scholarly journals Acute Myeloid Leukemia (AML) Hospitalizations: Racial Disparity in Outcomes of Patients with Comorbidities

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4135-4135
Author(s):  
Sara Taveras Alam ◽  
Deepa Dongarwar ◽  
Elyse Lopez ◽  
Sarvari Venkata Yellapragada ◽  
Gustavo Rivero ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hospital Death ◽  
Age Group ◽  
Hispanic Patients ◽  
Comorbidity Index ◽  
Race Ethnicity ◽  
Primary Payer ◽  
Acute Myeloid

Abstract Background: Acute Myeloid Leukemia (AML) outcomes are dependent on leukemia-specific factors, such as cytogenetics and patient-specific factors, such as age and performance status. Racial and socioeconomic disparities have become apparent with self-reported African American race associated with poor survival in AML pts < 60 years (y) of age. We analyzed in-hospital death among AML-related hospitalizations and evaluated differences in sociodemographic characteristics, focusing on the effect of age and race. Methods: We conducted a retrospective cohort study using the Nationwide Inpatient Sample (HCUP-NIS), the largest all-payer database of hospital admissions in the United States, from January 1 st, 2009 through December 31 st, 2018. The study sample consisted of AML-associated hospitalizations of patients aged 18 years of age and older, identified on the basis of the presence of any ICD-9 and 10 codes indicative of AML We categorized patients' ages in groups of <60 y and ≥ 60 y. Ethnicity was initially stratified by reported ethnicity (Hispanic, Non-Hispanic), and the Non-Hispanic group was subdivided into White, Black, or other. The primary payer for the hospitalization was classified. As a proxy for socioeconomic status, the HCUP-NIS provides zip-code-level estimates of median household income, grouped into quartiles based on the patient's residence. Hospital factors included census region, bed size, and hospital type. Patients' comorbidity status was captured using Elixhauser Comorbidity Index (0, 1-4, 5+). Outcome of interest was in-hospital death. Among different age groups and ethnic groups of patients with AML, we used survey logistic regression to generate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) that measured the independent associations between various patient hospitalization characteristics and inpatient death. We adopted a 5% type I error rate for the calculation of CIs, and used appropriate survey weighting to generate national prevalence estimates considering the complex sampling design of the NIS. Statistical analyses were performed using R (version 3∙6∙1) and RStudio (Version 1∙2∙5001). Results: Of 662,417 AML-related hospitalizations, 57.6% were in patients ≥60 y. Of AML-related hospitalizations in patients <60 y, 61.6% were in NH-White patients, 11.2% were in NH Blacks, and 11.7% were in Hispanics. Of AML-related hospitalizations in patients ≥60 y, 74.6% were in NH-Whites, 7.3% in NH-Blacks and 5.4% in Hispanics. Analysis of in-hospital death among AML-related hospitalizations, stratified by race/ethnicity revealed increased in-hospital death among male NH-Black AML patients ≥ 60 y as compared to NH-Black females in the same age group (OR 1.24; CI 1.04-1.47) and an increased in-hospital death among Hispanic patients ≥ 60 years with comorbidities relative to their counterparts in the same age group without comorbidities (OR 17.8; CI 11.32-29.37 for Elixhauser Comorbidity Index 1-4 and OR 2.69; CI 1.09-5.26 for Elixhauser Comorbidity Index ≥5). Differences in income, primary payer, hospital region, size, location or teaching status were not associated with in-hospital death among AML patients stratified by race/ethnicity. See Table 1. Conclusions: We found a significant increase in in-hospital death among Hispanic patients ≥ 60 y with comorbidities relative to their counterparts in the same age group without comorbidities. Yet, comorbidities did not appear to have a statistically significant impact in mortality for patients of other race/ethnicity or those <60 y. It is plausible that the relationship between comorbidities and re-hospitalizations might be impacting our data. Previous work not specific to acute myeloid leukemia has shown that higher comorbidity is associated with an increased risk of readmission. Since our data was based on AML-related hospitalizations rather than patients with AML, it is possible that we are dealing with a false negative error because of patients with comorbidities being readmitted more. The lack of cytogenetic data in NIS is another notable limitation to our work. Nonetheless, we have found striking differences in the outcomes of elderly Hispanic comorbid patients and further evaluations are needed for correlation and to identify areas of optimization in their care. Figure 1 Figure 1. Disclosures Mims: Incyte: Research Funding; AVEO: Research Funding; Pfizer: Research Funding; IDEC: Current holder of individual stocks in a privately-held company; Celgene: Research Funding; Biogen: Current holder of individual stocks in a privately-held company.

Defining the Genomic Make up of Acute Myeloid Leukemia in Adolescents and Young Adults (AYA): Report from COG AAML03P1, AAML531 and SWOG S0106

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2576-2576
Author(s):  
Fabiana Ostronoff ◽  
Todd A. Alonzo ◽  
Megan Othus ◽  
Matthew A. Kutny ◽  
Robert B. Gerbing ◽  
...  
Keyword(s):  
Older Adults ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Somatic Mutations ◽  
Disease Risk ◽  
Age Groups ◽  
Therapeutic Strategies ◽  
Age Group ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a genetically heterogeneous and highly resistant hematopoietic malignancy. Despite survival gains over the past several decades, adolescent and young adult (AYA) with AML demonstrate a consistent survival disadvantage as compared to younger patients (age < 15 years). This discrepancy in outcome is likely due to distinct aspects of disease biology in this patient population. In recent years several somatic mutations with biological, prognostic and therapeutic significance have been identified in patients with AML. Nonetheless, these studies have been conducted in pediatric and older adult patients only. Therefore, the prevalence of these somatic mutations remains largely unknown in AYA patients. Herein, we investigate the prevalence of common AML-associated mutations in AYA, here defined as age 15 to 39 years, aiming to characterize the disease and identify mutations that are relevant for therapeutic strategy in this age group. We compare the distribution of these mutations in the 3 age groups: children (age< 15 years), AYA (age 15 to 39 years) and older adults (age> 39 years). Patients enrolled in the COG trials AAML03P1 and AAML0531 and in the SWOG trial S0106 were eligible for this study. Acute promyelocytic leukemia patients were excluded. AAML03P1 enrolled patients 0 to 21 years, AAML0531 enrolled patients 0 to 30 years and S0106 enrolled patients 18 to 60 years of age. We analyzed 1722 patients (age range 0 to 60 years) with newly diagnosed AML. Pre-treatment samples were obtained from AAML03P1 and AAML531 (N=1361) and S0106 (N=361). Mutation analyses were performed by a combination of targeted capture and fragment length analysis. Chi-square test was used to compare variables. The prevalence of each mutation according to age groups is shown on Table 1. Similarly to what is observed in children and older adults, NPM1 and FLT3- ITD are the two most common mutations in AYA patients with a prevalence of 19% and 14%, respectively. When compared to the other age groups, we observe a significant increase in prevalence of both FLT3- ITD and NPM1 with aging, with a significant higher prevalence of these mutations in older adults as compared to AYA and children. Previous studies have shown that mutations in epigenetic modifier genes are enriched in adults with AML as compared to pediatric patients. We evaluated the prevalence of mutations in these genes in the 3 age groups. We observed a significant increase in prevalence in mutations in all epigenetic modifiers genes with aging (Table 1). The combined prevalence of mutation in these genes (IDH1, IDH2, DNMT3A, ASXL1 and IDH1/2) in children, AYA and older adults were 9%, 19% and 39% (P< 0.0001), respectively, highlighting the clinical and biological importance of this class of genes in older patients. In this large collaborative study, we define for the first time the prevalence of common mutations in AYA with AML. Our study shows that the genomic make up of patients with AYA are different from children and older adults, suggesting unique biology of the disease in this age group. Our data raise questions about future therapeutic strategies, which should take into account the age distribution of these genetic lesions. Finally, clinical correlations to determine the prognostic significance of these mutations in AYA are underway and should provide a framework for future disease risk stratification in this age group. In summary, our data shows the distinct genomic profiling of common mutations in AYA, arguing for age specific disease risk stratification as well as therapeutic strategies in this age group. Table 1. Prevalence of common mutations in children, adolescents and young adults (AYA) and older adults with AML Children (<15 years) AYA (15-39 years) Older adults (>40 years) P value FLT3-ITD 13% 19% 23% 0.0006 NPM1 6% 14% 32% < 0.00001 CEBPA 5% 8% 3% 0.02 WT1 6% 9% 5% 0.154 IDH1/2 3% 7% 17% < 0.00001 DNMT3A 0% 2% 16% < 0.00001 ASXL1 2% 4% 7% 0.007 TET2 4% 7% 11% 0.002 Disclosures Radich: Novartis: Consultancy, Research Funding; Incyte: Consultancy; Gilliad: Consultancy; Ariad: Consultancy. Erba:GlycoMimetics; Janssen: Other: Data Safety & Monitoring Committees; Sunesis; Pfizer; Daiichi Sankyo; Ariad: Consultancy; Millennium/Takeda; Celator; Astellas: Research Funding; Seattle Genetics; Amgen: Consultancy, Research Funding; Novartis; Incyte; Celgene: Consultancy, Patents & Royalties.

scholarly journals Infant Acute Myeloid Leukemia: A Unique Clinical and Biological Entity

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 777
Author(s):  
Charlotte Calvo ◽  
Odile Fenneteau ◽  
Guy Leverger ◽  
Arnaud Petit ◽  
André Baruchel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Age Groups ◽  
Study Groups ◽  
Biological Entity ◽  
Age Group ◽  
Older Children ◽  
Megakaryoblastic Leukemia ◽  
Acute Myeloid

Infant acute myeloid leukemia (AML) is a rare subgroup of AML of children <2 years of age. It is as frequent as infant acute lymphoblastic leukemia (ALL) but not clearly distinguished by study groups. However, infant AML demonstrates peculiar clinical and biological characteristics, and its prognosis differs from AML in older children. Acute megakaryoblastic leukemia (AMKL) is very frequent in this age group and has raised growing interest. Thus, AMKL is a dominant topic in this review. Recent genomic sequencing has contributed to our understanding of infant AML. These data demonstrated striking features of infant AML: fusion genes are able to induce AML transformation without additional cooperation, and unlike AML in older age groups there is a paucity of associated mutations. Mice modeling of these fusions showed the essential role of ontogeny in the infant leukemia phenotype compared to older children and adults. Understanding leukemogenesis may help in developing new targeted treatments to improve outcomes that are often very poor in this age group. A specific diagnostic and therapeutic approach for this age group should be investigated.

scholarly journals Discovery of a Novel Dihydroorotate Dehydrogenase Inhibitor That Induces Differentiation and Overcomes Ara-C Resistance of Acute Myeloid Leukemia Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2663-2663
Author(s):  
Satoshi Kitazawa ◽  
Yukiko Ishii ◽  
Keiko Makita-Suzuki ◽  
Koichi Saito ◽  
Kensuke Takayanagi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Oral Administration ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Dihydroorotate Dehydrogenase ◽  
Once Daily ◽  
Hl60 Cells ◽  
Pyrimidine Nucleotide ◽  
Acute Myeloid

Cancer initiating cells (CIC) are suggested to be responsible for drug resistance and cancer relapse that are associated with poor prognosis. Therefore, drugs effective for CIC could fulfill an unmet clinical need. We performed a drug screen with chemical libraries to find out new compounds which specifically eradicated CIC established in the previous report (Yamashita et al., Cancer Research, 2015). We obtained compounds with a carboxylic acid skeleton as hit compounds. Interestingly, FF1215T, one of the hit compounds, was shown to inhibit growths of CIC by decreasing intracellular pyrimidine nucleotide levels. Finally, we identified dihydroorotate dehydrogenase (DHODH), which was essential for de novo pyrimidine synthesis as the target of the hit compounds in a ligand fishing assay. FF1215T inhibited DHODH enzymatic activity with the 50% inhibitory concentration value of 9 nM, which showed greater potency than well-known DHODH inhibitors brequinar (12 nM), teriflunomide (262 nM), and vidofludimus (141 nM). Growing evidence suggests that DHODH is considered to be a promising target to overcome a differentiation blockade of acute myeloid leukemia (AML) cells (Sykes et al., Cell, 2016).Therefore, we explored the effect of FF1215T on AML growth and differentiation. FF1215T demonstrated growth inhibitory effect in multiple human AML cell lines such as U937, MOLM13, HL60, and MV4-11 with the 50% growth inhibition values of 90-170 nM. FF1215T decreased intracellular pyrimidine nucleotide levels, induced DNA damage marker γ-H2AX possibly due to the replication stress, and finally led to apoptosis in HL60 cells. Cell cycle analysis revealed that FF1215T treatment arrested HL60 and THP1 cells at S phase and increased sub-G1 population in these cells. In addition, our DHODH inhibitors induced upregulation of cell-surface CD11b and CD86, which are monocyte and macrophage differentiation markers, morphological changes, and phagocytic activities in several AML cells, indicating differentiation of AML cells toward monocyte and macrophage by DHODH inhibition. FF1215T also depleted UDP-GlcNAc, a substrate for Protein O-GlcNAcylation, and diminished global O-GlcNAcylation and O-GlcNAcylated protein expressions such as c-Myc, SOX2, and OCT4, which play important roles in maintenance and self renewal of stem cells. We also found that our DHODH inhibitors induced CD11b and CD86, and increased the ratio of macrophage-like cells in primary patient-derived AML cells and these effects were rescued by uridine supplementation (Fig). Inhibitions of colony formations of primary AML cells were also shown after 14 days of FF1215T treatment. In exploring the value of DHODH inhibitors in the clinic, we identified that our DHODH inhibitors worked to overcome the resistance of standard therapy Ara-C. Our DHODH inhibitors were effective against Ara-C-resistant models of HL60 cells as well as HL60 parental cells. Notably, our DHODH inhibitors synergistically inhibited growths of Ara-C-resistant THP1 cells and enhanced CD11b upregulation of THP1 cells when combined with Ara-C by activating conversion of Ara-C to its active form Ara-CTP. Next, we optimized the hit compounds and identified an orally available DHODH inhibitor FF14984T that achieved high and prolonged plasma concentrations in vivo. Oral administration of 10 and 30 mg/kg FF14984T once daily for 10 days exhibited significant anti-tumor effects in mice xenografted with HL60 cells. These treatments showed strong reduction of CTP in tumor and induction of DHO in tumor and plasma. When 30 mg/kg FF14984T was orally administrated to orthotropic MOLM13-xenografted mice once daily for 12 days, hCD45+ cells proportions in bone marrow were decreased whereas hCD11bhigh/hCD45+ ratio increased, indicating that FF14984T induced AML differentiation in vivo. Finally, oral administration of 30 mg/kg FF14984T once daily significantly prolonged survival of mice in U937 orthotropic models. Taken together, we developed a novel potent DHODH inhibitor FF14984T that induced cellular differentiation and anti-leukemic effects on cell lines and primary AML cells. FF14984T is possibly a promising therapeutic option for Ara-C-resistant AML patients that can also benefit from the combination therapy of FF14984T and Ara-C. Identifying the precise mechanism of AML differentiation by DHODH inhibitor and its effects on CIC are currently ongoing. Disclosures Kitazawa: FUJIFILM Corporation: Employment. Ishii:FUJIFILM Corporation: Employment. Makita-Suzuki:FUJIFILM Corporation: Employment. Saito:FUJIFILM Corporation: Employment. Takayanagi:FUJIFILM Corporation: Employment. Sugihara:FUJIFILM Corporation: Employment. Matsuda:FUJIFILM Corporation: Employment. Yamakawa:FUJIFILM Corporation: Employment. Tsutsui:FUJIFILM Corporation: Employment. Tanaka:FUJIFILM Corporation: Employment. Hatta:FUJIFILM Corporation: Research Funding. Natsume:FUJIFILM Corporation: Research Funding. Kondo:FUJIFILM Corporation: Research Funding. Hagiwara:FUJIFILM Coporation: Employment. Kiyoi:FUJIFILM Corporation: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; Perseus Proteomics Inc.: Research Funding.

scholarly journals PKR-like Endoplasmic Reticulum Kinase Mediates Apoptosis Induced By Pharmacological AMP-Activated Protein Kinase Activation in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2552-2552
Author(s):  
Laury Poulain ◽  
Adrien Grenier ◽  
Johanna Mondesir ◽  
Arnaud Jacquel ◽  
Claudie Bosc ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Endoplasmic Reticulum Stress Response ◽  
Ampk Activation ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Amp Activated Protein Kinase ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a myeloid progenitor-derived neoplasm of poor prognosis, particularly among the elderly, in whom age and comorbidities preclude the use of intensive therapies. Novel therapeutic approaches for AML are therefore critically needed. Adenosine monophosphate (AMP) activated protein kinase (AMPK) is a pleiotropic serine/threonine kinase promoting catabolism that represses anabolism and enhances autophagy in response to stress1. AMPK heterotrimers comprise catalytic α- and regulatory β- and γ-subunits, the latter harboring binding sites for AMP. Targets of AMPK include a host of metabolic pathway enzymes mediating carbohydrate, lipid and protein synthesis and metabolism. Accumulating evidence implicates AMPK in cancer biology, primarily as a tumor suppressor, although minimal AMPK activity may also be required for cancer cell growth under stress conditions2,3. Pharmacological activation of AMPK thus represents an attractive new strategy for targeting AML. We previously used the selective small molecule AMPK activator GSK621 to show that AMPK activation induces cytotoxicity in AML but not in normal hematopoietic cells, contingent on concomitant activation of the mammalian target of rapamycin complex 1 (mTORC1)4. However, the precise mechanisms of AMPK-induced AML cytotoxicity have remained unclear. We integrated gene expression profiling and bioinformatics proteomic analysis to identify the serine/threonine kinase PERK - one of the key effectors of the endoplasmic reticulum stress response - as a potential novel target of AMPK. We showed that PERK was directly phosphorylated by AMPK on at least two conserved residues (serine 439 and threonine 680) and that AMPK activators elicited a PERK/eIF2A signaling cascade independent of the endoplasmic reticulum stress response in AML cells. CRISPR/Cas9 depletion and complementation assays illuminated a critical role for PERK in apoptotic cell death induced by pharmacological AMPK activation. Indeed, GSK621 induced mitochondrial membrane depolarization and apoptosis in AML cells, an effect that was mitigated when cells were depleted of PERK or expressed PERK with a loss of function AMPK phosphorylation site mutation. We identified the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) as a downstream target of the AMPK/PERK pathway, as its expression was enhanced in PERK knockdown AML cells. Moreover, selective pharmacologic activation of ALDH2 by the small molecule ALDA-1 recapitulated the protective effects of PERK depletion in the face of pharmacological AMPK activation. Corroborating the impact of the AMPK/PERK axis on mitochondrial apoptotic function, BH3 profiling showed marked Bcl-2 dependency in AML cells treated with GSK621. This dependency was abrogated in PERK-depleted cells, suggesting a role for PERK in mitochondrial priming to cell death. In vitro drug combination studies further demonstrated synergy between the clinical grade Bcl-2 inhibitor venetoclax (ABT-199) and each of four AMPK activators (GSK621, MK-8722, PF-06409577 and compound 991) in multiple AML cell lines. Finally, the addition of GSK621 to venetoclax enhanced anti-leukemic activity in primary AML patient samples ex vivo and in humanized mouse models in vivo. These findings together clarify the mechanisms of cytotoxicity induced by AMPK activation and suggest that combining pharmacologic AMPK activators with venetoclax may hold therapeutic promise in AML. References 1. Lin S-C, Hardie DG. AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metabolism. 2018;27(2):299-313. 2. Hardie DG. Molecular Pathways: Is AMPK a Friend or a Foe in Cancer? Clinical Cancer Research. 2015;21(17):3836-3840. 3. Jeon S-M, Hay N. The double-edged sword of AMPK signaling in cancer and its therapeutic implications. Arch. Pharm. Res. 2015;38(3):346-357. 4. Sujobert P, Poulain L, Paubelle E, et al. Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia. Cell Rep. 2015;11(9):1446-1457. Figure Disclosures Tamburini: Novartis pharmaceutical: Research Funding; Incyte: Research Funding.

scholarly journals Myelodysplastic Syndrome with Excess Blasts and Secondary Acute Myeloid Leukemia: Same Disease with Different Blast Count

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2692-2692
Author(s):  
Xueyan Chen ◽  
Megan Othus ◽  
Brent L Wood ◽  
Roland B. Walter ◽  
Pamela S. Becker ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Mutational Analysis ◽  
World Health ◽  
Secondary Aml ◽  
Data Safety ◽  
Monitoring Committee ◽  
Mutational Hotspots ◽  
Acute Myeloid

Introduction: The World Health Organization (WHO) diagnoses acute myeloid leukemia (AML) if ≥20% myeloid blasts are present in peripheral blood or bone marrow. Consequently a patient with even 19% blasts is often ineligible for an "AML study". A less arbitrary means to define "AML" and myelodysplastic syndromes ("MDS") emphasizes biologic features. Here, focusing on patients with WHO-defined MDS with excess (5-19%) blasts (MDS-EB) or AML with myelodysplasia-related changes (AML-MRC) or therapy-related (t-AML) (WHO defined secondary AML), we compared morphologic blast percentage (MBP) with the frequency of mutations in genes belonging to different functional groups, and with the variant allele frequency (VAF) for individually mutated genes. Methods: 328 adults with WHO-defined AML (de novo and secondary; n=149) or MDS (n=179) and with mutational analysis by next-generation sequencing (NGS) performed at the University of Washington Hematopathology Laboratory between 2015-2017 were included. Of these, 86 had MDS-EB and 49 had secondary AML. Mutational analysis was performed using a customized, amplicon-based assay, TruSeq Custom Amplicon (Illumina, San Diego, CA). Custom oligonucleotide probes targeted specific mutational hotspots in ASXL1, CBL, CEBPA, CSF3R, EZH2, FBXW7, FGFR1, FLT3, GATA1, GATA2, HRAS, IDH1, IDH2, JAK2, KIT, KMT2A, KRAS, MAP2K1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PHF6, PTEN, RB1, RUNX1, SF3B1, SRSF2, STAG2, STAT3, TET2, TP53, U2AF1, WT1, and ZRSR2. VAF ≥5% was required to identify point mutations. Spearman's correlation coefficient was used to examine the relation between VAF of individually mutated genes and MBP. The Mann Whitney test served to compare the distribution of VAF in AML (≥20% blasts) vs. MDS (<20% blasts), before and after exclusion of subgroups as described below. Fisher's exact test was used to compare incidence of mutations. Results: 96% of cases had ≥one mutation in the 36 genes tested using NGS. Considering all 328 patients, mutations in tumor suppressor and cohesin complex genes were similarly frequent in MDS and AML, whereas spliceosomal genes, in particular SF3B1 and SRSF2, were more frequently mutated in MDS than in AML (46% vs. 26%, p<0.001). Mutations in epigenetic modifiers were more common in AML than MDS (54% vs. 42%, p= 0.035) as were transcription factor mutations (52% vs. 28%, p<0.001). However comparisons limited to MDS-EB vs. AML-MRC/t-AML, indicated the differences observed when comparing all MDS and all AML were less apparent, both statistically and more perhaps importantly with respect to observed frequencies. For example, spliceosomal gene mutations were found in 35% in MDS-EB and 27% in AML-MRC/t-AML (p=0.34) vs. 46% and 26% in all MDS and all AML. NPM1 mutations were detected in only 8% of AML-MRC/t-AML vs. 3% in MDS-EB but 29% for all AML. Results were analogous with FLT3 ITD, FLT3 TKD, and JAK2 mutations. Examining 20 individually mutated genes detected in ≥ 10 patients only with SRSF2 (p=0.04), did distribution of VAF differ statistically according to whether blast percentage was <20% versus ≥20%. Conclusions: The similar prevalence of mutations in different functional categories in MDS-EB and AML-MRC/t-AML suggests these entities are two manifestations of the same disease. We believe it appropriate to combine these WHO entities allowing patients in each to be eligible for both AML and MDS trials. Disclosures Othus: Glycomimetics: Other: Data Safety and Monitoring Committee; Celgene: Other: Data Safety and Monitoring Committee. Walter:Amgen: Consultancy; Boston Biomedical: Consultancy; Agios: Consultancy; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Amphivena Therapeutics: Consultancy, Equity Ownership; Boehringer Ingelheim: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding. Becker:Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; The France Foundation: Honoraria.

scholarly journals Prospective Identification of Acute Myeloid Leukemia Patients Who Benefit from Gene-Expression Based Risk Stratification

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1397-1397
Author(s):  
Diego Chacon ◽  
Ali Braytee ◽  
Yizhou Huang ◽  
Julie Thoms ◽  
Shruthi Subramanian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Genetic Risk ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Risk Groups ◽  
High Fidelity ◽  
Improve Outcome ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is a highly heterogeneous malignancy and risk stratification based on genetic and clinical variables is standard practice. However, current models incorporating these factors accurately predict clinical outcomes for only 64-80% of patients and fail to provide clear treatment guidelines for patients with intermediate genetic risk. A plethora of prognostic gene expression signatures (PGES) have been proposed to improve outcome predictions but none of these have entered routine clinical practice and their role remains uncertain. Methods: To clarify clinical utility, we performed a systematic evaluation of eight highly-cited PGES i.e. Marcucci-7, Ng-17, Li-24, Herold-29, Eppert-LSCR-48, Metzeler-86, Eppert-HSCR-105, and Bullinger-133. We investigated their constituent genes, methodological frameworks and prognostic performance in four cohorts of non-FAB M3 AML patients (n= 1175). All patients received intensive anthracycline and cytarabine based chemotherapy and were part of studies conducted in the United States of America (TCGA), the Netherlands (HOVON) and Germany (AMLCG). Results: There was a minimal overlap of individual genes and component pathways between different PGES and their performance was inconsistent when applied across different patient cohorts. Concerningly, different PGES often assigned the same patient into opposing adverse- or favorable- risk groups (Figure 1A: Rand index analysis; RI=1 if all patients were assigned to equal risk groups and RI =0 if all patients were assigned to different risk groups). Differences in the underlying methodological framework of different PGES and the molecular heterogeneity between AMLs contributed to these low-fidelity risk assignments. However, all PGES consistently assigned a significant subset of patients into the same adverse- or favorable-risk groups (40%-70%; Figure 1B: Principal component analysis of the gene components from the eight tested PGES). These patients shared intrinsic and measurable transcriptome characteristics (Figure 1C: Hierarchical cluster analysis of the differentially expressed genes) and could be prospectively identified using a high-fidelity prediction algorithm (FPA). In the training set (i.e. from the HOVON), the FPA achieved an accuracy of ~80% (10-fold cross-validation) and an AUC of 0.79 (receiver-operating characteristics). High-fidelity patients were dichotomized into adverse- or favorable- risk groups with significant differences in overall survival (OS) by all eight PGES (Figure 1D) and low-fidelity patients by two of the eight PGES (Figure 1E). In the three independent test sets (i.e. form the TCGA and AMLCG), patients with predicted high-fidelity were consistently dichotomized into the same adverse- or favorable- risk groups with significant differences in OS by all eight PGES. However, in-line with our previous analysis, patients with predicted low-fidelity were dichotomized into opposing adverse- or favorable- risk groups by the eight tested PGES. Conclusion: With appropriate patient selection, existing PGES improve outcome predictions and could guide treatment recommendations for patients without accurate genetic risk predictions (~18-25%) and for those with intermediate genetic risk (~32-35%). Figure 1 Disclosures Hiddemann: Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Vector Therapeutics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Metzeler:Celgene: Honoraria, Research Funding; Otsuka: Honoraria; Daiichi Sankyo: Honoraria. Pimanda:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Beck:Gilead: Research Funding.

scholarly journals Mini- Vs. Regular-Dose CLAG-M (Cladribine, Cytarabine, G-CSF, and Mitoxantrone) in Medically Less Fit Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) and Other High-Grade Myeloid Neoplasms

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1364-1364 ◽  
Author(s):  
Anna B. Halpern ◽  
Megan Othus ◽  
Kelda Gardner ◽  
Genevieve Alcorn ◽  
Mary-Elizabeth M. Percival ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Intensive Therapy ◽  
Treatment Intensity ◽  
High Grade ◽  
Intensive Chemotherapy ◽  
Myeloid Neoplasms ◽  
Acute Myeloid

Background: Optimal treatment for medically less fit adults with acute myeloid leukemia (AML) remains uncertain. Retrospective data suggest intensive therapy may lead to better outcomes in these patients. However, these findings must be interpreted cautiously because of the possibility of selection bias and other confounders. Ideally, the optimal treatment intensity is defined via randomized trial but whether patients and their physicians are amenable to such a study is unknown. We therefore designed a trial (NCT03012672) to 1) evaluate the feasibility of randomization between intensive and non-intensive therapy in this population and 2) examine the impact of treatment intensity on response rate and survival. We used CLAG-M as high-dose cytarabine-based intensive induction therapy. Rather than selecting different classes of drugs in the 2 treatment arms- which may have different modes of action and therefore confound the question of treatment intensity - we used reduced-dose ("mini") CLAG-M as the non-intensive comparator. Methods: Adults ≥18 years were eligible if they had untreated AML or high-grade myeloid neoplasms (≥10% blasts in blood or marrow) and were medically less fit as defined by having a "treatment related mortality" (TRM) score of ≥13.1, corresponding to a &gt;10-15% 28-day mortality with intensive chemotherapy. Left ventricular ejection fraction ≤45% was the only organ function exclusion. Patient-physician pairs were first asked if they were amenable to randomized treatment allocation. If so, they were randomized 1:1 to mini- vs. regular-dose CLAG-M. If not, in order to evaluate our secondary endpoints, the patient or physician could choose the treatment arm and still enroll on study. Patients and physicians then completed surveys elucidating their decision-making processes. Up to 2 induction courses were given with mini- vs. regular-dose CLAG-M: cladribine 2 or 5 mg/m2/day (days 1-5), cytarabine 100 or 2,000 mg/m2/day (days 1-5), G-CSF 300 or 480µcg/day for weight &lt;/≥76kg in both arms (days 0-5), and mitoxantrone 6 or 18 mg/m2/day (days 1-3). CLAG at identical doses was used for post-remission therapy for up to 4 (regular-dose CLAG) or 12 (mini-CLAG) cycles. The primary endpoint was feasibility of randomization, defined as ≥26/50 of patient-physician pairs agreeing to randomization. Secondary outcomes included rate of complete remission (CR) negative for measurable ("minimal") residual disease (MRD), rate of CR plus CR with incomplete hematologic recovery (CR+CRi), and overall survival (OS). Results: This trial enrolled 33 patients. Only 3 (9%) patient/physician pairs agreed to randomization and thus randomization was deemed infeasible (primary endpoint). Eighteen pairs chose mini-CLAG-M and 12 regular-dose CLAG-M for a total of 19 subjects in the lower dose and 14 subjects in the higher dose arms. The decision favoring lower dose treatment was made largely by the physician in 5/18 (28%) cases, the patient in 11/18 (61%) cases and both in 2/18 (11%). The decision favoring the higher dose arm was made by the patient in most cases 9/12 (75%), both physician and patient in 2/12 (16%) and the physician in only 1/12 (8%) cases. Despite the limitations of lack of randomization, patients' baseline characteristics were well balanced with regard to age, performance status, TRM score, lab values and cytogenetic/mutational risk categories (Table 1). One patient was not yet evaluable for response or TRM at data cutoff. Rates of MRDneg CR were comparable: 6/19 (32%) in the lower and 3/14 (21%) in the higher dose groups (p=0.70). CR+CRi rates were also similar in both arms (43% vs. 56% in lower vs. higher dose arms; p=0.47). Three (16%) patients experienced early death in the lower dose arm vs. 1 (7%) in the higher dose arm (p=0.43). With a median follow up of 4.2 months, there was no survival difference between the two groups (median OS of 6.1 months in the lower vs. 4.7 months in the higher dose arm; p=0.81; Figure 1). Conclusions: Randomization of medically unfit patients to lower- vs. higher-intensity therapy was not feasible, and physicians rarely chose higher intensity therapy in this patient group. Acknowledging the limitation of short follow-up time and small sample size, our trial did not identify significant differences in outcomes between intensive and non-intensive chemotherapy. Analysis of differences in QOL and healthcare resource utilization between groups is ongoing. Disclosures Halpern: Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Othus:Celgene: Other: Data Safety and Monitoring Committee. Gardner:Abbvie: Speakers Bureau. Percival:Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding. Scott:Incyte: Consultancy; Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy. Walter:BioLineRx: Consultancy; Astellas: Consultancy; Argenx BVBA: Consultancy; BiVictriX: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Cladribine is FDA-approved for Hairy Cell Leukemia. Here we describe its use for AML, where is is also widely used with prior publications supporting its use

scholarly journals Phase I Study of Ixazomib with Conventional Chemotherapy in the Treatment of Acute Myeloid Leukemia in Older Adults

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Philip C. Amrein ◽  
Eyal C. Attar ◽  
Geoffrey Fell ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Remission Rate ◽  
Conventional Chemotherapy ◽  
Advisory Committees ◽  
Secondary Aml ◽  
Grade 3 ◽  
Acute Myeloid

Introduction: Outcomes for acute myeloid leukemia (AML) among older patients has remained largely unchanged for decades. Long-term survival for patients aged &gt;60 years is poor (median survival 10.5 months). Targeting the proteasome in AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition in preclinical models, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). AML cell lines are susceptible to synergistic cytotoxicity when bortezomib, a proteasome inhibitor, is combined with daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although grade 2 sensory neurotoxicity was noted in approximately 12% of treated patients. A newer generation proteasome inhibitor, ixazomib, is less frequently associated with neurotoxicity, and, therefore, was selected for combination with conventional chemotherapy in this phase I trial. The primary objective of this study was to determine the maximum tolerated dose (MTD) of ixazomib in combination with conventional induction and consolidation chemotherapy for AML. Herein are the initial results of this trial. Methods: Adults &gt;60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. There were 2 phases in this study. In the first phase (A), the induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3, and ixazomib was provided orally at the cohort dose, Days 2, 5, 9, and 12. Consolidaton or transplant was at the discretion of the treating physician in phase A. In the second phase (B), induction was the same as that with the determined MTD of ixazomib. All patients were to be treated with the following consolidation: cytarabine at 2 g/m2/day, days 1-5 with ixazomib on days 2, 5, 9, and 12 at the cohort dose for consolidation. A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction (phase A) and subsequently in consolidation (phase B). The determined MTD of ixazomib in the first portion (A) of the trial was used during induction in the second portion (B), which sought to determine the MTD for ixazomib during consolidation. Secondary objectives included rate of complete remission, disease-free survival, and overall survival (OS). Results: Thirty-six patients have been enrolled on study, and 28 have completed dose levels A-1 through A-3 and B1 through B-2. Full information on cohort B-3 has not yet been obtained, hence, this report covers the experience with the initial 28 patients, cohorts A-1 through B-2. There were 12 (43%) patients among the 28 with secondary AML, either with prior hematologic malignancy or therapy-related AML. Nineteen patients (68%) were male, and the median age was 68 years (range 61-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 4 platelet count decrease extending beyond Day 42). There has been no grade 3 or 4 neurotoxicity with ixazomib to date. Among the 28 patients in the first 5 cohorts, 22 achieved complete remissions (CR) and 2 achieved CRi, for a composite remission rate (CCR) of 86%. Among the 12 patients with secondary AML 8 achieved CR and 2 achieved CRi, for a CCR of 83%. The median OS for the 28 patients has not been reached (graph). The 18-month OS estimate was 65% [90% CI, 50-85%]. Conclusions: The highest dose level (3 mg) of ixazomib planned for induction in this trial has been reached safely. For consolidation there have been no serious safety issues in the first 2 cohorts with a dose up to 2.3 mg, apart from 1 DLT in the form of delayed platelet count recovery. The recommended phase 2 dose of ixazomib for induction is 3 mg. Accrual to cohort B-3 is ongoing. Notably, to date, no grade 3 or 4 neurotoxicity has been encountered. The remission rate in this older adult population with the addition of ixazomib to standard chemotherapy appears favorable. Figure Disclosures Amrein: Amgen: Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding. Attar:Aprea Therapeutics: Current Employment. Brunner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Hobbs:Constellation: Honoraria, Research Funding; Novartis: Honoraria; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria. Neuberg:Celgene: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Fathi:Blueprint: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kura Oncology: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy; Newlink Genetics: Consultancy; Forty Seven: Consultancy; Trovagene: Consultancy; Kite: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Amphivena: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz: Consultancy. OffLabel Disclosure: Ixazomib is FDA approved for multiple myeloma. We are using it in this trial for acute myeloid leukemia.

scholarly journals The Novel Dihydroorotate Dehydrogenase (DHODH) Inhibitor PTC299 Inhibit De Novo Pyrimidine Synthesis with Broad Anti-Leukemic Activity Against Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Sujan Piya ◽  
Marla Weetall ◽  
Josephine Sheedy ◽  
Balmiki Ray ◽  
Huaxian Ma ◽  
...  
Keyword(s):  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Dihydroorotate Dehydrogenase ◽  
Nucleotide Synthesis ◽  
Inhibition Of Proliferation ◽  
Acute Myeloid

Introduction: Acute myeloid leukemia (AML) is characterized by both aberrant proliferation and differentiation arrest at hematopoietic progenitor stages 1,2. AML relies upon de novo nucleotide synthesis to meet a dynamic metabolic landscape and to provide a sufficient supply of nucleotides and other macromolecules 3,4. Hence, we hypothesized that inhibition of de novo nucleotide synthesis would lead to depletion of the nucleotide pool and pyrimidine starvation in leukemic cells compared to their non-malignant counterparts and impact proliferative and differentiation inhibition pathways. PTC299 is an inhibitor of dihydroorotate dehydrogenase (DHODH), a rate limiting enzyme for de novo pyrimidine nucleotide synthesis that is currently in a clinical trial for the treatment of AML. Aim: We investigated the pre-clinical activity of PTC299 against AML in primary AML blasts and cytarabine-resistant cell lines. To confirm that PTC299 effects are due to inhibition of de novo pyrimidine nucleotide synthesis for leukemic growth, we specifically tested the impact of uridine and orotate rescue. In addition, a comprehensive analysis of alteration of metabolic signaling in PI3K/AKT pathways, apoptotic signatures and DNA damage responses were analyzed by Mass cytometry based proteomic analysis (CyTOF) and immunoblotting. The potential clinical relevance of DHODH inhibition was confirmed in an AML-PDX model. Results: The IC50s for all tested cell lines (at 3 day) and primary blasts (at 5-7 day) were in a very low nanomolar range: OCI-AML3 -4.43 nM, HL60 -59.7 nM and primary samples -18-90 nM. Treatment of AML in cytarabine-resistant cells demonstrated that PTC299 induced apoptosis, differentiation, and reduced proliferation with corresponding increase in Annexin V and CD14 positive cells (Fig.1). PTC299-induced apoptosis and inhibition of proliferation was rescued by uridine and orotate. To gain more mechanistic insights, we used an immunoblotting and mass cytometry (CyTOF) based approach to analyze changes in apoptotic and cell signaling proteins in OCI-AML3 cells. Apoptotic pathways were induced (cleaved PARP, cleaved Caspase-3) and DNA damage responses (TP53, γH2AX) and the PI3/AKT pathway were downregulated in response to PTC299. In isogenic cell lines, p53-wildtype cells were sustained and an increased DNA damage response with corresponding increase in apoptosis in comparison to p53-deficient cells was shown. (Fig.2) In a PDX mouse model of human AML, PTC299 treatment improved survival compared to mice treated with vehicle (median survival 40 days vs. 30 days, P=0.0002) (Fig.3). This corresponded with a reduction in the bone marrow burden of leukemia with increased expression of differentiation markers in mice treated with PTC299 (Fig.3). Conclusion: PTC299 is a novel dihydroorotate dehydrogenase (DHODH) inhibitor that triggers differentiation, apoptosis and/or inhibition of proliferation in AML and is being tested in a clinical trials for the treatment of acute myeloid malignancies. Reference: 1. Thomas D, Majeti R. Biology and relevance of human acute myeloid leukemia stem cells. Blood 2017; 129(12): 1577-1585. e-pub ahead of print 2017/02/06; doi: 10.1182/blood-2016-10-696054 2. Quek L, Otto GW, Garnett C, Lhermitte L, Karamitros D, Stoilova B et al. Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. The Journal of experimental medicine 2016; 213(8): 1513-1535. e-pub ahead of print 2016/07/06; doi: 10.1084/jem.20151775 3. Villa E, Ali ES, Sahu U, Ben-Sahra I. Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides. Cancers (Basel) 2019; 11(5). e-pub ahead of print 2019/05/22; doi: 10.3390/cancers11050688 4. DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv 2016; 2(5): e1600200. e-pub ahead of print 2016/07/08; doi: 10.1126/sciadv.1600200 Disclosures Weetall: PTC Therapeutic: Current Employment. Sheedy:PTC therapeutics: Current Employment. Ray:PTC Therapeutics Inc.: Current Employment. Konopleva:Genentech: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Ablynx: Research Funding; Ascentage: Research Funding; Agios: Research Funding; Kisoji: Consultancy; Eli Lilly: Research Funding; AstraZeneca: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AbbVie: Consultancy, Research Funding; Calithera: Research Funding; Cellectis: Research Funding; Amgen: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Sanofi: Research Funding. Andreeff:Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees. Borthakur:BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; Oncoceutics: Research Funding.

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