ALBERT

Description: Background: We have previously shown that the survival of patients with AML who fail to achieve complete remission (CR) with 7+3 has improved since the 1980s. However, although CR rates with 7+3 have improved over the last four decades, we have not previously evaluated how outcomes for patients who achieve a CR1 with 7+3 has changed over time. Here we evaluate if either length of first CR (CR1) after 7+3 or of survival after relapse from CR1 has changed over the last four decades. Patients and Methods:We analyzed 1247 patients randomized to 7+3 arms from 5 SWOG studies and restricted to patients age 65 or younger: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), S1203 (n=261). S8600 enrolled patients in the 1980s, S9031 and S9333 in the 1990s, S0106 in the 2000s, and S1203 in the 2010s. S9031 and S9333 were analyzed together. All 5 protocols gave 7+3 per existing standard, which changed over time. In S8600, S9031, and S9033 the ara-C and daunorubicin doses were 200mg/m2and 45mg/m2, in S0106 100mg/m2and 60mg/m2, and in S1203 200mg/m2and 90mg/m2. CR was defined morphologically. To account for censoring in the dataset, we used landmark analyses. To evaluate patterns in length of CR1, among patients achieving CR1 and alive at 2 and 3 years, we calculated the proportion of 2 (or 3) years spent in CR1. To evaluate survival after relapse, among patients who achieved CR1 but who relapsed in next 2 (or 3) years we calculated the proportion of patients alive at least 1 year after relapse. To account for changing patient characteristics over time, multivariate linear and logistic regression models were fit. Results:Overall survival has improved dramatically over the last 4 decades (Figure 1). Additionally, among patients who achieved CR1 and were alive 2 years later, the proportion of those 2 years spent in CR1 has significantly improved over the last 4 decades (Figure 2) from a median of 58% to a median of 96% (p

Description: Although deferasirox use is established in clinical practice for iron overload, there have been a spate of case reports describing hematologic improvement attributed to use of this agent in myelodysplastic syndrome (MDS) patients (Guariglia et al, Leuk Res, 2011, 35 (5), 566-570). In addition, a post-hoc analysis was conducted assessing hematologic improvement in patients enrolled on the Evaluation of Patients' Iron Chelation with Exjade (EPIC) trial of deferasirox chelation therapy in low or intermediate-1 risk MDS. Erythroid, platelet, and neutrophil responses were observed in 21.5%, 13.0%, and 22.0% of 341 patients after a median of 109, 169, and 226 days, respectively (Gattermann, N et al, Haematologica, 2012, 97 (9), 1364-1371). There has even been a case report of a patient with acute monocytic leukemia who achieved a complete remission after deferasirox therapy (Fukushima et al, Anticancer Res, 2011, 31 (5) 1741-1744). Preclinical data has suggested potential mechanisms for hematologic improvement, including modulation of reactive oxygen species and activating the MAP kinase pathway (Callens et al, J Exp Med, 2010, 37 (4), 731-750), increased labile plasma iron leading to reactive oxygen species induction (Naka K et al, Antiox Redox Signal, 2008, 10 (11) 1883-1894), or inhibition of nuclear factor Kappa B (Messa et al, Haematologica, 95 (8) 1308-1316). Given these intriguing findings, we performed a single-center, investigator-initiated pilot study of deferasirox in MDS International Prognostic Scoring System (IPSS) 1.5 or greater, intolerant of or with lack of response to hypomethylating agents, and acute myeloid leukemia (AML), either relapsed or refractory after treatment with a non-intensive regimen or newly diagnosed and not appropriate candidates for induction chemotherapy. As an inclusion criterion, baseline serum ferritin was 〉 or = to 500 ng/mL. Prior therapy with iron chelating agents within the last 6 months was an exclusion criterion. Current therapy for AML or MDS, including hydroxyurea to control leukocytosis, was prohibited. Thirteen patients consented to the study. There was one screen failure and one patient withdrew from the study after one day. Eleven patients received deferasirox at an initial dose of 10 mg/kg/day which was increased to 20 mg/kg/day if tolerating well. Three of 11 patients (27%) responded. One of the three responding patients achieved red blood cell (RBC) transfusion independence (no RBC transfusions for 6 weeks before death related to infectious complications), one improved bone marrow blasts from 57% to 30% after one month of therapy and the third patient improved bone marrow blasts from 13% to 8% after one month of therapy. The patient who achieved RBC transfusion independence did not achieve any other measures of response. The two patients who responded in the bone marrow did not achieve a concomitant hematologic response. Of the 8 non-responding patients, one patient had stable disease and was on study for one year. One patient withdrew in the setting of neutropenic fever and mild transaminitis that was possibly attributable to deferasirox and was terminated from the study. One patient withdrew from the study due to personal choice and the remaining 5 patients came off study in the setting of complications from progressive disease. Study drug was generally well tolerated. Grade 3 adverse events (AEs) included three patients with elevated creatinine (27%) and 2 patients with diarrhea (18%). One responding patient had a lower gastrointestinal bleed that was possibly attributable to deferasirox and was terminated from the study for this reason. One patient had grade 4 dry mouth immediately after drinking deferasirox slurry that resolved by 30 minutes after ingestion. No other significant AEs occurred that were possibly attributable to deferasirox. In conclusion, deferasirox was generally well tolerated and showed modest activity as a single agent in higher risk MDS or non-proliferative acute myeloid leukemia. Further study of deferasirox in the phase II setting as monotherapy or in combination with other therapies such as hypomethylating agents (HMAs) or HMAs in combination with venetoclax is probably warranted. Disclosures Frey: Novartis: Research Funding. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy. Luger:Agios: Honoraria; Ariad: Research Funding; Biosight: Research Funding; Celgene: Research Funding; Cyslacel: Research Funding; Daichi Sankyo: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Kura: Research Funding; Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding. OffLabel Disclosure: Presentation will discuss the off-label use of Exjade (deferasirox) as therapy for higher risk MDS or AML. Deferasirox on-label use is for iron chelation.

Description: Abstract Background: The development of tyrosine kinase inhibitors (TKIs) has dramatically changed the landscape of chronic myelogenous leukemia (CML) treatment. Dosing of TKIs is based on the phase of disease at presentation, but is not altered based on body surface area (BSA), gender, or other patient characteristics. Although TKIs are generally well tolerated, lower grade hematologic and non-hematologic toxicities are not infrequent. Inability to maintain dosing during the first year of therapy (missing as few as 10% of doses per month) has been associated with lower rates of major molecular response (MMR), which might have survival implications and/or prevent treatment-free remission attempts. While the package insert of three TKIs (imatinib, dasatinib, nilotinib) commonly used in first line therapy provides specific dose-reduction instructions for hematologic toxicity, only nilotinib has recommendations for non-hematologic toxicities. Long-term outcome data on the effects of dose-reduction of TKI therapy based on toxicity is lacking. Furthermore, there is little data on risk factors for TKI intolerance. Thus, we sought to identify characteristics of patients requiring dose reductions as a part of first-line TKI treatment for chronic phase CML who successfully achieved an MMR 4 or greater as well to determine the long-term outcome of these patients in a retrospective fashion. Methods: Using electronic medical records, we identified patients seen at the John Theurer Cancer Center for treatment of newly diagnosed chronic phase CML between November 1, 2012 and July 1, 2016 who had successfully achieved an MMR 4 or greater. These records were screened for individuals requiring chronic dose reductions as part of first-line treatment for chronic phase CML. We identified 35 consecutive patients that were able to tolerate full dose TKI therapy per package insert. This control group was used to determine risk factors for TKI intolerance compared to patients that required dose reduction. Results: A total of 20 patients were identified who achieved an MMR 4 or greater and required long-term dose reduction of first-line TKI therapy with a median follow up of 48.5 months (range 18.7-172.6). The median time on full dose therapy prior to dose reduction was 7.7 months (range 0-40.2). The median time spent on reduced dose therapy was 43.5 months (range 12.1-159.0). The time to MMR was 8.3 months (1.8-40.2). The majority of patients remained in MMR 4 despite maintenance on dose reduction. Median progression free survival (PFS), as defined by loss of MMR, of dose-reduced patients had not yet been reached. One, two, and three year PFS rates were 100%, 95.0%, and 88.7% respectively. When compared to the control group of patients tolerating front line therapy at full-dose, patients requiring dose reduction were more likely to be female: 80% vs 46% (P=0.028) and have a lower BSA: 1.78 versus 2.03 mg/m2 (P=0.0014). Other variables including age, TKI, Sokol score, and performance status were similar in both groups. Discussion: Among patients who achieved MMR4 or greater on first-line therapy, we noted that female sex and lower BSA were risk factors for TKI dose reduction. Based on the available control group, it cannot be determined if either of these are independent variables. This retrospective analysis demonstrates many patients are able to successfully achieve and maintain a deep molecular response with reduced doses of TKI therapy and perhaps provides justification for dose reduction to increase compliance and maximize treatment tolerability. The majority of patients remained in MMR4 despite dose reductions. Disclosures McCloskey: Celgene Pharmaceuticals: Consultancy, Speakers Bureau; Takeda Pharmaceuticals: Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Amgen: Speakers Bureau; COTA: Equity Ownership. Stanislaus:Celgene Pharmaceuticals: Consultancy, Speakers Bureau; Takeda Pharmacetucals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Koprivnikar:Otsuka Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Consultancy, Speakers Bureau; Amgen Pharmaceuticals: Speakers Bureau; COTA: Equity Ownership.

Description: Introduction: Venous thromboembolism (VTE) is a significant adverse event in adults receiving pegaspargase (PEG) for acute lymphoblastic leukemia (ALL). PEG increases VTE risk by depletion of antithrombin III (AT). Heparin requires adequate AT for anticoagulation. Younger adults with T-cell ALL receiving prednisone may be particularly at risk. Retrospective series (most with L-asparaginase) suggest AT supplementation may decrease VTE, however prospective data in adults beyond induction is limited while the optimal dose of AT remains undefined and varies across series. We reviewed adults at our institution who received PEG for ALL to assess the incidence of VTE within our AT supplementation practice. Laboratory and cost data for AT repletion were also analyzed. Methods: Adults who received PEG for ALL between 11/2015 and 7/2018 were retrospectively identified. Institutional recommendations were to supplement AT if serum AT 〈 60% following PEG for at least the first 2 courses (induction/consolidation). AT levels were assessed twice weekly until normalized. AT supplementation following additional cycles was recommended for all patients receiving therapeutic anticoagulation. Pharmacists calculated the AT dose using a repletion factor of 80-120%, rounded to the nearest vial. After VTE, patients received therapeutic enoxaparin throughout all remaining PEG doses, with enoxaparin held only if platelets 〈 50,000/mcL or for procedures. After 3/2018, all patients receiving PEG also received enoxaparin prophylaxis when platelets 〉30,000/mcL. A retrospective analysis was done to assess the incidence of VTE. Secondary endpoints included an assessment of VTE risk factors, ability to achieve therapeutic AT levels with supplementation and to characterize drug therapy costs with AT supplementation. Results: Thirty-one patients (30 newly diagnosed, 1 in relapse) with ALL received ≥ 1 dose of PEG followed by AT supplementation. Seventeen of 31 patients were adolescent/young adults (AYA) and 13/31 had T cell ALL. Additional patient characteristics are summarized in table 1. The incidence of VTE was 19%, with 7 VTEs identified in 6 patients. Two patients developed CNS thrombosis (1 fatal), 1 had a pulmonary embolism, and the remainder were upper extremity VTE. Six of 7 VTE occurred during the first two courses at a mean of 66 days (range 6-225) following the first PEG dose. Patients with VTE had a median platelet count of 118/mcL (range 34-377) and a mean AT nadir of 53% (36-98) within 72 hours of VTE. Two of 7 events occurred despite enoxaparin prophylaxis. Five of 6 (83%) patients with VTE had T-ALL; which was more common in the VTE vs. no-VTE group (p = 0.01). The incidence of VTE within the T-ALL group was 38%. Patients with VTE were all AYA and were younger than those without VTE (median 31 vs. 42 years, p = 0.06). Patients with VTE received a higher mean PEG dose than patients without VTE (4589 vs. 3504 units, p 〈 0.0001), reflective of the more aggressive dosing in the AYA regimen. Six of 7 VTEs occurred during a course containing prednisone (p = 0.08 vs. dexamethasone). AT nadirs during cycles with VTE were similar to cycles without VTE. No clinically significant bleeding occurred. Characteristics of patients with VTE are summarized in table 2. Overall the mean time to AT nadir was 11 days. Therapeutic AT (〉 60%) following supplementation occurred 56% of the time. Most AT doses (89%) were calculated with a correction factor of 80-89%. The probability of obtaining a therapeutic AT increased when a higher repletion factor (〉 90%) was used (76% vs. 52%, p = 0.06). Patients received a mean of 1.9 (0-6) doses of AT per PEG dose, and a mean of 5.9 (1-21) AT doses throughout treatment. The mean AT supplementation cost per PEG dose was $11,663 with 186 doses administered ($3.22/unit). Conclusions: VTE occurred in 19% of patients receiving AT supplementation following PEG, with 2/7 events involving the CNS. The risk of VTE was greatest in younger adults with T-ALL receiving concurrent prednisone and higher doses of PEG. AT levels were low at the time of VTE in most patients, however nadirs were similar compared to courses not complicated by VTE. Routine or augmented VTE prophylaxis and a higher AT repletion goal (〉 90%) may further limit VTE risk but given the cost and patient inconvenience, prospective evaluation is needed to confirm the benefit. Disclosures Frey: Servier Consultancy: Consultancy; Novartis: Consultancy. Perl:Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy; Astellas: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees. Porter:Genentech: Other: Spouse employment; Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board.

Description: Warfarin is an effective, commonly prescribed anticoagulant used to treat and prevent thrombotic events. Because of historically high rates of drug-associated adverse events, warfarin remains underprescribed. Further, interindividual variability in therapeutic dose mandates frequent monitoring until target anticoagulation is achieved. Genetic polymorphisms involved in warfarin metabolism and sensitivity have been implicated in variability of dose. Here, we describe a novel variant that influences warfarin requirements. To identify additional genetic variants that contribute to warfarin requirements, screening of DNA variants in additional genes that code for drug-metabolizing enzymes and drug transport proteins was undertaken using the Affymetrix drug-metabolizing enzymes and transporters panel. A DNA variant (rs2108622; V433M) in cytochrome P450 4F2 (CYP4F2) was associated with warfarin dose in 3 independent white cohorts of patients stabilized on warfarin representing diverse geographic regions in the United States and accounted for a difference in warfarin dose of approximately 1 mg/day between CC and TT subjects. Genetic variation of CYP4F2 was associated with a clinically relevant effect on warfarin requirement.

Description: Abstract 2453 Background: Quizartinib (AC220) is a potent, highly selective inhibitor of FLT3, KIT, and FMS tyrosine kinases with promising clinical activity in AML patients, particularly those with FLT3 internal tandem duplication (FLT3-ITD) mutations. However, limited biochemical FLT3 inhibition in leukemic blasts in vivo by AC220 has been previously described (Perl, et al ASH 2012 #3502). As a biomarker for FLT3 inhibition, we assessed monitoring of phosphorylated ribosomal protein S6 (pS6) at serines 235/236 by flow cytometry. S6 is a downstream target of the PI3 kinase/mammalian target of rapamycin (mTOR) pathway, is constitutively phosphorylated in nearly all FLT3-ITD+ samples, and its phosphorylation shows dynamic changes in response to FLT3 ligand (FL) or FLT3 inhibitors in vitro. We hypothesized that S6 phosphorylation would be a biomarker for FLT3 inhibition and here provide final analysis of AC220 phamacodynamic monitoring at our center. Methods: Serial peripheral blood samples were collected during a phase 2 AC220 clinical trial (Cortes, et al. ASH 2011, #2576). Blood was aliquoted within four hours of collection and a subset was exposed to signaling inhibitors (ex vivo AC220, rapamycin × 30 min.) or activators (phorbol ester/PMA or FL × 10 min.) to establish dynamic controls. Following incubation, samples were formaldehyde-fixed and red cells lysed with the permeabilizing agent triton X-100. Samples were stored at −20C in glycerol-containing medium. After collecting all time points, samples were simultaneously thawed, denatured with ice-cold methanol, and stained for flow cytometry. Blasts were identified by using CD45 and side scatter and confirmed by expression of multiple surface markers (CD33, CD34, CD117, HLA-DR, etc.). Constitutive S6 phosphorylation was defined by comparing unstained (fluorescence minus one, FMO) and PMA and/or cytokine-stimulated cells. Biochemical sensitivity to AC220 was defined as a reduction in the percentage of positive phospho-S6 blasts by 〉50% as compared to baseline. Results: 21 subjects provided whole blood samples (15 FLT3-ITD+, 6 FLT3-WT), 15 had evaluable peripheral blasts (〉100 blasts/microliter) for p-S6 monitoring. Only one subject with FLT3-WT had sufficient circulating blasts for analysis. By contrast, 13/15 FLT3-ITD+ subjects' blasts were evaluable. As previously described by our group and others using flow cytometry, pS6 is heterogeneous in primary AML samples and, at basal state, frequently only demonstrable in a subset of blasts. The mean percentage of blasts demonstrating S6 phosphorylation (pS6+) prior to AC220 therapy was 15% (median 4%, range

Description: Thrombotic microangiopathy (TMA) is seen in up to 30% of patients receiving solid organ transplantation and almost always occurs in the setting of calcineurin inhibitor (CNI) therapy. The underlying pathophysiology of calcineurin induced TMA is poorly understood. Long term follow up in non renal transplant patients with TMA suggests that in spite of plasma exchange therapy the 1 year mortality following TMA is up to 70%. Between November 2010 and August 2012, 7 patients at our institution who underwent organ transplants ( 5 small bowel, 2 orthotopic liver) developed clinical and laboratory evidence of TMA while receiving CNI therapy. TMA was diagnosed from 3 to 13(median 11) months post transplant and none of the patients responded symptomatically or by laboratory parameters to a reduction in dose of CNI. Other unsuccessful therapies included substitution of other immunosuppressive agents (N=1) and 11 daily plasma exchanges (N=1). At the time of TMA diagnosis notable laboratory values included platelets 22-73 (median 46) K/UL, hemoglobin 4.5 to 8.1(median 6.9) GM/DL, serum creatinine 1.16-5.4 (median 2.66)MG/DL, LDH 262-2903(median 435) Units/L, and ADAMSTS13 37-137%. All patients had a negative DAT, schistocytes on peripheral smear and all but one had undetectable haptoglobin. ( Table 1 ) Clinical symptoms at diagnosis included nausea, vomiting, abdominal pain, fever, hypertension, cerebral vascular accident (N=1), acute coronary syndrome (N=1). None of the patients had evidence of graft rejection on biopsy of the transplanted organ at the time of TMA diagnosis however 2 patients with small bowel transplants had pathologic evidence of ischemic changes and vascular thrombi on biopsy of the small bowel graft.Table 1Comparison of Medians of TMA Laboratory ParametersMedian ValuesPreTransplantTMA Diagnosis4 weeks post eculizumabPlatelet count K/UL12046202Hemoglobin GM/DL11.06.99.0Serum Creatinine MG/DL0.832.661.7LDH Units/L174435322HaptoglobinNT

Description: Background: Many factors have been found to impact the treatment outcomes of acute myeloid leukemia (AML) patients including age of patient at diagnosis, race, cytogenetic risk grouping, and white blood cell count. Although these clinical and demographic features might be easy to measure and identify, models using socioeconomic factors predicting treatment outcomes of AML have not been as rigorously explored. This study aims to investigate how some socioeconomic factors may impact the treatment outcomes of patients with newly diagnosed AML. Methods: We retrospectively analyzed patients from January 2000 to June 2012 diagnosed with AML over 18 years of age, who were treated at the University of Oklahoma with induction chemotherapy. 215 AML patients were identified. The AML patient, or next of kin, was contacted and asked to complete a telephone-based questionnaire with 11 questions. A total of 181 patients or next of kin responded to questions regarding marital status, dependency on another, difficulty with transportation, renting hotel/motel for treatment, car ownership, and whether the patient's life was stressful. Simple descriptive statistics were created for all covariates [n (%)] overall. Kaplan-Meier survival curves and log-rank tests of homogeneity identified which covariates were associated with survival (α=0.25) and would be included in a multivariable Cox proportional hazards regression model. In this model, all two-way interactions were explored and backward selection was used to identify the variables included in the final model. If the exclusion of a variable changed the estimate of a significant covariate by ≥ 20%, it was deemed a confounder and retained in the model. A similar approach was used to assess complete remission (CR); however, binary logistic regression models were used to examine the univariate association of each covariate with CR to identify associated variables to include in the multivariable model (α=0.25). Results: The majority of patients were males (61%), married (45%), and achieved CR (64%). The median age was 52 years. Most patients reported not being dependent on another (65%), not having served in the military (94%), and not having difficulty with travel (73%), although most reported owning a car (70%). After adjusting for age and risk grouping, military status is marginally associated with overall survival (OS) (p-value =0.0548). The hazard of death for those in the military is 2.36 times higher for patients with AML relative to those who have never been part of the military (95% CI: 0.98, 5.69). Marital status is not associated with OS. There is a significant association between difficulty with transportation (p-value=0.0440) and CR. Patients who reported difficulty with transportation have 0.35 times the odds of CR (or 65% lower) relative to those who do not report this difficulty (95% CI: 0.13, 0.97). Marital status is marginally significant (p-value=0.0698) when comparing married vs widowed patients. Married patients have 1.35 times the odds of remission relative to those patients who are widowed (95% CI: 0.32, 5.68). Conclusion: There is evidence that those who served in the military have lower OS relative to those who have not. We also find that patients who reported having difficulty with transportation have lower rates of CR. Further exploration of how these variables might be associated with OS and CR is warranted given evidence from this study. Disclosures No relevant conflicts of interest to declare.

Description: Background: Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are heterogeneous groups of disorders with a spectrum of clinical presentations and outcomes. Prognosis depends on various factors including age, karyotype, performance status, previous treatments and mutation status. Genetic profiling with next generation sequencing (NGS) is increasingly being used at diagnosis to detect presence of somatic mutations for prognostic risk stratification, and identification of therapeutic targets. Here we seek to identify epidemiologic differences in genetic mutations based on population and demographic data in patients with a preliminary diagnosis of AML or MDS. Methods: NGS mutation data were collected for 62 genes related to AML/MDS on a total of 10,934 patient samples submitted for testing for suspected AML/MDS. Samples were run on either the 54-gene NeoType Myeloid Disorders Profile (Neogenomics) or the 37-gene OnkoSight Myeloid Malignancies Panel (Genpath). The frequency of gene mutations (i.e., the number of patient samples with mutations for each gene) was identified for 58 counties in the USA. Counties in which fewer than 50 patient samples were tested were excluded from the dataset to minimize sampling bias. The counties were then grouped into 3 categories ranging from most urban to most rural based on a modified version of the 2013 National Center for Health Statistics classification system G-1 - 〉 1,000,000 (N=34), G2 - 250,000 - 1,000,000 (N=16) and G3 〈 250,000 (N=8). One-way ANOVA and subsequent T-tests were performed for all genes based on the 3 urban-rural groupings to determine if significant differences in frequency of mutations exist between the 3 groupings. Difference of proportions tests were performed to identify variations in the patterns of frequency between counties. Results: The top 10 most frequent mutations were TET2, ASXL1, DNMT3A, SRSF2, TP53, RUNX1, SF3B1, U2AF1, NRAS, and NPM1(highest to lowest). The three mutations with the widest range of variability across counties were DNMT3A, TET2, and ASXL1 (DTA mutations). The median age across all counties was 68 (range 44-77). The county with the youngest and highest median age was Montgomery, CA and Pinellas, FL, with ASXL1 and TET2 as the most frequent mutation, respectively. Sacramento, CA had an unusually high rate of ASXL1 mutations (〉 24%). ASXL1 was also significantly higher than TET2 in Essex, NJ; Montgomery, MD; and Sacramento, CA. (p=0.0287, p 〈 0.0001, p 〈 0.0001, respectively). IDH1was higher than IDH2 for Martin, FL (p= 0.0481). The highest frequency of TP53 mutation (24%) was in Bexar, TX compared to Montgomery, MD which had the lowest (2%). When counties were grouped based on population density, the frequency of RUNX1 and SF3B1 were statistically different across the counties, highest in G2 compared to G1 and G3 (p= 0.0294 and 0.0010 respectively). Conclusion: Our retrospective observational study is the first of its kind to look at genetic mutations in AML/MDS patients across the United States using commercially available NGS platforms. In general, patients had analogous combinations and frequencies of mutations commonly seen in AML and MDS, and the wide variation in frequency of DTA mutations is consistent with information known about age-related clonal hematopoiesis. In counties that showed a higher rate of ASXL1 〉 TET2, there may be a potential environmental factor accounting for this difference as the reverse is more commonly seen. Likewise, IDH1 mutations are typically seen at a lower frequency compared to IDH2, and it is interesting to note the reverse in Martin, FL (G2) despite the mutation frequency of all other genes being similar compared to the median for all counties. Our data analysis also showed a significant difference in frequency of mutations for TP53, RUNX1 and SF3B1. These variations have important implications in regard to prognosis, and the approach to treatment. Our observations suggest further investigation is warranted to explore potential environmental exposures related to somatic mutational patterns in patients with AML and MDS. Disclosures McCloskey: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Celgene Pharmaceuticals: Honoraria, Speakers Bureau; Amgen Pharmaceuticals: Speakers Bureau; Pfizer: Consultancy; Takeda Pharmaceuticals: Consultancy, Speakers Bureau; COTA: Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Otsuka: Consultancy; Alexion: Consultancy, Speakers Bureau.

Description: Introduction: Older patients with high-risk myeloid malignancies are now eligible for either induction chemotherapy (IC) or novel treatment strategies including liposomal cytarabine and daunorubicin (Vyxeos) or hypomethylating agent (HMA)/venetoclax. Vyxeos and HMA/venetoclax may be associated with less early mortality, but no trials have demonstrated significantly less mortality compared to IC. In this context, we need a better tool to determine a patient's risk of early mortality by strategy in order to inform therapy selection for older patients. The current methods to assess a patient's fitness for IC are the Eastern Cooperative Oncology Group (ECOG) or Karnofsky Performance Status (KPS) assessments, clinician subjective evaluations [i.e. gestalt (CG)], and often age itself (〉75-80 years). None of these include objective measures of fitness. The Fried frailty phenotype (FP) uses both subjective (exhaustion and activity level) and objective measures (weight loss, gait speed, and grip strength) of frailty to categorize patients into fit, pre-frail, and frail. We hypothesized that FP would correlate with early mortality in this population and could be used to guide initial treatment selection. Methods: From September, 2018 to June, 2019 we prospectively enrolled 30 patients age 60 years or older with newly diagnosed, untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) on an ongoing institutional review board approved clinical trial. We performed FP, CG, hematopoietic cell transplantation-comorbidity index (HCT-CI), and ECOG assessments on all patients prior to initiation of any therapy for their high grade myeloid disease. The primary endpoints were 60 and 100-day mortality. Results: Median patient age and follow up were 70.9 (range 61-82) years and 111 days, respectively. Patients had high-risk disease features as shown in Table 1, with the vast majority of AML patients being adverse risk by European Leukemia Network criteria and all MDS patients being high or very high-risk by the Revised International Prognostic Scoring System. The most common molecular mutations were TP53, ASXL1, RUNX1, IDH1/2, FLT3, and DNMT3A. IC consisting of either 7+3 or Vyxeos was used in 11 patients, HMA alone or in combination in 16, targeted therapy with enasidenib alone in 1, and best supportive care (BSC) in 2 (Table 1). Four patients who were frail by FP received IC (3 with Vyxeos). By FP assessments, 17% of patients were fit (score 0), 33% were pre-frail (score 1-2), and 50% were frail (score 3-5). In contrast, CG categorized 37% of patients as fit, 30% as pre-frail, and 33% as frail. Seven of 15 frail patients by FP were categorized as pre-frail or fit by CG. FP and ECOG scores also differed with 7 patients having low-risk ECOG scores of 0-1 and a high-risk FP of ≥3 (frail). For entire cohort, 60- and 100-day mortality rates were 15% and 25%, respectively. Frail patients by FP had 60-day and 100-day mortality rates of 32% and 51%, respectively, which was significantly worse than fit and pre-frail patients, all of whom were alive at 100 days (Figure 1/2, p=.016). Of the 6 out of 15 FP frail patients who died, 1 received a HMA alone, 3 HMA with venetoclax, and 2 BSC. In patients with ECOG scores of 0-1 or those categorized as fit by CG, 100-day mortalities were 8% and 10%, respectively. Mortality for patients with HCT-CI scores of 1-2 was unexpectedly higher (34% at both 60 days and 100 days) than for patients with higher risk HCT-CI scores ≥3 (13% and 29%, respectively). Conclusion: In newly diagnosed older patients with advanced myeloid neoplasms, being frail by FP was associated with increased 60 and 100-day mortality, owing to high mortality rates with HMA based therapies. While HCT-CI scores have been significantly associated with mortality after allogeneic transplantation, we observed that these scores were not linearly associated with survival or mortality in newly diagnosed AML and high/very-high risk MDS patients. By ECOG and CG, even the low risk groups contained patient deaths, suggesting that these standard metrics may not capture certain at-risk patients. CG tended to down grade frailty scores, categorizing patients as fitter than they were by FP. As such, FP may be a useful tool to predict early mortality. Further research is warranted to determine whether mortality differs by treatment within a given FP category, which may support the use of FP to select initial therapy. Disclosures Frey: Novartis: . Gill:Novartis: Research Funding; Tmunity Therapeutics: Research Funding; Carisma Therapeutics: Research Funding; Amphivena: Consultancy; Aro: Consultancy; Intellia: Consultancy; Sensei Bio: Consultancy; Carisma Therapeutics: Equity Ownership. Perl:Bayer: Research Funding; BioMed Valley Discoveries: Research Funding; FujiFilm: Research Funding; Novartis: Honoraria, Other: Advisory board, Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of the data., Research Funding; Jazz: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; NewLink Genetics: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Takeda: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Astellas: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings as well as a medical writing company that assisted with manuscript preparation/submission and slide deck assembly for academic meeting presentations of trial data., Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Non-financial support included travel costs for advisory board meetings.; Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding; Arog: Consultancy, Other: Non-financial support included travel costs for advisory board meetings.; AbbVie: Consultancy, Honoraria, Other: Non-financial support included travel costs for advisory board meetings.; Actinium Pharmaceuticals: Consultancy, Honoraria, Other: Clinical Advisory Board member, Research Funding. Maillard:Genentech: Consultancy; Regeneron: Consultancy. Pratz:Millenium/Takeda: Research Funding; AbbVie: 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, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees, Research Funding. Porter:Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Immunovative: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Wiley and Sons: Honoraria; Genentech: Employment. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy. Luger:Seattle Genetics: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria; Genetech: Research Funding; Daichi Sankyo: Honoraria; Onconova: Research Funding; Kura: Research Funding; Jazz: Honoraria; Celgene: Research Funding; Cyslacel: Research Funding; Pfizer: Honoraria.