Citations

Abstract Background: DDX41 gene is located on chromosome 5q35 and is believed to be a tumor suppressor gene involved in splicing of mRNA. Mutated DDX41 have been identified as germline mutation (m) in families with cases of myeloid neoplasm and have shown to cause acquisition of other somatic mutations resulting in MDS/AML. At the same time, somatic pathogenic DDX41 mutations are known to occur. Variant of unknown significance (VUS) is an intermediate tier between benign and pathogenic (path) mutations (hence uncertain) and can be re-classified based on their clinical impact. In this report we analyzed the clinical impact and relevance of DDX41VUS in patients (pts) being evaluated for myeloid disorders. Methods: We reviewed 4,524 consecutive pts who underwent NGS (MC OncoHeme 42 genes panel) testing between 2018 and 2021 performed on cases of suspected or known myeloid disorders. We identified 58 (1%) consecutive pts with DDX41VUS, among them one pt had proven concurrent DDX41 germline VUS and 7 pts with DDX41VUS had concurrent DDX41path mutation. We analyze clinical characteristics of pts with DDX41VUS and compared it with cohort of 32 DDX41path mutated pts. Results: Baseline characteristics are summarized in Table 1, and Figure 1 illustrates DDX41VUS per case with variant allele frequency (VAF) and observed concurrent mutations. The median VAF for DDX41 VUS was 48 % (range, 14-91%). Co-mutations were found in 14 (28%) pts with VUS, and the reminder (n=44, 72 %) had isolated DDX41VUS. Among them AML (16 [32%]), MDS (14 [28%]), cytopenia (14 [28%]) MPN (3 [6%]), CNL (1 [2%]) and aplastic anemia (1 [2%]) were the commonly occurring myeloid disorder (Table 1, Figure 1). Eleven of 14 pts with isolated cytopenia had isolated DDX41VUS. Conversely, among 15 evaluable pts with isolated DDX41VUS, 13 (87%) pts had normal cytogenetics and 40% of pts had family history of solid or hematological malignancies. We observed a significant difference in hematologic diagnoses: DDX41VUS patients were significantly less often diagnosed with MDS or CCUS, and more often associated with cytopenias NOS. Recurrent, non-random DDX41VUS sequences were observed; most frequent occurring amino acid change among the 58 pts were Gly173Arg (n=6), Met155lle (n=5), Pro258Leu (n=3) Arg479Gln (n=3), Val303Met (n=2), Lys331del (n=2), Arg479His (n=2) and Tyr33His (n=2) (Figure 1). 5 of 6 pts with Gly173Arg had isolated DDX41VUS, and among them 4 were diagnosed with MDS suggesting this could be a clonal event, and possible driver mutation, notable in Figure 1. The median overall survival (OS) of pts with high risk MDS/AML harboring DDX41VUS was not reached (60% alive at 2 years). Between pts with DDX41path and DDX41VUS, proportion of pts with co-mutations (p >0.99), cytogenetic abnormalities (p >0.99), family history of malignancies (p 0.52), time to treatment (p >0.99), MDS progression to AML (p 0.36) and OS (among high risk MDS/AML pts) (p 0.55) was not significantly different, suggesting that phenotypic features of DDX41VUS are similar to DDX41path , and that both carry a similar, more indolent prognosis (Table 1). Conclusion: Our reports demonstrated that DDX41VUS occurs in 1% of patients with myeloid disorders and shares distinct diagnostic features but comparable prognostic features vs. DDX41path, including family history of hematological malignancies. It is possible that many of the cases with 'cytopenias' and DDX41VUS would meet criteria for CCUS if the variant was isolated classified as pathogenic, confirming the importance of extending our understanding of DDX41 variants. Further analysis to characterize the biological impact of DDX41VUS is underway. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Litzow: Astellas: Research Funding; Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Pluristem: Research Funding; Amgen: Research Funding; Biosight: Other: Data monitoring committee; Actinium: Research Funding; AbbVie: Research Funding. Foran: boehringer ingelheim: Research Funding; abbvie: Research Funding; takeda: Research Funding; trillium: Research Funding; revolution medicine: Honoraria; bms: Honoraria; servier: Honoraria; novartis: Honoraria; pfizer: Honoraria; aptose: Research Funding; taiho: Honoraria; certara: Honoraria; sanofi aventis: Honoraria; syros: Honoraria; actinium: Research Funding; gamida: Honoraria; OncLive: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

Abstract Background: The DEAD-box helicase 41 (DDX41), an RNA helicase, have been described as a component of the RNA spliceosome (Cheah et al. International Journal of Hematology 2017). Although DDX41 mutations predispose to late-onset higher grade myeloid neoplasms (MN), these patients may have a trend toward favorable prognosis and outcomes. In this work, we describe the clinical characteristics and survival outcomes of isolated and co-mutated DDX41 patients (pts). Methods: We retrospectively analyzed 4,524 consecutive pts who underwent next-generation sequencing (NGS) (OncoHeme 42 genes panel, Mayo Clinic) testing and included 32 pts harboring pathogenic DDX41 mutation and one pt with proven DDX41 germline variant of unknown significance (VUS). Chart review of DDX41-mutated (m) cases between 2009 and 2021 was conducted after IRB approval. We compared overall survival (OS) of unmatched 27 t(8;21)AML and 40 inv(16) AML pts with 10 m DDX41-AML pts. JMP® Pro 14.1.0 Software was used for statistical analysis. Results: DDX41 mutations characteristics: Our cohort included 19 (58%) myelodysplastic syndromes (MDS), 10 (30%) acute myelogenous leukemia (AML), 2 (6%) myeloproliferative neoplasms (MPN), one clonal cytopenia of undetermined significance (CCUS) (3%) and one (3%) germline carrier. Germline testing was carried out in 10 pts, 9 of whom (90%) were confirmed to be germline). The start-loss variant (p.M1I) was the most common mutation type (N=10, 31%). Other types were frameshift (N=9, 28%), missense mutation (N=8, 25%), nonsense (N=3, 9%), and splice site mutation (N=2, 2%). Twenty-one (65.6%) DDX41 mutations clustered in the N-terminus (NT), 7 (22%) in the helicase-C domain (HCD), and 4 (12.5%) in the DEAD-box domain. Compared to NT mutations, patients with HCD mutation had no family history of solid tumors and were more likely to have an accompanying additional DDX41-VUS (0% vs 70%; p=.001) and (N=6, 86% vs. N=2,10%; p=.0001); respectively. I solated vs. co-mutated DDX41: Twenty (60%) pts were isolated-DDX41 and 13 (40%) were co-mutated. The median DDX41-VAF was 48% vs. 45% (p= .2) in the isolated compared to the co-mutated cases, respectively. The median number of co-mutations in the 13 co-mutated cases was 1 (range,1-3) with DNMT3A (38%), ASXL1 (30%), JAK2 (N=3, 23%), and EZH2 (N=2, 15%) were the most common co-mutations detected. Isolated DDX41 had more males (85% vs. 54%, p=.05), the p.M1I variant (47% vs. 8%, p=.02), normal cytogenetics (100% vs. 91%, p= .02), and less family history of solid tumors (77% vs. 33%, p= .02) compared to their co-mutated counterparts. However, there was no difference in OS (p=.99). Comparison of clinical characteristics and hematological features of isolated and co-mutated DDX41 pts are reported in (Table 1). Treatment and survival outcomes in DDX41-MDS/AML : Twenty-three (80%) patients were treated, MDS pts received hypomethylating agents (HMA) (N=10, 71%), HMA plus Venetoclax (HMA+VEN) (N=1, 7%), erythropoiesis-stimulating agents (N=2, 14%) and lenalidomide (N=1 ,7%). AML pts were treated with induction chemotherapy (N=6, 67%) and HMA+VEN (N=3, 33%). Overall response rate of MDS/AML patients was 77% and 100% of AML pts achieved complete remission (CR) when treated with induction chemotherapy or HMA+VEN regimen. There was no significant difference in OS between responders vs. non-responders 2-yr-OS (90% vs. 50%; p=.38) and treated vs. untreated 2-yr-OS (83% vs. 100%; p=.52). Comparing m DDX41-AML vs. core binding factor-AML: After a median follow-up of 33.3 months, all m DDX41-AML patients were alive. There was a significantly better OS in mDDX41-AML patients compared to pts with t(8;21) AML with 2-yr-OS (100% vs. 51%; p=.024) and a trend of better survival when compared to inv(16) AML 2-yr-OS (100% vs. 84%; p=.2). Conclusion We describe the characteristics and outcomes of m DDX41 patients. We demonstrated that isolated and co-mutated m DDX41 patients have different features. Isolated DDX41 patients had male predominance, more p.M1I variant, normal cytogenetics and less family history of solid tumors. In this study we found that m DDX41 AML has high response to treatment and has comparable (if not possibly better) OS compared to other "favorable risk" AML. This study, although limited by the small number of patients, supports the universal testing for DDX41 mutation in adults with MN diagnosis. Figure 1 Figure 1. Disclosures Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Foran: abbvie: Research Funding; OncLive: Honoraria; boehringer ingelheim: Research Funding; trillium: Research Funding; pfizer: Honoraria; takeda: Research Funding; revolution medicine: Honoraria; bms: Honoraria; gamida: Honoraria; actinium: Research Funding; aptose: Research Funding; novartis: Honoraria; servier: Honoraria; taiho: Honoraria; syros: Honoraria; sanofi aventis: Honoraria; certara: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Salama: Mayo Clinic: Current Employment, Other: Mayo Clinic had the contractual work for the central pathology review for this study and I was one of the reviewing pathologists; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Litzow: Astellas: Research Funding; Biosight: Other: Data monitoring committee; Amgen: Research Funding; AbbVie: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board. Patnaik: Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Allogeneic stem cell transplantation (allo-SCT) can be curative for patients with hematologic malignancies. Despite optimization of supportive measures, the risk of non-relapse mortality is a particularly important consideration in older individuals. Sarcopenia, defined as low skeletal muscle mass, has been shown to be associated with decreased overall survival in cancer patients and may identify individuals at higher risk of treatment-related complications. Methods: Using Mayo Clinic Arizona's hematopoietic stem cell transplantation database, patients aged 60 years or older who underwent allo-SCT between 2008 and 2018 were identified. Patients who underwent abdominal computed tomography (CT) at our institution within 90 days prior to their transplant date were included in the study. The skeletal muscle area (SMA) was obtained using a fully automated algorithm for segmenting abdominal CT images to quantify body composition based on a deep learning approach (Weston et al., Radiology, 2019). The skeletal muscle index (SMI) was then calculated using the SMA and the subject's height at the time the CT was obtained. Sarcopenia was defined based on previously described consensus (Cruz-Jentoft et al., Age Ageing, 2010; Magudia et al., Radiology, 2021). T-tests and Fisher's exact tests compared patient characteristics between groups, where appropriate. Kaplan-Meier methods were used to construct survival times. Log-rank tests compared survival distributions and Cox proportional hazards models estimated hazard ratios. Results: A total of 79 patients met inclusion criteria (Table 1). Of these, 50 (63%, n=50/79) had sarcopenia, and 29 (37%, n=29/79) had normal skeletal muscle mass. Among the sarcopenia group, 43 (86%, n=43/50) had SMI measurements. No differences were seen between groups in age at transplant, sex, Karnofsky performance scale, disease risk index, or conditioning regimen intent. There was no statistically significant difference in overall survival between those with sarcopenia and those with normal skeletal muscle mass (log-rank p=0.18). Median survival was 3.3 years (95% CI: 0.8, not estimable (NE)) for those with sarcopenia and 3.6 years (95% CI: 1.3, NE) for those with normal skeletal muscle mass. Given the infrequency of events, the upper bounds of the median survival confidence intervals were not estimable. The unadjusted hazard ratio (HR) for sarcopenia versus normal skeletal muscle mass was 1.65 (95% CI: 0.79, 3.47; p=0.18). Males had a higher mean SMI than females, as expected (50.4 versus 37.5, p<0.001; mean difference 13.0, 95% CI: 8.9, 17.1). Without considering sex, higher or lower SMI was not associated with survival time in a Cox model in those with sarcopenia (HR: 0.97, 95% CI: 0.92, 1.03; p=0.32). Sex alone was also not associated with any survival benefit among these 43 patients. After adjusting for the difference seen in SMI between sexes, on average, those with higher SMI were associated with a survival benefit (HR: 0.92, 95% CI: 0.84, 0.99; p=0.039). This amounts to roughly an 8% reduction in hazard rate as SMI increased. Conclusions: The presence of sarcopenia alone was not associated with overall survival in patients 60 years and older undergoing allo-SCT for hematologic malignancy. Rating sarcopenia severity using SMI may assist in identifying high risk individuals with sarcopenia as lower sarcopenia severity was associated with improved overall survival. Further studies are warranted to explore the possible impacts of interventions directed at improving skeletal muscle mass on transplant-related outcomes. Figure 1 Figure 1. Disclosures Gaulin: DeciBio: Honoraria; Olson Research Group: Honoraria. Jain: CareDx: Other: for advisory board participation; CTI Biopharma: Research Funding; Syneos Health: Research Funding; Bristol Myers Squibb: Other: for advisory board participation; Targeted Healthcare Communications: Consultancy. Palmer: PharmaEssentia: Research Funding; Incyte: Research Funding; Sierra Oncology: Consultancy, Research Funding; CTI BioPharma: Consultancy, Research Funding; Protagonist: Consultancy, Research Funding.

SummaryWe report a comparative analysis of patients with therapy‐related acute lymphoblastic leukaemia (tr‐ALL) vs de novo ALL. We identified 331 patients with B‐ALL; 69 (21%) were classified as tr‐ALL. The most common prior malignancies were breast (23·2%) and plasma cell disorders (20·3%). Patients with tr‐ALL were older (median 63·2 vs. 46·2 years, P < 0.001), more often female (66·7% vs. 43·5%, P < 0·001), and more likely to have hypodiploid cytogenetics (18·8% vs. 5·0%, P < 0·001). In multivariable analysis, patients with tr‐ALL were less likely to achieve complete remission [odds ratio (OR) = 0·16, P < 0·001] and more likely to be minimal residual disease‐positive (OR = 4·86, P = 0·01) but had similar OS after diagnosis and allo‐haematopoietic cell transplantation.

Abstract DDX41 mutations (germline and somatic) are associated with late onset myelodysplastic syndromes/acute myeloid leukemia (MDS/AML). Myeloid neoplasms (MN) with germline predisposition was identified as a distinct category in the 2016 WHO classification revision, including MN with germline DDX41 mutation. We retrospectively analyzed the molecular findings and clinical characteristics of thirty-three DDX41-mutated (mDDX41) patients at our institution. We identified 14 distinct pathogenic DDX41 variants in 32 patients and 8 DDX41 variants of unknown significance (VUS) in 9 patients. Five (16%) patients had a second DDX41 somatic mutation p.R525H and 13 (40%) had at least one additional oncogenic co-mutation in other genes. The median age at the time of diagnosis was 66 years, with male predominance (72%) and the majority of patients had normal cytogenetics (91%). Two-year overall survival (OS) was 86% and 6 (21%) MDS/AML patients with relatively preserved hematopoietic function were observed without further intervention. In comparison to AML patients with prognostically more favorable subtypes [t(8;21), n=27 and inv(16), n=40], mDDX41 patients in our cohort showed similarly favorable OS. Our study highlights that mDDX41-MN patients often have an indolent course and mDDX41-AML has comparable OS to favorable-risk AML.

e19023 Background: Acute GVHD (aGVHD) is a major cause of mortality and morbidity following stem cell transplantation (HCT). In effort to prognostic patients with aGVHD, the Mount Sinai Acute GVHD International Consortium (MAGIC) combined two biomarkers, ST2 and REG3α to generate an algorithm known as the Ann Arbor (AA) biomarker risk. This is now available as a commercial test to help predict risk for severe acute GVHD and non-relapse mortality when done at the onset of symptomatic aGVHD. Our institution began utilizing these lab values and here we report our “real world” experience. The primary aim was to correlate AA risk probabilities with recently defined endpoints including day 28 overall response rate (ORR) and 6 month freedom from treatment failure (6mFFTF) and overall survival (OS). Methods: 58 HCT patients who underwent HCT between October 2018 and November 2019 and had the biomarker assay at the onset of aGVHD were identified from the institutional database and clinical information about disease, transplant and outcomes was obtained from the medical records. Clinical staging of aGVHD was documented per standardized published guidelines. Day 28 ORR was defined as complete response by day 28. 6mFFTF was defined as a patient being alive, without relapse of underlying disease or addition of new systemic therapy for aGVHD, and prior to the development of cGVHD. Results: When comparing low (n = 39), intermediate (n = 11), and high (n = 8) AA risk, there was no difference in age ( p =0.254), primary disease ( p =0.10), DRI ( p =0.994), donor source ( p =0.193), conditioning regimen intent ( p =0.537), GVHD prophylaxis ( p =0.351) ATG use ( p =0.06). Low AA risk was associated with lower grades of aGVHD at onset (grade I = 15%, grade II = 80%, grade III = 5%, grade IV = 0%), whereas high AA risk was associated with higher grades of aGVHD at onset (grade I = 0%, grade II = 50%, grade III = 25%, grade IV = 25%) ( p =0.009). For low, intermediate, and high AA risk the day 28 ORR was 69%, 45% and 29% ( p = 0.083); the 6mFFTF was 82%, 82%, and 25% ( p = 0.0001); 6 month OS was 92%, 100%, and 50% ( p = 0.0006) respectively. Conclusions: Our study shows a high correlation between AA risk and outcomes. High risk AA risk was associated with inferior outcomes This study was limited by the retrospective single institutional experience with relatively small numbers. However, our findings using the commercial assay mirror that seen with the MAGIC studies. Our “real world data” can serve as a foundation and continued validation for institutional implementation of AA risk stratification for aGVHD.

7022 Background: Philadelphia-like Acute Lymphoblastic Leukemia (Ph-like ALL) is a high-risk subset of adult ALL. Until recently, there has not been a systematic platform to recognize this entity in clinical practice. Furthermore, data regarding the role of allogeneic hematopoietic cell transplantation (allo-HCT) is lacking. We conducted this study to identify patients with Ph-like ALL and describe their outcomes in comparison to Ph+ and Ph- ALL with emphasis on the role of allo-HCT. Methods: To identify cases of Ph-like ALL, available diagnostic cytogenetic pellets for patients in the Mayo Clinic ALL cohort (N=365) were tested using a targeted fluorescence in situ hybridization (FISH) panel developed by the Mayo Clinic Genomics Laboratory and includes probes to detect Ph-like-specific rearrangements (i.e., ABL1, ABL2, PDGFRB, JAK2 and CRLF2). Results: Thirty-three (9%) patients with Ph-like ALL were identified, the remaining patients were classified as Ph+ (N=132, 36%) or Ph- ALL (N=200, 55%). Patients with Ph-like ALL were younger (Median: 39 vs. 50 vs. 49 years, P=.01), had higher WBC (Median: 27.9 vs. 21.5 vs. 4.5 x109/L, P<.001), were less likely to achieve CR (91% vs. 99% vs. 96%, P=.02), more likely to be MRD+ (64% vs. 34% vs. 36%, P=.03), had a higher relapse rate (5-year: 39% vs. 24% vs. 38%, P=.01) and lower OS (5-year: 41% vs. 64% vs. 49%, P=.02), see Table. Patients who achieved MRD negativity had better OS (MRD+ vs MRD-, P=.01). Importantly, no statistically significant difference in OS, relapse or non-relapse mortality were noted between the 3 groups in patients who underwent allo-HCT in CR1. Conclusions: Ph-like ALL is a high risk subgroup with increased prevalence in younger adults. Allo-HCT appears to offset the poor prognosis associated with this entity. A targeted FISH panel offers timely recognition of this entity in a clinical setting.[Table: see text]

Background: Gilteritinib is approved for the treatment of relapsed/refractory (R/R) AML and FLT3-mutation (FLT3mut+). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) enrolled prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or post-transplant FLT3inhibitor (FLT3i) maintenance. Some mechanisms of drug resistance can be shared across FLT3i's, suggesting response to gilteritinib might differ in patients treated with frontline FLT3i. A better understanding of how prior therapy modulates response to gilteritinib is necessary to clarify this novel agent's role in the current FLT3-mutated AML treatment algorithm. Methods: This is an ongoing multi-institutional analysis from 13 US centers identifying patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. Patients who received gilteritinib as a part of an ongoing trial were excluded. Response criteria were identical to the ADMIRAL trial. For patients with available data and a composite complete remission (CRc), we defined clinically measurable residual disease (cMRD) negative status by bone marrow flow cytometry using a cutoff of &lt;1 x 10x105 cells as well as polymerase chain reaction (PCR) for FLT3 mutation with a minimum sensitivity of 5%. Survival from the time of gilteritinib initiation was recorded. Multivariate analysis included all variables collected to determine interaction with patient outcome (CR and survival data). Kaplan-Meier curves and log rank test were used for survival analysis after gilteritinib initiation. Results: 72 patients treated with prior FLT3i exposure received gilteritinib for treatment of R/R FLT3mut+ AML. Patient characteristics are presented in table-1 with 46 (64%) previously receiving midostaurin, 19 (26%) sorafenib, and 7 (10%) other FLT3i. 8 (11%) received more than one prior TKI. NGS at diagnosis were available in 66 patients (92%) and co-mutations in DNMT3A, NPM1 and NRAS were observed in more than 10% of patients. Average duration of gilteritinib therapy was 5.7 months (range: 0.2-25 months). 27 (37.5%) received stem cell transplant (SCT) before gilteritinib and 15 (21%) underwent SCT after gilteritinib. The composite CR rate (CRc, defined as CR + CRi + CRp) was 51.4% (n= 37 patients). With regard to specific FLT3i's, we found no significant difference in median survival (7.1 months and 6.4 months for midostaurin and sorafenib, respectively) or remission rates (CRc 54% and 47% for prior midostaurin and sorafenib, respectively). The CRc rate for patients who received only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. A trend toward higher CRc rate was noted in patients treated with gilteritinib in combination regimens rather than as a single agent (64% vs 43%, respectively, p=0.09 using Chi-square test). No survival advantage for combination therapy was seen over single agent. Survival was longest in patients who obtained a CR, particularly a cMRD negative response; this remained significant after censoring at the time of SCT (figures 1&2). Patients who received SCT after gilteritinib had significantly longer survival than non-transplanted patients (9.3 months vs 5.6 months, respectively, HR 0.44, 95% CI 0.2-0.8)(figure-3). Patients with concurrent mutations of NPM1/DNMT3A had a trend toward a higher CRc compared to FLT3 mutation alone (71% vs 50%, p= 0.2) but similar survival. With regard to mutations associated with drug resistance to other FLT3i's, patients with both FLT3-ITD and FLT3-D835 mutation had similar response and survival to FLT3-ITD alone. However, patients with MAPK pathway activating mutations (e.g. NRAS and PTPN11) had lower CRc (37.5% vs 59.5%) and poorer median survival than other patients (3.3 months vs 7.5 months) (HR 2.2- 95% CI 1.1-4.4) p value &lt;0.01(figure-4). Conclusions: In this multi-center, retrospective analysis, gilteritinib remains a clinically active agent after treatment failure of prior FLT3i's (midostaurin or sorafenib). Mutations activating MAPK pathway have been implicated in secondary gilteritinib resistance but are seldom co-mutated at initial FLT3mut+ AML diagnosis. While further study is required, we hypothesize that their detection after frontline FLT3i therapy may represent treatment-emergent clones with propensity for pan-FLT3i resistance. Disclosures Zeidan: Cardiff Oncology: Consultancy, Honoraria, Other; Trovagene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding; MedImmune/Astrazeneca: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Research Funding; CCITLA: Other; Leukemia and Lymphoma Society: Other; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Foran:Agios: Honoraria, Research Funding; H3Biosciences: Research Funding; Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy. Daver:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Perl:Novartis: Honoraria, Other, Research Funding; Agios: Consultancy, Honoraria, Other; Biomed Valley Discoveries: Research Funding; Jazz: Honoraria, Other; FORMA Therapeutics: Consultancy, Honoraria, Other; Syndax: Consultancy, Honoraria; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other; Bayer HealthCare Pharmaceuticals: Research Funding; New Link Genetics: Honoraria, Other; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; Leukemia & Lymphoma Society, Beat AML: Consultancy; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; Takeda: Honoraria, Other: Travel costs for meeting. Altman:Kartos: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; ImmunoGen: Research Funding; Amgen: Research Funding; Aprea: Research Funding; Amphivena: Research Funding; Genentech: Research Funding; Novartis: Consultancy; Syros: Consultancy; Janssen: Consultancy; Immune Pharmaceuticals: Consultancy; ASH: Consultancy; Bristol-Myers Squibb: Consultancy; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; AbbVie: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding; Theradex: Other: Advisory Board; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; PrIME Oncology: Consultancy; PeerView: Consultancy; Cancer Expert Now: Consultancy; France Foundation: Consultancy; Fujifilm: Research Funding. OffLabel Disclosure: Some of the patients we are reporting on received gilteritinib in combination with other agents which is off-label use.

Introduction: Population studies have identified genes with germline polymorphisms associated with acute myeloid leukemia (AML) risk and outcome. However, somatic mutations in these genes have not been reported in an AML clinical population and whether they are associated with epidemiologic exposures, clinical AML phenotypes and outcome after therapy. Methods: We systemically interrogated PubMed database (1998-2018), to identify genes with germline polymorphisms associated with AML risk, response to chemotherapy or outcome. To determine the prevalence and relevance of somatic mutations in these genes in an unselected AML population, we performed an analysis using Whole-Exome Sequencing (WES) on remnant diagnostic cytogenetic pellets from 98 patients from the Mayo Clinic AML Epidemiology Cohort, a detailed and highly-annotated cohort of 295 consecutive AML patients treated at Mayo Clinic Florida & Arizona between October, 2000 and December, 2011. Patient characteristics are shown in Table 1. Samples were sequenced at a depth of ~100 million paired-end 100bp reads using Agilent SureSelectXT Human All Exon V5 + UTRs target enrichment kit. Sequencing reads were aligned to human reference genome, and somatic mutations including non-synonymous and truncating single nucleotide variants and small INDELs were identified and filtered using Exome Sequencing Project, 1000 genome, HapMap, & Mayo Clinic internal biobank genetic variants database. Copy number aberrations were identified & filtered using public copy number polymorphism databases. The association analyses were performed at the gene level, with a primary endpoint of whether a given patient harbored a somatic mutation in any genes linked to AML risk or outcome in literature, and to determine the associations of these mutations with epidemiologic exposures, AML phenotype and clinical outcomes. Results: From the literature search, we identified 77 unique genes with known germline polymorphisms associated with AML risk, response to chemotherapy or outcome. Fifty-eight of these were found to be somatically mutated in our WES dataset, with subsequent analysis focusing on the 11 genes (ABCB1, CYP1A1, CYP2B6, EPHX1, ERCC1, ERCC2, ERCC5, JAK2, MEFV, MTRR, and TERT) that had greater than 5 patients with nonsynonymous somatic mutations in the given gene. Significant associations with epidemiologic exposures and outcomes were noted in patients with somatic mutations in ERCC2, CYP1A1 and ERCC5 genes. Table 2 shows a comparison of patient characteristics and associations according to the presence of somatic mutations in these genes. Patients with mutations in CYP1A1 had a significantly younger age at AML diagnosis (Median: 51.7 vs. 71.0 years, P=.02) and significantly shorter OS in age-adjusted analysis (HR=4.45, P=.003). The former is a novel finding, whereas the latter is consistent with previous reports. Patients with mutations in ERCC2 more commonly used statins (66.7% vs. 21.7%, P=.03). Patients with ERCC5 mutations had a lower rate of tobacco use (20.0% vs. 54.5%, P=.049). In unadjusted analysis, there was a significant association between presence of somatic mutations in JAK2 and poorer survival after AML diagnosis (HR=2.83, P=.017), but this attenuated and did not retain significance when adjusting for age at AML diagnosis (HR=2.22, P=.067). Conclusion: Our exploratory study describes a novel association of CYP1A1 somatic nonsynonymous mutations with age of AML onset, as well as novel associations of ERCC2 and ERCC5 mutations with epidemiologic exposures in an unselect cohort of patients with AML. We confirm the association of CYP1A1 with inferior overall survival after AML diagnosis. These findings suggest that some genes associated with AML risk may also harbor somatic mutations that are clinically relevant. These results will guide a planned confirmatory prospective study to determine frequency and impact of both germline and somatic mutations of risk genes in AML patients, and may contribute to a better understanding leukemia risk assessment and potentially to prevention strategies. Disclosures Finn: Jazz Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding. Foran:Revolution Medicine: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; H3Biosciences: Research Funding; Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Agios: Honoraria, Research Funding.