Search

EZH2 mutations in myeloid neoplasms are loss of function type, and have been linked to poor overall survival (OS) in patients with myelodysplastic syndrome (MDS). However, the specific determinants of outcomes in EZH2-mutant (mut) MDS are not well characterized. In this single-center retrospective study, clinical and genomic data were collected on 1774 patients with MDS treated at Moffitt Cancer Center. In our cohort, 83 (4.7%) patients had a pathogenic EZH2 mutation. Patients with EZH2mut MDS were older than EZH2-wild type (wt) group (median age- 72 vs. 69 years, p = 0.010). The most common co-occurring mutation in EZH2mut MDS was ASXL1, with a significantly higher frequency than EZH2wt (54% vs. 19%, p 0.001). Patients with EZH2mut MDS had lower response rates to hypomethylating agents compared to EZH2wt MDS (26% vs. 39%; p = 0.050). Median OS of patients with EZH2mut MDS was 30.8 months, with a significantly worse OS than EZH2wt group (35.5 vs. 61.2 months, p = 0.003) in the lower-risk IPSS-R categories. Among patients with EZH2mut MDS, co-presence of ASXL1 or RUNX1 mutations was associated with inferior median OS compared to their wt counterparts (26.8 vs. 48.7 months, p = 0.031). Concurrent chromosome 7 abnormalities (12%) were also associated with significantly worse OS (median OS- 20.8 vs. 35.5 months, p = 0.002) in EZH2mut MDS. Future clinical trials should explore the potential role of novel targeted therapies in improving outcomes in patients with EZH2mut MDS.

Transient cytopenias and bone marrow hypoplasia commonly occur during treatment of CML with TKIs (tyrosine kinase inhibitors). This is usually related to the eradication of CML clones that initially compose the majority of hematopoietic cells in the bone marrow at the time of diagnosis. With continuation of effective therapy, normal blood counts return as normal hematopoiesis is restored and CML clones are reduced. Though rare and more unusual than myelodysplastic syndrome (MDS), isolated instances of persistent marrow aplasia have been documented with chronic use of TKIs. We describe two such instances of chronic phase CML where no significant reduction of CML clones was achieved following treatment with TKIs, but bone marrow aplasia occurred resulting in persistent dysfunctional hematopoiesis. Due to prolonged aplasia/hypoplasia, such patients are no longer amenable to TKI treatment. CML progression to accelerated or blast phase in that setting would likely be fatal.

7055 Background: CMML is a heterogenous disease exhibiting features innate to MPN and MDS. Increasing evidence supports a close interplay between systemic inflammation and risk of myeloid malignancies, notably for those with history of infection or autoimmune disease. CMML has been associated with inflammation and end-organ damage related to CKD and CVD. Analysis of gene signatures from CMML-derived monocytes has shown them to be highly proinflammatory. High ferritin may serve as a practical biomarker of disease activity to help identify pts at higher risk of poor outcomes. Methods: Retrospective data was collected from a database of CMML pts treated at Moffitt Cancer Center. Pts were stratified in 2 cohorts based on ferritin levels ( < 1000 or ≥1000 ng/mL). Hyperferritinemia was defined as ferritin > 1000 as seen at diagnosis or during follow-up. Kaplan–Meier was used to estimate OS. Cox regression was used for multivariate analysis. Results: Between August 1995 and October 2020 729 pts with CMML were identified. Median age at diagnosis was 71 (17-95). Out of 571 pts with available ferritin levels 29% (n = 168) developed hyperferritinemia vs 71% (n = 403) who did not. mOS was 32.4 mos (95%CI 30-35 mos). Pts with higher ferritin tended to present with CMML-2 (p = 0.001) and harbor a proliferative phenotype (p = 0.01). They presented with higher marrow cellularity (mean 83%, p = 0.08), PLT (mean 177k, p = 0.038), and lower Hb (mean 9.5, p < 0.05). There was no association with % circulating IMC, monocytes, WBC or ANC at baseline. Hyperferritinemia was associated with more profound fibrosis (p = 0.007), cytopenias (p < 0.05), % peripheral blasts (p < 0.05), RBC and PLT transfusion dependence (p < 0.05). Pts with hyperferritinemia had higher risk disease per IPSS-R, CPSS and all CMML models (p < 0.05); and had higher rates of AML transformation (p < 0.05). Pts were also more likely to require treatment earlier (within 3 yrs of diagnosis) (p < 0.05). ASXL1 (p = 0.002), EZH2 (p = 0.003), and SETBP1 (p = 0.019) mutations were more common among pts with hyperferritinemia. Conversely, TET2 (p = 0.001), CBL (p = 0.028) and SRSF2 (p = 0.003) mutations were less common. mOS for pts with hyperferritinemia was 23.9 mos (95%CI 19.9-27.9 mos), much lower than for those with ferritin < 1000 (mOS 40.5 mos, 95%CI 35.4-45.5 mos) (p < 0.05). In multivariate analysis, hyperferritinemia was a significant independent covariate for OS after adjusting for CPSS, transfusion dependence and disease phenotype (dysplastic vs proliferative) (HR = 0.69; 95%CI 0.53-0.89; p = 0.005). Conclusions: Almost 1/3 of pts with CMML will develop hyperferritinemia. This is associated with more aggressive disease and higher rates of AML transformation leading to dismal outcomes. ASXL1, EZH2, and SETBP1 MTs confer a higher risk of hyperferritinemia. Our findings indicate that hyperferritinemia is an independent prognostic biomarker that may serve as a surrogate representative of disease biology and comorbidities in CMML.

Context: Chronic myelomonocytic leukemia (CMML) is characterized by marked clinical heterogeneity. Generally associated with poor outcomes, median overall survival (mOS) is 3 years. Multiple prognostic models consider cardinal clinical, cytogenetic, and molecular features as critical for estimating individual risk and outlining treatment. Identification and longitudinal assessment of features of interest have become important for predicting which patients tend to have a more indolent course compared to those who will progress. Objective: To identify patients with more indolent CMML and analyze disease features at the time of diagnosis. Design: Retrospective cohort of patients with CMML treated at Moffitt between 1995–2020. Patient Population: 729 patients with CMML. Interventions: Data were collected retrospectively. Patients were stratified into 2 cohorts: those remaining in observation for >3 years versus those who required treatment Main Outcome Measures: Correlation between baseline characteristics and treatment initiation within 3 years, OS. Results: Out of 729 patients, 68.3% were male (498), and 88.5% were Caucasian (645). Median age at diagnosis was 71 (17–95) years. A total of 123 patients (17%) did not require treatment within 3 years of diagnosis. mOS was 70 mo among those who did not require early treatment, compared to 25 mo for those who did (p Conclusions: A small subset of CMML patients (17%) have a more indolent disease course. Clinical and molecular features at diagnosis can be assessed to identify them. Next, we aim to identify changes in clinical and molecular features from baseline immediately anteceding the need for treatment to establish whether they predict disease evolution.

Acute myeloid leukemia (AML) is defined by the presence of ≥ 20% myeloblasts in the blood or bone marrow. Spontaneous remission (SR) of AML is a rare event, with few cases described in the literature. SR is generally associated with recovery from an infectious or immunologic process, and more recently possibly with clonal hematopoiesis. We review the literature and assess the trends associated with SR, and report a new case of a 58-year-old man with a morphologic diagnosis of AML associated with a severe gastrointestinal (GI) tract infection. The patient had an NF1 variant that was previously unreported in AML as the only clonal abnormality. After treatment of the infection, the increased blast population subsided with no leukemia-directed therapy, and the patient has remained in a continuous, spontaneous complete remission for > 2 years.

341 Background: Brain metastases from esophageal cancer are extremely rare with an estimated incidence of 1.7% but limited survival. Some reports highlight the rich microvascular density of such tumors and their distinctive degree of HER2, HIF1-a and EGFR expression, further emphasizing the potential role of angiogenesis in their neurotropic behavior. With this in mind, we aimed to illustrate the transcriptomic landscape of brain metastases from esophageal cancers and better understand the disease biology. Methods: Following IRB approval, we collected retrospective data on patients with a diagnosis of esophageal cancer with histology-proven brain metastases treated at our institution between 2008 and 2020. We identified 10 adequate, paired samples with available tissue for RNA extraction. Expression data was generated using NanoString TS 360 panels to characterize gene signatures of interest and analyzed using GSEA_4.1.0. Results: All 10 patients were Caucasian, 90% were male. Median age was 63 years. All had adenocarcinoma with G2-G3 histology. Median follow-up was 39.4 mos (95%CI, 27.4 to 51.4). At data cutoff, 6 patients had died. Median OS was 24.6 mos. Median time from curative surgery to CNS recurrence was 8.3 mos. Ninety percent of patients developed brain metastases within 24 mos of surgery. Median time from brain metastases to death was 4.7 mos. Almost a third of patients had HER2 positive disease. 48 gene signatures were analyzed; 5 being significantly enriched between metastatic and primary site accounting for cell cycle, DNA damage repair, MYC, mTOR signaling and immortality and stemness. Out of a pool of 760, significant overlap was seen between 12 genes across the 5 signatures of interest: POLE, LIG1, FEN1 (involved in DNA repair and replication); AURKA and PLK1 (cell proliferation and triggers for G2/M transition), BUB1 (establishment of the mitotic spindle checkpoint and chromosome congression), MCM2 and MCM4 (initiation of genome replication); BRIP1 and RAD51 (critical in homologous recombinational repair); CCNE1 (cell cycle G1/S transition) and WRAP53 (dual role as p53 regulator and protein involved in telomere elongation and DNA repair). ERBB2 was similarly enriched in primary and metastatic sites. Conclusions: These preliminary data demonstrate that the genomic basis of brain metastases in esophageal cancer goes beyond EGFR/ERBB2 signaling. A complex genomic interaction is present in brain metastases as compared to primary site that offers these cells the advantage for neurotropism. To our knowledge this is the first study attempting to illustrate genomic differences between primary and matched brain metastasis sites in esophageal cancer.

Background It is well known that the state of immune tolerance induced by broad immunosuppression to prevent allograft rejection leads to an increased risk of the development of cancer. One of the most promising new areas of cancer treatment has been the development of immune checkpoint inhibitors that target the cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death protein 1/programmed death-ligand 1 (PD-L1) pathways. As a logical consequence, growing interest in these agents translated into their implementation in patients with transplant-related malignancies. Because of overlapping and perhaps mutually exclusive mechanisms of action of transplant immunosuppression and cancer immunomodulation, it is critical to examine these interactions. Materials and Methods We carried out a systematic search for review articles and case reports published between July 2014 and November 2017 using three engines: Usearch, PubMed, and Up-to-date. Results Overall, there were 20 cases with 12 allograft rejections. The rejection rate associated with nivolumab was 73% (8/11) and with pembrolizumab it was 100% (2/2). The use of ipilimumab did not lead to rejection in any instance (0/4, 0%). Of the two patients treated with the sequential use of ipilimumab/nivolumab, one lost his allograft, yielding a rejection rate of 50%. The sequential use of ipilimumab/pembrolizumab led to a rejection rate of 100% (1/1, 100%). Conclusion The use of agents that act on the PD-L1 pathway are contraindicated in the face of solid organ allografts because of unacceptably high rates of irreversible allograft rejection. It appears that the use of ipilimumab may be tolerated as the mechanism is different from that of the PD-L1 agents. Implications for Practice Transplant rejection is a complex process that puts stress on patients and their families and can lead to tragic results. Significant advancements in the field of immunosuppression have led to the engenderment of agents devised to extend the survival of transplant recipients. The advent of immunomodulators in cancer therapy has been paradigm-shifting; however, because of their mechanism of action, their use must be carefully considered in patients with allografts and concomitant cancer. It appears that ipilimumab can be administered safely in these patients but that agents acting on the programmed death-ligand 1 pathway are contraindicated because of high rates of irreversible rejection.

Higher risk myelodysplastic syndromes are defined as a subset of disease with higher risk of AML transformation and poor overall survival. For decades, therapeutic options for high-risk MDS have been limited to allogeneic stem cell transplant (the only option for cure but limited to only a handful of patients) or hypomethylating agents, with the goal to alter the natural history of disease, delay progression and improve survival, while addressing cytopenias, transfusion requirements and improving quality of life. Recent developments in DNA sequencing and other technologies have shed significant light into the pathogenesis of MDS and led to rational and targeted drug development across a variety of therapeutic vulnerabilities, including disruption of protein ubiquitination through NAE inhibition, selective modulation of macrophage activity and immune checkpoint inhibition through blockade of TIM-3. This review highlights some of the most promising agents in recent drug development and their therapeutic efficacy in the management of high-risk MDS, and further explores the rationale behind potential combinatorial approaches using an HMA backbone to synergistically improve treatment outcomes.

Background Myelofibrosis (MF) is the most aggressive subtype among classical BCR-ABL1 negative myeloproliferative neoplasms (MPN). Approximately 90% of patients harbor a mutation affecting JAK2, MPL, or CALR which results in constitutive activation of the JAK/STAT pathway, resulting in proliferative and dysfunctional blood cell production, extramedullary hematopoiesis, and constitutional symptoms. Remaining patients are deemed to be "triple-negative" (TN), a designation associated with a poor prognosis. Methods We identified patients with confirmed MF (inclusive of primary MF and MF occurring after essential thrombocythemia or polycythemia vera) treated at Moffitt Cancer Center between 2003-2021. Patients were deemed to be TN if they had tested negative for mutations involving JAK2, MPL and CALR. TN patients were compared to non-TN patients who exhibited a mutation in at least one of these genes. Patients with incompletely driver mutation testing were excluded. Baseline demographic, clinical and molecular characteristics were assessed. Kaplan-Meier method was used to determine overall survival (OS) and leukemia-free survival (LFS). Results 626 patients with a diagnosis of MF were identified, among which 6% (n=38) were confirmed to harbor TN disease. See Table 1 for baseline characteristics of TN vs non-TN patients. Thrombocytopenia was more common in TN disease (28.9% vs 12.2%, p=0.003), as well as elevated EPO titers at baseline (88.9% vs 56.8%, p=0.007). Elevated LDH titers at baseline were less common with TN disease (78% vs 91%, p=0.009). Baseline Hb (p=.009), and % of marrow myeloblasts (p < .005) were lower in the TN cohort. Clinically, there were no differences regarding transfusion dependence, presence of constitutional symptoms or splenomegaly (Table 1). Regarding prognostic scores, patients with TN MF exhibited higher-risk disease per DIPSS+ (65.8% vs 58.1%, p=.034) and GIPSS (62.5% vs 47.1%, p=.001) compared to their non-TN counterparts. There were no significant differences in IPSS, DIPSS+, MIPSS70 or MIPSS70+ stratifications. The median OS (mOS) for the entire population was 82.5 months (95%CI 69.4-95.5). Patients with TN MF had shorter survival rates with a mOS of 37.4 months (95%CI 19.2-55.5) compared to 85.7 mo (95% CI 74.6-96.85) for non-TN disease (p=.009). The rate of transformation to AML was 10.5% for TN MF, 9.7% for JAK2, 7.3% for MPL and 5.2% for CALR MF (TN vs non-TN MF p=0.7). Median LFS was 65.2 mo for CALR, 34.1 mo for TN, 21.9 for JAK2 and 16.9 mo for MPL mutant MF (p = 0.498 for TN vs non-TN phenotypes). Nominally, TN patients had fewer responses (46.2% vs 63.4%) and shorter duration of response to ruxolitinib (8.0 mo vs 12.5 mo), though this did not meet significance (p = 0.21 and 0.5, respectively). There were no differences in response rate to lenalidomide/thalidomide, HMA, HMA/venetoclax (Table 1) Mutations involving SRSF2, SETBP1, IDH2, CBL, and GNAS were significantly enriched in TN disease (see table 2). U2AF1 mutations were more frequently seen in the non-TN cohort (11.2% vs 0%, p=0.032) (Table 2). Conclusion In our independent database of MF, we confirmed the unfavorable prognosis of TN-MF in terms of shorter OS and LFS. While lacking classic driver mutations, TN-MF frequently harbors mutations impacting splicing, epigenetic modification, and signaling that likely drive this aggressive clinical course, and may account for suboptimal responses to JAK inhibition. Figure 1 Figure 1. Disclosures Tinsley-Vance: Taiho: Consultancy; Jazz: Consultancy, Speakers Bureau; Astellas: Speakers Bureau; Fresenius Kabi: Consultancy; Abbvie: Honoraria; Novartis: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Sallman: 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; Incyte: Speakers Bureau; Intellia: 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; Agios: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; 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. 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; 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: ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy; Celgene/BMS: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy; BerGenBio: Consultancy; Jazz: Consultancy; Astellas: Consultancy. Padron: Stemline: Honoraria; Taiho: Honoraria; BMS: Research Funding; Blueprint: Honoraria; Incyte: Research Funding; Kura: Research Funding. 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. Komrokji: AbbVie: Consultancy; Geron: 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; Acceleron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction: Elderly fit patients (pts) with favorable risk (ELN 2017) acute myeloid leukemia (FR-AML) are traditionally treated with intensive chemotherapy (IC-most commonly 7+3) as induction treatment, based on data extrapolated from studies in pts 65 yrs) reported improved outcome (1-yr survival rate- 80%) with the combination of hypomethylating agent and venetoclax (HMA-Ven) compared to HMA alone. However, real world evidence continues to lack on efficacy and long-term outcome of intensive and non-intensive induction strategies in very elderly pts (≥70 yrs) with FR-AML, including core-binding factor (CBF)-AML. Methods: In this multicenter retrospective study, clinical, demographic, and genomic data were collected by review of records of pts aged ≥70 yrs with FR-AML (ELN 2017), treated at Moffitt Cancer Center, University of Colorado, Yale Cancer Center, and University of Miami. Patients who received IC, HMA-Ven, or HMA alone as induction treatment were included in the final analyses. Survival estimates using Kaplan-Meier statistics and multivariate analysis with Cox regression were performed in SPSS (v.26). Results: Out of 101 pts included in our study, 45 (45%) received IC, whereas induction regimens were HMA-Ven in 32 (32%) and HMA alone in 24 (24%) pts [Table 1]. Median age at diagnosis was 74 yrs (range 70-92); pts receiving HMA or HMA-Ven were older (p=0.005) than those on IC. Majority of pts were white (90%), and gender was distributed equally. A performance status (PS) of ECOG ≥2 was noted in 18% pts. Abnormalities in CBF were detected in 29% of pts overall (more commonly in IC group), and 26% had secondary AML. Median bone marrow blast counts were comparable across three groups. No significant difference was observed among groups in frequencies of NPM1, CEBPA, IDH1, IDH2, and FLT3-ITD mutations. Median duration of follow up was 31.7 months (mo). Among evaluable pts (n=95), the composite complete remission [cCR- CR + CR with incomplete count recovery (CRi)] rate was significantly better in pts on HMA-Ven, compared to IC (97% vs. 66%, p= 0.002) or HMA alone [Table 2]. CR was noted in 20 (69%) pts receiving HMA-Ven vs. 22 (50%) with IC- based induction (p= 0.237). Overall, 10 (10%) pts died within 30 days of induction, with a trend for higher 30-day and 60-day mortality (18%) with IC (p=0.059). In our study, 34% pts relapsed, with similar early (12 mo) relapse rates across groups. In pts achieving a CR or CRi, median relapse free survival was 7.93 mo, with no significant difference between cohorts. Total 9 pts (IC-8, HMA-Ven-1), including 3 with relapsed AML, underwent allogeneic stem cell transplant (allo-SCT). Median overall survival (mOS) was 25.5 mo in pts with CBF-AML (n=29) and 16.5 mo in NPM1-mutant (n= 67) cohort. Patients on IC had significantly improved mOS than those on HMA alone (24.7 vs. 14.3 mo, p= 0.008, Figure 1); however, it was not an independent predictor in multivariate analysis after adjusting for age, PS, and allo-SCT. No significant mOS difference was observed between pts treated with IC and HMA-Ven as induction regimen (24.7 vs. 19.6 mo, p= 0.836). Estimated 5-yr survival rate was 30% with HMA-Ven, 22% with IC, and 4% with HMA. In pts with NPM1-mutant AML, mOS was not significantly different between IC and HMA-Ven groups (16.6 mo vs. 29.2 mo, p= 0.364). In CBF-AML, mOS was not reached in pts on IC vs. 7.27 mo in HMA-Ven group (p= 0.076). Conclusions: Induction treatment with HMA-Ven led to a significantly high cCR rate (97%) in elderly (≥ 70 yrs) pts with FR-AML. There was no significant difference in mOS in pts treated with IC and HMA-Ven, both overall and in NPM1-mutant cohort. Among pts with CBF-AML, mOS was not reached in IC group, with a 5-year survival rate of 47%, although small sample size in the HMA-Ven group limits inference from this comparison. NPM-1 mutant elderly FR-AML pts can be treated with HMA-Ven regimen, whereas elderly pts with CBF-AML should be treated with IC if fit, until further data with HMA-Ven combination is available. Figure 1 Figure 1. Disclosures Sallman: Novartis: Consultancy, 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; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Magenta: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; 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; Takeda: Consultancy; Incyte: Speakers Bureau. Padron: Stemline: Honoraria; BMS: Research Funding; Incyte: Research Funding; Taiho: Honoraria; Kura: Research Funding; Blueprint: Honoraria. 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; 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; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; BerGenBio: Consultancy; Agios: Consultancy; Celgene/BMS: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Jazz: Consultancy; ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy. Watts: Takeda: Consultancy, Research Funding; Genentech: Consultancy; Rafael Pharma: Consultancy; Celgene/BMS: Consultancy. Pollyea: AbbVie: Consultancy, Research Funding; Syndax: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Agios: Consultancy; Glycomimetics: Other. Zeidan: Genentech: Consultancy; Daiichi Sankyo: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Jazz: Consultancy; Amgen: Consultancy, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; Geron: Other: Clinical Trial Committees; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Agios: Consultancy; Epizyme: Consultancy; Jasper: Consultancy; BioCryst: Other: Clinical Trial Committees; Janssen: Consultancy; AstraZeneca: Consultancy; Aprea: Consultancy, Research Funding; BeyondSpring: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Astex: Research Funding; Astellas: Consultancy; Ionis: Consultancy; Incyte: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Acceleron: Consultancy, Research Funding; ADC Therapeutics: Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Komrokji: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; Geron: Consultancy; 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; AbbVie: Consultancy.

Background Primary myelofibrosis (PMF) is the most aggressive subtype among classical BCR-ABL1 negative myeloproliferative neoplasms (MPN). Driven by constitutive activation of the JAK/STAT pathway, its prognosis is defined by cardinal clinical, cytogenetic and molecular features. While most patients require therapy for symptomatic splenomegaly, disease-related symptoms, or cytopenias, asymptomatic lower-risk patients may be appropriately monitored with active surveillance. The aim of this study was to explore disease characteristics and outcomes among pts who remained on prolonged active surveillance compared to those who received early treatment. Methods We identified patients with confirmed MF (inclusive of primary MF and MF occurring after essential thrombocythemia or polycythemia vera) treated at Moffitt Cancer Center between 2003-2021. Patients were stratified into two cohorts: those remaining on active surveillance for ≥ 36 months following diagnosis and those who received within 36 months of diagnosis. Results Between August 2000 and March 2021, we identified 626 patients with a diagnosis of MF. Among these, 48 (8%) did not receive treatment for at least 3 years. Table 1 summarizes the baseline characteristics comparing those pts who remained on active surveillance for ≥ 36 months (LTO-MF) to those who received treatment within 36 months of diagnosis (ET-MF). The LTO cohort presented at a younger age (median age 63 vs 68; p = 0.001), but otherwise demographic variables were balanced between the two cohorts. LTO patients were more likely to have primary MF (85.4% vs 60.9%, p=0.003). LTO patients were less likely to have leukocytosis (28.2% vs 49.9%, p=0.01), and constitutional symptoms (29.8% vs 44.6%, p=0.05), while having a higher reticulocyte percentage (81.4% vs 64.1%, p=0.02). LTO patients also had lower platelet counts (mean: 274k vs 359k, p=0.006), lower percentage of circulating blasts (0.4% vs 1.2%, p Interestingly, the cohorts were well-balanced in terms of risk score based across all major prognostic scoring systems: IPSS (p=0.356), DIPSS (p=0.764), DIPSS+ (p=0.148), GIPSS (p=0.125), MIPSS70 (p=0.924) and MIPSS70+ (p=0.407). There was no association between GPSS karyotype risk and need to start treatment earlier (p=0.481) (Table 1). LTO patients were less likely to harbor JAK2 mutations (58.3% vs 72.4%, p=0.04). No significant differences were seen regarding CALR (p=0.144), MPL (p= 0.271), or triple-negative disease (p=0.521) (Table 2). The median OS (mOS) for the entire population was 82.5 months (95%CI 69.4-95.5). LTO patients had longer OS (mOS 170.3 mo vs 63.9 mo; (p Expectedly, time to first treatment longer for LTO patients (62.1 mo vs 0.9 mo; (p Conclusion In this single-center study of patients seen at a tertiary referral center, the vast majority of MF patient required treatment within 36 months of diagnosis. Those monitored with active surveillance were younger, had less proliferative signs/symptoms, were less likely to have JAK2 mutations, and more favorable outcomes. Figure 1 Figure 1. Disclosures Tinsley-Vance: Fresenius Kabi: Consultancy; Novartis: Consultancy; Incyte: Consultancy, Speakers Bureau; Abbvie: Honoraria; Jazz: Consultancy, Speakers Bureau; Taiho: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau; Astellas: Speakers Bureau. Sallman: Magenta: Consultancy; Takeda: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Kite: 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; 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; 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. 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; 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; AROG: Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; BerGenBio: Consultancy; ElevateBio Management: Consultancy; Celgene/BMS: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; Jazz: Consultancy. Padron: Incyte: Research Funding; BMS: Research Funding; Taiho: Honoraria; Kura: Research Funding; Blueprint: Honoraria; Stemline: Honoraria. Kuykendall: Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; BluePrint Medicines: Honoraria, Speakers Bureau; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; PharmaEssentia: Honoraria; Abbvie: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; CTI Biopharma: Honoraria. Komrokji: AbbVie: Consultancy; Geron: Consultancy; Acceleron: 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; 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.

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.

Context: Real-world evidence is lacking regarding the effectiveness of intensive and non-intensive induction strategies in elderly patients with favorable-risk acute myeloid leukemia (AML). Objectives: To estimate the rates of complete remission (CR), CR+ CR with incomplete count recovery (CRi), and overall survival (OS) in patients receiving intensive chemotherapy (IC) and hypomethylating agent (HMA)-based induction regimens. Design: In this retrospective study, clinical and genomic data were collected by review of records of eligible patients treated at Moffitt Cancer Center. Statistical analyses were performed using SPSS. Patients: Elderly (age > 70 years) patients with newly diagnosed, favorable-risk (ELN 2017) AML. Main Outcomes Measures: CR, CR+ CRi, OS. Results: Out of total 53 patients, 36 (68%) received IC, and 17 (32%) received HMA-based induction regimen. Median age at diagnosis was 74 years (range 70–85). Core binding factor (CBF) abnormalities were detected in 47% patients; 28% had secondary AML. Median blast count was significantly higher in patients receiving IC vs HMA (58% vs 32%, p=0.01). Predominant induction regimen was “7+3” (86%) in the IC group and azacytidine alone (n=11) in HMA cohort. Rate of composite CR (CR+ CRi) was significantly better at 69% (50% CR) in the IC group, compared to 35% (24% CR) with HMA (p=0.01). Six patients on IC and 1 on HMA had early ( Conclusions: Elderly favorable-risk AML patients had a significantly better composite CR rate on induction treatment with IC than with HMA, with a trend toward improved OS with IC-based induction. A multicenter study with a larger sample size is ongoing to address this question further.

Gastric cancer represents the fifth most common cancer diagnosis worldwide and the third leading cause of cancer-related mortality. In the USA, the overall 5-year survival rate is 31%, with distant disease nearing 5%. The most common sites of metastasis are the liver and peritoneum. Skeletal muscle involvement has been rarely reported. Since clinical and imaging findings overlap with primary sarcomas, a confirmatory biopsy is required for diagnosis. Prognosis remains poor with treatment options including palliative chemotherapy, radiotherapy and surgical resection. We report the case of a 57-year-old female presenting with extensive involvement of skeletal muscle 10 years after achieving remission. In addition to illustrating the refractoriness and poor outcomes associated with muscle involvement, this case and comprehensive review of the literature highlights important characteristics of disease biology and tumor genomics that warrant detailed discussion and exposition to a wider audience.

Kaposiform hemangioendothelioma (KHE) is a rare and locally aggressive vascular tumor with histological features resembling Kaposi sarcoma and capillary hemangioma mainly occurring in children and adolescents. Approximately 200 cases have been reported since its original description in 1993, with the vast majority presenting at an early age as raised ill-defined lesions with a red-blue hue mainly involving the skin and soft tissues in the extremities. Cases in adults remain extremely rare. Herein, we describe the case of a 29 year-old man who presented with progressive abdominal pain for 4 months and signs of obstipation found to be consistent with small bowel volvulus. The patient underwent exploratory laparotomy and resection of 55 cm of necrotic small bowel followed by enteroenterostomy and anastomosis. Microscopic examination revealed KHE involving small intestinal mesentery, muscularis propria, and submucosa. His recovery was uneventful and he was discharged after stabilization, opting to manage him expectantly with abdominopelvic imaging and to monitor for development of Kasabach-Merritt phenomenon. To our knowledge, this represents the first reported case of this entity presenting as intestinal obstruction in an adult for which we also present a review of the existing literature and possible treatment options.

Metastatic breast cancer is regarded as an incurable entity. In heavily pretreated patients with increasingly limited options for palliative management, ensuring proper quality of life continues is to be an elusive issue. With this in mind, the authors evaluated the efficacy and safety of the Vinorelbine/Capecitabine doublet (VINOCAP). The investigators retrospectively analyzed a cohort of 67 women with HER2 negative MBC treated at a large breast cancer practice and a local cancer center with Vinorelbine 22.5 mg/m2 IV on days 1 and 8 combined with Capecitabine 1 g PO BID for 14 consecutive days of 21 day cycles. Patients had been treated with an average of 4 prior lines of chemotherapy. Patient characteristics and outcomes were evaluated. A total of 67 patients received VINOCAP, and an additional 2 underwent repeat exposure yielding a cohort of 69. Clinical benefit rate, defined as complete response (CR), partial response (PR) or stable disease ≥ 6 months (SD), was 55.07%. Complete response was seen in 4.34%, PR in 18.8% and SD ≥ 6 months in 31.9%. Median progression-free survival was 6.2 months and overall survival 35.47 months after VINOCAP exposure. The most common grade 3–4 toxicity was neutropenia in 10% of cases. Dose had to be reduced in 18% of cases due to toxicity of any type. The regimen was well tolerated, and serious side effects were uncommon. Vinorelbine/Capecitabine appears to be an active and well-tolerated regimen in women with MBC. In particular, encouraging was the efficacy of VINOCAP as fourth or greater line of chemotherapy.

415 Background: Immune checkpoint inhibitors (ICI) have been approved in solid tumors with dMMR. However, only limited data are available for PDAC with dMMR given the rarity of dMMR in PDAC. We evaluated efficacy of ICIs in PDAC with dMMR. Methods: Retrospective clinical and pathologic data were collected for patients (pts) with pancreatic adenocarcinoma from May 2017 to June 2020 at Moffitt cancer center. Results: We identified 10 pts with dMMR PDAC. The median age was 64.5 years (range: 42-86) and 4 pts were male. 4 pts had resectable disease, 3 had locally advanced and 3 had metastatic disease at initial diagnosis. MSH6 deficiency (def) was found in 2 cases, PMS2 def in 2, MLH/PMS2 def in 5, and MSH2/MSH6 in 1. 7 pts were treated with ICIs. 3 pts had locally advanced and 4 had metastatic disease when they started ICIs. 5 received Pembrolizumab (pem), 1 received ipilimumab/ nivolumab (ipi/nivo), and 1 received pem then ipi/nivo after progressive disease (PD) on pem. The median number of prior lines of chemotherapy was 1 (range 0-2). 6 pts were evaluable, and 1 had rapid disease progression after 1 dose of pem. Among 6 evaluable pts, 3 had an objective response (1: complete response and 2: partial response), and 2 had stable disease (SD). Median progression-free survival was 8.2 mo, and median overall survival was not reached with median follow-up (FU) of 6.8 mo. The median duration of response was not reached with a median FU of 22.6 mo. The pt with CR remained disease-free for up to 22 months. The pt whose treatment was switched to ipi/nivo after PD on pem achieved SD > 4mo on ipi/nivo. While on immunotherapy, one patient with ipi/nivo developed immunotherapy associated rash requiring systemic steroids, and another on pem developed hypothyroidism requiring levothyroxine. Conclusions: This series suggest ICIs can provide durable clinical efficacy in pts with dMMR PDAC.

7547 Background: Allogeneic Stem Cell Transplant (alloSCT) continues to be the optimal consolidation strategy for many patients with AML; cytogenetic and molecular abnormalities are known predictors of post-transplant outcomes. There is increasing evidence that Molecular Minimal Residual Disease (MMRD) following induction has important prognostic implications and its value in the prediction of post-transplant relapse continues to be elucidated. We aim to evaluate the impact of genetics and pre-transplant MMRD on clinical outcomes following alloSCT. Methods: We retrospectively evaluated eighty-nine patients, ≥18 years with a diagnosis of AML in complete morphologic remission (i.e. < 5% BM blasts by morphologic assessment) who received alloSCT between 01/2012-05/2018 at the University of Miami and for whom cytogenetic and comprehensive molecular data was available prior to transplantation. Patients were stratified into favorable, intermediate and poor-risk categories based on 2017 ELN criteria. MMRD was defined as persistent leukemia-specific mutations prior to transplantation (i.e. NPM1, FLT3, CEBPA, IDH1-2, RUNX1 and TP53). Persistence of DTA mutations (DNMT3A, TET2 and ASXL1) was not considered MMRD, patients with unavailable cytogenetic/molecular data at diagnosis were excluded. Results: Seventy-four (83%) patients were transplanted in CR1, myeloablative conditioning was used in 72% of patients. Two-year OS and LFS were 69.4% and 78.2%, respectively. Stratification by ELN criteria resulted in prognostic separation for patients transplanted in CR1: 2-year OS for favorable (87%), intermediate (68%) and adverse risk (51%) patients (p = 0.0417). The presence of MMRD was the strongest predictor of post-transplant outcomes for the whole cohort with 2-year OS and LFS of 29.4% and 37.1% (HR 5.45 [95%CI 2.43-12.3] p = 0.0001; HR 12.4 [95%CI: 3.76 to 39.8] p = 0.0001); respectively. Subgroup analysis confirmed that MMRD was associated with significantly inferior LFS for IM/favorable and adverse risk patients (HR: 6.76 [95% CI 1.12 to 40.9], p = 0.038). Conclusions: Pre-transplant MMRD was the most important prognostic factor for relapse and survival in our cohort of AML patients undergoing alloSCT. Correlation of MMRD with other transplant variables such as conditioning intensity, MRD status by MFC and the impact of pre-emptive/therapeutic strategies in high-risk patients continues to be explored.