Abstract: The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

Abstract: Background: High-risk AML including relapsed and/or refractory (R/R) disease remains largely incurable. There is no standard therapy for R/R AML but HiDAC based regimens are commonly employed. We hypothesized that the use of azacitidine (AZA), a DNA methyltransferase inhibitor and epigenetic modulator, followed by HiDAC and Mito would sensitize leukemia cells to chemotherapy. Methods: We performed a phase I dose escalation trial in cohorts of patients (pts) with high risk AML that combined increasing doses of AZA with a fixed dose/schedule of HiDAC/Mito. The primary endpoint of the study was to determine the maximum tolerated dose (MTD) of AZA when given in combination with HiDAC/Mito. AZA was given daily on days 1-5 followed by single doses of HiDAC 3 gm/m2 and Mito 30 mg/m2 on days 6 and 10. Dose reductions were made to 2mg/m2 and 20 mg/m2 for HiDAC and Mito, respectively, for pts 〉 70. Cohorts of 3-6 pts were treated in a dose escalation design to a maximum AZA dose of 75 mg/m2. Dose limiting toxicity (DLT) was defined as any grade 4 or greater non hematologic toxicity, grade 3 non hematologic toxicity lasting 〉 7 days, or persistent bone marrow aplasia in the absence of bone marrow involvement for 〉 56 days. Once a dose level had been declared tolerable, additional pts could be enrolled at that level to provide additional toxicity and efficacy experience while further dose escalation was ongoing. Results: As of July 2015, 46 pts had enrolled. AZA dose levels were 37.5mg/m2 (n=18), 50 mg/m2 (n=16), 75mg/m2 (n=12). Median age = 66 (range, 21-83). R/R AML = 25 (54%), de novo t-MN =10 (22%), de novo AML arising from antecedent myeloid neoplasm = 6 (13%), untreated de novo AML in pts age 〉 60 = 5 (11%). 17 (37%) of pts were in first relapse, 4 (9%) were beyond first relapse, and 4 (9%) were primary refractory. Median number of prior therapies was 1 (range of 0-4 prior therapies). Prior therapies included cytarabine and anthracycline =21 (46%), HiDAC =14 (30%), AZA =9 (20%) and allogeneic stem cell transplant (alloSCT) =9 (20%). Molecular/genetic group profiles by European Leukemia Net (ELN) criteria included adverse =21 (46%), intermediate I =10 (22%), intermediate II =7 (15%), favorable =7 (15%) and unknown in 1 patient. Pts in the favorable ELN group all had R/R AML, AML from antecedent myeloid neoplasm, or age 〉 60. Myelosuppression was the most common toxicity and universal. Both median and average times to count recovery (defined as ANC 〉 1000, platelet count 〉 100,000, and independent of RBC transfusions) from initiation of AZA (Day 1) was 42 days and from initiation of HiDAC (Day 6) was 37 days. Common toxicities included 38 cases of febrile neutropenia (87%) and pneumonia (20%). This was similar to our prior published retrospective experience with only the HiDAC/Mito regimen; 64% had neutropenic fever and a 20% had pneumonia (Larson S et al, Leuk Lymphoma 2012). There was 1 DLT from reversible acute liver failure at the 37.5mg/m2 dose level in a pt with relapsed t-MN and prior chemoradiotherapy for both breast cancer and mantle cell lymphoma. 30 day and 60 day induction mortality was 2% (1 pt with refractory AML died from sepsis). Pts in the highest AZA dose cohort had similar rates of hematologic and non-hematologic toxicity as well as time to count recovery as lower dose cohorts. 45 pts were evaluable for response: CR =19 (42%), CRi= 7 (16%), ORR (CR/CRi/PR) =27 (60%). Among pts with R/R AML, CR = 8 (32%), CRi = 5 (20%); among pts with untreated de novo AML and age 〉 60, CR = 4 (80%). In first relapse, CR = 7 (41%) with an ORR =11 (65%). Response rates were similar at all 3 AZA dose levels (Table 1). All 7 pts with favorable ELN risk entered CR including 5 with R/R disease. Overall, 18 (40%) pts proceeded to alloSCT after treatment. Conclusions: The AZA/HiDAC/Mito regimen is feasible and tolerable. AZA dose escalation was feasible up to 75 mg/m2/day. It is associated with significant clinical activity with an ORR of 60% and allowed 40% of pts to proceed to alloSCT. The recommended phase II dose is 75 mg/m2 of AZA given daily on days 1-5 followed by 3g/m2 HiDAC and 30mg/m2 Mito on days 6 and 10. A randomized study is required to assess the relative contribution of AZA to HiDAC/Mito for remission induction in high risk AML. Correlative laboratory studies to analyze the effects of AZA on deoxycytidine kinase and related enzymes involved in cytarabine metabolism are ongoing. Table 1. AZA Dose Level # Pts Evaluated CR CRi PR TF DLT 37.5 mg/m2 18 10 2 0 6 1 50 mg/m2 16 5 3 1 7 0 75 mg/m2 11 4 2 0 5 0 Disclosures Off Label Use: Azacitidine (DNA methyltransferase inhibitor) used in combination with high dose cytarabine and mitoxantrone for induction therapy in acute myeloid leukemia. Liu:Pfizer: Consultancy; Pfizer: Consultancy; Astra Zeneca/Medimmune: Consultancy; Astra Zeneca/Medimmune: Consultancy. Thirman:AbbVie: Research Funding; Gilead: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Merck: Research Funding. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Introduction B progenitor acute lymphoblastic leukemia (B-ALL) is a leading cause of childhood cancer death. Many chimeric genes have been identified and led to a refined classification of B-ALL and tailored therapies. Still, up to 30% of B-ALL cannot be classified into established subtypes, and the outcome for many is poor. Methods To identify novel subtypes of B-ALL, we performed integrative genomic analysis including transcriptome sequencing (RNA-seq) of 1,988 cases from St. Jude, Children's Oncology Group and adult cooperative group studies and analyzed chromosomal rearrangements, gene-expression profiles (GEP), somatic mutations and chromosome-level copy-number alterations. Cases lacking known or putative subtype-defining alterations underwent whole genome sequencing. Effects on proliferation and transformation of novel lesions were assessed by retroviral expression in cell lines and point-mutation knock-in mice using CRISPR/Cas9 genome editing. Results Using integrated genetic alterations and gene expression profiling, we classified 23 B-ALL subtypes (Table and Figure). Three groups included cases with similar GEP as canonical subtypes (ETV6-RUNX1, KMT2A-rearranged, and ZNF384-rearranged), but lacking the expected drivers (e.g., ETV6-RUNX1-like, n=42). Eighteen cases (0.9%) had rearrangements of BCL2, MYC and/or BCL6 showing a distinct GEP; they were mostly adults (n=16) with very poor outcome. These alterations, rarely seen in ALL, are identical to those observed in "double/triple hit" lymphoma, and are of pre-B immunophenotype. Eight cases with tightly clustered GEP comprised a novel subtype defined by IKZF1 N159Y missense mutation. N159Y is in the DNA-binding domain of IKZF1, and is known to perturb IKZF1 function, with distinct nuclear mislocalization and induction of aberrant intercellular adhesion. We identified two subtypes with distinct GEP characterized by PAX5 alterations. One, herein termed PAX5 altered (PAX5alt), comprised 148 (7.4%) cases, was characterized by diverse PAX5 alterations including rearrangements (n=57), sequence mutations (n=46) and/or focal intragenic amplifications (n=8). These PAX5 alterations were found in 73.6% of PAX5alt cases and different alteration types were mutually exclusive. Other PAX5 alterations, including deletions and large-scale amplifications were also assessed using SNP array, but were not enriched in the PAX5alt group. Clinically, PAX5alt pediatric and adult patients had favorable (96.8±3.2%) and intermediate (42.1±10.2%) 5-year overall survival (OS), respectively. The other GEP distinct subtype comprised 44 cases, all with PAX5 P80R missense mutations. In 30 of these cases, PAX5 P80R was homozygous due to deletion of the wild-type (WT) PAX5 allele or copy-neutral loss of heterozygosity. Of the other 14 cases with heterozygous PAX5 P80R mutations, 13 had a second frameshift (n=7), nonsense (n=2) or deleterious missense (n=4) PAX5 mutation. Four of the remaining 1,944 cases also had the PAX5 P80R mutation, but all were heterozygous with preservation of a WT PAX5 allele, consistent with the notion that homozygous or compound heterozygous PAX5 P80R mutation is the hallmark of this subtype. Adult PAX5 P80R cases (n=14) showed better 5-year OS (61.9±13.4%) than those in PAX5alt subtype (42.1±10.2%). To examine the effects of PAX5 P80R on B-cell maturation, WT PAX5, PAX5 P80R, V26G and P34Q were expressed in Pax5-/- lineage-depleted bone marrow cells. Expression of WT PAX5, PAX5 V26G and P34Q resulted in near complete rescue of B cell differentiation; however, expression of PAX5 P80R blocked the differentiation at the pre-pro-B stage of B-cell maturation. Further, Pax5 P80R heterozygous or homozygous mice developed pre-B-ALL with a median latency of 166 and 87 days, respectively, with heterozygous mice acquiring alterations on the second allele. In contrast, Pax5+/- mice, and those harboring G183S mutation observed in familial leukemia, do not spontaneously develop B-ALL. Conclusions These results show the utility of transcriptome sequencing in defining subtypes and founding genetic alterations in B-ALL, provide a revised taxonomy of the disease across the age spectrum, and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis. Disclosures McKay: ImmunoGen Inc.: Employment. Tallman:Orsenix: Other: Advisory board; AROG: Research Funding; BioSight: Other: Advisory board; Cellerant: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Konopleva:Stemline Therapeutics: Research Funding. Relling:Shire Pharmaceuticals: Research Funding. Mullighan:Cancer Prevention and Research Institute of Texas: Consultancy; Amgen: Honoraria, Speakers Bureau; Abbvie: Research Funding; Loxo Oncology: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau.

Abstract: Background: Selinexor, an exportin 1 (XPO1) inhibitor, has demonstrated anti-leukemic effect as a single agent. There are also data demonstrating synergistic killing of leukemia cells with the combination of selinexor with anthracyclines and/or DNA damaging agents. The HiDAC/Mito combination is an effective induction regimen for relapsed/refractory (R/R) AML patients with a reported overall response rate (ORR) of 55% at our institution. We hypothesize that adding selinexor to HiDAC/Mito is feasible and has synergistic anti-leukemic effects. Methods: We performed a phase I dose escalation trial with cohort expansion in patients with AML that combined increasing doses of selinexor with age-adjusted HiDAC/Mito (NCT02573363). The primary endpoint was to determine the maximum tolerated dose of selinexor when given in combination with HiDAC/Mito. Selinexor was given orally on days 2, 4, 9, and 11 during the induction phase of the study. HiDAC (1.5 to 3 gm/m2 depending on age, IV over 3 hours) followed immediately by Mito (20 to 30 mg/m2 IV over 1 hour) was administered on day 1 and 5. Initial selinexor dose was 60mg (~35mg/m2) followed by a dose escalation to a target level of 80mg (~50mg/m2). Patients who entered remission proceeded to stem cell transplantation (SCT) or consolidation chemotherapy with HiDAC/selinexor followed by maintenance therapy with weekly selinexor alone for up to one year. Dose limiting toxicity (DLT) was defined as any grade 3 or greater non-hematologic toxicity, except transient ( 〈 48 hours) nausea/vomiting or liver function abnormalities, or by persistent bone marrow aplasia lasting 〉 56 days in the absence of disease. Once a dose level was declared tolerable, more patients could be enrolled at that level to provide additional safety, tolerability, and efficacy data. Results: As of July 2016, 12 patients had enrolled. Selinexor dose levels were 60mg (n=3) and 80mg (n=9). Median age = 61 (range 44 - 74). De novo AML = 5 (42%); secondary AML = 3 (25%), R/R AML = 4 (33%). Eight (67%) patients were previously untreated, 1 (8%) was beyond the first relapse, and 3 (25%) had primary refractory disease. Prior therapies included combination cytarabine with anthracycline, HiDAC, decitabine, and clinical trial agents. Molecular/genetic subgroup profiles by European Leukemia Net (ELN) criteria included favorable = 1 (8%), intermediate I = 5 (42%), intermediate II = 1 (8%), and adverse = 5 (42%). Only 10 patients are evaluable for safety and efficacy at the time of analysis. Myelosuppression was the most common side effect and was universal. Median and average times to count recovery for responding patients from day 1 were 38 and 47 days, respectively. Febrile neutropenia was observed in 8 patients (80%), compared to our historical experience of 64% for HiDAC/Mito alone. Other significant adverse events included line-associated thromboses (n=3), cardiac toxicity (n=3), cerebellar toxicity (n=1), arm cellulitis (n=1), and syncope (n=1). No DLTs were observed. 30 and 60-day induction mortality was 10% (1 patient with R/R AML died from progressive disease). Ten patients are evaluable for response: complete remission (CR) = 4 (40%), CR with incomplete count recovery (CRi) = 1 (10%), partial remission (PR) = 1 (10%), and treatment failure (TF) = 4 (40%). Thus, the ORR is 60%. Of those who responded, 2 patients proceeded to consolidation, 1 underwent allo-SCT, and 3 are in preparation for allo-SCT. No response was achieved in patients with R/R AML. Bone marrow samples from screening and day 12 of treatment were used for biomarker analysis in three CR patients. A marked reduction in KI67, MYC, FLT3, KIT, and DNA damage response proteins was observed in the remaining tumor cells in the post-treatment samples. Staining for P53 showed an increase in nuclear staining intensity, which is consistent with the known effect of selinexor on tumor cells. Conclusions: The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses up to 80mg/day or ~50 mg/m2/day twice weekly. It yields an ORR of 60% based on currently available data. The recommended phase II dose is 80mg of selinexor. Additional molecular correlative studies are evaluating patients' marrow and blood samples for markers that predict response and relapse. Disclosures Odenike: Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stock:Sigma-Tau: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Gilead Sciences: Honoraria; Amgen: Honoraria; Royalties for a chapter in Up to Date: Patents & Royalties. Liu:Karyopharm: Research Funding; BMS: Research Funding.

Abstract: Abstract 496 HCT may provide long-term disease control for patients (pts) with relapsed and/or refractory acute leukemias (AL) and advanced myelodysplastic syndromes (MDS). Active disease burden at HCT is associated with high relapse rates and poor long-term outcomes. We hypothesized tolerable intensification would be achieved safely by clofarabine cytoreduction followed by HCT conditioning at the nadir and would result in improved outcomes. We performed a prospective study (3/08 – 9/10) to examine the feasibility and efficacy of clofarabine (Clo) cytoreduction prior to HCT for relapsed or refractory AL and MDS with 〉 5% marrow blasts. Clo was administered at 30mg/m2/day IV over 2 hours for 5 consecutive days. On Day 12 post Clo initiation, a bone marrow (BM) biopsy determined cytoreduction, followed by HCT conditioning by day 21 post-Clo. Our primary endpoint was to assess the proportion of pts who achieved effective cytoreduction, defined as BM cellularity 〈 20% and BM blasts 〈 10% on Day 12 post Clo initiation. Our secondary endpoints included (a) the proportion of pts able to proceed to HCT within 21 days of initiating Clo bridge, (b) Clo-related toxicities, and (c) disease free (DFS) and overall survival (OS) on Day 100 post HCT. 29 pts were enrolled and evaluable; 11 AML, 7 MDS, 3 t-MN, 4 secondary AML, 2 CML, 2 ALL; median age was 51 years (range 23–69); sex: 16 M, 13 F. 16 pts had high risk and 13 had intermediate risk cytogenetic profiles. 3 of 12 pts evaluated showed a FLT3 ITD mutation. 18 of 23 evaluable pts had high C-reactive protein levels at study entry ( 〉 5mg/L). All pts had ECOG performance status of 0 to 1. The median Charlson co-morbidity index was 1 (range 0–8). Effective cytoreduction was achieved in 15/29 pts (52%). Clo bridge therapy was well tolerated with mild toxicities (CTCAE v.3) prior to HCT as follows: 7% with grade (gr.) 1 creatinine elevation; 46% gr.1–2 and 7% gr.3 bilirubin elevation; 50% gr.1–2 and 25% gr.3 SGOT elevation, which were reversible. There were no hand-foot syndrome, cardiac, or CNS toxicities. All 29 pts (100%) successfully proceeded to HCT conditioning after clofarabine bridge – one pt with refractory AML, who achieved cytoreduction and conditioning, died one day before HCT due to sepsis. Median time from Clo initiation to HCT was 21 days (range 18–77). Two pts were delayed due to infection and/or failure to cytoreduce; both received second bridge with HiDAC mitoxantrone and achieved cytoreduction followed by HCT. 25 of 29 underwent reduced intensity conditioning (flu-mel-campath-17, clo-mel-campath 3, flu-mel-atg 5) and 26 of 28 received T-cell depletion (campath 22, ATG 5). Among the 28 transplanted pts, graft sources included: 23 PBSC (11 matched related, 12 matched unrelated), and 5 haploidentical PBSC plus a cord blood unit. With a median follow up 343 days after HCT, the median PFS = 353 days (95% CI 229–573) and the median OS = 381 days (95% CI 229–649). One year PFS is 65% by Kaplan-Meier estimate for cytoreduced pts compared to 33% in non-cytoreduced pts. Of the 28 pts who received transplant, 3 pts died before Day 100 – one due to sepsis before Day 28 post HCT, and two due to disease progression. At Day 28 post HCT, 26/27 pts (96%) had BM biopsies showing no evidence of residual disease – one pt had residual AML. The cumulative incidence of gr.2–3 acute GVHD by Day 100 was 9/27 pts, and 2/25 pts developed mild or moderate chronic GVHD within the first year. The Kaplan Meier estimate for one year survival is 65% (95% CI 35–84%) for the cytoreduced pt group and 41% (95% CI 16–65%) for the non-cytoreduced pt group. In summary, clofarabine bridge achieved cytoreduction in 52% of very high risk pts with advanced hematologic malignancies with low toxicity. Cytoreduction was associated with prolonged PFS, but late relapse remains problematic. Despite RIC and T-cell depletion, most pts achieved remission post-HCT with low rates of acute and chronic GVHD. This bridging approach provides a platform for testing novel post-transplant interventions. Disclosures: Off Label Use: Clofarabine is being used for treatment of advanced leukemia for cytoreduction prior to HCT. Locke:Genzyme: Honoraria. van Besien:Genzyme: Research Funding. Odenike:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stock:Genzyme: Research Funding.

Abstract: In this phase 1 study, azacitidine (AZA) was given before high-dose cytarabine (HiDAC) and mitoxantrone (mito) based on the hypothesis that epigenetic priming with a hypomethylating agent before cytotoxic chemotherapy would improve response rates in patients with high-risk acute myeloid leukemia (AML), including relapsed/refractory disease. The primary objective was to establish the recommended phase 2 dose of AZA given before standard HiDAC/mito. In a dose escalation scheme, 46 patients (median age, 66 years) received AZA at 37.5, 50, or 75 mg/m2 subcutaneously or IV once daily on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10 (the HiDAC/mito dose was reduced 33% in elderly subjects). Two dose-limiting toxicities occurred (both in the same patient): acute liver failure and kidney injury at the 50 mg/m2 dose. The 30-day induction death rate was 2.2% (1 of 46). The overall response rate, including complete remission and complete remission with incomplete count recovery, was 61% (28 of 46). Previously untreated patients aged ≥60 years with therapy-related AML and de novo AML were more likely to respond than untreated patients with AML progressing from an antecedent hematologic disorder (myelodysplastic syndrome and chronic myelomonocytic leukemia). Patients with favorable European Leukemia Network risk (P = .008), NPM1 mutations (P = .007), or IDH2 mutations (P = .03) were more likely to respond, and those with TP53 mutations (P = .03) were less likely to respond. The recommended phase 2 dose of AZA is 75 mg/m2 per day on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10. This trial was registered at www.clinicaltrials.gov as #NCT01839240.

Abstract: Introduction Improving therapy for rel/ref AML remains a challenge. Decitabine, a DNA methyl-transferase inhibitor, initially showed promise in AML as a 5-day, first-line induction regimen and more recently as a 10-day regimen in older and unfit patients (1). However, little is known about the activity of decitabine in the rel/ref patient population despite increased use. Therefore, we sought to analyze the outcomes of these pts treated at our institution. Methods To obtain data regarding decitabine efficacy in rel/ref AML, we performed a retrospective analysis of outcomes following decitabine treatment in 34 adult pts treated at The University of Chicago from January 2009 to June 2014. Permission to access patient charts was granted by the medical centerÕs Institutional Review Board. AML was defined by WHO criteria, genetic risk grouping and complete remission (CR) was according to ELN classification; PR was defined as 〉 50% decrease in bone marrow blasts and normalization of blood counts. Rel/ref AML was defined as either having had a prior CR with recurrence of disease or having received a prior induction regimen (1-2 cycles) without CR. Results Median pt age was 62 yrs (range, 18-81) and 60% were male. Median Charlson comorbidity index (CCI) was 5 (range, 0-8); 29% had ECOG performance status 0-1 and 71% had 〉 2. 21 pts (62%) had de novo AML (7 with myelodysplasia-related changes), 3 (9%) had therapy-related myeloid neoplasm (t-MN), and 10 (29%) had secondary AML after myelodysplastic syndrome. 6% were in the ELN favorable genetic group, 3% intermediate-I, 18% intermediate-II, and 67% adverse; 2 cases were unevaluable. The median number of prior treatment regimens was three. 9% had received prior azacitidine, 85% had received prior HiDAC, and 38% had a prior allogeneic stem cell transplant (SCT). 34 pts received a total of 71 cycles of decitabine, 20 mg/m2 daily, in 5 or 10-day cycles every 28 days. All patients received 10-day courses, 91% had an initial 10-day course, and 74% had only 10-day courses. The median number of cycles per pt was 2; 59% received 〉 1 cycle. 7 (21%) achieved CR and 4 (12%) had a partial response (PR), for an overall response rate (OR) of 33%. Responses occurred in 24% of pts with de novo AML, 66% with t-MN, and 50% with secondary AML. Intermediate and adverse group pts had OR of 14% and 39%, respectively. All pts achieving CR did so after 1 cycle; PR required a median of 3 cycles. Pts who achieved CR or PR had a significantly lower pretreatment WBC count (median, 9.5 vs 49.5 x 103/µL in non-responders; p=0.015) and blast percentage (44 vs 59.4; p=0.035) than those who did not. Pts with secondary AML or t-MN had a higher probability of OR compared to those with de novo AML (54 vs 23%; p=0.042). Median overall survival (OS) of all pts was 256 days; prior SCT was associated with reduced OS (p=0.017). When comparing de novo to secondary AML & t-MN, 1-year OS was not significantly different (Figure 1). Responders had a significantly longer OS (median, 622 days vs 278 days for non-responders; p=0.012). Age, race, CCI, ECOG PS, genetic risk group, prior HiDAC, dysplasia, azacitidine, and number of prior treatments did not impact OR or OS. 16 (47%) pts proceeded to SCT. During treatment, 70% had a grade 3-4 non-hematologic toxicity (based on NCI CTACE v4.0); the most common was fatigue. The median number of hospitalizations for complications per patient was 2 (range, 0-7). Causes of hospitalization were febrile neutropenia (40%), infection (22%), cytopenias (18%), rash (6%), acute kidney injury (6%), and 8% were for other causes. Conclusion Decitabine treatment of 34 adults with rel/ref AML resulted in an OR of 33% (21% CR) and allowed nearly one-half of these pts to proceed to SCT. All pts achieving CR did so after 1 cycle. Responding pts had improved OS over those without response (p=0.012). Interestingly, secondary AML or t-MN were 7.8 times more likely to achieve a response compared to de novo AML (p=0.046); lower WBC count and marrow blast percentage also correlated with higher OR. Further delineation of molecular subsets associated with response to decitabine should be evaluated in a larger prospective trial in this high-risk AML population. Citation 1. Blum KA, et al. Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation. Br J of Haem. Jul 2010;150(2):189-195. Figure 1. Figure 1. Disclosures Off Label Use: Decitabine is indicated for treatment of MDS but is often used to treat newly diagnosed or relapsed/refractory AML. In this study we analyzed results of patients with AML who were treated with decitabine in the relapsed/refractory setting.. Thirman:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Gilead: Research Funding; Merck: Research Funding. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy; Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees.

Abstract: *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 & lt; 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 & lt;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.