Baer, Maria R.

Abstract Introduction: Recent reviews indicate that transfusional hemosiderosis may be associated with an increased risk of mortality in lower-risk pts with MDS. This trial is designed to evaluate the efficacy and long-term safety of deferasirox (Exjade®, ICL670) in MDS. Deferasirox is an oral iron chelator approved for use in pts with transfusional iron overload. Methods: This is a Phase II, open-label, 3-yr clinical trial in 55 US centers, enrolling 150 pts (aged ≥18 years) with Low- or Int-1-risk MDS (by IPSS criteria) and transfusional iron overload (serum ferritin ≥1000 ng/mL and >20 units RBC transfusions). Deferasirox dosing is 20–30 mg/kg/day. Serum ferritin, iron, transferrin and transferrin saturation are being assessed at screening and monthly in yr 1, then quarterly in yrs 2 and 3, while labile plasma iron (LPI) is assessed quarterly in yr 1. In addition, creatinine, calculated creatinine clearance, echocardiograms and endocrine and hematological status are being assessed. This report describes baseline data in these pts. Results: As of June 2006, 84 pts have enrolled. Demographic data are available from 79 pts: median age 71 years (range 47–87); sex (52 male, 27 female); ethnicity (74 Caucasian, 2 Black, 2 Hispanic, 1 Oriental); and IPSS Risk Group (Low: 22 pts; Int-1: 56 pts). Iron status is summarized in the table: Parameter n Mean ± SD Median Range Normal range n/a, not applicable Serum ferritin,μg/L 84 3779 ± 4070 2951 1160–36280 12–370 Serum iron, μg/dL 84 205 ± 64 201 48–409 37–180 Transferrin, mg/dL 82 153 ± 31 152 83–244 190–375 Transferrin saturation, % 83 85 ± 15 91 20–94 15–50 LPI, μmol/L 38 0.52 ± 0.63 0.25 0–2.9 0 Total transfusions, n 78 63.3 ± 66.3 41.5 14–435 n/a Years of transfusion 75 3.4 ± 1.9 3 1–12 n/a Baseline concurrent therapies: 5-azacytidine (Vidaza): 5 pts; lenalidomide (Revlimid): 1 pt. Calculated creatinine clearance: normal (>80 mL/min): 37 pts; mildly abnormal (51–80 mL/min): 30 pts; moderately abnormal (30–50 mL/min): 9 pts. Hematological parameters: Anemia was present in all pts; other cytopenias included: neutropenia (<1800/μL): 13 pts, thrombocytopenia (<100,000/μL): 15 pts; neutropenia and thrombocytopenia: 12 pts. A total of 53 pts had received chelation prior to enrolling: 51 deferoxamine (Desferal®); and 2 deferasirox. Conclusions: Despite the prior availability of deferoxamine, these baseline data demonstrate significant levels of iron overload among transfused pts with myelodysplasia. Serum iron, ferritin and LPI are all well above the clinically significant thresholds associated with increased complications. Since recent data has suggested that iron overload may be a poor prognostic indicator in MDS, increased attention to maintaining appropriate iron balance is warranted. The recent availability of an oral iron chelator may be more acceptable to MDS pts and their physicians. This ongoing trial is designed to assess the long-term efficacy, safety, and clinical benefits of deferasirox in pts with MDS.

Abstract INTRODUCTION: The majority of patients (pts) with MDS require red blood cell transfusions, which can result in iron overload and its clinical sequelae. The US03 trial is designed to evaluate the long-term efficacy and safety of the once-daily, oral iron chelator, deferasirox (DFX), in pts with lower-risk MDS. In this ongoing study 93/176 pts have now completed 12 months of treatment. METHODS: US03 is a Phase II, open-label, 3-year trial in pts with Low- or Int-1 IPSS-risk MDS and transfusional iron overload (serum ferritin [SF] 1000 μg/L and >20 units RBC transfusions), with serum creatinine (SCr) 2-fold the upper limit of normal (ULN). Initial DFX dose was 20 mg/kg/day and could be increased to 40 mg/kg/day based on tolerability and response. SF was monitored monthly; labile plasma iron (LPI), the reactive species of non-transferrin-bound iron, was assessed quarterly. BASELINE FEATURES: 176 pts were enrolled at 45 centers. Mean age: 70 years (range 21–90); 105 men and 71 women; IPSS Low risk (n=47; 27%); Int-1 (n=126; 72%); other (n=3; 2%). Mean baseline iron status was: SF, 3397 μg/L (863–36,280); LPI, 0.4 μmol/L (0.0–3.6). Forty-one percent of pts had elevated LPI at baseline (≥0.5 μmol/L). Mean number of lifetime prior transfusions: 63; mean duration of transfusions: 3.5 years (0–34). MDS therapy at study entry included azacitidine, hydroxyurea, lenalidomide, thalidomide or decitabine in 25 pts, and growth factors in 48 pts. Calculated creatinine clearance was normal (>80 mL/min) in 77 pts and abnormal (abn) in 99: mildly abn (51– 80 mL/min) in 71; moderately abn (30–50 mL/min) in 25; severely abn (<30 mL/min) in 3. RESULTS: Over 12 months, the mean dose of DFX was 21 mg/kg/day, and the mean transfusion rate was 3.4 units/month. Mean SF±SEM (μg/L) values at baseline, 3, 6, 9 and 12 months were 3397±233 (n=176), 3057±144 (n=143), 2802±128 (n=126), 2635±148 (n=109) and 2501±139 (n=93), respectively. In pts with elevated baseline LPI, sustained suppression of mean LPI to the normal range was achieved after 3 months of treatment. The figures show reductions (±SEM) in SF, and in LPI in pts with baseline LPI ≥0.5 μmol/L. Hematological improvement by IWG 2000 criteria was achieved in 8 pts (5%): erythroid response in 5 (major 3; minor 2); platelet in 1 (major); neutrophil in 1 (major); and combined platelet and neutrophil in 1. SAFETY: Of 173 pts, 18 (10%) discontinued DFX because of suspected adverse events (AEs), and an additional 5 (3%) because of serious AEs (SAEs). The most common AEs were diarrhea (n=9), rash (n=3) and nausea (n=2), while the most common SAEs were rash (n=2) and diarrhea (n=1). Of 147 pts with normal baseline SCr, 26 (18%) increased >ULN on at least two occasions (3.0 mg/dL max SCr). There were 9/172 (5%) and 22/168 (13%) new onset cases of grade 3–4 thrombocytopenia and neutropenia, respectively, none suspected to be related to DFX; 7 and 11 of these pts, respectively, were receiving other MDS treatment therapies, including lenalidomide, decitabine, hydroxyurea and azacitidine. There were 17 deaths (10%), due to sepsis/infection (n=8), disease progression (n=4), intracranial bleed (n=2), cardio-respiratory arrest (n=2) and renal failure (n=1), all thought to be unrelated to DFX. CONCLUSIONS: In these heavily iron-overloaded pts, DFX was generally well tolerated. New onset cytopenias were consistent with the underlying disease. A 2-year extension phase of this study will assess the long-term safety and efficacy of DFX as well as the clinical impact on cardiac, hepatic and endocrine function. Figure Figure

Abstract Decitabine (Dacogen®), a hypomethylating agent, is FDA-approved for treatment of patients (pts) with all FAB subtypes of MDS. The approved regimen of 15 mg/m2 intravenously (IV) over 3 hours (hrs) every (q) 8 hrs for 3 days repeating q 6 wks demonstrated an overall improvement rate (CR+PR+HI) of 30% in MDS pts. An alternative regimen, in which decitabine is administered 20 mg/m2 IV over 1 hr once daily for 5 consecutive days repeating q 4 wks not only permits outpatient therapy, but also showed promising efficacy in a pilot study (Blood2007:109:52). This alternate regimen was evaluated in a multicenter study and preliminary results from this open-label single-arm Phase 2 study are reported. Eligible pts were ≥18 years (yrs) of age with MDS (de novo or secondary) of any FAB subtype (including chronic myelomonocytic leukemia with white count <12,000/μL) and International Prognostic Scoring System (IPSS) score ≥ 0.5 (Intermediate-1 (Int-1), Intermediate-2 (Int-2) and High-risk groups) as determined by complete blood counts, bone marrow assessment, and cytogenetics within 28 days of enrollment. Responses, the primary endpoint of the study, were assessed using International Working Group (IWG) criteria (Blood2000;96:3671), which existed at study initiation and also used in the Phase 3 trial with the FDA-approved 3-day regimen. Secondary objectives included evaluation of hematologic improvement, cytogenetic response, overall survival, time to acute myeloid leukemia progression or death, transfusion requirements, and toxicity. Ninety-nine pts enrolled: median age 72 yrs, 72% male, 89% de novo MDS, median time from diagnosis 153 days, and 29% with prior therapy for MDS. The distribution of IPSS risk groups was as follows: Low, 1%; Int-1, 53%; Int-2, 23%; and High, 23%. Pts have thus far been followed for one year after enrollment of the last pt, and the preliminary data are reported here. Investigator assessments of response, using pathology results at the individual study sites along with laboratory findings, demonstrated an overall improvement rate of 43%; central confirmation of results is ongoing. Pts received a median of 5 cycles of decitabine (range 1–17). Median survival has not been reached; a total of 62 pts continue to be followed. The most frequent adverse events were fatigue, fever, constipation, nausea, and neutropenia. Decitabine administered daily for 5 days in the outpatient setting demonstrated clinical activity with manageable toxicity profile in Int-1 to High risk MDS, suggesting that both the 3- and 5-day regimens provide meaningful clinical benefit to patients.

Abstract INTRODUCTION: The majority of patients (pts) with MDS become red blood cell (RBC) transfusion dependent with escalating risk for transfusional hemosiderosis and its adverse effect on morbidity and mortality. The US03 trial is designed to evaluate long-term efficacy and safety of the oral iron chelator, deferasirox (DFX), in pts with lower risk MDS. In this ongoing study 53 pts have completed 12 months’ (mos) treatment. METHODS: US03 is a Phase II, open-label, 3-year trial in pts with Low- or Int-1 IPSS risk MDS and transfusional iron overload (SF ≥1000 μg/L and >20 units RBC transfusions [tx]), with serum creatinine (SCr) ≤2-fold the upper limit of normal (ULN). Initial DFX dose was 20 mg/kg/day and could be increased to 40 mg/kg/day based on tolerability and response. SF was monitored monthly; LPI, the reactive species of non-transferrin-bound iron, was assessed quarterly. BASELINE FEATURES: 176 pts were enrolled at 45 centers. Mean age was 70 years (range, 21−90), including 102 men, 71 women; and IPSS risk groups of Low 46 pts (27%), Int-1 123 (71%), other 4 (2%). Mean baseline iron status: SF 3398 μg/L (range, 863−36,280); LPI 0.4 μmol/L (0.0−3.6); mean lifetime txs prior to study, 63; years of prior tx 3.5 (0−34). MDS therapy at study entry included chemotherapy, 22 pts; growth factors, 46. Estimated creatinine clearance: normal (>80 mL/min), 77 pts; mild (51−80 mL/min), 68; moderate, (30–50 mL/min) 25; severe (<30 mL/min) 2. Over 12 mos the mean dose was 21 mg/kg/day, and the mean tx rate was 4.1 units/mo. Forty percent of pts had elevated LPI at baseline (≥0.5 μmol/L). RESULTS: Mean SF±SD (μg/L) values: baseline 3398±3088; 3 mos 3065±1743; 6 mos 2775±1355; 9 mos 2759±1562; 12 mos 2603±1336. Sustained suppression of mean LPI to the normal range was achieved after 3 mos of treatment. (Figure shows changes in SF and LPI). Hematologic improvement by IWG criteria: 5 pts (6%); erythroid response: 3 (major 1; minor 2); platelet 2 (major); neutrophil 1 (major). SAFETY: Of 165 pts, only 10 (6%) discontinued secondary to suspected adverse events (AEs), and 7 (4%) serious AEs. There were 11 deaths (7%), all unrelated to DFX. Of 140 pts with normal baseline SCr, 35 (25%) increased >ULN (2.2 mg/dL max SCr). SCr increased >33% above baseline in 11 pts (8%) abnormal at baseline. New onset of thrombocytopenia and neutropenia were 52/165 (32%) and 22/165 (13%), respectively. CONCLUSIONS: DFX therapy decreased mean SF over 1 year in this heavily iron-replete MDS population. Trough LPI normalized in 100% of pts over 12 mos, indicating 24-hour sustained suppression. DFX had a manageable safety profile in this population; new cytopenias were consistent with hematologic progression of MDS. Recent reviews show a 30% increase in hazard ratio for every 500 ng/mL increase in SF >1000 ng/mL; NCCN guidelines recommend consideration of iron chelation in iron-overloaded MDS pts. Ongoing assessments evaluating cardiac, hepatic and endocrine function will evaluate the impact of iron reduction on morbidity and mortality in MDS. Figure Figure

7006 Background: KTE-X19 is an autologous anti-CD19 CAR T cell therapy under investigation for adult R/R ALL. In an interim analysis of Phase 1 of ZUMA-3, we reported manageable safety and encouraging efficacy of KTE-X19; 72% of pts achieved a complete remission (CR) or CR with incomplete bone marrow (BM) recovery (CRi; Wierda et al, ASH 2018. #897). Here, we present end of Phase 1 results. Methods: Adults with R/R B cell ALL, > 5% BM blasts, and ECOG 0-1 received 2, 1, or 0.5 × 106 KTE-X19 cells/kg after conditioning chemotherapy. Revised adverse event management (rAE mgmt) was implemented for additional pts in a 1 × 106 dose cohort: corticosteroids were given earlier at onset of Grade ≥ 2 neurologic events (NEs) and tocilizumab was used only for active toxicity. The primary endpoint was the dose-limiting toxicity (DLT) rate. Key additional endpoints were KTE-X19 levels, incidence of AEs, minimal residual disease (MRD), and CR/CRi rate. Results: As of 9/27/18, 45 pts had received KTE-X19 (median follow-up [f/u], 16 mo). The median age was 46 y (range, 18–77); 30 pts (66%) had ≥ 3 prior therapies and the median pre-conditioning BM blasts was 70% (range, 0–97). Six, 23, and 16 pts received 2, 1, and 0.5 × 106 cells/kg, respectively. There were no DLTs in the DLT-evaluable pts. The most common Grade ≥ 3 AEs were hypotension (38%), pyrexia (38%) and thrombocytopenia (31%). There were 2 previously reported KTE-X19–related Grade 5 AEs of cerebral infarction and multiorgan failure, both in the context of CRS. Grade ≥ 3 CRS and NEs occurred in 13 (29%) and 17 (38%) pts, respectively. Of 41 pts with ≥ 2 mo of f/u, 68% had CR/CRi, and 73% had undetectable MRD. Of 19 pts with ≥ 2 mo of f/u treated with 1 × 106 cells/kg, 16 (84%) had a CR/CRi and the median event-free survival was 15 mo. In 9 pts treated with 1 × 106 cells/kg and rAE mgmt, 2 (22%) had Grade 3 CRS and 1 (11%) had Grade 3 NE with no Grade 4/5 events. Conclusions: KTE-X19 dosing and safety mgmt have been successfully refined by testing 3 cell doses and evaluating a new AE mgmt guideline with altered corticosteroids/tocilizumab use for NE/CRS. Pivotal Phase 2 is ongoing at the 1 × 106 dose with rAE mgmt. Clinical trial information: NCT02614066.

Introduction: Inherited predisposition to myeloid malignancies in adults may be more common than previously suggested with recent studies suggesting a prevalence of candidate predisposition alleles in 15-20% of patients. An inherited predisposition may not be considered in older AML patients despite significant clinical implications for family members as potential stem cell transplant donors. To better define the role of inherited genetic alterations in older AML patients , we analyzed a unique cohort of newly diagnosed older (>60 years) patients enrolled in) Beat AML® Master Trial(BAMT) for candidate genes associated with a known or putative inherited cancer predisposition. Methods: We analyzed extracted DNA from skin and/or saliva samples compared to paired leukemia samples of 176 AML patients enrolled in the BAMT. All samples underwent genomic profiling using a modified FoundationOne®Heme platform (capture-based) and/or the Oregon Health Sciences University panel (amplicon-based), evaluating 477 and 220 genes respectively, with a known role in hematologic malignancies. Germline(GL) variants were identified by the haplotype-based Bayesian genetic variant detector FreeBayes and using variant allele frequency(VAF) values. The pathogenicity and clinical significance of the variants was interpreted according to the 2015 ACMG/AMP guidelines while the AMP/CAP/ASCO guidelines and various disease databases were used in the somatic variant calls. Results: -The mutational landscape of the 176 newly diagnosed older AML patients is detailed in Table 1. Our cohort has a higher proportion of adverse risk patients, consistent with an older AML patient population. 27 pathogenic or likely pathogenic GL variants were detected in 24 AML patients, with a germline mutation prevalence of 14% in this cohort. Deleterious GL mutations were found in the gene DDX41 (5), followed by SBDS (4), CHEK2 (4), MPL (3), BRCA2 (2), HAX1 (2), DNAH9 (2), FANCA (1), FANCL (1), SAMD9 (1), BLM (1), and ATM (1) (Table 2). The types of mutations included missense mutations (9), nonsense mutations (8), frameshift mutations (7), splice site mutations (2), and an exonic deletion (1). Family history of leukemia was available on 129 patients from this cohort. 12 patients have at least one family member with AML. Of these 12 patients, 2 had a deleterious GL alteration identified. Along with the 14% prevalence of pathogenic/likely pathogenic GL mutations , there were an additional 181 GL variants of unknown significance (VUS) in 102 patients, seen in genes implicated in inherited predisposition to hematologic malignancies, most commonly variants in DOCK8 and CREBBP(>5% VUS) with both genes being implicated in leukemogenesis . As skin and/or saliva samples were collected at the time of AML diagnosis, tumor-in-normal presence was expectedly observed. The median VAF for somatic mutations was significantly lower (p < 0.0001) in skin (median 6%; mean 9%; standard deviation (SD) 10%; N=562 variants) than in saliva (median 17%; mean 21%; SD 16%; N=368 variants). In 37 patients who had both saliva and skin tissue concomitantly ,skin had a significantly lower tumor-in-normal presence (median VAF 5%, mean 8%, SD 8%;) than saliva (median 15%, mean 20%, SD 16%)(p < 0.0001). Conclusions: We found a prevalence of 14% pathogenic/ likely pathogenic GL mutations in cancer predisposition genes in this unique cohort of newly diagnosed older AML patients. This finding has potential clinical implications for patients and family members. We also found a large number of VUS in genes implicated in hematological malignancies. Additional studies linking candidate VUS' to familial predisposition to understand contribution to AML predisposition are needed. We are in the process of comparing the manual curation of ACMG classification of pathogenicity with a computational curation algorithm to assess the potential for automated classification of GL variants. Our study suggests the choice of source for germline DNA in patients with AML is variably impacted by leukemic contamination. Cultured skin fibroblasts are the current standard for tumor-normal paired genotyping, with the caveat of being labor intensive and not routinely performed in clinical diagnostic laboratories. This is a critical consideration for rapid GL screening of patients and family members with hematologic malignancies and suspected cancer predisposition. Disclosures Borate: Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Mims:Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Stein:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Patel:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Honoraria; France Foundation: Honoraria. Baer:Astellas: Research Funding; Abbvie: Research Funding; AI Therapeutics: Research Funding; Forma: Research Funding; Incyte: Research Funding; Kite: Research Funding; Takeda: Research Funding. Stock:Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Daiichi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria. Schiller:Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding. Blum:AmerisourceBergen: Consultancy; Forma: Research Funding; Xencor: Research Funding; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Astellas,: Research Funding. Shami:JSK Therapeutics: Employment, Equity Ownership; Amgen: Research Funding; Pfizer: Research Funding; Cantex: Research Funding; Aptevo: Research Funding; Jazz: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Lone Star Thiotherapies: Equity Ownership. Foran:Agios: Honoraria, Research Funding. Byrd:Acerta: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau. Druker:OHSU (licensing fees): Patents & Royalties: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees ; Bristol-Myers Squibb: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Novartis: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Patents & Royalties: Patent 6958335, Treatment of Gastrointestinal Stromal Tumors, exclusively licensed to Novartis, Research Funding; Monojul: Other: former consultant; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Beat AML LLC: Other: Service on joint steering committee; Merck & Co: Patents & Royalties: Dana-Farber Cancer Institute license #2063, Monoclonal antiphosphotyrosine antibody 4G10, exclusive commercial license to Merck & Co; Dana-Farber Cancer Institute (antibody royalty): Patents & Royalties: #2524, antibody royalty; Aileron Therapeutics: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees , Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Patents & Royalties, Research Funding; Pfizer: Research Funding; ALLCRON: Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptose Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Beta Cat: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; GRAIL: Equity Ownership, Other: former member of Scientific Advisory Board; Cepheid: Consultancy, Honoraria; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Pfizer: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; ICON: Other: Scientific Founder of Molecular MD, which was acquired by ICON in Feb. 2019; CureOne: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Other: former member of Scientific Advisory Board. Vergilio:Foundation Medicine, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Levine:Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Honoraria; Gilead: Consultancy; Lilly: Honoraria; Qiagen: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Loxo: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy.

*equal contribution of AB, RLL, BD and JCB Background: Acute myeloid leukemia (AML) is common with increasing age, and older adults with AML rarely achieve long-term remission with chemotherapy. Gene discovery studies in older adults with AML have shown that this malignancy is characterized by a multitude of somatic genomic alterations beginning with initiating somatic events followed by acquisition of collaborative transforming mutations. Despite these important biologic insights, current therapeutic approaches to AML remain limited, particularly in adults ≥ 60 years of age. The Beat AML trial was designed to assess the feasibility of using genetic profiling to assign patients (pts) to molecularly defined, subtype-specific therapies within 7 days of the initial diagnosis in a multi-center clinical trial setting, and to delineate the role of molecularly informed first-line treatment of AML with mechanism based novel therapies. Methods: Treatment-naïve patients with AML were enrolled in this prospective trial which offered accelerated cytogenetic and comprehensive mutational testing within 7 days followed by treatment assignment using these molecular data. Pt eligibility included age ≥ 60 years with non-APML AML, no known CNS leukemia, no prior hypomethylating agent (HMA) therapy and no clinical need for emergent therapy. Eligible pts were profiled by local cytogenetics analysis and using a central next generation sequencing (NGS) assay (Foundation Medicine, Inc.) with all molecular data required for treatment assignment (TA) obtained < 7 days. TA was made centrally using a pre-determined algorithm considering somatic cytogenetic and molecular alterations in the dominant clone, available targeted therapeutics for specific AML subsets, and the likelihood of cure with intensive chemotherapy. Results: From November 2016 to January 2019, 487 pts with a suspected diagnosis of AML had enrolled at 14 clinical sites; 395 were eligible for the study (77% of the patients not eligible for the study had an alternative diagnosis). The median age of eligible patients was 72 years (range: 60 to 92) with 38% being≥ 75 years and 16% with treatment-related AML. From the 395 eligible patients, 374 (94.7%) were centrally assigned to the different cytogenetic/genomic groups within 7 days. The most common groups were TP53 mutated (19%) and marker negative (18%) molecular groups. The Beat AML trial is dynamic by design, thereby allowing different arms to open over time; all trial arms are designed to evaluate for substantial clinical efficacy in small, molecularly defined patient subsets. As shown in Figure 1, 224 patients (57%) had a TA and consented to a BEAT AML sub-study. Of the remaining 171 patients, 103 received standard therapy defined as induction therapy (7+3) or hypomethylation agent (25 before TA and 78 after TA), 28 received an alternative investigational agent (5 before TA and 23 after TA), 38 received palliative care, and 2 had an unknown treatment status and are grouped with the palliative care patients in subsequent analyses; 9 patients died before TA (2 who received standard therapy and 7 in the palliative care group). Demographic, clinical, performance and molecular characteristics were not largely different between pts who elected targeted therapy as part of the BEAT AML trial versus those who elected standard therapy. As shown in Figure 2, the overall survival was significantly longer for patients enrolled in a targeted therapy arm as part of the BEAT AML trial compared to those who elected standard therapy. (p<0.0001). The 30-day estimated death rate was 3.7% (95% CI: 1.9-7.2) for patients electing treatment on a BEAT AML sub-study, 20.4% (95% CI: 13.0-31.2) for those receiving standard therapy, 0% for those receiving an investigational therapy, and 72.6% (95% CI: 57.8-85.7) for the palliative care group. Conclusion: Our data support the feasibility of a rapid precision medicine approach in older patients with previously untreated AML. Patients with AML who elected treatment assigned based upon cytogenetic and molecular alterations in the dominant clone using a novel precision medicine approach had significantly improved overall survival versus those who elected standard of care treatment. Disclosures Levine: Gilead: Consultancy; Prelude Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees; Loxo: Membership on an entity's Board of Directors or advisory committees; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Lilly: Honoraria. Mims:Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Borate:Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Stein:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baer:Takeda: Research Funding; Incyte: Research Funding; Kite: Research Funding; Forma: Research Funding; AI Therapeutics: Research Funding; Abbvie: Research Funding; Astellas: Research Funding. Stock:Daiichi: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; UpToDate: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Deininger:Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma: Consultancy, Honoraria; TRM: Consultancy; Sangoma: Consultancy; Fusion Pharma: Consultancy; Adelphi: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Humana: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Sangamo: Consultancy; Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Blum:Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Astellas,: Research Funding; Xencor: Research Funding; Forma: Research Funding; AmerisourceBergen: Consultancy. Schiller:Amgen: Other, Research Funding; Agios: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Bristol Myer Squibb: Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding. Olin:Daiichi Sankyo: Research Funding; Astellas: Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Revolution Medicine: Consultancy; AstraZeneca: Research Funding; Clovis: Research Funding; Ignyta: Research Funding; MedImmune: Research Funding; Mirati Therapeutics: Research Funding; Novartis: Research Funding; Spectrum: Research Funding. Foran:Agios: Honoraria, Research Funding. Lin:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria. Traer:AbbVie: Consultancy; Agios: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Notable Labs: Equity Ownership. Odenike:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding; Astex Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Gilead Sciences: Research Funding; Janssen Oncology: Research Funding; Oncotherapy: Research Funding; Agios: Research Funding; CTI/Baxalta: Research Funding. Arellano:Gilead: Consultancy. Vergilio:Roche Holding AG: Equity Ownership; Foundation Medicine: Employment. Brennan:Foundation Medicine: Employment. Vietz:Foundation Medicine: Employment. Druker:ALLCRON: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Aileron Therapeutics: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees , Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Patents & Royalties, Research Funding; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy, Honoraria; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; GRAIL: Equity Ownership, Other: former member of Scientific Advisory Board; Patient True Talk: Consultancy; Dana-Farber Cancer Institute (antibody royalty): Patents & Royalties: #2524, antibody royalty; Pfizer: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Merck & Co: Patents & Royalties: Dana-Farber Cancer Institute license #2063, Monoclonal antiphosphotyrosine antibody 4G10, exclusive commercial license to Merck & Co; OHSU (licensing fees): Patents & Royalties: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees ; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptose Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Beta Cat: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Beat AML LLC: Other: Service on joint steering committee; CureOne: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Gilead Sciences: Other: former member of Scientific Advisory Board; ICON: Other: Scientific Founder of Molecular MD, which was acquired by ICON in Feb. 2019; Monojul: Other: former consultant; Novartis: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Patents & Royalties: Patent 6958335, Treatment of Gastrointestinal Stromal Tumors, exclusively licensed to Novartis, Research Funding; Bristol-Myers Squibb: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding. Byrd:Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau.

Background Interferons are recognized as active agents in the treatment of patients with high risk essential thrombocythemia (ET) or polycythemia vera (PV), both in the upfront setting as well as beyond. Several trials have shown high rates of hematologic and molecular responses with the use of interferons, however, data on direct comparison of interferon activity in patients with early disease in comparison to patients refractory or resistant to prior therapies, such as hydroxyurea (HU) are lacking. We conducted a controlled analysis of the activity of pegylated interferon alfa-2a (PEG) in two prospective parallel clinical trials conducted in these two unique patient populations. Methods The MPD-RC 111 (NCT01259817) was an international, multicenter, phase 2 open-label clinical trial that evaluated PEG therapy in patients with high risk PV and high-risk ET who were either refractory or intolerant (R/I) to HU by modified ELN criteria. The MPD-RC 112 trial (NCT01258856) enrolled patients with high risk ET/PV who were treatment-naïve (TN) (HU <3 months) and randomized them (1:1) to PEG or HU. All patients randomized to PEG were included in this analysis. Both protocols were conducted concurrently at the MPD-RC member institutions and utilized a similar primary endpoint of overall response rate (complete and partial response rates) by ELN Criteria at 12 months confirmed by the same blinded central review committee. Both studies utilized the same PEG starting dose of 45 mcg weekly and was titrated for response to a maximum of 180 mcg weekly. Secondary endpoints included safety information, impact on disease biomarkers, bone marrow (BM) response, and quality of life data. Results Patients ET: 39 TN and 65 R/I ET patients were available for this analysis. Median disease duration was 2.9 months in TN and 37.3 months in R/I patients. Baseline characteristics and demographics were similar in the two cohorts except lower baseline hemoglobin level in RI patients. (Table1A) PV: 43 TN and 50 R/I PV patients were included. Median disease duration was 2.5 months in TN and 54.8 months in R/I patients. Baseline characteristics only differed by lower frequency of phlebotomy rate in R/I patients. (Table1B) Baseline symptoms scores and quality of life were similar in TN and RI groups (Table 2) Response ET: CR/PR/ORR at 12 months were observed in 43.1%/26.2%/69.2% in R/I ET patients and in 43.6%/25.6%/69.2% in TN ET patients (p=0.99 for ORR). (Table 3, Figure 1) PV: CR/PR/ORR at 12 months were observed in 22%/38%/60% in R/I PV patients, and in 27.9%/58.1%/86% in TN PV patients (p=0.005 for ORR). (Table 3, Figure 1) Safety PEG was equally well tolerated throughout both treatment groups with treatment discontinuation due to adverse events occurring in 14.6% in TN patients and 13.9% in R/I patients. The mean (SD) dose of PEG was 102.7 (52.3) mcg in R/I ET patients and 128.7mcg (46.4) in R/I PV patients. For TN patients, mean dose was 85.7mcg (59.7) in ET and 93.5 mcg (44.0) in PV. Adverse events were consistent with historic reports of PEG use and the distribution of events was similar in R/I and TN patients. (Table 4) Conclusion This intention to treat response analysis included TN and R/I ET and PV patients with balanced baseline characteristics who received prospective therapy with PEG. Patients with ET had a higher overall response rate at 12 months that was equivalent in patients who were treatment-naïve and in patients who were intolerant or refractory to HU. By contrast, patients with PV who were treatment-naïve had a higher ORR than patients those intolerant or refractory to HU. We conclude that treatment with PEG is an effective therapeutic option both treatment naïve PV and ET as well as those previously treated with HU, however PEG as a second line agent is especially effective in ET patients. Disclosures Yacoub: Hylapharm: Equity Ownership; Agios: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Equity Ownership; Cara: Equity Ownership; Dynavax: Equity Ownership. Mascarenhas:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche: Consultancy, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding. Mesa:AbbVie: Research Funding; Samus: Research Funding; Incyte: Research Funding; Sierra Onc: Consultancy; Genotech: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; CTI Biopharma: Research Funding; La Jolla Pharma: Consultancy. Rampal:Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. McMullin:Daiko Sanyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Italopharma: Membership on an entity's Board of Directors or advisory committees. Ewing:Novartis: Honoraria, Other: Meeting attendance sponsorship ; Bristol Myers-Squibb: Other: Meeting attendance sponsorship . O'Connell:Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Mead:Bristol Myers-Squibb: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; CTI: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Pfizer: Consultancy. De Stefano:Alexion: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Baer:Astellas: Research Funding; Al Therapeutics: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Forma: Research Funding; Kite: Research Funding; Takeda: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kremyanskaya:La Jolla: Consultancy; Incyte, Celgene, Constellation, Protagonist.: Research Funding. Hexner:novartis: Research Funding. Rambaldi:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support. Ritchie:Genentech: Other: Advisory board; Tolero: Other: Advisory board; agios: Other: Advisory board; Pfizer: Other: Advisory board, travel support; Celgene: Other: Advisory board; Jazz Pharmaceuticals: Research Funding; Celgene, Novartis: Other: travel support; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Celgene, Incyte, Novartis, Pfizer: Consultancy. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy. Harrison:Promedior: Honoraria; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Celgene: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; CTI: Speakers Bureau; AOP: Honoraria; Shire: Speakers Bureau; Roche: Honoraria; Gilead: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hoffman:Merus: Research Funding. OffLabel Disclosure: Pegylated Interferon Alfa-2a for in Patients with Polycythemia Vera or Essential Thrombocythemia

Background: NGS of myeloid mutations is an integral part of AML clinical decision-making. There is currently no information regarding concordance between NGS panels in AML using samples from the same patient across various platforms in different diagnostic laboratories. To study this important question, we analyzed NGS of myeloid mutations in diagnostic samples from The Beat AML Master Trial (BAMT) for newly diagnosed older AML patients, and compared variant calls made between institutional laboratories enrolling the study subject with those made by Foundation Medicine (FM), the central laboratory used for treatment assignment in this precision medicine trial. Methods: We identified newly diagnosed AML patient samples (peripheral blood (PB) and/or bone marrow (BM)) from 2 lead institutions in the BAMT(Ohio State, OSU and Oregon Health and Sciences University, OHSU) that were analyzed by both the institutional and by FM from Nov 15, 2016 to Apr 15, 2019. Samples sent to both laboratories >3 days apart were excluded. Samples were analyzed at the institutional laboratories using their respective NGS mutational panels and by FM using the FoundationOne®Heme(FMH) NGS panel which utilizes capture based sequencing. The OSU NGS assay utilizes sequencing on Illumina MiSeq. The OHSU NGS assay employs semiconductor-based sequencing (Ion Torrent PGM platform). The variant allele frequency (VAF) sensitivity for detection for all 3 laboratories range from 1-2%. We evaluated the ability to identify mutations in 8 genes : FLT3, IDH1/ 2, NPM1, TET2, DNMT3A, WT1 and TP53 used in treatment assignment in theBAMT. A detection cutoff of 2% was used to define the presence or absence of a mutation. Overall, agreement was defined as the number of times the local and central laboratories made the same call divided by the total number of patients. Sensitivity was defined as the number of present calls made locally divided by the number of present calls made centrally, and specificity as the number of absent calls made locally divided by the number of absent calls made centrally. The overall kappa statistic, controlling for institution, provided another measure of agreement between local and central calls, where a value of 1 indicates perfect agreement. Results: 194 patient samples were identified using methods above and analyzed locally at the screening institution (125 at OSU, 69 at OHSU) and centrally at FM. Type of tissue analyzed for variants between local site and FM were 59 PB, 129 BM, and 6 with BM/PB mismatch. Overall agreement in presence/absence calls between local and central results for each of the 8 genes was over 95% (Table 1). There was perfect agreement for NPM1. The sensitivity was above 94% for all genes except TP53 (88.6%) and WT1 (63.6%). Failure to detect a mutation locally was primarily due to reporting of all TP53 variants, including variants of unknown significance (VUS) (5) by FM as agreed upon in the study protocol, detection at low levels below local site sensitivity cutoff (1), detection of variants in a portion of gene not covered at the local site(1)and possible artifact (1). For the WT1 gene, discordance in 5 samples included VUS (3) reported by FM ,a variant detected in a portion of the gene not covered at the local site(1).and difference in leukemic tissue analyzed with mutation not detected by the central laboratory on a PB sample, and present at the institutional lab on a BM sample; affecting the overall agreement and specificity but not sensitivity. Specificity was at least 98% for each of the 8 genes. Finally, most discrepancies in reported mutations in FLT3 (n=2), IDH1 (n=1), IDH2 (n=2), DNMT3A (n=4) and TET2 (n=5) were due to reporting of VUS in one laboratory and not by another. Conclusion: Detection of pathogenic myeloid mutations using orthogonal assays showed a high degree of concordance for genes used in therapeutic assignment on the BAMT.The small number of discordant results, in TP53 and WT1, were attributed to the reporting of VUS. This study illustrates the importance of quality control and standardization as NGS continues to be widely utilized in AML for clinical decision making, with a variety of platforms across multiple laboratories. Our next steps involve evaluating the differences in VAFs reported between local and central laboratories when a given mutation is identified, as well as the potential reasons for observed differences and clinical implications of known pathogenic mutations vs putative VUS. Disclosures Borate: Daiichi Sankyo: Consultancy; AbbVie: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy. Vergilio:Foundation Medicine: Employment; Roche Holding AG: Equity Ownership. Stein:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baer:Astellas: Research Funding; Abbvie: Research Funding; AI Therapeutics: Research Funding; Forma: Research Funding; Incyte: Research Funding; Kite: Research Funding; Takeda: Research Funding. Stock:Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; UpToDate: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Schiller:Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Agios: Research Funding, Speakers Bureau. Blum:AmerisourceBergen: Consultancy; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Astellas,: Research Funding; Xencor: Research Funding; Forma: Research Funding. Kovacsovics:Pfizer: Research Funding; Jazz: Consultancy; Novartis: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding. Foran:Agios: Honoraria, Research Funding. Druker:Pfizer: Research Funding; OHSU (licensing fees): Patents & Royalties: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees ; Cepheid: Consultancy, Honoraria; Aileron Therapeutics: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees , Membership on an entity's Board of Directors or advisory committees; ALLCRON: Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptose Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Beta Cat: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; GRAIL: Equity Ownership, Other: former member of Scientific Advisory Board; Patient True Talk: Consultancy; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Beat AML LLC: Other: Service on joint steering committee; CureOne: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Gilead Sciences: Other: former member of Scientific Advisory Board; ICON: Other: Scientific Founder of Molecular MD, which was acquired by ICON in Feb. 2019; Monojul: Other: former consultant; Novartis: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Patents & Royalties: Patent 6958335, Treatment of Gastrointestinal Stromal Tumors, exclusively licensed to Novartis, Research Funding; Bristol-Myers Squibb: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Pfizer: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Merck & Co: Patents & Royalties: Dana-Farber Cancer Institute license #2063, Monoclonal antiphosphotyrosine antibody 4G10, exclusive commercial license to Merck & Co; Dana-Farber Cancer Institute (antibody royalty): Patents & Royalties: #2524, antibody royalty; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Patents & Royalties, Research Funding. Byrd:Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Ohio State University: Patents & Royalties: OSU-2S. Levine:C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Prelude Therapeutics: Research Funding; Novartis: Consultancy; Gilead: Consultancy; Lilly: Honoraria; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees. Mims:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Although approximately half of adult patients with acute lymphoblastic leukemia (ALL) achieve long-term survival, those who relapse have poor long-term outcomes (El Fakih et al. Hematol Oncol Stem Cell Ther. 2017; Oriol et al. Haematologica. 2010). The initial report of Phase 1 of ZUMA-3, the Phase 1/2 trial of KTE-C19 for treatment of relapsed/refractory (R/R) ALL (NCT02614066), has thus far demonstrated promising efficacy among patients infused with KTE-C19, with a 71% complete remission (CR) rate (CR or CR with incomplete hematologic recovery [CRi]), 88% undetectable minimal residual disease (MRD), and manageable toxicity across all doses (Shah et al. ASH 2017. #888). Here, we present updated safety and efficacy data from Phase 1 of ZUMA-3. Methods: Adult patients (≥ 18 y) with R/R ALL (Ph+ allowed), > 5% bone marrow blasts, and ECOG 0-1 received 2, 1, or 0.5 × 106 CAR T cells/kg after low-dose conditioning chemotherapy with fludarabine 25 mg/m2/day for 3 days and a single dose of cyclophosphamide 900 mg/m2 on the third day of conditioning. The primary endpoint for Phase 1 was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included incidence and time to onset and resolution of adverse events (AEs), rate of undetectable MRD remission in the bone marrow using flow cytometry, and duration of remission. KTE-C19 expansion and persistence were also assessed. Safety analyses included all patients who received KTE-C19, and patients with ≥ 2 months of follow-up were evaluated for efficacy. Results: As of April 12, 2018, 35 patients have received KTE-C19 with a median follow-up of 11 months (range, 2 - 25 months). The median age was 40 years (range, 18 - 69 years), 51% of patients were male, 66% had ECOG 1, 13 patients (37%) had prior blinatumomab, and 60% had received ≥ 3 prior lines of treatment. The median bone marrow blast burden at screening was 70% (range, 5 - 100). Six patients received the 2 × 106 cells/kg dose, 14 received 1 × 106 cells/kg, and 15 received 0.5 × 106 cells/kg. No DLTs were observed in the DLT period. The most common Grade ≥ 3 AEs were hypotension (40%), pyrexia (34%), decreased platelet counts (34%), and anemia (31%). Grade ≥ 3 CRS occurred in 9 patients (26%), with a median time to onset of 5 days (range, 1 - 15 days). There were 2 KTE-C19-related Grade 5 events: 1 cerebral infarction at the 0.5 × 106 cells/kg dose and 1 previously reported multiorgan failure secondary to cytokine release syndrome (CRS) at the 2 × 106 cells/kg dose. Grade ≥ 3 CRS resolved in all patients (not including 2 patients with a Grade 5 event), and the median time to resolution was 11 days (range, 7 - 42 days). Grade ≥ 3 treatment-emergent neurologic events occurred in 16 patients (46%), and the median time to onset was 7 days (range, 4 - 24 days). With the exception of 2 patients with unresolved neurologic events due to death, Grade ≥ 3 neurologic events resolved in all patients (14/14), with a median time to resolution of 17 days (range, 6 - 53 days). Among the 32 patients evaluable for response, the overall rate of undetectable MRD was 78% (95% CI, 60% - 91%). CR or CRi was achieved by 23 patients (72%), and 1 patient (3%) had blast-free BM. KTE-C19 levels were examined in 23 patients as of July 31, 2017. Robust KTE-C19 expansion was observed across all dose levels assessed. Conclusion: High rates of remission were achieved by adult patients with R/R ALL, with approximately three-quarters of patients achieving CR or CRi with undetectable MRD after a single dose of KTE-C19 in ZUMA-3. The safety profile was generally manageable, and most cases of high-grade CRS and neurologic events resolved. These results demonstrate that KTE-C19 offers clinical benefit for patients with otherwise limited treatment options. Disclosures Wierda: AbbVie, Inc: Research Funding; Genentech: Research Funding. Bishop:United Healthcare: Employment; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Speakers Bureau; Juneau Therapeutics: Speakers Bureau; Novartis Pharmaceuticals Corporation: Speakers Bureau. Logan:Adaptive Biotech: Consultancy; Napajen: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Schiller:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Holmes:Unum: Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; Novartis: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Rigel: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy. Abedi:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Research Funding; CIRM: Research Funding; BMS: Speakers Bureau; Takeda: Speakers Bureau; Gilead: Speakers Bureau; Celgene: Research Funding. Arellano:Cephalon: Research Funding. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Mardiros:Kite, a Gilead Company: Employment; Kite, a Gilead Company: Equity Ownership; Mustang Bio: Patents & Royalties; Kite, a Gilead Company: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Shen:Zhejiang DTRM Biopharma LLC: Other: Clinical Operations Director. Vezan:Kite Pharma: Employment; Kite, Gilead, Abbv, MRK: Equity Ownership. Jain:Kite Pharma, Amgen: Equity Ownership; Kite Pharma: Employment; Kite Pharma: Patents & Royalties.