors remain a reasonable option for the refractory/relapsed IDH1/2mut AML. However, significant number of patients failed to show any response and many of the patients who showed initial response had short response duration. These findings warrant further studies to identify underlying resistance mechanisms of IDH1/2 inhibitors and the optimal combination therapeutic strategies.

7024 Background: Extramedullary (EM) involvement, including myeloid sarcoma (MS) and leukemia cutis (LC), is uncommon in patients with acute myeloid leukemia (AML). Mutational landscape of EM-AML is not well characterized, including concordance of sequencing data from EM vs. non-EM site (blood or bone marrow) and the potential for personalized targeted therapy in this patient cohort. Methods: In a multicenter retrospective study, clinical and genomic data were collected on EM-AML patients treated at Moffitt Cancer Center, Memorial Healthcare System, and University of Miami, as well as sequenced cases at a central laboratory. Next generation sequencing (NGS) data come from panels that interrogated 24- 406 genes, with 15 genes covered by all panels, including notably, IDH1, IDH2, KIT, KRAS, NPM1, NRAS, and TP53. Survival estimates using Kaplan-Meier statistics and multivariate analysis with Cox-regression were performed in SPSS (v.26). Results: Our study included 58 patients with EM-AML. Median age at diagnosis was 62 years; 55% of patients were males. In our cohort, 34 (59%) patients had MS, and 19 (33%) had LC. EM-AML was noted during relapse in 60% of evaluable patients (n=45), and 31% had isolated EM disease. Patients with LC had a significantly worse median overall survival (OS) than those with MS (5.7 months vs. 21.9 months, p= 0.008); Pattern of EM involvement (MS vs. LC) remained an independent prognostic factor for OS (p= 0.04) in a multivariate analysis including disease setting (new diagnosis vs. relapse) and ELN risk category. Results of NGS performed during EM presentation were available in 48 patients, 19 of which had NGS data from EM site. Most commonly mutated genes were NRAS on EM site NGS (37%) and NPM1 on non-EM site NGS (28%). Based on EM NGS, 52% patients had a targetable genomic alteration, with 37% mutations in IDH, 21% NPM1, 5% FLT3, and 11% MLL-PTD. Five (two with concurrent M+EM disease) out of nine evaluable patients had significant discordance in targetable mutations between EM and non-EM NGS at EM-AML. Three of four patients who received treatment with IDH1/2 inhibitors based on EM NGS achieved complete response. Conclusions: EM-AML has a distinct molecular architecture with an inferior OS in LC vs. MS patients. We conclude that EM site NGS is critical in patients with EM-AML, as 52% have potentially targetable mutations and could benefit from specific targeted therapies.[Table: see text]

Patient: Male, 27 Final Diagnosis: Burkitt lymphoma with intracardiac mass Symptoms: Dizziness • fatigue • palpitations • weight loss Medication: — Clinical Procedure: Catheter-directed thrombolytic therapy with intracardiac infusion of alteplase Specialty: Hematology Objective: Rare disease Background: Non-neoplastic causes such as infections and thrombi account for most intracardiac masses. Primary tumors such as myxomas and metastasis from breast cancer, lung cancer, or melanomas account for many of the remaining cases. Burkitt lymphoma manifesting as an intracardiac mass is a rare entity, with 21 cases reported in the English literature. Case Report: We report the case of a man infected with human immunodeficiency virus (HIV) who presented with non-specific cardiac symptoms and was later found to have intracardiac mass caused by Burkitt lymphoma. His rapid decline with unexpected complications was reversed with prompt management. Subsequent to induction, the patient achieved a near complete response with considerable improvement in his condition. Conclusions: Lymphoma should be considered in the differential diagnosis of intracardiac masses. Associated cardiac symptoms are frequently non-specific and can often be overlooked or underappreciated. Burkitt lymphoma has a short doubling time and an intracardiac lesion can become life-threatening in a matter of days. Early recognition and prompt treatment are crucial to achieving optimal outcomes.

Background: TP53 mutations confer dismal prognosis in many hematologic malignancies, including MDS in general. It is frequently found in higher-risk/therapy-related MDS. However, 15-20% can occur in patients with del(5q), a subgroup that is known to have a more favorable risk. A prior study suggests TP53 mutations are associated with worse outcomes in del(5q) MDS. Objective: To assess the prognostic impact of TP53 mutations in del(5q) MDS patients and to report response to lenalidomide. Methods: This is a retrospective study of del(5q) MDS patients who were treated at the Moffitt Cancer Center from 2001 to 2019. Out of 132 patients identified, 63 had molecular data available and represent the cohort of present study. Univariate (log-rank), multivariate (Cox regression), and Kaplan-Meier (log-rank) analyses were performed. Results: Of the 63 patients (26M/37F), 23.8% were found to have TP53 mutation. Majority had isolated del(5q) (85%) with the remaining del(5q) plus other aberration(s) but not meeting criteria as complex. A total of 43 patients (68.3%) received lenalidomide (73.3% TP53 MT and 66.7% TP53 WT, p=NS) with 37.2%, 55.8%, and 7% achieving HI, NR, and DP/death, respectively. AML transformation occurred in 14.3% (20% TP53 MT and 12.5% TP53 WT, p=NS). Other common mutations include TET2 (19%), DNMT3A (17%), and SF3B1 (10%). The median OS was 76.6 months (median follow-up: 71.3 months). There was no significant difference in OS regardless of TP53 mutational status (p=0.72). Among patients who received lenalidomide, mOS for HI, NR, and DP/death were 142.2, 66, and 25.6 months, respectively (p ≤ 0.001). Univariate analysis showed lenalidomide response significantly impacted OS (HI:HR 0.02, 95% CI: 0.00-0.11, p ≤ 0.001; NR:HR 0.08, 95% CI: 0.02-0.43, p=0.003). Multivariate regression using covariates including TP53 status confirmed lenalidomide response to be independently associated with outcomes. Conclusions: There was no significant difference in OS in patients with TP53 MT vs. TP53 WT. A substantial portion of del(5q) MDS patients benefited from lenalidomide. Despite the known overall adverse association between TP53 and MDS, our data suggests the del(5q) subset behaves differently, which adds to the heterogeneity of the disease. Further studies are needed to clarify the impact of treatments and somatic mutations on outcomes.

Background Outcomes in patients (pts) with secondary acute myeloid leukemia (sAML) (therapy related myeloid neoplasms and AML with myelodysplasia related changes (MRC) per WHO 2016 classification (Arber et al, Blood 2016)) are poor. Pts treated with hypomethylating agents (HMAs) have suboptimal responses to induction chemotherapy (IC) upon transformation to AML. Previously, it was retrospectively demonstrated that the IC with cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) yields significantly higher response rates (64%) than 7+3 (cytarabine and anthracycline) (29%) in pts with prior HMA exposure (Jaglal et al, Leukemia Research 2014). Following the recent approval of CPX-351 for induction in sAML subgroup, we investigated outcomes after CPX-351 to cladribine based regimens and 7+3 in pts with sAML with prior HMA exposure. Methods We identified pts with sAML who had prior HMA treatment for an antecedent hematologic malignancy (AHM) and later received induction chemotherapy upon AML transformation from Moffitt Cancer Center (MCC) (n=229), Memorial Sloan Kettering Cancer Center (n=11) and Roswell Park Comprehensive Cancer Center (n=2). Patients were divided into 3 cohorts based on induction regimen: (A) cladribine based (CLA+/-G+/-M) (B) standard 7+3 and (C) CPX-351. Demographics, disease-specific variables, and outcomes were collected in accordance with the institutional review board approved protocol. Responders (R) were defined as pts achieving CR or CRi as defined by the 2003 International Working Group (IWG) criteria after 1 or 2 cycles of the either induction regimen whereas non-responders (NR) were defined as responses other than CR/CRi. Pts receiving a second induction with a different regimen were considered NR. Fisher's exact test and the ANOVA test were used to determine significance for continuous and categorical variables. Kaplan-Meier analysis with log-rank test was performed to estimate overall survival (OS). Results Among 242 pts who received IC for AML after HMA failure for prior AHM, 114 were treated with (A) cladribine based regimen (B) 94 pts with standard 3+7 and (C) 34 pts with CPX-351 (Cohort C). Baseline characteristics for all 3 cohorts are outlined in Table 1A. Median age for cohort A, B, and C were 65 (33-82), 66 (26-81), and 69 (36-82), respectively. Males comprised of 68.4%, 63% and 52.9% of the cohorts A, B and C, respectively. No pts had favorable-risk karyotype as defined by European LeukemiaNet (ELN) 2017 criteria. Adverse risk karyotype was noted in 42.1% of cohort A, 34.6% of cohort B and 22.7% of cohort C (p=.337). The majority of pts received azacitidine as their HMA for their AHM (88.7%, 84.9% and 82.4% in cohorts A, B, C, respectively) and median number of cycles administered prior to transformation to AML were 6, 4 and 5 for cohorts A, B, and C, respectively. Response rates in each cohort are summarized in Table 1B. The CR/CRi rate was 53% in cohort A, 32% in cohort B and 41.1% in cohort C (p=.005 between cohort A and B) (p=.329 between cohorts A and C) (p=.526 between cohorts B and C). The early death rates ( In pts who received ≤ 4 cycles of HMAs prior to AML transformation, response rates to CPX-351 were higher (64.3%) than in pts who received >4 cycles of HMAs (25.0%) (p=.0397). Cohort A (56.5% vs. 50.0%, p=.288) and B (39.1% vs. 25.5%, p=.175) did not demonstrate such a difference (Table 1C and 1D). There was a trend towards better OS (19.9 vs. 5.5mo) with CPX-351 treated pts with ≤ 4 cycles of HMAs compared to >4 cycles (p=.092) (Figure 1). To date, 70.0% of responding pts in cohort A have undergone an allogeneic stem cell transplant compared to 31.0% in cohort B and 28.6% in cohort C (p=.15). There was no significant difference in median OS among the 3 groups, cohort A (7.27 months), cohort B (7.63 months) and cohort C (7.07 months) (p=.887). Among responders, the mOS did not differ (12.93, 21.7, and 19.9 months for cohorts A, B, and C respectively, p=.635). Conclusions We demonstrate that cladribine-based induction regimens and CPX-351 yield higher CR/CRi rates compared to 7+3 in pts with sAML after HMA failure. Prolonged duration of HMA exposure may lower response potential with CPX-351 upon AML transformation. Median OS remains poor and did not differ among the 3 groups illustrating the unmet need for therapy for sAML pts after HMA failure. Disclosures Goldberg: AROG: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Research Funding. Sallman:Celgene: Research Funding, Speakers Bureau. List:Celgene: Research Funding. Wang:Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: 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; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau. Tallman:AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; ADC Therapeutics: Research Funding; Orsenix: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; BioSight: Other: Advisory board. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sweet:Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Agios: Consultancy; Astellas: Consultancy; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Jazz: Speakers Bureau; BMS: Honoraria; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria.

Philadelphia chromosome, reciprocal translocation between chromosome 9 and 22, leading to a constitutively active fusion protein BCR-ABL1 is the common feature among Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML). The discovery of tyrosine kinase inhibitors (TKIs) has led to significant improvement in the treatment of CML and Ph+ ALL. Ponatinib is a third-generation TKI that is currently approved as per label when no other TKIs are indicated for the treatment of patients with CML and Ph+ ALL after failing treatment with second-generation TKIs or if presence of T315I mutation is discovered. This review summarizes the ponatinib development, approved indications as well as ongoing clinical studies in CML and Ph+ ALL.

Background The therapeutic landscape for acute myeloid leukemia (AML) has become complex with recent drug approvals. CPX-351 has become standard-of-care for patients (pts) with therapy-related AML and AML with myelodysplasia-related changes. Moreover, earlier phase studies combining hypomethylating agents (HMA) and Venetoclax (HMA+Ven) in the frontline setting for elderly patients have demonstrated high response rates and improved survival. Given the overlapping indications, yet lack of comparative outcome data between these therapeutic regimens, treatment decisions have become challenging in the frontline setting. Therefore, we compared the outcomes of newly diagnosed AML pts receiving HMA+Ven vs. CPX-351. Methods We retrospectively annotated 119 pts that received frontline treatment with HMA+Ven and CPX-351 at Moffitt Cancer Center and Memorial Healthcare System between 2013 and 2019. Pts were divided in two cohorts: HMA+Ven (Cohort A) or CPX-351(Cohort B). Via comprehensive chart review of each patient that received HMA+Ven, we further classified a subgroup of pts meeting criteria to receive CPX-351 as CPX-351eligible. Clinical and molecular data were abstracted for each patient in accordance with IRB requirements. Overall response rate (ORR) was the combined total of complete remission (CR), complete remission with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Fisher's Exact method was used to determine significance. Kaplan-Meier analysis was performed to estimate median overall survival (mOS) with log-rank test to determine significance. All p-values are two-sided. Results Out of 119 total pts, 41 pts received HMA+Ven (Cohort A) and 78 pts received CPX-351 (Cohort B) with baseline characteristics outlined in Table 1. Among 111 response evaluable pts, ORR was 64.1% in Cohort A, including 28.2% with CR and 28.2% with CRi (Table 2). ORR was 50.0% in Cohort B, comprised of CR in 29.2% and CRi in 18.1%. There was no difference in ORR between Cohort A and Cohort B (64.1% vs. 50%, p 0.17). A significantly greater fraction of pts in Cohort B underwent allogeneic stem cell transplant (allo-SCT) (24.4% vs. 2.4%, p=0.004). ORR was higher in pts with European LeukemiaNet (ELN)-defined favorable/intermediate (fav/int) risk compared to adverse risk group in Cohort A (100% vs. 58.3%, p=0.03), however there was no difference in Cohort B (52.6% vs. 49.1%, p=1.0). ORR was similar among adverse risk groups in both cohorts (58.3% in Cohort A vs. 49.1% in Cohort B, p=0.47). Among responders, median time to best response was significantly longer in Cohort A (61.0 days vs. 40.5 days, p Median follow-up was 6.5 months (mo) in Cohort A and 13.0mo in Cohort B. Median OS was similar in both cohorts (A vs. B, 13.8mo vs. 11.1mo, p=0.82) (Figure 1). Among responders, mOS was NR in Cohort A and 18.2mo in Cohort B (p=0.88) (Figure 2). Compared to Cohort B, mOS was superior for pts with fav/int risk disease in Cohort A (14.2mo (B) vs. NR (A), p=0.045) and not different for adverse risk group (11.1mo (B) vs. 7.3mo (A), p=0.2). Prior HMA exposure was 26.8% in Cohort A and 29.5% in Cohort B for an antecedent hematologic malignancy, however it did not impact mOS (p=0.86) or ORR (p=0.7). Early mortality rates for Cohort A and B were similar at day 30 (2.4% vs. 0%) and day 60 (4.9% vs. 3.8%). Rate of relapse was similar between cohorts A and B (16.0% vs. 30.6%, p=0.24). We then compared the outcomes of pts in Cohort B to CPX-351eligible arm from Cohort A (n=14). ORR and mOS were similar in Cohort B and CPX-351 eligible arm (ORR: 50% vs. 50%, p=1.0; mOS 11.1mo vs. 13.8mo, p=0.43). Only 1 patient (7.1%) of the CPX-351eligible arm underwent allo-SCT. Conclusion Our study demonstrates that HMA+Ven results in comparable response rates and survival outcomes to patients receiving CPX-351 when used as an initial remission therapy for patients with newly diagnosed AML, however the median follow up for patients receiving HMA+Ven was short. Survival did not appear to be impacted by a significantly greater proportion of patients proceeding to allo-SCT in the CPX-351 arm. Overall, HMA+Ven may represent a reasonable frontline remission therapeutic choice in patients with AML and a randomized trial would seem justified. Disclosures Kuykendall: Abbvie: Honoraria; Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:celgene: Consultancy; Agios: Consultancy; pfizer: Consultancy; DSI: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; Agios: 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; Incyte: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau. Talati:Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria.