Demographic Disparities in Acute Myeloid Leukemia Mortality Trends in the United States.

BACKGROUND/AIM: Acute myeloid leukemia (AML) is a hematological malignancy with an overall poor prognosis; however, survival rates vary widely by clinical and demographic characteristics. This study sought to identify historical trends in AML mortality in the US and to identify any disparities by sex, race or ethnicity. PATIENTS AND METHODS: For each demographic population, the age adjusted mortality rate (AAMR) per 1,000,000 for AML-related deaths from 1999 to 2020 in the United States was accessed from the CDC Wonder Database. These values were then used to calculate the average Annual Percent Change (AAPC) from 1999 to 2020 using the National Cancer Institute (NCI)'s Joinpoint Regression Program (Joinpoint V 4.9.0.0, NCI) with log-linear regression models. Statistical significance for all reported findings was determined using a 2-tailed t-test or parallel pairwise comparison with significance defined as p<0.05. RESULTS: The overall population had a significant downtrend in mortality rate between 2011 and 2020 with an APC of -0.61% [95% confidence interval (CI)=-1 to -0.2]. In 2020, the AAMR due to AML for males was 32 and for females was 20.2. Females did not have a significant overall AAPC from 1999 to 2020. Males had a significant AAPC of 0.5% (95%CI=0-0.9) from 1999 to 2020, signifying an overall uptrend. In 2020, the White population had the greatest mortality rate (29.6), followed by the Black or African American population (20.9), Asian or Pacific Islander (AAPI) population (18.6), and the American Indian/Alaska Native population (8.8). American Indian and Alaska Native population data could not be reliably compared. No race/ethnic group had a significant AAPC trend from 1999 to 2020. However, parallel pairwise comparison found a significant difference in the trend of mortality rates between the Black or African American and AAPI, Black or African American and White, and White and AAPI populations. CONCLUSION: Our findings highlight disparities in mortality due to AML and underscore the need for additional resources and support in affected populations and areas.

High early death rates, treatment resistance, and short survival of Black adolescents and young adults with AML.

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<.001) compared with White patients. Survival disparities persisted across cytogenetic groups: Black patients aged 18 to 29 years with non-core-binding factor (CBF)-AML had worse OS than White patients (5-year rates: 12% vs 44%; P<.001), including patients with cytogenetically normal AML (13% vs 50%; P<.003). Genetic features differed, including lower frequencies of normal karyotypes and NPM1 and biallelic CEBPA mutations, and higher frequencies of CBF rearrangements and ASXL1, BCOR, and KRAS mutations in Black patients. Integrated genomic analysis identified both known and novel somatic variants, and relative clonal stability at relapse. Reduced response rates to induction chemotherapy and leukemic clone persistence suggest a need for different treatment intensities and/or modalities in Black AYA patients with AML. Higher early death rates suggest a delay in diagnosis and treatment, calling for systematic changes to patient care.

Whole exome sequencing of pediatric leukemia reveals a novel InDel within FLT-3 gene in AML patient from Mizo tribal population, Northeast India.

BACKGROUND: Leukemia is the most common type of cancer in pediatrics. Genomic mutations contribute towards the molecular mechanism of disease progression and also helps in diagnosis and prognosis. This is the first scientific mutational exploration in whole exome of pediatric leukemia patients from a cancer prone endogamous Mizo tribal population, Northeast India. RESULT: Three non-synonymous exonic variants in NOTCH1 (p.V1699E), MUTYH (p.G143E) and PTPN11 (p.S502P) were found to be pathogenic. A novel in-frame insertion-deletion within the juxtamembrane domain of FLT3 (p.Tyr589_Tyr591delinsTrpAlaGlyAsp) was also observed. CONCLUSION: These unique variants could have a potential mutational significance and these could be candidate genes in elucidating the possibility of predisposition to cancers within the population. This study merits further investigation for its role in diagnosis and prognosis and also suggests the need for population wide screening to identify unique mutations that might play a key role towards precision medicine.

In-hospital Mortality and Racial Disparity in Children and Adolescents With Acute Myeloid Leukemia: A Population-based Study.

Survival disparities in children and adolescents with acute myeloid leukemia (AML) are documented, however, the etiology of these disparities is understudied. Few studies have evaluated factors that predict in-hospital mortality in childhood AML and racial/ethnic disparities associated with in-hospital death. Our study aimed to investigate factors associated with the risk of in-hospital death among childhood AML hospitalizations. We conducted a retrospective study of childhood AML hospitalizations using the National Inpatient Sample (NIS) from 2003 to 2017. We estimated incidences of in-hospital death among AML hospitalizations. We performed survey logistic regression models to measure the association between patient and hospital characteristics and in-hospital mortality. We identified 71,050 hospitalizations of children with AML. Compared with non-Hispanic (NH) whites, NH-black children had a higher risk of in-hospital mortality (adjusted odds ratio: 1.41, 95% confidence interval: 1.06-1.87, P<0.02). Further, NH-black patients with hematopoietic stem cell transplant experienced the highest risk of mortality (adjusted odds ratio: 5.88, 95% confidence interval: 3.13-11.06, P<0.001) as compared with NH-black children who did not receive hematopoietic stem cell transplant. Our findings highlight that NH-black children with AML continue to experience a disproportionately higher likelihood of in-hospital mortality when compared with their NH-white counterparts. Further studies are needed to delineate the etiology of these disparities.

Clinical insights into hematologic malignancies and comparative analysis of molecular signatures of acute myeloid leukemia in different ethnicities using an artificial intelligence offering.

ABSTRACT: Next generation sequencing generates copious amounts of genomics data, causing manual interpretation to be laborious and non-scalable while remaining subjective (even for highly trained specialists). We evaluated the performance of the artificial intelligence-based offering Watson for Genomics (WfG), a variant interpretation platform, in hematologic malignancies for the first time.Next generation sequencing was performed for patients treated for various hematological malignancies at Hallym University Sacred Heart Hospital, South Korea, between December 2017 and August 2020 using a 54-gene panel. Both WfG and expert manual curation were used to evaluate the performance of WfG. Acute myeloid leukemia (AML) molecular profiles were compared between Koreans and other ethnic groups using a publicly available dataset.Seventy-seven patients were analyzed (AML: 45, myeloproliferative neoplasms: 12, multiple myeloma: 7, myelodysplastic syndromes: 6, and others: 7). The concordance between the manual and WfG interpretations of 35 variants in 11 random patients was 94%. Among all patients, WfG identified 39 (51%) with at least 1 clinically actionable therapeutic alteration (i.e., a variant targeted by a United States Food and Drug Administration [US FDA]-approved drug, off-label drug, or clinical trial). Moreover, 46% of these patients (18/39) had genes that were targeted by a US FDA-approved therapy. WfG identified diagnostic or prognostic insights in 65% of the patients with no targetable alterations. In those with AML, FLT3-internal tandem duplications or tyrosine kinase domain mutations were less frequent among Koreans than among Caucasians (6.7% vs 30.2%, P < .001) or Hispanics (6.7% vs 28.3%, P = .005), suggesting ethnic differences.Variant interpretation using WfG correlated well with manually curated expert opinions. WfG provided therapeutic insights (including variant-specific drugs and clinical trials that cannot easily be provided by expert manual curation), as well as diagnostic and/or prognostic information.

Impact of race on outcomes in intermediate-risk acute myeloid leukemia.

PURPOSE: Racial disparities in acute myeloid leukemia (AML) have been reported but the relative contribution of disease versus patient-specific factors including comorbidities and access to care is unclear. METHODS: We conducted a retrospective analysis of patient characteristics, treatment patterns and outcomes in a racially diverse patient cohort controlling for cytogenetic risk group. Patients were classified into four groups: non-Hispanic White (NHW), non-Hispanic Black (NHB), Hispanic and Other. RESULTS: We evaluated 106 patients from 84 zipcodes incorporating demographics, clinicopathologic features, treatment patterns and outcomes. We identified significant differences in BMI and geographic poverty based on ethnoracial group, while prognostic mutations in NPM1 and FLT3 did not differ significantly. Utilization of intensive chemotherapy and transplant rate did not differ by ethnoracial group. However, there was a significantly higher use of alternate donor transplants in minority populations. There was a notably increased rate of clinical trial enrollment in NHW patients compared to other groups. In log-rank analysis, NHW patients had increased overall survival (OS) compared to NHB, Hispanic and Other patients (31.6 months vs. 16.7 months vs. 14.3 months, vs 18.1 months, p = 0.021). In bivariate analysis, overall survival was negatively influenced by advanced age and race. Obesity and zip code poverty levels approached statistical significance in predicting OS. In multivariate analysis, the only factors independently influencing OS were race and allogeneic stem cell transplant. CONCLUSION: These results suggest that race impacts survival in intermediate-risk AML, highlighting the need to dissect biologic and nonbiologic factors that contribute to this disparity.

Ethnic and border differences on blood cancer presentation and outcomes: A Texas population-based study.

BACKGROUND: The Texas/Chihuahua (US/Mexico) border is a medically underserved region with many reported barriers for health care access. Although Hispanic ethnicity is associated with health disparities for many different diseases, the population-based estimates of incidence and survival for patients with blood cancer along the border are unknown. The authors hypothesized that Hispanic ethnicity and border proximity is associated with poor blood cancer outcomes. METHODS: Data from the Texas Cancer Registry (1995-2016) were used to investigate the primary exposures of patient ethnicity (Hispanic vs non-Hispanic) and geographic location (border vs non-border). Other confounders and covariates included sex, age, year of diagnosis, rurality, insurance status, poverty indicators, and comorbidities. The Mantel-Haenszel method and Cox regression analyses were used to determine adjusted effects of ethnicity and border proximity on the relative risk (RR) and survival of patients with different blood cancer types. RESULTS: Hispanic patients were diagnosed at a younger age than non-Hispanic patients and presented with increased comorbidities. Whereas non-Hispanics had a higher incidence of developing blood cancer compared with Hispanics overall, Hispanics demonstrated a higher incidence of acute lymphoblastic leukemia (RR, 1.92; 95% CI, 1.79-2.08; P < .001) with worse outcomes. Hispanics from the Texas/Chihuahua border demonstrated a higher incidence of chronic myeloid leukemia (RR, 1.28; 95% CI, 1.07-1.51; P = .02) and acute myeloid leukemia (RR, 1.17; 95% CI, 1.04-1.33; P = .0009) compared with Hispanics living elsewhere in Texas. CONCLUSIONS: Hispanic ethnicity and border proximity were associated with a poor presentation and an adverse prognosis despite the younger age of diagnosis. Future studies should explore differences in disease biology and treatment strategies that could drive these regional disparities.

[Indications and management of hematologic microtransplantation: Recommendations of the French Society of Bone Marrow transplantation and cellular Therapy (SFGM-TC)]. / Atelier d'harmonisations 2019 : indications et organisation d'une microtransplantation de cellules souches hématopoïétiques.

Microtransplantation (MT) is based on injection of HLA-mismatched G-CSF mobilized hematopoietic stem cells, in combination with chemotherapy but without use of conditioning regimen nor immunosuppressive drugs. As a result, a transient microchimerism is induced without engraftment. Its efficacy relies both on host immune system stimulation (recipient versus tumor) and on a graft versus tumor effect. Data are scarce and concern mostly Asian patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (HR-MDS). In comparison to conventional treatment without MT, higher complete remission rates and longer disease free survival and overall survival have been reported. Safety seems acceptable. The most frequent adverse event is non-severe cytokine release syndrome. Risk of GVHD remains very low. Here, we summarize the published data and detail the practical aspects of the procedure. Current data are not strong enough to provide recommendations on indications. Nevertheless, it seems reasonable to propose MT to patients with AML or HR-MDS, regardless of age, presenting an indication for allogeneic stem cell transplantation but ineligible for it. MT is still under investigation and rather be proposed within clinical trials.

Increased Risk of Severe Sepsis in Hispanic Children Hospitalized With Acute Myeloid Leukemia.

The purpose of this study, a secondary analysis of a publicly available database, was to identify racial and ethnic disparities in the risk of severe sepsis facing children undergoing the intensive therapy necessary to treat acute myeloid leukemia (AML). The sample consisted of 1,913 hospitalizations of children, younger than 21 years, in the United States during the year 2016 with documentation of both AML and at least one infectious complication. Binary logistic regression models were used to examine the association between race/ethnicity and severe sepsis in children with AML and infection. We found that, after controlling for potential confounding variables, the odds of developing severe sepsis were significantly increased for Hispanic children compared with White children. There were no significant differences in the likelihood of the development of sepsis in Black, Asian, or other race children. The increased risk of severe sepsis for Hispanic children may contribute to the disparate rates of overall survival in this group. This inequitable rate of severe sepsis was evident despite the generally accepted practice of retaining children in the hospital throughout recovery of blood counts following AML therapy. Nurses are in a position to identify and eliminate modifiable risk factors contributing to this disparity.

Dectin-1 rs3901533 and rs7309123 Polymorphisms Increase Susceptibility to Pulmonary Invasive Fungal Disease in Patients with Acute Myeloid Leukemia from a Chinese Han Population.

This study aimed to assess whether genetic variants of dendritic cell-associated C-type lectine-1 (Dectin-1), Toll-like receptor 2 (TLR2), Toll-like receptor 4 (TLR4), and myeloid differentiation primary response 88 (MyD88) influence the susceptibility to pulmonary invasive fungal disease (IFD) in patients with acute myeloid leukemia (AML) from a Chinese Han population. Eight single nucleotide polymorphisms (SNPs) of Dectin-1 (rs16910526, rs3901533, and rs7309123), TLR2 (rs5743708), TLR4 (rs4986790 and rs4986791) and MyD88 (rs4988453 and rs4988457) in the genomic DNA of 172 adult AML patients were genotyped. Pulmonary IFD was diagnosed as proven or probable according to the 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus guidelines. SNPs that were significant in the univariate analysis were further analyzed using the multiple logistic regression analysis to determine their association with the occurrence of pulmonary IFD. The mRNA expression of Dectin-1 was detected according to the genotype by quantitative realtime PCR (qRT-PCR), and the correlation of this expression with the occurrence of pulmonary IFD in AML patients was analyzed. Two Dectin-1 intron SNPs (rs3901533 and rs7309123) were found to be significantly associated with the susceptibility to pulmonary IFD in AML patients in a Chinese Han population. Significant associations were noted between pulmonary IFD and Dectin-1 rs3901533 dominant model (G/T+G/G vs. T/T, OR: 2.158; 95% CI: 1.109-4.2, P=0.02), Dectin-1 rs3901533 G allele (OR: 2.201; 95% CI: 1.206-4.019, P=0.01), or Dectin-1 rs7309123 C allele (OR: 1.919; 95% CI: 1.047-3.518, P=0.03). There were no significant associations between pulmonary IFD and the remaining Dectin-1 SNPs (rs16910526), TLR2 (rs5743708), TLR4 (rs4986790 and rs4986791) or MyD88 (rs4988453 and rs4988457). In conclusion, two Dectin-1 SNPs (rs3901533 and rs7309123) are associated with increased susceptibility to pulmonary IFD in AML patients in a Chinese Han population.

Outcomes of haploidentical vs matched sibling transplantation for acute myeloid leukemia in first complete remission.

HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy-based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P = .15), leukemia-free survival (P = .50), nonrelapse mortality (P = .16), relapse (P = .90), or grade II-IV acute GVHD (P = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P < .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease-donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy-based Haplo-HCT vs MSD using calcineurin inhibitor-based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.

Survival and risk factors for mortality in pediatric patients with acute myeloid leukemia in a single reference center in low-middle-income country.

Despite advances in therapy and care for children with acute myeloid leukemia (AML), survival rates for children in low- and middle-income countries (LMICs) remain poor. We studied risk factors for mortality and survival in children with AML in a LMIC to develop strategies to improve survival for AML children in these countries. This retrospective cohort (2000-2014) analyzed newly diagnosed AML patients (age < 19 years) at a reference center in Brazil. Demographic and clinical variables were reviewed by AML subtype: acute promyelocytic leukemia (APL), AML with Down syndrome (AML-DS), and other AML subtypes. Cumulative hazard risk for early death (ED) until 6 weeks of treatment and risk factors for mortality were determined by the multivariate Cox hazard models. Survival was assessed for each AML subtypes. A total of 220 patients were diagnosed: APL 50 (22.7%), AML-DS 16 (7.3%), and other AML subtypes 154 (70.0%). The cumulative hazard function values for ED for all patients with AML were 12.5% (95% CI 8.5-18.4%); for each AML patients subtypes: APL, 21.7% (95% CI 11.7-40.5%); AML-DS, 6.2% (95% CI 0.9-44.4%); and other AML subtypes, 10.2% (95% CI 6.2-17.0%). White blood cell count (cutoff 10 × 109/L for APL and 100 × 109/L for other AML subtypes) and Afro-descendance were significant risk factors for mortality in APL and other AML subtypes, respectively. Overall survival for patients with APL, AML-DS, and other AML subtypes was 66.8%, 62.5%, and 38.0%, respectively. APL patients had the highest incidence of ED and those with other subtypes had increased relapse risk. We also observed high rates of death in complete remission mainly due to infection. Better risk classification and identification of risk factors for infection may improve the survival of these patients.

Population Pharmacokinetic Modeling of Gemtuzumab Ozogamicin in Adult Patients with Acute Myeloid Leukemia.

BACKGROUND AND OBJECTIVE: Gemtuzumab ozogamicin is an antibody-drug conjugate composed of the anti-CD33 monoclonal antibody hP67.6 covalently linked to N-acetyl-gamma-calicheamicin dimethylhydrazide, a potent cytotoxic antibiotic. The aim of this study was to characterize the population pharmacokinetics of gemtuzumab ozogamicin, represented by total hP67.6 antibody and unconjugated calicheamicin, in adult patients with acute myeloid leukemia to support drug dosing strategies and explore intrinsic and extrinsic factors that may influence exposure. Pharmacokinetic data from seven previous phase I and II studies in adult patients with relapsed, refractory, or de novo acute myeloid leukemia were integrated and analyzed using nonlinear mixed-effects modeling. METHODS: The pharmacokinetics of total hP67.6 antibody was described in 407 patients (5643 concentrations) who received gemtuzumab ozogamicin doses ranging from 0.25 to 9 mg/m2 using a two-compartment model with linear and time-dependent clearance components. The pharmacokinetics of unconjugated calicheamicin was characterized in 338 patients (4281 concentrations) using a two-compartment model with an input rate of formation dependent on the amount of hP67.6 eliminated. No statistically significant baseline covariates (sex, albumin, bone marrow, and peripheral blast percentage) demonstrated a clinically meaningful impact. RESULTS AND CONCLUSION: Total hP67.6 antibody disposition did not appear altered in patients with mild or moderate renal disease or hepatic impairment. Gemtuzumab ozogamicin was approved for the treatment of acute myeloid leukemia by the US Food and Drug Administration in September 2017. The model-based simulations described here provided a pharmacokinetic rationale for the approved dosing regimen of 3 mg/m2 on days 1, 4, and 7, and served as the basis for all exposure-response modeling included in the recent Biologics License Application submission. Clinical trials identifiers: 0903A1-101-US; 0903A1-103-JA; 0903B1-201-US/CA (NCT00003131); 0903B1-202-EU; 0903B1-203-US/EU (NCT00003673); 0903B1-205-US/EU/AU (NCT00037596); and 0903B1-206-US/EU/AU (NCT00037583).

Comparable on-therapy mortality and supportive care requirements in Black and White patients following initial induction for pediatric acute myeloid leukemia.

BACKGROUND: Black patients with acute myeloid leukemia (AML) are more likely to present with high acuity and consequently experience higher rates of induction mortality than white patients. Given the consistently identified racial disparities in overall survival (OS) among patients with AML, we aimed to evaluate whether there were sustained on-therapy racial differences in inpatient mortality, intensive care unit (ICU) requirements, or supportive care beyond initial induction. PROCEDURE: Within a retrospective cohort of 1239 children diagnosed with AML between 2004 and 2014 in the Pediatric Health Information System (PHIS) database who survived their initial course of induction chemotherapy, we compared on-therapy inpatient mortality, ICU-level care requirements, treatment course duration, cumulative length of hospital stay (LOS), and resource utilization after induction I by race. RESULTS: Over the period from the start of induction II through completion of frontline chemotherapy, there were no significant differences in mortality (adjusted odds ratios [OR], 1.01; 95% confidence intervals [CI], 0.41-2.48), ICU-level care requirements (adjusted OR, 0.93; 95% CI, 0.69-1.26), LOS (adjusted mean difference, 3.2 days; 95% CI, -2.3-9.6), or supportive care resource utilization for black patients relative to white patients. Course-specific analyses also demonstrated no differences by race. CONCLUSION: Although black patients have higher acuity at presentation and higher induction mortality, such disparities do not persist over subsequent frontline chemotherapy treatment. This finding allows interventions aimed at reducing disparities to be directed at presentation and induction.

Outcomes of Adolescents and Young Adults With Acute Myeloid Leukemia Treated in a Single Latin American Center.

INTRODUCTION: The outcomes for adolescents and young adults (AYAs) with acute myeloid leukemia (AML) have been poorly characterized in Hispanics in low- to middle-income countries. The results are influenced by biologic and socioeconomic factors. The clinical paths for AYA patients with AML are reported. PATIENTS AND METHODS: A retrospective analysis of AYA and pediatric AML patients aged 1 to 39 years during 2003 to 2016 from a single reference center in Northeast Mexico treated with a 7+3 standard protocol was performed. The 5-year overall survival (OS) and event-free survival (EFS) were estimated using Kaplan-Meier analysis. The hazard ratios for relapse and death were estimated using a Cox regression model. The patients with promyelocytic leukemia were analyzed separately. RESULTS: The study included 110 non-PML AML patients, 39 children and 71 AYAs. No difference in complete remission was found (P = .446), although the overall response rate was greater in the children (87.2% vs. 69% in AYAs; P = .034). The 5-year EFS rate was 33% for the children versus 9.3% in the AYAs at a median follow-up of 22 and 9 months, respectively (P = .008). The 5-year OS rate was 51% in the children and 22% in the AYAs (P = .001). Of the 44 AYAs with complete remission, 29 (65%) developed a relapse. Of the 39 children and 71 AYAs, 20 children (51.3%) and 21 AYAs (29.6%) underwent transplantation (P = .024). Patients with refractory disease had a 1-year OS rate of 14.4%. Older age (hazard ratio [HR], 2.55; P = .002) and white blood cell count > 50 × 109/L (HR, 1.79; P = .023) were significant for death, and transplantation was protective (HR, 0.57; P = .023). CONCLUSION: Low EFS and OS rates were found for AML patients in the AYA group. To improve survival rates, intensified chemotherapy regimens and early hematopoietic stem cell transplantation are needed.

Whole exome sequencing identifies novel mutations of epigenetic regulators in chemorefractory pediatric acute myeloid leukemia.

Genomic alterations underlying chemotherapy resistance remains poorly characterized in pediatric acute myeloid leukemia (AML). In this study, we used whole exome sequencing to identify gene mutations associated with chemo-resistance in 44 pediatric AML patients. We identified previously unreported mutations involving epigenetic regulators such as KDM5C, SRIT6, CHD4, and PRPF6 in pediatric AML patients. Despite low prevalence in general pediatric AML, mutations involving epigenetic regulators including splicing factors, were collectively enriched as a group in primary chemo-resistance AML patients. In addition, clonal evolution analysis of secondary chemo-resistance AML patients reveals dominant clone at diagnosis could survive several course of intensified chemotherapy. And gain of new mutations in genes such as MVP, TCF3, SS18, and BCL10, may contribute to chemo-resistance at relapse. These results provide novel insights into the genetic basis of treatment failure in pediatric AML.

Complications preceding early deaths in Black and White children with acute myeloid leukemia.

Black patients have a twofold increased risk of induction mortality compared to White patients with acute myeloid leukemia (AML). We reviewed diagnosis and billing data from Pediatric Health Information System for 28 AML Induction I deaths to investigate conditions preceding death in White and Black patients. Half of deaths occurred within 10 days of initial diagnostic admission. Respiratory, cardiac, renal, and infectious complications were common prior to both White and Black deaths. Deaths in White patients were more commonly preceded by intracranial hemorrhage compared to deaths in Black patients. Future studies should assess management approaches of complications by race to identify modifiable processes that reduce mortality.

Clinical implications of DNMT3A mutations in a Southeast Asian cohort of acute myeloid leukaemia patients.

AIMS: In recent years, genomic technologies have enabled the identification of mutations in acute myeloid leukaemia (AML). DNMT3A is a recurrently mutated epigenetic modifier gene in AML. To date, the prognostic significance of DNMT3A mutations has not been studied in a Southeast Asian AML population. We sought to investigate the clinical implications of DNMT3A mutations in a Southeast Asian cohort of AML patients. METHODS: DNMT3A mutations were identified using a targeted next-generation sequencing panel in 157 AML patients. We studied the molecular and clinical features of patients with DNMT3A mutations and assessed the prognostic impact of DNMT3A mutations. RESULTS: DNMT3A mutations were found in 33 of 157 (21.0%) AML patients. 114 patients were included for statistical analysis. Pretreatment data revealed that patients with DNMT3A mutations were older (≥60 years old), had a higher white blood cell count at diagnosis, had more adverse cytogenetic risk profiles and were more often associated with NPM1 mutations compared with patients with wild-type DNMT3A. Survival analysis showed that DNMT3A mutations were associated with poorer clinical outcomes. This was especially when associated with NPM1 and FLT3-ITD mutations (AML NPM1/FLT3/DNMT3A ), which are common. The AML NPM1/FLT3/DNMT3A subtype was an independent predictor for poorer overall survival (OS). Other independent risk factors for poorer OS include advanced age at diagnosis and adverse cytogenetic risk stratification. CONCLUSIONS: DNMT3A mutations are associated with an unfavourable clinical outcome in our Southeast Asian AML patient cohort. In particular, AML NPM1/FLT3/DNMT3A patients had the poorest prognosis.