Disparities in acute lymphoblastic leukemia risk and survival across the lifespan in the United States of America

Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer but is less frequent in adolescents and young adults (AYAs) and is rare among older adults. The 5-year survival of ALL is above 90% in children, but drops significantly in AYAs, and over half of ALL-related deaths occur in older adults. In addition to diagnosis age, the race/ethnicity of patients consistently shows association with ALL incidence and outcomes. Here, we review the racial/ethnic disparities in ALL incidence and outcomes, discuss how these vary across the age spectrum, and examine the potential causes of these disparities. In the United States, the incidence of ALL is highest in Hispanics/Latinos and lowest in Black individuals across all age groups. ALL incidence is rising fastest in Hispanics/Latinos, especially in AYAs. In addition, survival is worse in Hispanic/Latino or Black ALL patients compared to those who are non-Hispanic White. Different molecular subtypes of ALL show heterogeneities in incidence rates and survival outcomes across age groups and race/ethnicity. Several ALL risk variants are associated with genetic ancestry, and demonstrate different risk allele frequencies and/or effect sizes across populations. Moreover, non-genetic factors including socioeconomic status, access to care, and environmental exposures all likely influence the disparities in ALL risk and survival. Further studies are needed to investigate the potential joint effects and interactions of genetic and environmental risk factors. Improving survival in Hispanic/Latino and Black patients with ALL requires advances in precision medicine approaches, improved access to care, and inclusion of more diverse populations in future clinical trials.

Keywords

Acute lymphoblastic leukemia / disparities / race/ethnicity / genetic variation / socioeconomic status / access to care / recruitment to clinical trials / children / adolescents and young adults

References

[1] PaulS,JabbourEJ.Adult acute lymphoblastic leukemia.Mayo Clin Proc2016;91:1645-66

[2] HungerSP.Acute lymphoblastic leukemia in children.N Engl J Med2015;373:1541-52

[3] HowladerN,KrapchoM. SEER Cancer Statistics Review 1975-2017. Available from: https://seer.-cancer.gov/csr/1975_2017/. [Last accessed on 15 Jun 2021]

[4] SiegelRL,FuchsHE.Cancer Statistics, 2021.CA Cancer J Clin2021;71:7-33

[5] DoresGM,CurtisRE,MortonLM.Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007.Blood2012;119:34-43 PMCID:PMC3251235

[6] WardE,RobbinsA,JemalA.Childhood and adolescent cancer statistics, 2014.CA Cancer J Clin2014;64:83-103

[7] WilliamsLA,HirschBA,SpectorLG.Is there etiologic heterogeneity between subtypes of childhood acute lymphoblastic leukemia?.Cancer Epidemiol Biomarkers Prev2019;28:846-56 PMCID:PMC6500468

[8] WiemelsJ.Perspectives on the causes of childhood leukemia.Chem Biol Interact2012;196:59-67 PMCID:PMC3839796

[9] PrestonDL,TomonagaM.Cancer incidence in atomic bomb survivors. Part III: leukemia, lymphoma and multiple myeloma, 1950-1987.Radiat Res1994;137:S68-97

[10] DollR.Risk of childhood cancer from fetal irradiation.Br J Radiol1997;70:130-9

[11] BartleyK,SelvinS,BufflerP.Diagnostic X-rays and risk of childhood leukaemia.Int J Epidemiol2010;39:1628-37 PMCID:PMC2992630

[12] LinetMS,RajaramanP.Children's exposure to diagnostic medical radiation and cancer risk: epidemiologic and dosimetric considerations.Pediatr Radiol2009;39 Suppl 1:S4-26 PMCID:PMC2814780

[13] CurtinK,FraserA,KohlmannW.Familial risk of childhood cancer and tumors in the Li-Fraumeni spectrum in the Utah Population Database: implications for genetic evaluation in pediatric practice.Int J Cancer2013;133:2444-53 PMCID:PMC4058884

[14] KlcoJM.Advances in germline predisposition to acute leukaemias and myeloid neoplasms.Nat Rev Cancer2021;21:122-37

[15] TreviñoLR,FrenchD.Germline genomic variants associated with childhood acute lymphoblastic leukemia.Nat Genet2009;41:1001-5 PMCID:PMC2762391

[16] PapaemmanuilE,VijayakrishnanJ.Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia.Nat Genet2009;41:1006-10 PMCID:PMC4915548

[17] SherborneAL,PrasadRB.Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk.Nat Genet2010;42:492-4 PMCID:PMC3434228

[18] EllinghausE,RichterG.Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia.Leukemia2012;26:902-9 PMCID:PMC3356560

[19] XuH,Perez-AndreuV.Novel susceptibility variants at 10p12.31-12.2 for childhood acute lymphoblastic leukemia in ethnically diverse populations.J Natl Cancer Inst2013;105:733-42 PMCID:PMC3691938

[20] MiglioriniG,HoskingFJ.Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype.Blood2013;122:3298-307

[21] Perez-AndreuV,HarveyRC.Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse.Nat Genet2013;45:1494-8 PMCID:PMC4039076

[22] WalshKM,HansenHM.A heritable missense polymorphism in CDKN2A confers strong risk of childhood acute lymphoblastic leukemia and is preferentially selected during clonal evolution.Cancer Res2015;75:4884-94 PMCID:PMC4651745

[23] HungateEA,GamazonER.A variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology.Nat Commun2016;7:10635 PMCID:PMC4754340

[24] VijayakrishnanJ,HenrionMY.A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1.Leukemia2017;31:573-9 PMCID:PMC5336191

[25] Clay-GilmourAI,PreusLM.Genetic association with B-cell acute lymphoblastic leukemia in allogeneic transplant patients differs by age and sex.Blood Adv2017;1:1717-28 PMCID:PMC5728332

[26] WiemelsJL,deSmith AJ.GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21.Nat Commun2018;9:286 PMCID:PMC5773513

[27] VijayakrishnanJ,BroderickP.PRACTICAL ConsortiumGenome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia.Nat Commun2018;9:1340 PMCID:PMC5890276

[28] deSmith AJ,FrancisSS.BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia.Int J Cancer2018;143:2647-58 PMCID:PMC6235695

[29] QianM,Perez-AndreuV.Novel susceptibility variants at the ERG locus for childhood acute lymphoblastic leukemia in Hispanics.Blood2019;133:724-9 PMCID:PMC6376278

[30] QianM,DevidasM.Genome-wide association study of susceptibility loci for T-cell acute lymphoblastic leukemia in children.J Natl Cancer Inst2019;111:1350-7 PMCID:PMC6910193

[31] deSmith AJ,MorimotoLM.Heritable variation at the chromosome 21 gene ERG is associated with acute lymphoblastic leukemia risk in children with and without Down syndrome.Leukemia2019;33:2746-51 PMCID:PMC6858994

[32] VijayakrishnanJ,StuddJB.Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk.Nat Commun2019;10:5348 PMCID:PMC6877561

[33] ShahS,WaandersE.A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia.Nat Genet2013;45:1226-31 PMCID:PMC3919799

[34] GuZ,RobertsKG.PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia.Nat Genet2019;51:296-307 PMCID:PMC6525306

[35] NoetzliL,Lee-SherickAB.Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia.Nat Genet2015;47:535-8 PMCID:PMC4631613

[36] ZhangMY,KeelSB.Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy.Nat Genet2015;47:180-5 PMCID:PMC4540357

[37] MoriyamaT,WuG.Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study.Lancet Oncol2015;16:1659-66 PMCID:PMC4684709

[38] MelazziniF,BalduiniA.Clinical and pathogenic features of ETV6-related thrombocytopenia with predisposition to acute lymphoblastic leukemia.Haematologica2016;101:1333-42 PMCID:PMC5394865

[39] NishiiR,YangW.Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia.Blood2021;137:364-73 PMCID:PMC7819760

[40] KuehnHS,Cunningham-RundlesC.Loss of B cells in patients with heterozygous mutations in IKAROS.N Engl J Med2016;374:1032-43 PMCID:PMC4836293

[41] YoshidaN,MuramatsuH.Germline IKAROS mutation associated with primary immunodeficiency that progressed to T-cell acute lymphoblastic leukemia.Leukemia2017;31:1221-3

[42] ChurchmanML,TeKronnie G.Germline genetic IKZF1 variation and predisposition to childhood acute lymphoblastic leukemia.Cancer Cell2018;33:937-48.e8 PMCID:PMC5953820

[43] HolmfeldtL,Diaz-FloresE.The genomic landscape of hypodiploid acute lymphoblastic leukemia.Nat Genet2013;45:242-52 PMCID:PMC3919793

[44] QianM,DevidasM.TP53 germline variations influence the predisposition and prognosis of B-cell acute lymphoblastic leukemia in children.J Clin Oncol2018;36:591-9 PMCID:PMC5815403

[45] GreavesM.A causal mechanism for childhood acute lymphoblastic leukaemia.Nat Rev Cancer2018;18:471-84 PMCID:PMC6986894

[46] WhiteheadTP,WiemelsJL,MillerMD.Childhood leukemia and primary prevention.Curr Probl Pediatr Adolesc Health Care2016;46:317-52 PMCID:PMC5161115

[47] LiuR,McHaleCM.Paternal smoking and risk of childhood acute lymphoblastic leukemia: systematic review and meta-analysis.J Oncol2011;2011:854584 PMCID:PMC3132639

[48] MetayerC,WiemelsJL.Tobacco smoke exposure and the risk of childhood acute lymphoblastic and myeloid leukemias by cytogenetic subtype.Cancer Epidemiol Biomarkers Prev2013;22:1600-11 PMCID:PMC3769478

[49] deSmith AJ,GonsethS.Correlates of prenatal and early-life tobacco smoke exposure and frequency of common gene deletions in childhood acute lymphoblastic leukemia.Cancer Res2017;77:1674-83 PMCID:PMC5380517

[50] BaileyHD,MetayerC.Home pesticide exposures and risk of childhood leukemia: findings from the childhood leukemia international consortium.Int J Cancer2015;137:2644-63 PMCID:PMC4572913

[51] HylandC,MetayerC,WesselingC.Maternal residential pesticide use and risk of childhood leukemia in Costa Rica.Int J Cancer2018;143:1295-304 PMCID:PMC6099525

[52] ColtJS.Parental occupational exposures and risk of childhood cancer.Environ Health Perspect1998;106 Suppl 3:909-25 PMCID:PMC1533069

[53] BaileyHD,MilneE.Home paint exposures and risk of childhood acute lymphoblastic leukemia: findings from the Childhood Leukemia International Consortium.Cancer Causes Control2015;26:1257-70 PMCID:PMC5257283

[54] WardMH,DezielNC.Residential levels of polybrominated diphenyl ethers and risk of childhood acute lymphoblastic leukemia in California.Environ Health Perspect2014;122:1110-6 PMCID:PMC4181922

[55] BootheVL,WendelAM.Residential traffic exposure and childhood leukemia: a systematic review and meta-analysis.Am J Prev Med2014;46:413-22 PMCID:PMC5779082

[56] WhiteheadTP,ColtJS.Dust metal loadings and the risk of childhood acute lymphoblastic leukemia.J Expo Sci Environ Epidemiol2015;25:593-8 PMCID:PMC4560677

[57] KarczewskiKJ,TiaoG.Genome Aggregation Database ConsortiumThe mutational constraint spectrum quantified from variation in 141,456 humans.Nature2020;581:434-43 PMCID:PMC7334197

[58] WangK,HakonarsonH.ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.Nucleic Acids Res2010;38:e164 PMCID:PMC2938201

[59] BorrellLN,Fuentes-AfflickE.Race and genetic ancestry in medicine-A time for reckoning with racism.N Engl J Med2021;384:474-80

[60] BorrellLN,Fuentes-AfflickE.Race and genetic ancestry in medicine - a time for reckoning with racism.N Engl J Med2021;384:474-80

[61] AlvidrezJ,Laude-SharpM,TaborD.The national institute on minority health and health disparities research framework.Am J Public Health2019;109:S16-20 PMCID:PMC6356129

[62] Barrington-TrimisJL,MetayerC,WiemelsJ.Rising rates of acute lymphoblastic leukemia in Hispanic children: trends in incidence from 1992 to 2011.Blood2015;125:3033-4 PMCID:PMC4424421

[63] GiddingsBM,MetayerC.Childhood leukemia incidence in California: high and rising in the Hispanic population.Cancer2016;122:2867-75 PMCID:PMC5542672

[64] Barrington-TrimisJL,MetayerC,WiemelsJ.Trends in childhood leukemia incidence over two decades from 1992 to 2013.Int J Cancer2017;140:1000-8 PMCID:PMC5550103

[65] SiegelDA,LiJ,VanDyne EA.Rates and trends of pediatric acute lymphoblastic leukemia - United States, 2001-2014.MMWR Morb Mortal Wkly Rep2017;66:950-4 PMCID:PMC5657918

[66] FengQ,Vergara-LluriM.Trends in acute lymphoblastic leukemia incidence in the United States by race/ethnicity from 2000 to 2016.Am J Epidemiol2021;190:519-27

[67] PuiCH.A 50-year journey to cure childhood acute lymphoblastic leukemia.Semin Hematol2013;50:185-96 PMCID:PMC3771494

[68] AlvarnasJC,AounP.Acute lymphoblastic leukemia, version 2.2015.J Natl Compr Canc Netw2015;13:1240-79

[69] MohseniM,BrandweinJM.Advances in biology of acute lymphoblastic leukemia (ALL) and therapeutic implications.Am J Blood Res2018;8:29-56 PMCID:PMC6334189

[70] CarobolanteF,SkertC.Practical guidance for the management of acute lymphoblastic leukemia in the adolescent and young adult population.Ther Adv Hematol2020;11:2040620720903531 PMCID:PMC6997963

[71] Cancer Facts & Figures 2020. Available from: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. [Last accessed on 15 Jun 2021]

[72] InabaH.Pediatric acute lymphoblastic leukemia.Haematologica2020;105:2524-39 PMCID:PMC7604619

[73] RyttingME,O'BrienSM.Augmented Berlin-Frankfurt-Münster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL).Cancer2014;120:3660-8 PMCID:PMC4239168

[74] StockW,AdvaniAS.Favorable outcomes for older adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL): early results of U.S. intergroup trial C10403.Blood2014;124:796

[75] DeAngeloDJ,DahlbergSE.Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia.Leukemia2015;29:526-34 PMCID:PMC4360211

[76] RyttingME,JorgensenJL.Final results of a single institution experience with a pediatric-based regimen, the augmented Berlin-Frankfurt-Münster, in adolescents and young adults with acute lymphoblastic leukemia, and comparison to the hyper-CVAD regimen.Am J Hematol2016;91:819-23 PMCID:PMC5558853

[77] SiveJI,FieldingA.Outcomes in older adults with acute lymphoblastic leukaemia (ALL): results from the international MRC UKALL XII/ECOG2993 trial.Br J Haematol2012;157:463-71 PMCID:PMC4188419

[78] PulteD,GondosA.GEKID Cancer Survival Working GroupSurvival of adults with acute lymphoblastic leukemia in Germany and the United States.PLoS One2014;9:e85554 PMCID:PMC3903479

[79] BaileyC,AllemaniC.CONCORD Working Group (US members)Adult leukemia survival trends in the United States by subtype: A population-based registry study of 370,994 patients diagnosed during 1995-2009.Cancer2018;124:3856-67 PMCID:PMC6392057

[80] HuguetF,LeguayT.Group of Research on Adult ALL (GRAALL)Intensified therapy of acute lymphoblastic leukemia in adults: report of the randomized GRAALL-2005 clinical trial.J Clin Oncol2018;36:2514-23

[81] O'DwyerKM.Philadelphia chromosome negative B-cell acute lymphoblastic leukemia in older adults: Current treatment and novel therapies.Best Pract Res Clin Haematol2017;30:184-92

[82] LuskinMR.Mini-Hyper-CVD combinations for older adults: results of recent trials and a glimpse into the future.Clin Lymphoma Myeloma Leuk2020;20:S44-7

[83] WangL,GomezSL.Differential inequality trends over time in survival among U.S. children with acute lymphoblastic leukemia by race/ethnicity, age at diagnosis, and sex.Cancer Epidemiol Biomarkers Prev2015;24:1781-8 PMCID:PMC5746177

[84] GogginsWB.Racial and ethnic disparities in survival of US children with acute lymphoblastic leukemia: evidence from the SEER database 1988-2008.Cancer Causes Control2012;23:737-43

[85] KahnJM,TaoL,BleyerA.Racial disparities in the survival of American children, adolescents, and young adults with acute lymphoblastic leukemia, acute myelogenous leukemia, and Hodgkin lymphoma.Cancer2016;122:2723-30 PMCID:PMC4992431

[86] KahnJM,BlonquistTM.An investigation of toxicities and survival in Hispanic children and adolescents with ALL: results from the Dana-Farber Cancer Institute ALL Consortium protocol 05-001.Pediatr Blood Cancer2018;65:e26871 PMCID:PMC5766393

[87] AbrahãoR,RibeiroRC.Racial/ethnic and socioeconomic disparities in survival among children with acute lymphoblastic leukemia in California, 1988-2011: A population-based observational study.Pediatr Blood Cancer2015;62:1819-25

[88] MurphyCC,RothME,PruittSL.Disparities in cancer survival among adolescents and young adults: a population-based study of 88,000 patients.J Natl Cancer Inst2021:djab006

[89] PulteD,JansenL,JeffreysM.Recent trends in survival of adult patients with acute leukemia: overall improvements, but persistent and partly increasing disparity in survival of patients from minority groups.Haematologica2013;98:222-9 PMCID:PMC3561429

[90] QuirozE,PullarkatV,MarcucciG.The emerging story of acute lymphoblastic leukemia among the Latin American population - biological and clinical implications.Blood Rev2019;33:98-105

[91] Pérez-SaldivarML,Bernáldez-RíosR.Childhood acute leukemias are frequent in Mexico City: descriptive epidemiology.BMC Cancer2011;11:355 PMCID:PMC3171387

[92] Santamaría-QuesadaC,VenegasP.Molecular and epidemiologic findings of childhood acute leukemia in Costa Rica.J Pediatr Hematol Oncol2009;31:131-5

[93] MooreKJ,WilliamsLA.Childhood cancer incidence among specific Asian and Pacific Islander populations in the United States.Int J Cancer2020;147:3339-48 PMCID:PMC7736474

[94] ShahN,KazemiM.Ethnic disparities in survival of adult B-cell acute lymphoblastic leukemia in modern era - a SEER analysis.Leuk Lymphoma2020;61:3503-6

[95] ChiarettiS,DellaStarza I.Philadelphia-like acute lymphoblastic leukemia is associated with minimal residual disease persistence and poor outcome. First report of the minimal residual disease-oriented GIMEMA LAL1913.Haematologica2021;106:1559-68 PMCID:PMC8168510

[96] RobertsKG,Payne-TurnerD.Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.N Engl J Med2014;371:1005-15 PMCID:PMC4191900

[97] HeroldT,GökbugetN.Ph-like acute lymphoblastic leukemia in older adults.N Engl J Med2014;371:2235

[98] RobertsKG,Payne-TurnerD.High frequency and poor outcome of Philadelphia chromosome-like acute lymphoblastic leukemia in adults.J Clin Oncol2017;35:394-401 PMCID:PMC5455698

[99] JainN,JabbourE.Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.Blood2017;129:572-81 PMCID:PMC5290985

[100] YoungRP.A review of the Hispanic paradox: time to spill the beans?.Eur Respir Rev2014;23:439-49

[101] FranziniL,KeddieAM.Understanding the Hispanic paradox.Ethn Dis2011;11:496-518

[102] SwanJ.Cancer rates among American Indians and Alaska Natives: is there a national perspective.Cancer2003;98:1262-72

[103] NathanPC,JanzenLA.Long-term outcomes in survivors of childhood acute lymphoblastic leukemia.Hematol Oncol Clin North Am2009;23:1065-82, vi

[104] EssigS,ChenY.Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort.Lancet Oncol2014;15:841-51 PMCID:PMC4142216

[105] GofmanI.Risk factors for the development of obesity in children surviving ALL and NHL.J Pediatr Hematol Oncol2009;31:101-7

[106] SadighiZS,HudsonMM.Headache types, related morbidity, and quality of life in survivors of childhood acute lymphoblastic leukemia: a prospective cross sectional study.Eur J Paediatr Neurol2014;18:722-9 PMCID:PMC4253065

[107] ShoagJM,LossosIS.Acute lymphoblastic leukemia mortality in Hispanic Americans.Leuk Lymphoma2020;61:2674-81

[108] EcheIJ.A literature review of racial disparities in overall survival of black children with acute lymphoblastic leukemia compared with white children with acute lymphoblastic leukemia.J Pediatr Oncol Nurs2020;37:180-94

[109] BryantC,FleitesJ,SaundersJM.Comparison of five-year survival rate between black and white children with acute lymphoblastic leukemia.Cureus2020;12:e11797 PMCID:PMC7779168

[110] SiegelSE,JohnsonRH.Pediatric-inspired treatment regimens for adolescents and young adults with philadelphia chromosome-negative acute lymphoblastic leukemia: a review.JAMA Oncol2018;4:725-34 PMCID:PMC7534395

[111] National Cancer Institute. Cancer Stat Facts: leukemia - acute lymphocytic leukemia (ALL). Available from: https://seer.cancer.gov/statfacts/html/alyl.html. [Last accessed on 15 Jun 2021]

[112] BurmeisterT,BartramCR,HoelzerD.GMALL study groupPatients' age and BCR-ABL frequency in adult B-precursor ALL: a retrospective analysis from the GMALL study group.Blood2008;112:918-9

[113] ByunJM,ShinDY.Korean Adult ALL Working PartyKorean Society of HematologyBCR-ABL translocation as a favorable prognostic factor in elderly patients with acute lymphoblastic leukemia in the era of potent tyrosine kinase inhibitors.Haematologica2017;102:e187-90 PMCID:PMC5477621

[114] MoormanAV,WilkinsonJ,BownN.A population-based cytogenetic study of adults with acute lymphoblastic leukemia.Blood2010;115:206-14

[115] PaulssonK,BiloglavA.The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia.Nat Genet2015;47:672-6

[116] GeyerMB,DevlinSM,DouerD.Overall survival among older US adults with ALL remains low despite modest improvement since 1980: SEER analysis.Blood2017;129:1878-81 PMCID:PMC5374292

[117] BassanR,DeAngeloDJ.New approaches to the management of adult acute lymphoblastic leukemia.J Clin Oncol2018;JCO2017773648

[118] WenzingerC,GruAA.Updates in the pathology of precursor lymphoid neoplasms in the revised fourth edition of the WHO classification of tumors of hematopoietic and lymphoid tissues.Curr Hematol Malig Rep2018;13:275-88

[119] IacobucciI.Genetic basis of acute lymphoblastic leukemia.J Clin Oncol2017;35:975-83 PMCID:PMC5455679

[120] YouMJ,HsiED.T-lymphoblastic leukemia/lymphoma.Am J Clin Pathol2015;144:411-22

[121] RoweJM,BurnettAK.ECOGMRC/NCRI Adult Leukemia Working PartyInduction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993.Blood2005;106:3760-7

[122] MarksDI,MoormanAV.T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993).Blood2009;114:5136-45 PMCID:PMC2792210

[123] PapaemmanuilE,LiY.RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia.Nat Genet2014;46:116-25 PMCID:PMC3960636

[124] BhojwaniD,SandlundJT.ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy.Leukemia2012;26:265-70 PMCID:PMC3345278

[125] ChokkalingamAP,MetayerC.Genetic variants in ARID5B and CEBPE are childhood ALL susceptibility loci in Hispanics.Cancer Causes Control2013;24:1789-95 PMCID:PMC3771434

[126] AldrichMC,WiemelsJL.Cytogenetics of Hispanic and White children with acute lymphoblastic leukemia in California.Cancer Epidemiol Biomarkers Prev2006;15:578-81

[127] KurzrockR,DrukerBJ.Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics.Ann Intern Med2003;138:819-30

[128] IgweIJ,MerchantA.The presence of Philadelphia chromosome does not confer poor prognosis in adult pre-B acute lymphoblastic leukaemia in the tyrosine kinase inhibitor era - a surveillance, epidemiology, and end results database analysis.Br J Haematol2017;179:618-26 PMCID:PMC7546179

[129] UckunFM,SatherHN.Clinical significance of Philadelphia chromosome positive pediatric acute lymphoblastic leukemia in the context of contemporary intensive therapies: a report from the Children’s Cancer Group.Cancer1998;83:2030-9

[130] SawalhaY.Management of older adults with acute lymphoblastic leukemia: challenges & current approaches.Int J Hematol Oncol2018;7:IJH02 PMCID:PMC6176956

[131] KozlowskiP,AhlbergL.Swedish Adult Acute Lymphoblastic Leukemia Group (SVALL)Age but not Philadelphia positivity impairs outcome in older/elderly patients with acute lymphoblastic leukemia in Sweden.Eur J Haematol2017;99:141-9

[132] HarveyRC,ChenIM.Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia.Blood2010;115:5312-21 PMCID:PMC2902132

[133] YangH,LuanY.Non-coding germline GATA3 variants alter chromatin topology and contribute to pathogenesis of acute lymphoblastic leukemia.Cancer Biology2020;

[134] HeroldT,MetzelerKH.Adults with Philadelphia chromosome-like acute lymphoblastic leukemia frequently have IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis.Haematologica2017;102:130-8 PMCID:PMC5210243

[135] Perez-AndreuV,XuH.A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults.Blood2015;125:680-6 PMCID:PMC4304112

[136] EvansTJ,AndersonD.Confirmation of childhood acute lymphoblastic leukemia variants, ARID5B and IKZF1, and interaction with parental environmental exposures.PLoS One2014;9:e110255 PMCID:PMC4195717

[137] WalshKM,HsuLI.Associations between genome-wide Native American ancestry, known risk alleles and B-cell ALL risk in Hispanic children.Leukemia2013;27:2416-9 PMCID:PMC3864612

[138] WalshKM,ChokkalingamAP.GATA3 risk alleles are associated with ancestral components in Hispanic children with ALL.Blood2013;122:3385-7 PMCID:PMC3821727

[139] XuH,DevidasM.ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia.J Clin Oncol2012;30:751-7 PMCID:PMC3295551

[140] WolfeD,RitchieMD.Visualizing genomic information across chromosomes with PhenoGram.BioData Min2013;6:18 PMCID:PMC4015356

[141] BunielloA,CerezoM.The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019.Nucleic Acids Res2019;47:D1005-12 PMCID:PMC6323933

[142] YangJJ,YangW.Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia.J Clin Oncol2015;33:1235-42 PMCID:PMC4375304

[143] DioufB,LewG.Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia.JAMA2015;313:815-23 PMCID:PMC4377066

[144] FernandezCA,YangW.Genome-wide analysis links NFATC2 with asparaginase hypersensitivity.Blood2015;126:69-75 PMCID:PMC4492197

[145] LiuC,DevidasM.Clinical and genetic risk factors for acute pancreatitis in patients with acute lymphoblastic leukemia.J Clin Oncol2016;34:2133-40 PMCID:PMC4962704

[146] LiuY,SmithC.Genome-wide study links PNPLA3 variant with elevated hepatic transaminase after acute lymphoblastic leukemia therapy.Clin Pharmacol Ther2017;102:131-40 PMCID:PMC5511775

[147] HøjfeldtSG,TulstrupM.Nordic Society of Paediatric Haematology Oncology (NOPHO) groupGenetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008.Br J Haematol2019;184:405-17

[148] LiuC,PeiD.Genomewide approach validates thiopurine methyltransferase activity is a monogenic pharmacogenomic trait.Clin Pharmacol Ther2017;101:373-81 PMCID:PMC5309133

[149] TulstrupM,NielsenSN.NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia.Leukemia2018;32:2527-35

[150] YangJJ,DevidasM.Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia.Blood2012;120:4197-204 PMCID:PMC3501717

[151] SpearML,ZivE.Recent shifts in the genomic ancestry of Mexican Americans may alter the genetic architecture of biomedical traits.Elife2020;9:e56029 PMCID:PMC7771964

[152] KarolSE,ChengC.Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia.Leukemia2017;31:1325-32 PMCID:PMC5462853

[153] YangJJ,DevidasM.Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia.Nat Genet2011;43:237-41 PMCID:PMC3104508

[154] ZhangH,DevidasM.Association of GATA3 polymorphisms with minimal residual disease and relapse risk in childhood acute lymphoblastic leukemia.J Natl Cancer Inst2021;113:408-17

[155] JainN,RobertsK G.GATA3 rs3824662A allele is overrepresented in adult patients with Ph-like ALL, especially in patients with CRLF2 abnormalities.Blood2017;130:1430

[156] MoriyamaT,Perez-AndreuV.NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity.Nat Genet2016;48:367-73 PMCID:PMC5029084

[157] GreavesM.Childhood leukaemia.BMJ2002;324:283-7 PMCID:PMC1122200

[158] WiemelsJ,DaniottiM.Prenatal origin of acute lymphoblastic leukaemia in children.Lancet1999;354:1499-503

[159] GreavesMF,WiemelsJL.Leukemia in twins: lessons in natural history.Blood2003;102:2321-33

[160] BatemanCM,ChaplinT.Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia.Blood2010;115:3553-8

[161] TorowN.The neonatal window of opportunity: setting the stage for life-long host-microbial interaction and immune homeostasis.J Immunol2017;198:557-63

[162] OlszakT,ZeissigS.Microbial exposure during early life has persistent effects on natural killer T cell function.Science2012;336:489-93 PMCID:PMC3437652

[163] BiesbroekG,SandersEA.Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children.Am J Respir Crit Care Med2014;190:1283-92

[164] UrayamaKY,GallagherER,MaX.A meta-analysis of the association between day-care attendance and childhood acute lymphoblastic leukaemia.Int J Epidemiol2010;39:718-32 PMCID:PMC2878455

[165] MaX,WiemelsJL.Ethnic difference in daycare attendance, early infections, and risk of childhood acute lymphoblastic leukemia.Cancer Epidemiol Biomarkers Prev2005;14:1928-34

[166] UrayamaKY,SelvinS.Early life exposure to infections and risk of childhood acute lymphoblastic leukemia.Int J Cancer2011;128:1632-43 PMCID:PMC3165002

[167] VonBehren J,MuellerBA.Birth order and risk of childhood cancer: a pooled analysis from five US States.Int J Cancer2011;128:2709-16 PMCID:PMC3008504

[168] MarcotteEL,CockburnM,HeckJE.Exposure to infections and risk of leukemia in young children.Cancer Epidemiol Biomarkers Prev2014;23:1195-203 PMCID:PMC4100471

[169] MarcotteEL,Infante-rivardC.Caesarean delivery and risk of childhood leukaemia: a pooled analysis from the Childhood Leukemia International Consortium (CLIC).Lancet Haematol2016;3:e176-85 PMCID:PMC5283076

[170] FrancisSS,WendtGA.In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia.Blood2017;129:1680-4 PMCID:PMC5364339

[171] FrancisSS,MetayerC.Mode of delivery and risk of childhood leukemia.Cancer Epidemiol Biomarkers Prev2014;23:876-81

[172] WangL,YasuiY.Racial and ethnic differences in socioeconomic position and risk of childhood acute lymphoblastic leukemia.Am J Epidemiol2017;185:1263-71

[173] BonaK,NeubergDS,WolfeJ.Impact of socioeconomic status on timing of relapse and overall survival for children treated on Dana-Farber Cancer Institute ALL Consortium Protocols (2000-2010).Pediatr Blood Cancer2016;63:1012-8

[174] AcharyaS,ShinoharaET,FrangoulH.Effects of race/ethnicity and socioeconomic status on outcome in childhood acute lymphoblastic leukemia.J Pediatr Hematol Oncol2016;38:350-4

[175] KehmRD,PoynterJN,AltekruseSF.Does socioeconomic status account for racial and ethnic disparities in childhood cancer survival?.Cancer2018;124:4090-7 PMCID:PMC6234050

[176] BhatiaS,HeeremaNA,GaynonPS.Racial and ethnic differences in survival of children with acute lymphoblastic leukemia.Blood2002;100:1957-64

[177] BhatiaS,ShangguanM.Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the children's oncology group.J Clin Oncol2012;30:2094-101 PMCID:PMC3601449

[178] RosenbergAR,ChenL,JonesB.Insurance status and risk of cancer mortality among adolescents and young adults.Cancer2015;121:1279-86 PMCID:PMC5231922

[179] KrakoraR,PopliP.Impact of insurance status on survival outcomes in adults with acute lymphoblastic leukemia (ALL): a single-center experience.Clin Lymphoma Myeloma Leuk2020;20:e890-6

[180] HalpernMT,PavluckAL,BianJ.Association of insurance status and ethnicity with cancer stage at diagnosis for 12 cancer sites: a retrospective analysis.Lancet Oncol2008;9:222-31

[181] ButowP,PaiA,LuckettT.Review of adherence-related issues in adolescents and young adults with cancer.J Clin Oncol2010;28:4800-9

[182] SchmiegelowK,GustafssonG.Nordic Society of Paediatric Haematology and Oncology (NOPHO)The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse.Leukemia2010;24:715-20

[183] LandierW,CalvilloER.A grounded theory of the process of adherence to oral chemotherapy in Hispanic and caucasian children and adolescents with acute lymphoblastic leukemia.J Pediatr Oncol Nurs2011;28:203-23 PMCID:PMC3131415

[184] KorenG,SulhH.Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children.N Engl J Med1990;323:17-21

[185] BhatiaS,HagemanL.6MP adherence in a multiracial cohort of children with acute lymphoblastic leukemia: a Children's Oncology Group study.Blood2014;124:2345-53 PMCID:PMC4192748

[186] WuYP,LinderLA.Adherence to oral medications during maintenance therapy among children and adolescents with acute lymphoblastic leukemia: a medication refill analysis.J Pediatr Oncol Nurs2018;35:86-93 PMCID:PMC5935503

[187] RyttingME,O'BrienSM.Acute lymphoblastic leukemia in adolescents and young adults.Cancer2017;123:2398-403

[188] SharibJ,GrayHazard FK.Comparison of Latino and non-Latino patients with Ewing sarcoma.Pediatr Blood Cancer2014;61:233-7 PMCID:PMC4206264

[189] PuiCH,PeiD.Results of therapy for acute lymphoblastic leukemia in black and white children.JAMA2003;290:2001-7

[190] BleyerA,SiegelS.Role of clinical trials in survival progress of American adolescents and young adults with cancer-and lack thereof.Pediatr Blood Cancer2018;65:e27074 PMCID:PMC6077840

[191] PulteD,BrennerH.Improvement in survival in younger patients with acute lymphoblastic leukemia from the 1980s to the early 21st century.Blood2009;113:1408-11

[192] TalaricoL,PazdurR.Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration.J Clin Oncol2004;22:4626-31

[193] ParsonsHM,LiQ.Increased clinical trial enrollment among adolescent and young adult cancer patients between 2006 and 2012-2013 in the United States.Pediatr Blood Cancer2019;66:e27426 PMCID:PMC6249090

[194] HamelLM,AlbrechtTL,GwedeCK.Barriers to clinical trial enrollment in racial and ethnic minority patients with cancer.Cancer Control2016;23:327-37 PMCID:PMC5131730

[195] TasianSK,HungerSP.Philadelphia chromosome-like acute lymphoblastic leukemia.Blood2017;130:2064-72 PMCID:PMC5680607