Poor Survival and Differential Impact of Genetic Features of Black Patients with Acute Myeloid Leukemia.
ABSTRACT: 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 <60 years, after adjustment for socioeconomic (SEER) and molecular (Alliance) factors. Black race was an independent prognosticator of poor survival. Gene mutation profiles showed fewer 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.
Project description:Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML.We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients.We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67).We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.).
Project description:To illustrate the clinical and genetic features of elderly and secondary acute myeloid leukemia (AML) patients, we compared 145 elderly AML (e-AML) and 55 secondary AML (s-AML) patients with 451 young de novo AML patients. Both e-AML and s-AML patients showed lower white blood cell (WBC) and bone marrow (BM) blasts at diagnosis. NPM1, DNMT3A, and IDH2 mutations were more common while biallelic CEBPA and IDH1 mutations were less seen in e-AML patients. s-AML patients carried a higher frequency of KMT2A-AF9. In treatment response and survival, e/s-AML conferred a lower complete remission (CR) rate and shorter duration of event-free survival (EFS) and overall survival (OS) compared with young patients. In multivariate analysis, s-AML was an independent risk factor for OS but not EFS in the whole cohort. Importantly, intensive therapy tended to improve the survival of e/s-AML patients without increasing the risk of early death, and hematopoietic stem cell transplantation (HSCT) could rescue the prognosis of s-AML, which should be recommended for the treatment of fit patients.
Project description:PURPOSE To analyze the frequency and associations with prognostic markers and outcome of mutations in IDH genes encoding isocitrate dehydrogenases in adult de novo cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS Diagnostic bone marrow or blood samples from 358 patients were analyzed for IDH1 and IDH2 mutations by DNA polymerase chain reaction amplification/sequencing. FLT3, NPM1, CEBPA, WT1, and MLL mutational analyses and gene- and microRNA-expression profiling were performed centrally. Results IDH mutations were found in 33% of the patients. IDH1 mutations were detected in 49 patients (14%; 47 with R132). IDH2 mutations, previously unreported in AML, were detected in 69 patients (19%; 13 with R172 and 56 with R140). R172 IDH2 mutations were mutually exclusive with all other prognostic mutations analyzed. Younger age (< 60 years), molecular low-risk (NPM1-mutated/FLT3-internal tandem duplication-negative) IDH1-mutated patients had shorter disease-free survival than molecular low-risk IDH1/IDH2-wild-type (wt) patients (P = .046). R172 IDH2-mutated patients had lower complete remission rates than IDH1/IDH2wt patients (P = .007). Distinctive microarray gene- and microRNA-expression profiles accurately predicted R172 IDH2 mutations. The highest expressed gene and microRNAs in R172 IDH2-mutated patients compared with the IDH1/IDH2wt patients were APP (previously associated with complex karyotype AML) and miR-1 and miR-133 (involved in embryonal stem-cell differentiation), respectively. CONCLUSION IDH1 and IDH2 mutations are recurrent in CN-AML and have an unfavorable impact on outcome. The R172 IDH2 mutations, previously unreported in AML, characterize a novel subset of CN-AML patients lacking other prognostic mutations and associate with unique gene- and microRNA-expression profiles that may lead to the discovery of novel, therapeutically targetable leukemogenic mechanisms.
Project description:BACKGROUND: Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes encode cytosolic and mitochondrial enzymes that catalyze the conversion of isocitrate to ?-ketoglutarate. Acquired somatic mutations of IDH1 and IDH2 have recently been reported in some types of brain tumors and a small proportion of acute myeloid leukemia (AML) cases. METHODS: Two-hundred and thirty newly diagnosed AML patients were analyzed for the presence of IDH1 and IDH2 heterozygous mutations by polymerase chain reaction-denaturing high performance liquid chromatography (PCR-DHPLC) followed by direct sequencing. Clinical and biological characteristics were analyzed and correlated to the IDH mutational status. Coexisting mutations such as FLT3, PML-RARA, RAS, AML1, and NPM1 mutations were additionally explored. RESULTS: The prevalence of IDH1 and IDH2 mutations was 8.7% (20/230) and 10.4% (24/230), respectively. Six missense mutations were identified among IDH1-mutated cases; p.R132H (n = 8), p.R132C (n = 6), p.R132S (n = 2), p.R132G (n = 2), p.R132L (n = 1), and p.I99M (n = 1). Two missense mutations were found in IDH2-mutated cases; p.R140Q (n = 20) and p.R172K (n = 4). No patients had dual IDH1 and IDH2 mutations. About 18% of AML with normal cytogenetics and 31% of acute promyelocytic leukemia had IDH mutations. Half of the IDH-mutated cohort had normal karyotype and the major FAB subtype was AML-M2. Interestingly, IDH1- and IDH2-mutated cases predominantly had NPM1 mutations (60-74%) as compared to the wild type (P < 0.001). Very few IDH-mutated cases had FLT3 and/or RAS abnormalities and none of them had AML1 mutations. Older age and higher median platelet counts were significantly associated with IDH2 mutations although the clinical impact of either IDH1 or IDH2 mutations on patients' overall survival could not be observed. CONCLUSION: Overall, 19% of newly diagnosed AML patients had alterations of IDH genes. No patients concurrently carried both IDH1 and IDH2 mutations suggesting that these mutations were mutually exclusive. NPM1 mutation appears as a major coexisting genetic mutation in IDH-mutated patients. Our present data failed to support the prognostic relevance of IDH mutations although alterations of these metabolic genes potentially have an important role in leukemia development.
Project description:The pathophysiology of IDH mutations in tumorigenesis is increasingly described, yet the prognostic significance of IDH1 and IDH2 mutations in AML remains controversial. The primary objective of this study was to define the natural history and prognosis of patients with AML and IDH1 or IDH2 mutations and provide historical survival expectations. A total of 826 patients treated from 2010 to 2014 at a single institution were evaluated, including 167 patients (20%) with AML and IDH1 or IDH2 mutations. Median age was 62 years (range 18-92). There were 59 IDH1-R132, 83 IDH2-R140, and 23 IDH2-R172 mutations. Clinicopathologic characteristics associated with IDH-mutations included older age, less frequent therapy-related status, and increased incidence of intermediate-risk cytogenetics, FLT3-ITD mutations, and NPM1 mutations. Remission rates (CR/CRi) by AML treatment status were: induction, 68%; Salvage-1 (S1), 42%; and Salvage-2 and beyond (S2+), 27%. No difference in response was identified by IDH mutation status. Similarly, overall survival (OS) was not dependent on IDH status within any cohort. The median OS was 15.4 months in induction, 8.7 months in S1, and 4.8 months in S2+. This analysis defines the clinical outcome associated with IDH-mutations in both the front-line and salvage AML treatment settings, and confirms that response rate and OS for both IDH-mutated and IDH wild-type AML patients is comparable. This provides contemporary data to be used for comparison with results of novel investigational (e.g., selective IDH inhibitor) strategies.
Project description:<h4>Background</h4>In head and neck squamous cell carcinoma (HNSCC), Black patients continue to have worse survival when compared with White patients. The cause of this disparity is multifaceted and cannot be explained by one etiology alone. To investigate this disparity, we used the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to examine adherence to guideline-concordant care (GCC) as defined by the National Comprehensive Cancer Network.<h4>Patients and methods</h4>In this retrospective study, Medicare beneficiaries diagnosed with nonmetastatic HNSCC as their first cancer between 1992 and 2011 and a random sample of Medicare controls matched to cases (2:1) diagnosed between 2004 and 2011 (n = 16,378), were included in this analysis.<h4>Results</h4>Black patients were less likely to receive GCC in advanced-stage oropharyngeal (66% vs. 74%; p = .007) and oral cavity (56% vs. 71%; p = .002) squamous cell carcinoma (SCC). On multivariate analysis, Black patients demonstrated an increased risk of death in advanced oropharyngeal (p < .001), oral cavity (p = .01), and hypopharyngeal (p = .01) SCC.<h4>Conclusion</h4>Black patients did not consistently receive GCC across HNSCC subsites, contributing to the poorer outcomes seen when compared with White patients. Future research should focus on elucidating the mechanisms behind the non-GCC given to Black patients with HNSCC and other factors that may contribute to this disparity such as tumor biology.<h4>Implications for practice</h4>Black patients with head and neck cancer (HNC) continue to have worse survival than White patients. This study examined if the racial disparity in survival from curable HNC is affected by adherence to guideline-concordant care (GCC). It was discovered that Black patients were less likely to receive appropriate treatment in certain HNCs. Although adherence to proper therapy was associated with improved survival in patients with HNC, the difference in survival, where Black patients had inferior outcomes, remained. This analysis uncovered a major contributor to the disparity seen in patients with HNC. As such, cancer centers serving a predominantly Black population with HNC can design specific clinical interventions to ensure GCC for all patients, potentially improving outcomes for everyone.
Project description:Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are reported in acute myeloid leukemia (AML). We studied the frequency and the clinicopathologic features of IDH1 and IDH2 mutations in AML. Mutations in IDH1 (IDH1(R)¹³²) and IDH2 (IDH2(R)¹?²) were assessed by Sanger sequencing in 199 AML cases. Point mutations in IDH1(R)¹³² were detected in 12 (6.0%) of 199 cases and in IDH2(R)¹?² in 4 (2.0%) of 196 cases. Of the 16 mutated cases, 15 (94%) were cytogenetically normal, for an overall frequency in this group of 11.8%. IDH1(R)¹³² and IDH2(R)¹?² mutations were mutually exclusive. Concurrent mutations in NPM1, FLT3, CEBPA, and NRAS were detected only in AML with the IDH1(R)¹³² mutation. The clinical and laboratory variables of patients with AML with IDH mutations showed no significant differences compared with patients with wild-type IDH. We conclude that IDH1(R)¹³² and IDH2(R)¹?² mutations occur most often in cytogenetically normal AML cases with an overall frequency of approximately 11.8%.
Project description:IDH1 and IDH2 gene mutations are novel, recurring molecular aberrations among patients with normal karyotype acute myeloid leukemia (AML).Among 358 patients with AML treated on 4 protocols using high-dose ara-C plus idarubicin induction, pretreatment samples were available for 170 (median age 53 years, [range, 17-73]; 96% ?65) and were evaluated for IDH1R132, IDH2R172, and IDH2R140 mutations or the codon 105 single nucleotide polymorphism (SNP) in IDH1.IDH1 and IDH2 mutations were present in 12 (7%) and 24 (14%) of patients, and IDH1 G105 SNP in 24 (14%). Overall, 52 (30%) patients had IDH gene alterations. There was no association with complete response (CR), remission duration, overall survival, and event-free survival and any of the IDH alterations, and no association with a higher CR rate or survival with the 4 regimens for the 52 patients with aberrant IDH. Among the patients with diploid karyotype and NPM1(mut) FLT3(WT) genotype, those with IDH1 or IDH2 mutations had an inferior outcome.IDH aberrations and IDH1 codon 105 SNP occur in about 30% of younger patients with AML, mostly with diploid karyotype. Using high-dose ara-C-based induction regimens, we did not detect an association with outcome for any of the aberrations.
Project description:Mutations in the DNMT3A, TET2, IDH1, and IDH2 genes carry prognostic significance and occur frequently in adult acute myeloid leukemia (AML). Leukemic mutations in all four genes have recently been implicated in aberrant DNA methylation, a hallmark of neoplasia. We previously reported that IDH1 mutations were absent, whereas TET2 mutations were present in 6%, of pediatric AML patients; in the present study, we determined the prevalence of DNMT3A and IDH2 mutations in pediatric AML.We screened for DNMT3A and IDH2 mutations by direct sequencing of diagnostic specimens from 180 children treated on the Children's Oncology Group clinical trial AAML03P1. Clinical characteristics, the presence of other leukemic mutations, and survival outcome was determined for mutation-positive patients.No disease-associated DNMT3A mutations were detected. IDH2 mutations were detected in 4/180 patients (2.2%), affecting codons R140 (n?=?3) and R172 (n?=?1). Two patients with IDH2 mutations harbored t(8;21), one patient harbored an MLL translocation, and one patient had a concomitant NPM1 mutation. FLT3, CEBPA, and WT1 mutations did not occur together with IDH2 mutations in our study.DNMT3A and IDH2 mutations are uncommon in pediatric AML. The low prevalence of methylation-associated mutations in our study highlights the differences in the pathogenesis of pediatric versus adult AML, at the genetic as well as potentially at the epigenetic level. The age-specific characteristics of AML underscore the importance of studying the molecular biology of both childhood and adult forms of this leukemia in parallel, as the development of novel therapeutics should account for these biologic differences.
Project description:Policy Points Patients with low socioeconomic status (SES) experience poorer survival rates after diagnosis of breast cancer, even when enrolled in Medicare and Medicaid. Most of the difference in survival is due to more advanced cancer on presentation and the general poor health of lower SES patients, while only a very small fraction of the SES disparity is due to differences in cancer treatment. Even when comparing only low- versus not-low-SES whites (without confounding by race) the survival disparity between disparate white SES populations is very large and is associated with lower use of preventive care, despite having insurance.<h4>Context</h4>Disparities in breast cancer survival by socioeconomic status (SES) exist despite the "safety net" programs Medicare and Medicaid. What is less clear is the extent to which SES disparities affect various racial and ethnic groups and whether causes differ across populations.<h4>Methods</h4>We conducted a tapered matching study comparing 1,890 low-SES (LSES) non-Hispanic white, 1,824 black, and 723 Hispanic white women to 60,307 not-low-SES (NLSES) non-Hispanic white women, all in Medicare and diagnosed with invasive breast cancer between 1992 and 2010 in 17 US Surveillance, Epidemiology, and End Results (SEER) regions. LSES Medicare patients were Medicaid dual-eligible and resided in neighborhoods with both high poverty and low education. NLSES Medicare patients had none of these factors.<h4>Measurements</h4>5-year and median survival.<h4>Findings</h4>LSES non-Hispanic white patients were diagnosed with more stage IV disease (6.6% vs 3.6%; p < 0.0001), larger tumors (24.6 mm vs 20.2 mm; p < 0.0001), and more chronic diseases such as diabetes (37.8% vs 19.0%; p < 0.0001) than NLSES non-Hispanic white patients. Disparity in 5-year survival (NLSES - LSES) was 13.7% (p < 0.0001) when matched for age, year, and SEER site (a 42-month difference in median survival). Additionally, matching 55 presentation factors, including stage, reduced the disparity to 4.9% (p = 0.0012), but further matching on treatments yielded little further change in disparity: 4.6% (p = 0.0014). Survival disparities among LSES blacks and Hispanics, also versus NLSES whites, were significantly associated with presentation factors, though black patients also displayed disparities related to initial treatment. Before being diagnosed, all LSES populations used significantly less preventive care services than matched NLSES controls.<h4>Conclusions</h4>In Medicare, SES disparities in breast cancer survival were large (even among non-Hispanic whites) and predominantly related to differences of presentation characteristics at diagnosis rather than differences in treatment. Preventive care was less frequent in LSES patients, which may help explain disparities at presentation.