Abstract: Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. Arm A (T 600 mg twice a day × 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day × 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771.

Abstract: Among mechanisms underlying cytotoxic drug resistance is activation of diverse DNA damage response (DDR) pathways. Poly(ADP-ribose) polymerases (PARP)-1/2 facilitate both single- and double-strand break (DSB) repair and play a key role in the base excision repair (BER) of chemotherapy-damaged DNA. The PARP inhibitor veliparib (V) potentiates the cytotoxicity of different chemotherapeutics, including temozolomide (TEM). TEM induces distinct alkylating events in neoplastic cells whose ultimate outcome depends on the interaction of BER, mismatch repair (MMR), O(6)-methylguanine-DNA methyltransferase (MGMT), and DSB repair. While clinical activity of TEM has been mainly observed in MGMT-deficient AML, V potentiated cytotoxicity of TEM in leukemia cells in vitro in the setting of MGMT overexpression or deficient MMR pathway (Mol Cancer Ther, 2009). Methods: We conducted a Phase I study to determine maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of V+TEM, using a 3+3 dose escalation. Patients (pts) ≥60 years (yrs) with newly diagnosed poor cytogenetic-risk AML/ALL who were not candidates for intensive therapy, or ≥18 yrs with relapsed/refractory AML/ALL, secondary AML (therapy-related or arising from MDS or MPN), and CMMoL-2 were eligible. Any number of prior regimens, including allogeneic transplant (alloSCT), were allowed. V was given orally day (d)1 once, then twice a day on d4-12 at one of 6 dose levels (DL) (DL1A-B 20mg; DL2-DL3-DL4-DL5-DL6: 40-80-120-150-200 mg). TEM was given orally once a day on d3-9 (DL1A 150 mg/m2/d; DL1B-DL6 200 mg/m2/d). 28-day cycles (cy) were repeated depending on response/tolerability (4-6 weeks delay allowed) with V on d1-8 and TEM d1-5. TEM was taken on empty stomach with antiemetics and V was taken irrespective of meals. Results: Forty-nine pts with median age 69 yrs (range, 22-88; 47% ≥70) were treated. Of 47 AML pts, 29 (62%) had secondary AML and 27 (57%) adverse karyotype. Median number of prior treatments for AML was 1 (range, 0-6): 18 (38%) had median 1 prior therapy (range, 1-3) for MDS; 30 (64%), 9 (18%), 34 (69%) received hypomethylating agents, alloSCT and intensive chemotherapy, respectively. Overall 42 (85%) pts were refractory to their last treatment. Pts received a median of 1 (range, 1-7) cy of therapy. Two did not complete cy 1, pt withdrawal d5 and progressive fungal pneumonia d9 with death d15 of progressive disease (PD). The MTD/RP2D was defined at V 150 mg and TEM 200 mg/m2; 2 of 4 pts treated at V 200 mg and TEM 200 mg/m2 developed dose-limiting toxicity of grade (gr) 3 oral mucositis/esophagitis. The most frequent drug-related toxicities (NCI CTC v4) were gr 1/2 nausea/vomiting (39%), fatigue (26%), oropharyngeal mucositis (26%), constipation (12%), and diarrhea (10%). Other common toxicities were infectious, including febrile neutropenia (29%), pneumonia (20%), bacteremia (18%). One (2%) pt died ≤d30 and 12 (24%) ≤d60 mainly of PD (1 pt fungal pneumonia before count recovery d31). Overall response rate was 33% (complete remission (CR), hematologic improvement (HI)/stable disease) with 8 (16%) pts achieving CR (1 CRi). Median overall survival was 5.03 months, for all responders 11.58 months, and for CR pts 19.89 months (Fig 1). Responses occurred at all DLs. Three CR pts underwent alloSCT; 2 remain in CR at ~3 yrs. Pharmacokinetics (PK): V or TEM PKs were not altered with co-administration. There was a correlation between the DLT of mucositis and V single (Cmax P=0.005; AUC P=0.009) and multiple dose exposure (Cmax P = 0.02; AUC P=0.03). Pharmacodynamics and pharmacoepigenetics: Four of 39 pts examined had MGMT methylation (3 CR; 75%) and 2 had BRCA-1 methylation (1 HI) in peripheral blood (PB) or bone marrow (BM) mononuclear cells (MC). Defective FancD2 pathway was observed in the BMMC of 19/19 pts using FancD2 ubiquitylation assays but did not correlate with response. V reduced PAR levels by 〉 75% in PBMC of most pts and in the presence of TEM. Induction of γ-H2AX in CD34+ cells was seen upon V/V+TEM treatment. Conclusion: V plus TEM demonstrated safety and activity in this resistant and elderly leukemia population. Response rate was higher in MGMT methylated pts, but responses were also seen in pts who had no MGMT methylation, had failed multiple therapies, had secondary AML and/or adverse karyotype. Future clinical study should aim to identify pts with defective DDR pathways who are most likely to respond to this therapeutic approach. Figure 1. Figure 1. Disclosures Off Label Use: Temozolomide is not approved for AML. Beumer:Millenium: Other: Research support. Gore:Celgene: Consultancy, Honoraria, Research Funding.

Abstract: Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is an aggressive hematologic malignancy derived from plasmacytoid dendritic cells. The clinical presentation of BPDCN typically involves the skin at outset and invariably progresses to a leukemic phase with or without lymph node and splenic involvement. BPDCN blasts have a distinctive phenotypic appearance with ubiquitous overexpression of CD4, CD56, and CD123 (interleukin-3 receptor [IL-3R]). Although rare, BPDCN has been estimated to affect at least two thousand patients in the United States and Europe annually. There is no standard therapy for BPDCN, but treatment usually incorporates intensive combination chemotherapy, occasionally with allogeneic stem cell transplant. Treatment-naïve patients generally respond to these measures, but disease-free survival is brief, and most patients relapse with chemo-resistant disease. Despite aggressive upfront therapies, BPDCN has a dismal prognosis with estimated median survival of 9-14 months. SL-401, a novel biologic targeted therapy directed to IL-3R, is being developed to treat BPDCN, acute myeloid leukemia (AML), and several other IL-3R-expressing hematologic malignancies. SL-401, which is comprised of IL-3 conjugated to a truncated diphtheria toxin, a potent inhibitor of protein synthesis, has demonstrated ultra-high anti-tumor potency against BPDCN cell lines and primary BPDCN tumor cells, with IC50 values in the femtomolar (10-15 M) range and robust activity after treatment of an in vivo model of human primary BPDCN cell engraftment (Angelot-Delettre et al; ASH 2013). This report serves to update the results of SL-401 treatment in BPDCN patients who are participating in a Phase 1/2 study of SL-401 administered as a single cycle (15 minute infusion daily for 5 days). To date, 6 subjects with BPDCN (5 male/1 female; ages 35-72 years) received a single cycle of SL-401. The BPDCN blasts of all 6 patients expressed CD123 (IL-3R) as well as CD4 and CD56. Five patients had failed previous chemotherapy regimens, with 3 of these subjects also having received allogeneic stem cell transplantation, whereas one patient was treatment naïve. There have been no serious adverse events. Two patients had SL-401-related Grade 3 liver function test (LFT) elevations that recovered to Grade ≤2 within 24 hours and one patient had a brief episode of SL-401-related Grade 3 neutropenia and thrombocytopenia; all other SL-401-related adverse events (AEs) were Grade ≤2. One patient was not evaluable for response. To date, 5 (100%) of the 5 evaluable patients have had major responses. All five responding patients were treated with SL-401 at 12.5 µg/kg/day for 5 days, and experienced either a complete response (CR; 4 patients) or a partial response (1 patient). The CRs included disappearance of BPDCN in the skin, bone marrow, peripheral blood, spleen, and lymph nodes. As of August 2013, CR durations following a single cycle of SL-401 treatment are 11+ (ongoing), 5, 3, and 1 months; the PR duration is 1 month. Given these promising clinical responses to this targeted therapy, additional BPDCN patients are being accrued to this study and a pivotal program will begin in 2014. Disclosures: Frankel: Stemline Therapeutics: Research Funding. Woo:Angimmune: Patents & Royalties, Research Funding. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Szarek:Stemline Therapeutics: Employment, Equity Ownership. Bergstein:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. Rowinsky:Stemline Therapeutics: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

Abstract: The high frequency of TET2 mutations in myelodysplastic syndromes (MDS) and the sole function of TET-dioxygenases as 5-hydroxymethylcytosine (5-hmC) hydroxylases emphasize the key role of this gene in disease pathogenesis. However, the broad down-regulation of 5-hmC argues for a role of DNA demethylation in MDS beyond TET2 lesions, which albeit the high frequency, do not convey any impact on survival outcomes. In fact, decrease in 5-hmC levels is by far more widely spread than TET2 lesions pointing towards other pathways affecting TET2 activity, thereby obscuring a precise determination of its mutational and clinical consequences. Herein, we investigated TETs expression to identify factors explaining the widespread deficiency of 5-hmC in MDS possibly determining clinical phenotypes and prognosis. An integrative data analysis of genomic studies (whole genome and deep targeted NGS), RNA-sequencing and 5-hmC quantification was performed on 1,665 patients with MDS and 91 healthy controls (HC). Meta-analytic studies of 5-hmC levels in myeloid neoplasia (n=598) and data of RNA-sequencing of fractionated CD34 (GSE63569) were also included as confirmatory cohorts. We started by analyzing the clinical impact of TET2 mutations carried by 23% of our study population. No impact on survival was found in carriers of TET2 lesions including those with biallelic, truncating or missense mutations compared to wild-type (WT) (Fig1A). By using 5-hmC levels as a functional readout of TET activity, we found a TET deficiency in about 70% of patients, a proportion higher than one would conclude by considering the mere presence of TET2 mutations (Fig1B). To explain the decrease in 5-hmC levels in WT cases, we next examined transcriptome modifications. Analysis of the expression of TET family of genes showed that MDS patients had lower TET2 mRNA levels in total and in CD34+ cells as compared to HC, irrespective of their TET2 status. Therefore, we reasoned that TET2 deficiency is more ubiquitously involved in MDS pathogenesis than what would be expected by the only estimation of mutant cases. Indeed, "low expressor" status (defined by TET2 expression & lt; 25%ile of HC) was found in 74% of MDS. Along with variable 5-hmC levels, concomitant differences in TET1/TET3 expression were also investigated. While TET1 levels were too low to be evaluated, TET3 expression levels were markedly higher in all and in WT MDS compared to HC, possibly in an attempt to compensate TET2 dysfunction (Fig1C). In addition, TET3 expression did not correlate with TET2 mutational burden, confuting a compensatory feedback mechanism in TET2 mutant cases. Further uni- and multivariate analyses showed that elevated TET3 levels compensated TET2 deficiency in terms of clinical outcomes (Fig1D) and linear regression analyses confirmed that indeed lack of compensation by TET3 (low TET3 expression) was associated with high risk features. To explore whether other factors might be associated with low TET2 levels, we studied TET2 expression in WT cases as to the presence of other mutations. We found that TET2 expression was significantly lower in patients harboring DNMT3A (P & lt; 0.0001), SF3B1 (P & lt; 0.0001) and SRSF2 (P= 0.04) compared to HC. However, lack of correlation between levels of TET2 and mutational burden failed to prove a direct relationship of these mutations (Fig1E). Decreased hydroxylation of 5-mC may also be caused by endogenous L-2-hydroxyglutarate (L2HG) produced via malate shunt. Accordingly, L2HG dehydrogenase (L2HGDH) levels catabolizing L2HG and malate dehydrogenases (MDH1/2) supplying L2HG, would influence TET2 activity in a reciprocal fashion. Consistently we found that MDH1/2 levels were increased in MDS and that L2HGDH showed also a likely compensatory increase to handle elevated L2HG loads. Further, linear regression analyses revealed that L2HGDH levels were correlated inversely with TET2 and positively with TET3 expression in WT cases (Fig1F). In sum, MDS can be considered a wide-ranging 5-hmC deficiency disorder driven by direct or indirect loss of TET2functions by mutations or down-modulation due to a variety of mechanisms. Disease phenotypes and outcomes are both influenced by counteracting factors such as expression of TET3. Application of precision therapeutic approaches should be informed by the analyses of all these factors. Figure 1 Figure 1. Disclosures Carraway: Astex: Other: Independent review committee; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Other: Independent review committee; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Other: Independent review committee; Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kim: Paladin: Consultancy, Honoraria, Research Funding; Bristol-Meier Squibb: Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Minden: Astellas: Consultancy. Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership. Maciejewski: Bristol Myers Squibb/Celgene: Consultancy; Novartis: Consultancy; Regeneron: Consultancy; Alexion: Consultancy.

Abstract: Background Acute myeloid leukemia (AML) is a complex, heterogeneous neoplasm characterized by the accumulation of complex genetic alterations that are responsible for the initiation and progression of the disease. Secondary AML (sAML) represents a progression from antecedent hematologic disorders such as myelodysplastic syndromes (MDS) or myeloprolifrative neoplasms (MPN). Certain acquired mutations have been reported to be specific for sAML when compared to primary AML (pAML), but many limitations exist when cytogenetic grouping or other parameters are taken into account. In addition, some mutations have been shown to impact survival in some studies, but not others. Methods We performed targeted deep sequencing on samples from bone marrow and peripheral blood of pts diagnosed with sAML and pAML and treated at our institution between 1/2003-1/2013. Additional data on pAML was added from The Cancer Genome Atlas (TCGA). A panel of 62 gene mutations described as frequently recurrent mutations in myeloid malignancies were assessed. Cytogenetic grouping was defined by CALGB/Alliance criteria. Differences were compared using Fisher's exact test and the Mann-Whitney U test for categorical and continuous variables, respectively. Overall survival (OS) was calculated from the time of diagnosis to last follow up or death. Results: A total of 496 pts included: 273 with pAML and 223 with sAML. Comparing pAML to sAML, pts were younger (median age 59 vs. 68 years, p 〈 .001) and had a higher WBC at diagnosis (13.5 vs. 3.9 X 109/L, p 〈 .001), respectively. Cytogenetic analysis showed significant differences: 58% of pAML pts had normal karyotype (NK) compared to 37% of sAML (p=.002), whereas 24% and 26% of sAML had intermediate risk (other than NK) and complex karyotype ( 〉 3 abnormalities) compared to 11% and 16% for pAML (p 〈 .001, .009), respectively. Mutations in ASXL1 (p 〈 .001), JAK2 (p=.014), CBL (p=.05), BCOR (p=.02), STAG2 (p =.003), SF3B1 (p=.04), SRSF2 (p=.001 ), and U2AF1 (p=.03) were highly specific for the sAML phenotype, whereas mutations in NPM1 (p 〈 .001 ), FLT3 (p 〈 .001), DNMT3A (p 〈 .001), and IDH2 (p=.02) were more specific for pAML. When the analysis was restricted to pts with NK cytogenetics, only ASXL1 (p 〈 .001) remained specific for sAML and DNMT3A (p 〈 .001) for pAML.Further, when the analysis was restricted to pts with unfavorable risk cytogenetics, only ASXL1 (p=.01) remained specific for sAML. No other mutations were specific for pAML. We then evaluated whether the mutations that were specific to each AML phenotype had an impact on OS. We observed different mutations that impacted OS in each phenotype: DNMT3A (HR 1.81, 95% CI 1.28-2.57, p 〈 .001), TP53 (HR 3.1, 95% 1.74-5.53, p 〈 .001), and SUZ12 (HR 3.18, 95% CI 1.01-10, p=.05) led to worse OS in pAML, whereas mutations in EZH2 (HR 2.12, 95% CI 1.07-4.21, p =.03), PRPF8 (HR 2.32, 95% CI 1.20-4.46, p=.01), and TP53 ( HR 2.92, 95% CI 1.69-5.04, p 〈 .001) lead to worse OS in sAML. Different mutations had a different impact on OS when cytogenetic analysis was taken into account. Mutations in FLT3 (HR 2.15, 95% CI 1.37- 3.35, p 〈 .001) and DNMT3A (HR 2.41, 95% CI 1.57-3.70, p 〈 .001) led to worse OS in NK pAML, whereas none of the mutations impacted OS in NK sAML. Further, in pAML with unfavorable cytogenetics, BCOR (HR 2.41, 95% CI 1.57-3.70, p 〈 .001) and TP53 (HR 2.41, 95% CI 1.57-3.70, p 〈 .001) had led to worse OS, whereas BOCR (HR 2.95, 95% CI 1.03-8.50, p 〈 .001), SF3B1 (HR .19, 95% CI .05-.82, p 〈 .001), SUZ12 (HR .12, 95% CI .01-.99, p 〈 .001),and TP53 (HR 1.9, 95% CI 1.09-3.46, p 〈 .001) only impacted OS in sAML. Conclusion Clear genomic variations exist between sAML and pAML. Although some of these genomic changes are more specific to each phenotype in general, this specificity and the impact on OS differed for each cytogenetic subgroup, highlighting the complexity of interpreting genomic information in pts with AML and the need to incorporate both cytogenetic and molecular data in prognosis-driven treatment decisions. Disclosures Sekeres: TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

Abstract: Acute myeloid leukemia (AML) is a disease marked by abnormal differentiation of the myeloid cell lineage. Leukemia stem cells differentiate to give rise to leukemic progenitor cells (LPC) and ultimately leukemic blasts which are not leukemia-initiating. Previous studies have revealed a diverse methylation landscape in AML, but have mostly relied on the blast population rather than more purified primitive populations. Consequently, the status of the leukemic methylome during expansion from LSC to LPC and finally blast remains largely unknown. We sorted HSC from the bone marrow of normal donors and LSC, LPC, and blasts from AML patients based on expression of CD34, CD38, CD45 and aldehyde dehydrogenase (ALDH) activity. Normal HSC were defined as CD34+CD38-ALDHhigh. In AML patients, LSC were either CD34+CD38-ALDHhigh or CD34+CD38-ALDHmid; LPC were CD34+CD38+; the blast population consisted of unsorted mononuclear cells. Though patients with an ALDHhigh LSC profile may have had some residual normal HSCs present, contribution of these cells was likely minimal and thus the overall population predominantly leukemic. Methylation profiles for each cell fraction in eight untreated AML patients and five normal donors were generated using the enhanced reduced representation bisulfite sequencing (ERRBS) assay. All sequenced ERRBS libraries were aligned against the human genome (hg19) and organized into 25 base pair tiles for analysis of differentially methylated regions (DMR) using a beta-binomial model that takes variation across samples into account during DMR identification. DMR classification required a difference in methylation of 〉 25% and false discovery rate (FDR) 〈 10%. Unsupervised correspondence analysis indicated that methylomes of two patients with ALDHhigh LSC were distinct from the six patients with ALDHmid LSC and therefore patients were grouped based on the ADLH activity of their LSCs for comparisons. Both ALDHhigh LSC and ALDHmid LSC had extensive alterations in methylation across their genomes when compared to HSC. The great majority of DMRs in ALDHhigh LSC were hypomethylated; of the 62,415 DMRs identified, 55,418 regions were hypomethylated while only 6,997 were hypermethylated in ALDHhigh LSC. In contrast, in ALDHmid LSC, 39,162 DMRs were hypermethylated and 5,408 regions hypomethylated compared to HSC. Despite opposing patterns of methylation, DMRs were enriched at intergenic and intragenic enhancers in both ALDHhigh and ALDHmid LSC. DMRs were functionally annotated to gene sets in the MSigDb database. Genes associated with ALDHhigh DMRs were enriched for genes with the binding motif for transcription factor Sp1 near their promoters (FDR = 2.55×10-79) and ALDHmid DMR associated genes were enriched for genes with H3K27 trimethylation in their promoters (FDR = 7.19×10-169). We compared methylation profiles of LSC to LPC and blasts in an effort to determine whether changes to the methylome occur with leukemic maturation. Interestingly, there were no significant changes in methylation between LSC and LPC in either ALDH population. However, we did see changes to the epigenome emerge when LSC or LPC were compared to leukemic blasts. In ALDHhigh patients, LSC and LPC were more hypomethylated than blasts while ALDHmid LSC and LPC were more hypermethylated than the more differentiated blasts. In conclusion, alterations to the LSC methylome were extensive and two patterns of methylation emerged based on the ALDH activity of LSC; ALDHhigh LSC displayed hypomethylated profiles and ALDHmid LSC were hypermethylated. Enrichment of DMRs at intra and intergenic enhancer regions in both LSC types despite their opposing methylation patterns highlights the importance of epigenetic marks in these regions and their role as regulators of gene expression. Significant changes in methylation between LSC or LPC and blasts, but not LSC and LPC suggest relative stability of the methylome during early leukemic differentiation with more substantial alterations occurring after the LPC level. Disclosures Gerber: Janssen: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Carraway:Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Baxalta: Speakers Bureau. Gore:Celgene: Consultancy, Honoraria, Research Funding.

Abstract: Background: African-American (AA) patients (pts) have a younger age at diagnosis and worse outcomes compared to whites (WTs) across many cancers, including acute myeloid and lymphoblastic leukemias. This difference may be related to disease biology rather than access to medical care or socioeconomic status. The incidence of MDS and age at diagnosis in national cancer registries in AAs is lower than in WTs. Detailed biological and clinical characteristics and outcome of AA pts with MDS compared to WTs have not been defined. Methods: We collected mutational and clinical data on MDS pts diagnosed from 1/2000-1/2012. Next-generation gene-targeted deep sequencing of 62 common gene mutations (selected based on frequencies established in a separate cohort of MDS pts studied by whole exome sequencing) were analyzed as individual mutations and then grouped into several functional pathways which were hypothesized to characterize MDS pathogenesis. International Prognostic Scoring System-Revised (IPSS-R) score was calculated as described previously. Overall survival (OS) was measured from the time of diagnosis to time of death or last follow up. Time-to-event analyses were performed by the Kaplan-Meier method, with curves compared by log rank test. Differences among variables were evaluated by the Fisher’s exact test and Mann-Whitney U test for categorical and continuous variables, respectively. Results: Of 341 pts, 44 (13%) were AA. Comparing WTs to AAs, pts had a similar median age (68 for both), absolute neutrophil count (1.6 vs 2.23) X 109/L, hemoglobin (9.7 vs 9.4) g/dL, platelets (93 vs 91) X 109/L, and bone marrow blasts (2% vs 3%), respectively. IPSS-R risk category distribution for WTs and AA was: very low 15% vs 9%, low 35% vs 30%, intermediate 18% vs 18%, high 16% vs 23%, very high 10% vs 18%, and not applicable 6% vs 2%, respectively. Among AA pts, 25% had very poor risk cytogenetics per IPSS-R criteria (complex 〉 3) compared to 10% of WTs (p=.008) which led to 41% of AA pts having high and very high risk IPSS-R scores compared to 26% of WTs (p=.035). Further, WTs were more likely to receive a treatment (86% vs 66%, p 〈 0.001) and allogeneic bone marrow transplant (15% vs 5%) compared to AAs; however, AML transformation rate was similar (21% vs 25%, p= .31, respectively). With a median follow up of 36 months (mo) (range .9-128.5), the median OS for AAs was 17.9 mo vs. 27.5 mo for WTs (p=.03, Figure 1). In a multivariable Cox analysis that include age and IPSS-R, AA pts retained their worse outcome compared to WTs (HR 1.68, CI 1.17-2.41, p= .005). Somatic mutational data were available on 321 pts (24 AAs). Overall, the most frequently mutated genes were: TET2 (16%), SF3B1 (13%), ASXL1 (13%), DNMT3A (10%), BCOR/BCORL1 (10%), STAG2 (10%), U2AF1 (8%), ZRSR2 (7%), and TP53 (5%). AA pts were more likely to have Tp53 (17% vs 4%, p = .04), and ZRSR2 mutations (21% vs 6%, p = .02). As a group, mutations in transcription factors (including SETBP1,RUNX1, BCOR, BCORL1, ETV6, NPM1, and CEBPA) and chromatin modifications (including ASXL1, SUZ12, EZH2, MLL, and KDM6A) were more common in WTs compared to AA pts (p= .02 and .049, respectively). Conclusion: In our cohort, AA pts with MDS had worse OS compared to WTs. Adjusting for IPSS-R risk categories and age did not negate this poor outcome. On a molecular level, AAs are more likely to have poor-risk mutations such as TP53, and less likely to have mutations in transcription factors and chromatin modifications pathways, which may have contributed to their inferior outcomes, and suggests that treatments targeting these pathways in AA pts may have less benefit. Figure 1: Overall survival by race Figure 1:. Overall survival by race Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction: Traditional prognostic factors for adult acute lymphocytic leukemia (ALL) include age, white blood count at diagnosis, and cytogenetic (CG) risk. We sought to identify a more detailed prognostic risk score for newly diagnosed adult patients (pts) based on these and other pre-treatment characteristics. Methods: 82 newly diagnosed ALL pts given induction chemotherapy (IC) at our institution between the years 2003-2011 were included, and data were obtained by chart review. Institutional review board approval was obtained. Variables examined included: gender, age, immunophenotype, CG risk, pre-IC body mass index (BMI), pre-IC and day 28 serum albumin, absolute lymphocyte (ALC) and neutrophil (ANC) counts, positive culture (blood or other) during IC, positive imaging suggestive of infection (during IC), and allogeneic hematopoietic cell transplant (AHCT). CG risk was ascribed by CALGB criteria (Blood 1999; 93: 3983). BMI was defined by: underweight (≤ 18.5), normal ( 〉 18.5-25.0), overweight ( 〉 25.0-30.0), moderately obese ( 〉 30.0-35.0), severely obese ( 〉 35.0-40.0), and very severely obese ( 〉 40.0). The primary endpoint was overall survival (OS) which was measured from IC to death or last follow-up. Proportional hazards models were used for univariable and multivariable analyses. In the multivariable analysis stepwise variable selection was used to identify independent predictors. Results were internally validated using a bootstrap algorithm. For convenience measured factors were discretized using a recursive partitioning algorithm. Prognostic groups were formed by assigning “points” to each factor that were based on the magnitude of the estimated regression coefficients of the final model, and then summing the total number of points present. Results: Median age at diagnosis was 43 yrs (range 18-78); 58% male. 71% of pts (58/82) had a B-cell immunophenotype. CG risk included: normal: 15 pts (18%), high: 41 pts (50%), miscellaneous: 9 pts (11%), and unknown: 17 pts (21%). Twenty-four pts (29%) were Ph+. The majority of pts (70%: 57/82) received the CALGB 19802 regimen (Cancer 2013; 119: 90) for IC +/- a tyrosine kinase inhibitor (if they were Ph+). 27% of pts (22/ 82) received AHCT in CR1. Estimated median OS is 41.5 months (95% CI: 15.5-N/A). In univariable analysis age, pre-induction BMI, Day 28 ALC, pre- and Day 28 albumin, Day 28 ANC, Day 28 platelet count, evidence of infection, and CG risk were all seen to impact outcome. In multivariable analysis pre-IC BMI and albumin, age, and Day 28 ALC were identified as independent predictors. Assigning 1 “points” each for age 〉 50, albumin prior to IC ≤ 3.2 g/dL, or Day 28 ALC ≤ 50 /uL and 2 points for BMI ≥ 35, 3 prognostic groups were defined: favorable (0 points) 32% of pts (26/80): estimated 5-yr OS of 68% +/-11%; intermediate (1 points) (29% of pts, 23/80): estimated 5 yr OS of 39% +/-11%, and unfavorable (≥ 2 points) (39% of pts, 31/80) with estimated 5 yr OS of 17% +/- 7% (Figure 1). Conclusion: We have constructed a simple prognostic model for newly diagnosed adults with ALL. This model will need to be validated in a larger group of uniformly treated patients. Table 1 Prognostic Factors for OS in Univariable and Multivariable Analysis Factor Univariable (HR (95% C.I.)) Multivariable (HR (95% C.I.)) Age at dx (≤50 vs. 〉 50) 3.29 (1.80-5.99), p=.0001 2.83 (1.45-5.53), p=.002 Pre-IC BMI ( 〈 35 vs. 〉 35) 2.95 (1.57-5.52), p=0.0008 3.88 (1.84-8.17), p=.0004 Pre-IC albumin (≥ 3.2 vs. 〈 3.2 g/dl) 2.61 (1.43-4.77), p=0.002 2.66 (1.33-5.30), p=.0006 Day 28 ALC ( 〉 50/uL vs. ≤50/uL) 3.57 (1.61-7.91), p=0.002 3.11 (1.33-7.28), p=.009 CG risk 2.03 (0.98-4.22); p=0.06 ------ Day 28 albumin ( 〉 2.3 vs. ≤2.3 g/dl) 3.37 (1.66-6.83), p=0.0008 ------ Day 28 ANC ( 〉 200/uL vs. ≤200/uL) 4.51 (1.94-10.51), p=.0005 ------ Day 28 platelets ( 〉 75K/uL vs. ≤75K/uL) 2.44 (1.26-4.72), p=.008 ------ Any positive culture (no vs. yes) 2.19 (1.19-4.04), p=0.01 ------ Blood culture positive for bacteria (no vs. yes) 2.34 (1.28-4.30), p=0.006 ------ Positive imaging suggestive of infection (no vs. yes) 2.44 (1.34-4.46), p=0.004 ------ Positive blood culture and image (no vs. yes) 1.96 (1.07-3.57), p=0.03 ------ Figure 1 Prognostic Groups Figure 1. Prognostic Groups Disclosures No relevant conflicts of interest to declare.