ALBERT

Description: In this phase 1 trial, inhibition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was associated with clinically meaningful responses in 5 of 15 patients with relapsed or refractory chronic myelomonocytic leukemia (CMML). Preliminary data suggest that this approach may be tractable in CMML bearing activating NRAS mutations.

Description: Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. Here we characterize the immunological features of the malignant clone and alterations in the immune microenvironment in TP53 mutant and wild type MDS and sAML patients. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of TP53 mutant patients, which is associated with MYC upregulation and marked down-regulation of MYC's negative regulator miR-34a, a p53 transcription target. Notably, TP53 mutant patients display significantly reduced numbers of bone marrow infiltrating OX40+ cytotoxic T-cells and helper T-cells, as well as decreased ICOS+ and 4-1BB+ NK cells. Further, highly immunosuppressive regulatory T-cells (i.e., ICOSHigh/PD-1neg) and MDSCs (PD-1low) are expanded in TP53 mutant cases. Finally, a higher proportion of bone marrow infiltrating ICOSHigh/PD-1neg Tregs is a highly significant independent predictor of overall survival. We conclude the microenvironment of TP53 mutant MDS and sAML has an immune privileged, evasive phenotype that may be a primary driver of poor outcomes, and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly-defined subpopulation.

Description: Introduction Hemolysis is a well-recognized clinical observation in a subset of myelodysplastic syndromes (MDS) patients (pts). However, the clinical consequence of hemolysis and the associated molecular phenotype in MDS is not well described in the literature. Nonimmune hemolysis in MDS is often attributed to ineffective intramedullary erythropoiesis or acquired hemoglobinopathies that have been described in rare cases of MDS. In this study, we report the prevalence of hemolysis among MDS pts, their clinical and genomic characteristics and its impact on outcomes. Methods We identified all pts in our institutional MDS database who had serum haptoglobin measured at time of diagnosis or referral. We considered serum haptoglobin 〈 10 mg/dl as a surrogate marker for intravascular hemolysis. We compared the baseline characteristics, response to treatment, and overall survival (OS) in those with hemolysis (haptoglobin 〈 10 mg/dl) to those in the non-hemolysis group. Further, we explored the mutational landscape among pts with hemolysis compared to the non-hemolysis group. Results Among 519 pts in our database with a known serum haptoglobin at first referral or diagnosis, 54 pts (10%) had serum haptoglobin 〈 10 mg/dl (the hemolysis group). The baseline characteristics were similar among the two groups except for a slightly younger age and lower platelets count in the hemolysis group. Other laboratory markers associated with hemolysis such as total bilirubin and LDH were significantly increased in the hemolysis groups. However, no difference was seen in coombs test results. Only 13% versus 9% were Coombs positive suggesting that hemolysis in MDS is typically not immune mediated (table 1). The median OS was 31 months versus 39 months among pts with hemolysis and no hemolysis respectively, (p=.98). There was a trend of inferior survival among pts with hemolysis in the low and intermediate risk revised IPSS (R-IPSS) risk groups. The median OS was 44 months with hemolysis compared to 89 months with no hemolysis in low risk R-IPSS (p=.2) and 19 months versus 34 months in intermediate risk group. (p=.7) The hematological improvement (HI) rate using erythroid stimulating agents (ESA) was 16% (3/19 pts) in the hemolysis group compared to 30% (39/130 pts) in the non-hemolysis group. (p=.2) The HI+ best response with hypomethylating agent (HMA) was 70% (22/31) compared to 45% (127/280) among hemolysis and non-hemolysis groups respectively, (p=.05). Table-2 summarizes the somatic mutations landscape between the hemolysis and non-hemolysis groups. U2AF1 and EZH2 hotspot mutations were statistically significantly more common among hemolysis group. Out of the 16 pts with U2AF1 mutations, 15 (94%) harbored a mutation at serine 34 (S34) in the hemolysis group while only 22 of 55 (40%) cases with U2AF1 mutation had an S34 hot spot mutation in the non-hemolysis group suggesting that the association between U2AF1 and hemolysis is allele specific. (p .0001) Conclusion Non immune hemolysis was observed in 10% of MDS patients. Inferior survival trends were observed among lower risk MDS patients with hemolysis. A decreased response rate to ESA and higher responses to HMA were also observed in the hemolysis group. U2AF1 mutation was observed in 30% of patients with hemolysis and occurred almost exclusively at the S34 hot spot. Our data suggest that nonimmune hemolysis is associated with allele specific somatic mutations and associated with key clinical outcomes. Future work will explore the contribution of altered splicing to these acquired hemoglobinopathies. Disclosures Komrokji: BMS: Honoraria, Speakers Bureau; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; Geron: Honoraria. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy. Padron:Novartis: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding.

Description: 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.

Description: Introduction Isocitrate dehydrogenase 2 (IDH2) is mutated in ~10% of acute myeloid leukemia (AML). However, the clonal evolution of IDH2 mutations through the course of AML has not been clearly elucidated. The presence of targeted therapy, Enasidenib, for the treatment of IDH2 mutated AML underscores the importance of understanding the clonal dynamics of IDH2 mutations. Methods IRB approval was obtained. In this study, we analyzed ~6000 patients with NGS results to identify 120 AML patients with IDH2 mutations and longitudinal next generation sequencing (NGS) testing. Disease status was determined for each NGS test date by chart review. IDH2 mutation status was chronicled for each of the following disease states: diagnosis, remission, relapse, and persistent disease. Cytogenetic risk category was based on ELN 2017 guidelines. Statistical analyses were performed using SPSS. Results Of the 120 patients, there were 62 patients (51.67%) with AML-NOS and 58 patients (48.33%) with AML with myelodysplasia-related changes (AML-MRC). The most commonly co-occurring mutated genes included DNMT3A, SRSF2, RUNX1, ASXL1, NRAS, BCOR, NPM1, STAG2, FLT3, and PHF6 in order of frequency. Concurrent IDH1 and IDH2 mutations were seen in 2 patients, although IDH1/2 mutations were previously reported to be mutually exclusive. Of the total patients with IDH2 mutations, 105 patients (88%) were IDH2-positive at the initial diagnosis and 15 patients (12%) were IDH2-negative at diagnosis and acquired the mutation later in disease. Of those 15 patients, 7 patients gained the mutation during persistent disease, 6 during relapse, and 2 at remission (neither of whom relapsed). Forty-eight patients (40%) who were IDH2-positive in a prior test were found to be IDH2-positive with persistent AML, while 11 patients (9%) with IDH2-positive AML lost the IDH2 mutation despite the presence of persistent AML. Twenty-one patients (18%) who were IDH2-positive in a prior test were found to remain IDH2-positive in remission, while 49 patients (41%) cleared the IDH2 mutation. Twenty-four patients (20%) with IDH2-positive AML were found to be IDH2-positive at disease relapse, while 7 patients (6%) lost the IDH2 mutation at relapse. Kaplan-Meier survival analysis and the log-rank test were used to analyze overall survival (OS) to control for confounding factors of AML category (AML-MRC vs AML-NOS) and cytogenetic risk (Figure 1). Patients who were IDH2-positive at diagnosis had significantly better survival than patients who gained the IDH2 mutation later in disease (Figure 1A, p=0.024). Patients who were IDH2-negative at remission had significantly improved survival compared to patients who were IDH2-positive at remission (Figure 1B, p=0.002). Patients who had lost the IDH2 mutation with persistent disease had significantly greater overall survival than those who remained IDH2-positive with persistent AML (Figure 1C, p=0.035). No significant difference in OS was found based on IDH2 mutation status at relapse. Conclusion In summary, in the largest study of IDH2 clonal dynamics to date, we found that IDH2 mutations are not stable during AML disease course and frequent genetic testing of AML patients in necessary to tailor personalized therapy. Most patients (70%) cleared IDH2 in disease remission. In those with refractory disease, 18% of IDH2+ AMLs lose IDH2. In the relapse setting, 22% of IDH2+ AML show loss of IDH2. Overall, 12% of patients gained IDH2 mutation later in disease course usually in the setting of refractory/relapsed AML. These patients, along with those who remained IDH2+ in remission and during refractory disease, fared worse than their counterparts. Thus, the longitudinal IDH2 mutation testing at different disease stages may be helpful in prognostic stratification. Figure 1 Disclosures Sallman: Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy; Celgene, Jazz Pharma: Research Funding. Padron:BMS: Research Funding; Novartis: Honoraria; Kura: Research Funding; Incyte: Research Funding. Talati:Pfizer: Honoraria; BMS: Honoraria; Astellas: Speakers Bureau; Jazz: Speakers Bureau; AbbVie: Honoraria. Hussaini:Boston Biomedical: Consultancy; Stemline: Consultancy; Adaptive: Honoraria.

Description: Background: Therapeutic options for relapse or refractory (r/r) acute myeloid leukemia (AML) and hypomethylating agent (HMA) failure higher risk myelodysplastic syndrome (MDS) pts are limited with median overall survival of 〈 6 months. Consequently, novel therapies are urgently needed. CD33 is highly expressed on most myeloid leukemia stem cells with lesser expression on normal hematopoietic stem cell populations and minimal non-hematopoietic expression making CD33 a leading target in chimeric antigen receptor therapy (CAR-T) development for myeloid malignancies. However, additional barriers of CAR-T development in myeloid malignancies include long manufacturing period, expansion of CAR-T cells and potential toxicity related to on-target, off-tumor toxicity. Scientific Rationale: Current CAR-T cells utilize viral vectors for gene transfer and subsequent lengthy ex vivo expansion at centralized manufacturing facilities, which is costly and leads to cell product that is exhausted and short lived in vivo. Time is of the essence for pts with rapidly progressing disease such as r/r AML and the prolonged interval between apheresis to product infusion with current CAR-T cell therapies can be a disadvantage. Although allogeneic "off-the-shelf" products allow for rapid administration, challenges remain with rapid rejection. Precigen has developed UltraCAR-T platform to overcome these limitations by utilizing an advanced non-viral gene delivery system and a rapid, decentralized manufacturing process. UltraCAR-T cells are manufactured overnight at medical center's cGMP facility using patient's autologous T cells and administered back to patient only one day after gene transfer with no need for ex vivo expansion. PRGN-3006 UltraCAR-T cells co-express CD33 CAR, membrane bound IL-15 (mbIL15) and a kill switch. Preclinical studies have demonstrated that the expression of the mbIL15 on UltraCAR-T cells leads to maintenance of preferred stem-like memory phenotype (TSCM). Superior efficacy of UltraCAR-T cells was demonstrated in an aggressive murine xenograft model of AML where a single administration of PRGN-3006, only one day after gene transfer, showed significantly higher expansion and persistence; effectively eliminated tumor burden; and significantly improved overall survival compared to traditional CD33 CAR-T cells lacking mbIL15 expression (Blood (2019) 134(S1): 2660). Study Design: The PRGN-3006 UltraCAR-T cells are currently being evaluated in a Phase 1/1b first-in-human dose escalation/dose expansion clinical trial (NCT03927261). The study population includes adult pts (≥ 18 years) with relapsed or refractory AML and HMA failure higher risk MDS or chronic myelomonocytic leukemia (CMML) with ≥ 5% blasts. Pts who have relapsed post allogeneic stem cell transplant are allowed if 〉 3 months out from transplant without evidence of active graft versus host disease and off immunosuppression for 6 weeks. Key inclusion criteria include an absolute lymphocyte count ≥ 0.2k/µL, KPS 〉 60%, absence of other active malignancy within 1 year of study entry, daily corticosteroid dose 〈 10mg of prednisone daily, adequate organ function and a backup allogeneic donor should bone marrow aplasia occur. Hydroxyurea is allowed for cytoreduction with cessation 3 days prior to apheresis/infusion but can be reinitiated post-infusion. To test the hypothesis that expression of mbIL15 on PRGN-3006 cells is sufficient to promote CAR-T cell expansion and persistence, study subjects will receive PRGN-3006 infusion either without prior lymphodepletion (Cohort 1) or following lymphodepleting chemotherapy (Cohort 2 with fludarabine 30mg/m2 and cyclophosphamide 500mg/m2 days -5 to -3). Up to 5 dose levels are planned in dose escalation. All subjects will be followed for adverse events, CAR-T-related toxicities, disease response and PRGN-3006 cell expansion and persistence in blood and bone marrow compartments. In addition, the mechanisms of safety and effectiveness of PRGN-3006 cells will be evaluated with correlative assays of specific immune response pathways. Currently, the study is in the dose escalation phase and has cleared the lower dose level while demonstrating successful manufacturing of UltraCAR-T cells. Additionally, multi-center expansion of the trial is in progress. Disclosures Sallman: Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy. Sweet:Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Stemline: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Talati:Astellas: Speakers Bureau; Jazz: Speakers Bureau; AbbVie: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Lankford:Precigen, Inc.: Current Employment. Chan:Precigen, Inc.: Current Employment, Current equity holder in publicly-traded company. Shah:Precigen, Inc.: Current Employment; Intrexon Corporation: Current equity holder in publicly-traded company. Padron:BMS: Research Funding; Novartis: Honoraria; Kura: Research Funding; Incyte: Research Funding. Komrokji:Novartis: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; AbbVie: Honoraria; JAZZ: Honoraria, Speakers Bureau; Incyte: Honoraria; Geron: Honoraria; BMS: Honoraria, Speakers Bureau. 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. Sabzevari:Precigen, Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Compass Therapeutics: Current equity holder in publicly-traded company. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

Description: Background: Gain of function mutations of the PTPN11 gene encoding SHP2 tyrosine phosphtase are commonly seen in juvenile myelomonocytic leukemia and rarely observed in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In AML, PTPN11 mutation (mt) is associated with poor outcomes (Alfayez et al. Leukemia 2020). However, PTPN11 is not well characterized in other myeloid malignancies. Patients and Methods: Between 2013 and 2019, all pts with myeloid malignancies and PTPN11 mt at Moffitt Cancer Center were identified with clinical variables obtained at time of diagnosis. Newly diagnosed and previously treated patients (pts) were included. Overall survival was calculated from time of PTPN11 detection by next generation sequencing. Results: We identified 78 PTPN11-mt pts, AML (56), MDS (14), MDS/MPN (4) and PMF (4). The majority (63%) of PTPN11-mt were detected at time of diagnosis. Median age was 68 years. Cytogenetics included normal (49%), complex (15%), chr. 7(19%) and chr. 5 (8%) abnormalities. Co-mutations observed in 〉10% were DNMT3A, NPM1, TET2, ASXL1, RUNX1, BCOR, FLT3 ITD, U2AF1, NRAS and SRSF2. In multivariate analysis including age, karyotype category and allogeneic hematopoietic stem cell transplant (AHSCT), U2AF1 was an independent covariate for inferior survival (HR 3.9 p=0.001). In newly diagnosed PTPN11-mt pts, PTPN11 VAF 〉20% was associated with worse outcomes (OS 8.9 vs 20.5mo p=0.043). AHSCT, which occurred 30% of pts, (n=23) was associated with improved OS (24.4 vs 5.5mo p

Description: Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is shown to be associated with dismal clinical outcomes and there remains a pressing need for new therapeutic strategies to improve survival outcomes. It is also important to identify targetable markers that could predict an earlier AML transformation from preexisting MDS. Our recent studies demonstrated that high expression level of MYC oncoprotein is associated inferior survival outcome in AML-MRC patients and that MYC plays an oncogenic role by epigenetic regulation of hydroxylation of 5-methylcytosine. However, the role of MYC in MDS to AML progression remain to be answered. Here, we investigated MYC protein expression levels in bone marrow (BM) specimens of patients with preexisting MDS and their subsequent AML-MRC specimens to determine whether increased MYC expression is associated with early AML progression. We retrospectively identified 32 patients with histologically confirmed AML-MRC evolving from MDS and evaluated MYC protein levels in BM biopsy specimens at the time of initial MDS diagnosis and at the time of disease transformation to AML-MRC, respectively. Clinical data including age at diagnosis, gender, CBC with differential count, cytogenetics, somatic mutations common in myeloid disease, blasts count, and IPSS were extracted at the time of MDS and AML-MRC diagnosis. MYC expression was assessed by immunohistochemistry on 4-5µm tissue sections. Deparaffinized slides were stained with anti-MYC antibody (clone Y69, Roche Diagnostics) using a Ventana Benchmark automated system. MYC expression was scored independently by two hematopathologists and categorized as low vs. high as previously described. The cut-off for high MYC expression is ≥5% positive cells. The MDS-to-AML progression free survival (PFS) and overall survival (OS) were calculated from the date of MDS diagnosis and outcomes were estimated with the Kaplan-Meier method and compared using the log-rank test. All statistical analyses were performed using SPSS v24.0. Among 32 patients, 69% (n=22) and 31% (n=10) patients had low and high MYC expression at MDS diagnosis (Table 1). The median age was 67.9 (33.5-78.7) and 61.1 (38.9-73.4) and the % of MYC positive blasts were 1% (range, 0-4.5) and 17.5% (range, 5-27.5) in low and high MYC groups, respectively, at the time of MDS diagnosis. There was no statistical difference in BM blast counts between low vs. high MYC groups (median 5% vs. 7.5%, p=0.4951). IPSS risk assessment in a total of 26 patients (19 in low MYC and 7 in high MYC) showed that 9% (n=2), 27% (n=6), 32% (n=7), and 18% (n=4) in low MYC group and 0% (n=0), 20% (n=2), 20% (n=2), and 30% (n=3) in high MYC groups had low, intermediate-I, intermediate-II, and high risk at the time of MDS diagnosis (Table 1). A total of 84% (86% [n=19] in low MYC and 80% [n=8] in high MYC) patients received treatments for MDS; ESA in 16% (n=5), hypomethylating agents in 81% (n=26), and Revlimid in 16% (n=5) (Table 1). Allogeneic stem cell transplant (allo-SCT) was performed in 12.5% (n=4) patients (n=3, low MYC; n=1, high MYC). Following AML progression, a total of 91% (n=29) patients received treatment for AML including induction chemotherapy (n=18), hypomethylating agents (n=7), and other therapies including trial (n=4) (Table 1). In the univariate analyses, patients with low MYC expression had significantly longer MDS-to-AML PFS (median 15.8 vs. 7.25 months, HR=0.1745, 95%CI=0.0591-0.5157, p=0.0016) (Figure 1), however, there was no OS difference between two groups (4.32 vs. 2.35 years, HR=0.5131, 95%CI=0.1064-2.475, p=0.6909). In a multivariate Cox model (adjusting for IPSS, age, front-line therapy, gender, allo-SCT, and MYC level), high MYC expression (HR=3.939, 95%CI=1.107-14.012, p=0.034) and IPSS risk (HR=1.903, 95%CI=1.139-3.181, p=0.014) were significant factor for MDS-to-AML PFS. In conclusion, high MYC expression at the MDS stage was associated with shorter time to AML progression, indicating that MYC plays an oncogenic role in MDS to AML transformation. Although our findings need further validation by prospective studies with greater sample size, our results support a combination treatment of hypomethylating agents with novel agents targeting MYC or/and its downstream pathways and warrant further study to identify underlying mechanisms of MYC-driven MDS to AML progression. Disclosures Talati: Pfizer: Honoraria; Astellas: Speakers Bureau; Jazz: Speakers Bureau; BMS: Honoraria; AbbVie: Honoraria. Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Padron:Novartis: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding. Komrokji:JAZZ: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria; Incyte: Honoraria; Acceleron: Honoraria; Geron: Honoraria; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau. 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. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy.

Description: Background: Checkpoint inhibitors, for example anti-PD-1 antibodies (e.g. nivolumab and pembrolizumab) and anti-CTLA-4 antibodies (e.g. ipilimumab), have changed the paradigm of many solid tumors although in myeloid malignancies responses have been low. Additionally, checkpoint inhibitors have a distinct toxicity profile collectively named immune-related adverse events (irAE) with unclear characterization in myeloid malignancies. Data is limited regarding predictors of irAEs and response to immunotherapy in myeloid malignancies. As we move forward in the era of immunotherapeutic agents in myeloid malignancies, better understanding of predictive biomarkers for toxicity and response is critical. Patients and Methods: Between 2015 and 2019, patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) who had been treated with checkpoint inhibitors at Moffitt Cancer Center were identified. Clinical and lab variables were obtained at date of first immunotherapy infusion. Baseline characteristics were compared using Fisher's exact test (categorical) and Mann-Whitney test (continuous). Survival estimates were calculated from date of first immunotherapy infusion. Patients receiving post induction maintenance (6) were excluded for survival analysis. Results: A total of 28 patients, 12 MDS and 16 AML, undergoing single or combined checkpoint inhibitor therapy with either PD-1, PD-L1, or CTLA-4 targeting agents were identified. 27 patients were evaluable for irAEs. In total, 10 irAEs occurred across 7 pts with all pts having at least 1 Grade 3 event (26%). The grade 3 or higher irAEs consisted of 4 severe skin reactions (15%), 3 hepatitis (11%), and 1 immune thrombocytopenia (4%). The only other irAE noted was grade 2 hypothyroidism in patient with hepatitis. Baseline characteristics between patients with irAEs vs without were reviewed (see table 1). Patients with irAEs appeared to have a lower neutrophil/lymphocyte (N/L) ratio (0.6 vs 1.5 p=0.116) and higher bone marrow blast % (12% vs 5% p=0.341). 0 of the patients that received immunotherapy as post induction maintenance had an irAE, compared to 33% (7/21) of non-maintenance patients. Interestingly, patients with a higher number of mutations were significantly more likely to experience irAE than those with a lower mutation burden (4 vs 1 in irAE pts vs not p=0.021). 57% of patients who received immunotherapy post bone marrow transplant (BMT) experienced an irAE, compared to 15% in the non-BMT group (p=0.050). We then looked at potential predictors of response in the 19 evaluable patients. In total, ORR was 21% (1CR, 2Cri and 1 marrow CR). ORR +SD rate was 63%. Patients with response or stable disease (SD) following immunotherapy had a trend for lower median WBC count (1.8 vs 4.6 p=0.179) and higher platelet counts (46 vs 18 p=0.151) at baseline. Also, a higher number of total mutations was seen in response/SD patients (3 v 2 p=0.148) however this was also not significant due to sample size. In MDS patients, ORR and response/SD rate was 33% and 100% in irAE patients vs 0% and 43% in patients that lacked irAE (p=0.3 and p=0.2). There was no significant difference in ORR (33% vs 20%) or response/SD rate (60% vs 67%) in AML patients with and without irAEs. Of the patients with response to immunotherapy, 50% (2/4) harbored a TP53 mutation. Finally, we evaluated impact of clinical and mutational factors on PFS and OS. Patients who experienced irAEs had a longer PFS compared to patients who did not; however this was not significant (5.6 vs 2.1 mo. p=0.280). OS was similar between groups (p=0.789). In MDS patients, having an irAE was associated with a statically significant improvement in PFS (9.4 vs 1.1 mo. p=0.012). Total number of mutations did not impact PFS or OS. On univariate analysis in total cohort, lower WBC and ANC were both significant independent positive predictors of PFS (p=0.032 and 0.022). On multivariate with age, disease type and BMT, low ANC only was an independent predictor of improved PFS (p=0.022). Conclusions: In conclusion, patients with higher number of mutations and who received checkpoint inhibitors post-BMT were significantly more likely to experience an irAE. In MDS patients, patients who had an irAE had a significantly longer PFS compared to those who did not. Further studies are needed to better understand clinical predictors of irAE and response rates in patients with myeloid malignancies undergoing immunotherapy. Table Disclosures Padron: Incyte: Research Funding; Kura: Research Funding; Novartis: Honoraria; BMS: Research Funding. Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Talati:AbbVie: Honoraria; Jazz: Speakers Bureau; Astellas: Speakers Bureau; BMS: Honoraria; Pfizer: Honoraria. Sweet:Stemline: Honoraria; Incyte: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria. 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:Geron: Honoraria; Jazz: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Agios: Speakers Bureau; Abbvie: Honoraria; Incyte: Honoraria; Acceleron: Honoraria; Novartis: Honoraria. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy.