Search

Recently, the European LeukemiaNet (ELN) revised its genetic-risk classification of acute myeloid leukemia (AML). We categorized 1637 adults with AML treated with cytarabine/anthracycline regimens according to the 2022 and 2017 ELN classifications. Compared with the 2017 ELN classification, 2022 favorable group decreased from 40% to 35% and adverse group increased from 37% to 41% of patients. The 2022 genetic-risk groups seemed to accurately reflect treatment outcomes in all patients and patients aged CEBPAbZIP mutations or core-binding factor AML, but changed risk assignment of NPM1-mutated/FLT3-ITD-negative patients to intermediate. NPM1-mutated patients with adverse-risk cytogenetic abnormalities were closer prognostically to the intermediate than adverse group. Our analyses both confirm and challenge prognostic significance of some of the newly added markers.

Chronic lymphocytic leukemia (CLL) is effectively treated with targeted therapies including Bruton tyrosine kinase inhibitors and BCL2 antagonists. When these become ineffective, treatment options are limited. Positive transcription elongation factor complex (P-TEFb), a heterodimeric protein complex composed of cyclin dependent kinase 9 (CDK9) and cyclin T1, functions to regulate short half-life transcripts by phosphorylation of RNA Polymerase II (POLII). These transcripts are frequently dysregulated in hematologic malignancies; however, therapies targeting inhibition of P-TEFb have not yet achieved approval for cancer treatment. VIP152 kinome profiling revealed CDK9 as the main enzyme inhibited at 100 nM, with over a 10-fold increase in potency compared with other inhibitors currently in development for this target. VIP152 induced cell death in CLL cell lines and primary patient samples. Transcriptome analysis revealed inhibition of RNA degradation through the AU-Rich Element (ARE) dysregulation. Mechanistically, VIP152 inhibits the assembly of P-TEFb onto the transcription machinery and disturbs binding partners. Finally, immune competent mice engrafted with CLL-like cells of Eµ-MTCP1 over-expressing mice and treated with VIP152 demonstrated reduced disease burden and improvement in overall survival compared to vehicle-treated mice. These data suggest that VIP152 is a highly selective inhibitor of CDK9 that represents an attractive new therapy for CLL.

Survival of patients with acute myeloid leukemia (AML) is inversely associated with age, but the impact of race on outcomes of adolescent and young adult (AYA; range, 18-39 years) patients is unknown. We compared survival of 89 non-Hispanic Black and 566 non-Hispanic White AYA patients with AML treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols. Samples of 327 patients (50 Black and 277 White) were analyzed via targeted sequencing. Integrated genomic profiling was performed on select longitudinal samples. Black patients had worse outcomes, especially those aged 18 to 29 years, who had a higher early death rate (16% vs 3%; P=.002), lower complete remission rate (66% vs 83%; P=.01), and decreased overall survival (OS; 5-year rates: 22% vs 51%; P

Survival of patients with acute myeloid leukemia (AML) is influenced by genetic factors, age, and race. Social deprivation is increasingly recognized as an important contributor to disparities in cancer outcomes, but studies of adult AML are lacking. We analyzed associations between social deprivation index (SDI) and outcome in 1,893 patients with AML treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology frontline protocols. Patients with low (first quartile, lowest deprivation) and high (quartiles 2-4) SDI were analyzed for associations with baseline clinical, cytogenetic and molecular features, and outcomes. Except for racial-ethnic identity, SDI was not associated with baseline clinical characteristics. Patients aged

Supplementary Figures and Tables

Clinical outcome of patients with acute myeloid leukemia (AML) is associated with cytogenetic and molecular factors and patient demographics (e.g., age and race). We compared survival of 25,523 non-Hispanic Black and White adults with AML using Surveillance Epidemiology and End Results (SEER) Program data and performed mutational profiling of 1,339 patients with AML treated on frontline Alliance for Clinical Trials in Oncology (Alliance) protocols. Black patients had shorter survival than White patients, both in SEER and in the setting of Alliance clinical trials. The disparity was especially pronounced in Black patients NPM1 and more IDH2 mutations in younger Black patients. Overall survival of younger Black patients was adversely affected by IDH2 mutations and FLT3-ITD, but, in contrast to White patients, was not improved by NPM1 mutations.Significance:We show that young Black patients have not benefited as much as White patients from recent progress in AML treatment in the United States. Our data suggest that both socioeconomic factors and differences in disease biology contribute to the survival disparity and need to be urgently addressed.See related commentary by Vyas, p. 540.This article is highlighted in the In This Issue feature, p. 521

PDF file, 38K, Distribution of FLT3 kinase domain mutations on FLT3-ITD alleles.

Purpose: To compare side-by-side the uptake of sorafenib and sunitinib in vitro by human uptake solute carriers of the SLC22A and SLCO families, the transport by and inhibition of efflux ATP-binding cassette (ABC) transporters, and the role of ABCB1 in the plasma pharmacokinetics and brain penetration of these agents.Experimental Design: Uptake of [3H]sorafenib or [3H]sunitinib was assessed in Xenopus laevis oocytes or mammalian cells transfected with cDNAs coding for human OATP1A2, OATP1B1, OATP1B3, OCT1, OAT2, OAT3, OCTN1, or OCTN2. Efflux and inhibition experiments were conducted in cells transfected with human ABCB1, ABCG2, ABCC2, or ABCC4. In vivo pharmacokinetic studies were done in knockout mice lacking Abcb1-type transporters.Results: Intracellular uptake was not appreciably affected by any of the studied solute carriers and was minute relative to the respective prototypical substrates. Sorafenib and sunitinib showed concentration-dependent (1 and 10 μmol/L), low to moderate affinity for ABCB1 but were not affected by the other ABC transporters. Both agents inhibited all tested ABC transporters. The absence of Abcb1 had no affect on plasma pharmacokinetics, but brain penetration was moderately increased by 1.9- and 2.9-fold for sorafenib and sunitinib, respectively, in knockout animals versus controls.Conclusions: Unlike other tyrosine kinase inhibitors, sorafenib and sunitinib do not appear to rely on active transport to enter the cell nor are they high-affinity substrates for ABC efflux transporters. Based on these characteristics, these two drugs may be less susceptible to transporter-mediated alterations in systemic exposure and transporter-related resistance mechanisms. (Clin Cancer Res 2009;15(19):6062–9)

PDF file, 76K.

Supplementary Table S1 from Comparison of antitumor effects of multitargeted tyrosine kinase inhibitors in acute myelogenous leukemia

Purpose: To evaluate the clinical activity of sequential therapy with sorafenib and sunitinib in FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive acute myelogenous leukemia (AML) and monitor the emergence of secondary FLT3 tyrosine kinase domain (TKD) mutations during treatment.Experimental Design: Six children with relapsed/refractory AML were treated with sorafenib in combination with clofarabine and cytarabine, followed by single-agent sorafenib if not a candidate for transplantation. Sunitinib was initiated after sorafenib relapse. Bone marrow samples were obtained for assessment of FLT3 TKD mutations by deep amplicon sequencing. The phase of secondary mutations with ITD alleles was assessed by cloning and sequencing of FLT3 exons 14 through 20. Identified mutations were modeled in Ba/F3 cells, and the effect of kinase inhibitors on FLT3 signaling and cell viability was assessed.Results: Four patients achieved complete remission, but 3 receiving maintenance therapy with sorafenib relapsed after 14 to 37 weeks. Sunitinib reduced circulating blasts in two patients and marrow blasts in one. Two patients did not respond to sorafenib combination therapy or sunitinib. FLT3 mutations at residues D835 and F691 were observed in sorafenib resistance samples on both ITD-positive and -negative alleles. Deep sequencing revealed low-level mutations and their evolution during sorafenib treatment. Sunitinib suppressed leukemic clones with D835H and F691L mutations, but not D835Y. Cells expressing sorafenib-resistant FLT3 mutations were sensitive to sunitinib in vitro.Conclusions: Sunitinib has activity in patients that are resistant to sorafenib and harbor secondary FLT3 TKD mutations. The use of sensitive methods to monitor FLT3 mutations during therapy may allow individualized treatment with the currently available kinase inhibitors. Clin Cancer Res; 19(20); 5758–68. ©2013 AACR.

Knockdown of selected genes has modest effects on MOLM13 responses to KPT-9274 treatment.

Monosomy of chromosome 7 is the most frequent autosomal monosomy in acute myeloid leukemia (AML), where it associates with poor clinical outcomes. However, molecular features associated with this sole monosomy subtype (-7 AML), which may give insights into the basis for its poor prognosis, have not been characterized. In this study, we analyzed 36 cases of -7 AML for mutations in 81 leukemia/cancer-associated genes using a customized targeted next-generation sequencing panel (Miseq). Global gene and miRNA expression profiles were also determined using paired RNA and small RNA sequencing data. Notably, gene mutations were detected in all the major AML-associated functional groups, which include activated signaling, chromatin remodeling, cohesin complex, methylation, NPM1, spliceosome, transcription factors, and tumor suppressors. Gene mutations in the chromatin remodeling groups were relatively more frequent in patients SMARCA2 gene. In patients ≥60 years of age, the presence of spliceosome mutations associated with a lower complete remission rate (P = 0.03). RNA sequencing revealed distinct gene and miRNA expression patterns between the sole -7 and non -7 AML cases, with reduced expression, as expected, of many genes and miRNAs mapped to chromosome 7, and overexpression of ID1, MECOM, and PTPRM, among others. Overall, our findings illuminate a number of molecular features of the underlying aggressive pathobiology in -7 AML patients. Cancer Res; 77(1); 207–18. ©2016 AACR.

PDF file, 33K, Primers used to sequence FLT3 exons 13 to 23.

Supplementary Methods, Supplementary References Supplementary Table S1: Inherited regions of homozygosity in >1% of 1,798 non-leukemic individuals Supplementary Table S2: Acquired uniparental disomies detected in 425 cytogenetically normal AML patients Supplementary Table S3. Associations between recurrent UPDs with pretreatment patient characteristics for patients with cytogenetically normal acute myeloid leukemia Supplementary Table S5. Variant allele fraction of gene mutations that co-occurred with UPDs Supplementary Table S6. Allelic ratio of FLT3 internal tandem duplications that co-occurred with UPDs Supplementary Table S7: Copy number gains and losses in 425 patients with cytogenetically normal acute myeloid leukemia

PDF file, 25K, Sorafenib and sorafenib N-oxide plasma concentrations.

We compared the antitumor activities of the multitargeted tyrosine kinase inhibitors imatinib, sorafenib, and sunitinib to determine which inhibitor is best suited to be used for the treatment of acute myelogenous leukemia (AML). In nine human AML cell lines, sorafenib and sunitinib were more potent inhibitors of cellular proliferation than imatinib (IC50, 0.27 to >40, 0.002-9.1, and 0.007-13 μmol/L for imatinib, sorafenib, and sunitinib, respectively). Sorafenib and sunitinib were potent inhibitors of cells with fms-like tyrosine kinase 3 internal tandem duplication (IC50, 2 and 7 nmol/L) and c-KIT N822K mutations (IC50, 23 and 40 nmol/L). In four cell lines (MV4-11, Kasumi-1, KG-1, and U937) that spanned a range of drug sensitivities, sorafenib and sunitinib had similar activity in apoptosis and cell cycle assays, except that sunitinib did not promote apoptosis in U937 cells. Both drugs inhibited mitogen-activated protein kinase signaling but had no effect on AKT signaling in most of the cell lines tested. Sorafenib was substantially more bound than sunitinib in human plasma (unbound fraction, 0.59% versus 8.4%) and cell culture medium (unbound fraction, 1.3% versus 39%), indicating that sorafenib was more potent than sunitinib and that unbound sorafenib concentrations with activity against most AML cell lines are achievable in vivo. There was more intracellular accumulation of sorafenib than of sunitinib and imatinib in AML cells. Between 1 and 10 μmol/L, sorafenib inhibited the proliferation of six of nine primary AML blast samples by ≥50%. Our results highlight the pharmacologic features of sorafenib that may provide it an advantage in the treatment of AML. [Mol Cancer Ther 2008;7(5):1110–20]

Suppl Figures 1-3, Suppl Table 1 Supplemental Figure 1. Study schema. Supplemental Figure 2. Overall survival in patients treated with ENTO + 7+3. OS is censored on the date the patient was last known to be alive (if it was not known the patient had died by the end of study follow-up). Supplemental Figure 3. Heat map showing single patients (each column) by HOXA9 and MEIS1 categorization, cytogenetic or molecular risk and outcomes.

PDF file, 76K, Identification of FLT3 tyrosine kinase domain mutations.

Purpose:Uniparental disomy (UPD) is a way cancer cells duplicate a mutated gene, causing loss of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We examined the prognostic significance of UPDs and frequency of LOH in patients with CN-AML.Experimental Design: We examined the frequency and prognostic significance of UPDs in a set of 425 adult patients with de novo CN-AML who were previously sequenced for 81 genes typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 patients with CN-AML younger than 60 years.Results:We detected 127 UPDs in 109 patients. Most UPDs were large and typically encompassed all or most of the affected chromosome arm. The most common UPDs occurred on chromosome arms 13q (7.5% of patients), 6p (2.8%), and 11p (2.8%). Many UPDs significantly cooccurred with mutations in genes they encompassed, including 13q UPD with FLT3-internal tandem duplication (FLT3-ITD; P < 0.001), and 11p UPD with WT1 mutations (P = 0.02). Among patients younger than 60 years, UPD of 11p was associated with longer overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In multivariable models that accounted for known prognostic markers, including FLT3-ITD and WT1 mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained association with longer OS.Conclusions:LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 13q and 11p might be useful for genetic risk stratification of patients with CN-AML.

Supplementary Data from Interaction of the Multikinase Inhibitors Sorafenib and Sunitinib with Solute Carriers and ATP-Binding Cassette Transporters

PDF file, 28K, Error rates and confidence levels for frequency of detection of FLT3 kinase domain mutations by next generation sequencing.

Purpose:Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (NAMPTi) are currently in development, but may be limited as single-agent therapy due to compound-specific toxicity and cancer metabolic plasticity allowing resistance development. To potentially lower the doses of NAMPTis required for therapeutic benefit against acute myeloid leukemia (AML), we performed a genome-wide CRISPRi screen to identify rational disease-specific partners for a novel NAMPTi, KPT-9274.Experimental Design:Cell lines and primary cells were analyzed for cell viability, self-renewal, and responses at RNA and protein levels with loss-of-function approaches and pharmacologic treatments. In vivo efficacy of combination therapy was evaluated with a xenograft model.Results:We identified two histone deacetylases (HDAC), HDAC8 and SIRT6, whose knockout conferred synthetic lethality with KPT-9274 in AML. Furthermore, HDAC8-specific inhibitor, PCI-34051, or clinical class I HDAC inhibitor, AR-42, in combination with KPT-9274, synergistically decreased the survival of AML cells in a dose-dependent manner. AR-42/KPT-9274 cotreatment attenuated colony-forming potentials of patient cells while sparing healthy hematopoietic cells. Importantly, combined therapy demonstrated promising in vivo efficacy compared with KPT-9274 or AR-42 monotherapy. Mechanistically, genetic inhibition of SIRT6 potentiated the effect of KPT-9274 on PARP-1 suppression by abolishing mono-ADP ribosylation. AR-42/KPT-9274 cotreatment resulted in synergistic attenuation of homologous recombination and nonhomologous end joining pathways in cell lines and leukemia-initiating cells.Conclusions:Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity toward normal cells, providing a rationale for a novel–novel combination-based treatment for AML.

Supplementary Figure S1. Unsupervised clustering of the sole -7 AML cohort and the complete TCGA AML patient data set. Supplementary Figure S2. SMARCA2 mutations in AML patients with sole -7. Supplementary Figure S3. Heatmap depicting the differential gene expression of AML patients with sole -7. Supplementary Figure S4. Heatmap visualizing the gene ontology (GO) analyses of the predicted target genes of the miRs upregulated in AML patients with sole -7. Supplementary Figure S5. Heatmap visualizing the gene ontology (GO) analyses of the predicted target genes of the miRs downregulated in AML patients with sole -7. Tables: Supplementary Table S1. Gene mutations detected in 36 patients with acute myeloid leukemia (AML) and sole -7 (DNA sequencing of 81 genes). Supplementary Table S2. Mutation analysis in paired germline-leukemic samples of 10 sole -7 patients. Supplementary Table S3. Genes significantly downregulated in 31 AML patients with sole -7 compared with gene expression of 136 AML patients from the TCGA cohort (14) who had other chromosome abnormalities that did not include abnormalities of chromosome 7 or a complex karyotype. Supplementary Table S4. Genes significantly upregulated in 31 AML patients with sole -7 compared with gene expression of 136 AML patients from the TCGA cohort (14) who had other chromosome abnormalities that did not include abnormalities of chromosome 7 or a complex karyotype. Supplementary Table S5. MicroRNAs (miRs) significantly downregulated in 31 AML patients with sole -7 compared with gene expression of 136 AML patients from the TCGA cohort who had other chromosome abnormalities that did not include abnormalities of chromosome 7 or a complex karyotype. Supplementary Table S6. MicroRNAs (miRs) significantly upregulated in 31 AML patients with sole -7 compared with gene expression of 136 AML patients from the TCGA cohort who had other chromosome abnormalities that did not include abnormalities of chromosome 7 or a complex karyotype. Supplementary Table S7. Gene ontogeny analyses of significantly downregulated genes located on chromosome 7 in 31 AML patients with sole -7.

Materials and Methods: Participating institutions. List of all institutions that participated in the study. Patients and treatments. Detailed information about patients included in the study and their treatments. Mutational profiling. Detailed information about the techniques used to perform the mutational profiling. Definition of clinical endpoints. Statistical definition of the used end point terms . Univariable outcome analysis. Listing of all parameters that were included in the univariable outcome analysis.

Mutations detected in 425 CN-AML patients

Supplementary Methods

PDF file, 242K, FLT3 tyrosine kinase domain mutations induce IL3-independent Ba/F3 cell transformation and show varying sensitivity to Quizartinib and Midostaurin.

Purpose:Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked to HOXA9 and MEIS1 overexpression in preclinical studies. This trial evaluated the safety and efficacy of entospletinib, a selective inhibitor of SYK, in combination with chemotherapy in untreated AML.Patients and Methods:This was an international multicenter phase Ib/II study, entospletinib dose escalation (standard 3+3 design between 200 and 400 mg twice daily) + 7+3 (cytarabine + daunorubicin) in phase Ib and entospletinib dose expansion (400 mg twice daily) + 7+3 in phase II.Results:Fifty-three patients (n = 12, phase Ib and n = 41, phase II) with previously untreated de novo (n = 39) or secondary (n = 14) AML were enrolled (58% male; median age, 60 years) in this study. The composite complete response with entospletinib + 7+3 was 70%. Patients with baseline HOXA9 and MEIS1 expression higher than the median had improved overall survival compared with patients with below median HOXA9 and MEIS1 expression. Common adverse events were cytopenias, febrile neutropenia, and infection. There were no dose-limiting toxicities. Entospletinib-related skin rash and hyperbilirubinemia were also observed.Conclusions:Entospletinib with intensive chemotherapy was well-tolerated in patients with AML. Improved survival was observed in patients with HOXA9/MEIS1 overexpression, contrasting published data demonstrating poor survival in such patients. A randomized study will be necessary to determine whether entospletinib was a mediator this observation.

PDF file, 53K.

Acute myeloid leukemia (AML) with mutations in the tumor suppressor gene TP53 confers a dismal prognosis with 3-year overall survival of

Background Older patients (≥ 60 years) with acute myeloid leukemia (AML) often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis and are associated with poor outcome. Beat AML is a Leukemia and Lymphoma Society-sponsored, multicenter umbrella study that algorithmically segregates AML patients based upon cytogenetic and dominant molecular abnormalities (variant allele frequencies (VAF) ≥ 0.2) into different cohorts to select for targeted therapies. During the conception of the Beat AML design, a historical dataset was needed to help in the design of the genomic algorithm for patient assignment and serve as the basis for the statistical design of individual genomic treatment substudies for the Beat AML study. Methods We classified 563 newly diagnosed older AML patients treated with standard intensive chemotherapy on trials conducted by Cancer and Leukemia Group B based on the same genomic algorithm and assessed clinical outcomes. Results Our classification identified core-binding factor and NPM1-mutated/FLT3-ITD-negative groups as having the best outcomes, with 30-day early death (ED) rates of 0 and 20%, respectively, and median overall survival (OS) of > 1 year and 3-year OS rates of ≥ 20%. All other genomic groups had ED rates of 17–42%, median OS ≤ 1 year and 3-year OS rates of ≤ 15%. Conclusions By classifying patients through this genomic algorithm, outcomes were poor and not unexpected from a non-algorithmic, non-dominant VAF approach. The exception is 30-day ED rate typically is not available for intensive induction for individual genomic groups and therefore difficult to compare outcomes with targeted therapeutics. This Alliance data supported the use of this algorithm for patient assignment at the initiation of the Beat AML study. This outcome data was also used for statistical design for Beat AML substudies for individual genomic groups to determine goals for improvement from intensive induction and hopefully lead to more rapid approval of new therapies. Trial registration ClinicalTrials.gov Identifiers: NCT00048958 (CALGB 8461), NCT00900224 (CALGB 20202), NCT00003190 (CALGB 9720), NCT00085124 (CALGB 10201), NCT00742625 (CALGB 10502), NCT01420926 (CALGB 11002), NCT00039377 (CALGB 10801), and NCT01253070 (CALGB 11001).

Purpose: Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked to HOXA9 and MEIS1 overexpression in preclinical studies. This trial evaluated the safety and efficacy of entospletinib, a selective inhibitor of SYK, in combination with chemotherapy in untreated AML. Patients and Methods: This was an international multicenter phase Ib/II study, entospletinib dose escalation (standard 3+3 design between 200 and 400 mg twice daily) + 7+3 (cytarabine + daunorubicin) in phase Ib and entospletinib dose expansion (400 mg twice daily) + 7+3 in phase II. Results: Fifty-three patients (n = 12, phase Ib and n = 41, phase II) with previously untreated de novo (n = 39) or secondary (n = 14) AML were enrolled (58% male; median age, 60 years) in this study. The composite complete response with entospletinib + 7+3 was 70%. Patients with baseline HOXA9 and MEIS1 expression higher than the median had improved overall survival compared with patients with below median HOXA9 and MEIS1 expression. Common adverse events were cytopenias, febrile neutropenia, and infection. There were no dose-limiting toxicities. Entospletinib-related skin rash and hyperbilirubinemia were also observed. Conclusions: Entospletinib with intensive chemotherapy was well-tolerated in patients with AML. Improved survival was observed in patients with HOXA9/MEIS1 overexpression, contrasting published data demonstrating poor survival in such patients. A randomized study will be necessary to determine whether entospletinib was a mediator this observation.

Prognostic factors associated with chemotherapy outcomes in patients with acute myeloid leukemia (AML) are extensively reported, and one gene whose mutation is recognized as conferring resistance to several newer targeted therapies is protein tyrosine phosphatase non-receptor type 11 (PTPN11). The broader clinical implications of PTPN11 mutations in AML are still not well understood. The objective of this study was to determine which cytogenetic abnormalities and gene mutations co-occur with PTPN11 mutations and how PTPN11 mutations affect outcomes of patients treated with intensive chemotherapy. We studied 1725 patients newly diagnosed with AML (excluding acute promyelocytic leukemia) enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials. In 140 PTPN11-mutated patient samples, PTPN11 most commonly co-occurred with mutations in NPM1, DNMT3A, and TET2. PTPN11 mutations were relatively common in patients with an inv(3)(q21q26)/t(3;3)(q21;q26) and a normal karyotype but were very rare in patients with typical complex karyotype and core-binding factor AML. Mutations in the N-terminal SH2 domain of PTPN11 were associated with a higher early death rate than those in the phosphatase domain. PTPN11 mutations did not affect outcomes of NPM1-mutated patients, but these patients were less likely to have co-occurring kinase mutations (ie, FLT3-ITD), suggesting activation of overlapping signaling pathways. However, in AML patients with wild-type NPM1, PTPN11 mutations were associated with adverse patient outcomes, providing a rationale to study the biology and treatment approaches in this molecular group. This trial was registered at www.clinicaltrials.gov as #NCT00048958 (CALGB 8461), #NCT00899223 (CALGB 9665), and #NCT00900224 (CALGB 20202).

Background: AML is a clinically and molecularly heterogeneous disease associated with poor survival. Multiple disease-related factors including cytogenetic findings and gene mutations, as well as patient-related factors, such as demographics and African American (AA) heritage, have been identified that impact on pt outcomes. However, with recent improved survival it is unknown whether racial health disparities persist. Moreover, we are not aware of a large study that assessed possible race-associated molecular differences. Thus, the goals of our study were to 1) analyze the outcomes of adult AML pts in a nationwide population study, including possible impacts of sociodemographic, financial and racial disparities and 2) characterize molecular features of AA compared with those of Caucasian AML pts. Methods: For a nationwide population analysis, the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute was used to identify 11,190 adults aged 18-60 years (y) diagnosed with AML (excluding acute promyelocytic leukemia) between 1986 and 2015. To characterize molecular features we performed targeted sequencing of 81 genes in 1,339 AML pts treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols based on standard intensity cytarabine/anthracycline induction followed by consolidation between 1986 and 2016. No Alliance pt received an allogeneic stem cell transplant in 1st complete remission (CR). Results: The associations between demographic parameters and risk of death among SEER registry AML pts are shown in Table 1. While there was a slightly higher risk of death for men (HR 1.09) and a lower risk of death for pts with a higher median household income (>79.6k vs Conclusion: Self-reported AA race is the most important pt-associated factor associated with poor survival in AML pts < 60 y of age based on SEER. Survival analyses in Alliance pts identify AA race as independent poor survival prognosticator in AML pts besides established molecular markers. . This disparity must be urgently addressed to ensure improved outcomes for AA AML pts, and larger studies to establish molecular risk profiles are needed. Support: U10CA180821, U10CA180882 U24CA196171, https://acknowledgments.alliancefound.org; Clinicaltrials.gov Identifiers: NCT00048958, NCT00899223, NCT00900224 Disclosures Bhatnagar: KaryoPharm Therapuetics: Research Funding; Cell Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees. Blachly:AbbVie, AstraZeneca, KITE Pharma: Consultancy. Mims:Novartis: Speakers Bureau; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Agios: Consultancy. Walker:Vigeo Therapeutics: Consultancy; Karyopharm: Current Employment, Current equity holder in publicly-traded company. Powell:Genentech: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Pfizer: Research Funding; Rafael Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Novartis: Research Funding. Kolitz:Magellan: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Stone:Biolinerx: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Other; Aztra-Zeneca: Consultancy; Jazz: Consultancy; Argenix: Other; Janssen: Consultancy; Daiichi-Sankyo: Consultancy; Pfizer: Consultancy; Gemoab: Consultancy; Syndax: Consultancy, Research Funding; Takeda: Other: DSMB; Macrogenics: Consultancy; Trovagene: Consultancy; Syntrix: Other: DSMB; Abbvie: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Arog: Consultancy, Research Funding; Syros: Consultancy; Stemline: Consultancy. Byrd:Trillium: Research Funding; Leukemia and Lymphoma Society: Other; Acerta Pharma: Research Funding; Syndax: Research Funding; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Kartos Therapeutics: Research Funding; Vincera: Research Funding; Novartis: Research Funding. Eisfeld:Karyopharm: Current Employment, Current equity holder in publicly-traded company; Vigeo Therapeutics: Consultancy.

Purpose:Uniparental disomy (UPD) is a way cancer cells duplicate a mutated gene, causing loss of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We examined the prognostic significance of UPDs and frequency of LOH in patients with CN-AML.Experimental Design: We examined the frequency and prognostic significance of UPDs in a set of 425 adult patients with de novo CN-AML who were previously sequenced for 81 genes typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 patients with CN-AML younger than 60 years.Results:We detected 127 UPDs in 109 patients. Most UPDs were large and typically encompassed all or most of the affected chromosome arm. The most common UPDs occurred on chromosome arms 13q (7.5% of patients), 6p (2.8%), and 11p (2.8%). Many UPDs significantly cooccurred with mutations in genes they encompassed, including 13q UPD with FLT3-internal tandem duplication (FLT3-ITD; P < 0.001), and 11p UPD with WT1 mutations (P = 0.02). Among patients younger than 60 years, UPD of 11p was associated with longer overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In multivariable models that accounted for known prognostic markers, including FLT3-ITD and WT1 mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained association with longer OS.Conclusions:LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 13q and 11p might be useful for genetic risk stratification of patients with CN-AML.

Current treatment options for older and relapsed or refractory (R/R) acute myeloid leukemia (AML) patients are limited and represent an unmet need. Based on preclinical studies showing strong anti-leukemic effects in vivo, this phase I dose-escalation study assessed the safety and preliminary clinical activity of the oral exportin-1 inhibitor, selinexor, in combination with the hypomethylating agent, decitabine 20 mg/m(2), in adults with R/R AML and in older (age ≥60) untreated AML patients. There were no protocol-defined dose limiting toxicities. The recommended phase 2 dose of selinexor was 60mg (~35 mg/m(2)) given twice-weekly. Notable grade ≥3 toxicities included asymptomatic hyponatremia (68%), febrile neutropenia (44%), sepsis (44%), hypophosphatemia (36%), and pneumonia (28%). In 25 patients, the overall response rate was 40%. Modification of selinexor to a flat dose of 60mg, twice-weekly for two weeks after decitabine, improved tolerability of the regimen and demonstrated preliminary clinical activity in poor-risk patients with AML.