Outcomes in Children, Adolescents, and Young Adults With Down Syndrome and ALL: A Report From the Children's Oncology Group

Abstract

PURPOSE

Patients with Down syndrome (DS) and B-ALL experience increased rates of relapse, toxicity, and death. We report results for patients with DS B-ALL enrolled on Children's Oncology Group trials between 2003 and 2019.

METHODS

We analyzed data for DS (n = 743) and non-DS (n = 20,067) patients age 1-30 years on four B-ALL standard-risk (SR) and high-risk trials.

RESULTS

Patients with DS exhibited more frequent minimal residual disease (MRD) ≥0.01% at end induction (30.8% v 21.5%; P < .001). This difference persisted at end consolidation only in National Cancer Institute (NCI) high-risk patients (34.0% v 11.7%; P < .0001). Five-year event-free survival (EFS) and overall survival (OS) were significantly poorer for DS versus non-DS patients overall (EFS, 79.2% ± 1.6% v 87.5% ± 0.3%; P < .0001; OS, 86.8% ± 1.4% v 93.6% ± 0.2%; P < .0001), and within NCI SR and high-risk subgroups. Multivariable Cox regression analysis of the DS cohort for risk factors associated with inferior EFS identified age >10 years, white blood count >50 × 10³/μL, and end-induction MRD ≥0.01%, but not cytogenetics or CRLF2 overexpression. Patients with DS demonstrated higher 5-year cumulative incidence of relapse (11.5% ± 1.2% v 9.1% ± 0.2%; P = .0008), death in remission (4.9% ± 0.8% v 1.7% ± 0.1%; P < .0001), and induction death (3.4% v 0.8%; P < .0001). Mucositis, infections, and hyperglycemia were significantly more frequent in all patients with DS, while seizures were more frequent in patients with DS on high-risk trials (4.1% v 1.8%; P = .005).

CONCLUSION

Patients with DS-ALL exhibit an increased rate of relapse and particularly of treatment-related mortality. Novel, less-toxic therapeutic strategies are needed to improve outcomes.

INTRODUCTION

Children with Down syndrome (DS) have a 10-fold higher risk of developing B-ALL, and experience increased rates of relapse and toxicity, including treatment-related mortality (TRM), but reasons for these differences are incompletely understood.^1-10 Although somatic genetic alterations are key prognostic factors in ALL, the spectrum of cytogenetic alterations differs markedly in DS-ALL, with lower frequencies of favorable cytogenetic lesions, rare unfavorable cytogenetic lesions, and approximately half of the cases bearing CRLF2 rearrangements (CRLF2-R), compared with only 5%-10% of non-DS cases.^2,5,11-14 Potential factors contributing to poorer outcomes include relatively lower frequency of favorable cytogenetic alterations, different prognostic impact of alterations in the context of DS, and/or increased TRM and frequent modifications of treatment.^15-17 We report on outcomes for DS patients with newly diagnosed B-ALL enrolled on four Children's Oncology Group (COG) trials from 2003 to 2018. Since almost no cases of ALL in children with DS are T-lineage, this study focuses solely on B-ALL. To our knowledge, this is the largest DS-ALL cohort (n = 743) reported to date, and the largest number of cases with CRLF2 status ascertained (n = 374; 205 with CRLF2 overexpression).

CONTEXT

• Key Objective

• Have outcomes improved for patients with Down syndrome (DS) and newly diagnosed B-ALL on modern Children's Oncology Group trials?

• Knowledge Generated

• In a large, modern cohort of 743 patients with DS and B-ALL, compared with over 20,000 patients without DS, patients with DS demonstrated a significant but narrower increased risk of relapse than in earlier eras, and a continued markedly increased risk of treatment-related mortality (TRM).

• Relevance (C.F. Craddock)

• Improving outcomes in children with DS ALL remains a major unmet need. Prospective randomized trials of emerging new treatment strategies with the potential to reduce both TRM and relapse rate are required.*

  *Relevance section written by JCO Associate Editor Charles F. Craddock, MD.

METHODS

Study Design

We analyzed clinical and outcome data for DS (n = 743) and non-DS (n = 20,067) B-ALL patients, age 1-30 years, enrolled on COG standard-risk (SR) trials AALL0331 and AALL0932 and high-risk trials AALL0232 and AALL1131 between 2003 and 2019^18-21 (Data Supplement, Table S1 [online only]).

Toxicities were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events versions 4.0 and 5.0. The studies were approved by the NCI, the Pediatric Central Institutional Review Board (IRB), and IRBs at participating institutions. All participants or legally authorized representatives provided written informed consent.

Treatment

Regimens for non-DS patients on the four trials have been previously described.^18-21 Descriptions of DS-specific eligibility criteria, treatment regimens, and supportive care guidelines are provided in the Data Supplement (Table S2), and summarized here. Initially, subjects with DS participated in the randomizations on AALL0331 and AALL0232 as a stratified subgroup, but in 2006, excessive mortality was observed in DS subjects, primarily because of overwhelming neutropenic sepsis (Data Supplement, Table S3). This prompted suspension of enrollment and implementation of enhanced supportive care guidelines and treatment modifications (Data Supplement, Table S2). Subsequent TRM was reduced on AALL0331 but remained excessive on AALL0232, leading to permanent closure to DS-ALL enrollment on AALL0232. On the subsequent SR trial AALL0932 and high-risk trial AALL1131, subjects with DS were treated nonrandomly, again with enhanced supportive care and treatment modifications.

Genetic alterations cytogenetics and fluorescent in situ hybridization were performed in approved laboratories with central review, and defined as favorable (ETV6::RUNX1 or simultaneous trisomies of chromosomes 4, 10 and 17 [triple trisomy on AALL0331 and AALL0232], or chromosomes 4 and 10 [double trisomy on AALL0932 and AALL1131]), unfavorable (BCR::ABL1, KMT2A-rearranged, intrachromosomal amplification of chromosome 21 [iAMP21] beginning in 2011, hypodiploidy [<44 chromosomes or DNA index <0.81]), or neutral (all others). CRLF2-R and JAK mutations were ascertained retrospectively in a subset of patients (Data Supplement, Methods), but were not used clinically for risk stratification or management.

Minimal Residual Disease

End of induction (EOI) minimal residual disease (MRD) was assessed by flow cytometry at central reference laboratories or COG-approved local laboratories. End of consolidation (EOC) MRD was assessed for patients with EOI MRD ≥0.1% for AALL0331/AALL0232, and ≥0.01% for AALL0932/AALL1131.

Statistical Analysis

Event-free survival (EFS) was defined as the time from study enrollment to first event (induction failure, induction death, relapse, second malignant neoplasm, or remission death) or date of last contact if event-free. Overall survival (OS) was defined as the time from study enrollment to death or date of last contact. Survival time postrelapse was calculated as the time from relapse to death or last contact if alive. Data reported are current as of March 31, 2023. Survival rates were calculated using the Kaplan-Meier method with SE of Peto et al.^22,23 Survival rates are presented as estimate ± SE. Log-rank tests were used to compare survival curves between groups, and proportions were compared using χ² or Fisher's exact test. Cumulative incidence rates were computed using the cumulative incidence function for competing risks, and comparisons were made using the K-sample test. Univariable and multivariable Cox regression analyses were used to assess the effect of factors on EFS. For all analyses, a P value <.05 was considered statistically significant. Analyses were conducted using SAS software, version 9.4 (SAS Institute, Cary, NC), and R version 4.0.0.²⁴

RESULTS

Patient and Case Characteristics

Patient characteristics are provided in Table 1. Patients with DS were slightly older (median age, 5 v 4 years; P < .0001) and more often White than non-DS patients. Other demographic features did not differ significantly. Patients with DS demonstrated highly significant differences in the spectrum of common cytogenetic lesions with significantly fewer cases with favorable cytogenetics compared with non-DS patients (14.4% v 46.7%), more cases with neutral cytogenetics (84.9% v 46.2%), and almost no cases with unfavorable cytogenetics (0.7% v 7.2%), including no cases of iAMP21. A subset of DS cases were retrospectively evaluated for CRLF2 (N = 374) and JAK (N = 165) status. CRLF2 overexpression occurred in 54.8% and JAK mutations in 25.5%, all of which were CRLF2-high. In cases with determination of CRLF2 partner, the majority were P2RY8::CRLF2 (130 of 157; 82.8%).

TABLE 1.

Patient Characteristics

MRD

Patients with DS exhibited EOI MRD ≥0.01% significantly more frequently than non-DS patients both overall (30.8% v 21.5%; P < .0001) and among NCI SR (25.9% v 17.8%; P = .0003) and NCI high-risk (41.4% v 28.9%; P = .0001) subgroups (Data Supplement, Fig S1). The difference persisted at EOC only in the NCI high-risk subgroup (34.0% v 11.7%; P < .0001).

Overall Outcomes

Patients with DS demonstrated inferior outcomes overall, and within the NCI SR and NCI high-risk subgroups (Fig 1). For DS versus non-DS patients overall, 5-year EFS was 79.2% ± 1.6% versus 87.5% ± 0.3% (P < .0001) and 5-year OS was 86.8% ± 1.4% versus 93.6% ± 0.2% (P < .0001).

FIG 1.

Kaplan-Meier estimates of EFS and OS among subjects with DS and non-DS ALL. 5-year EFS for (A) all, (B) NCI SR, and (C) NCI high-risk subjects. 5-year OS for (D) all, (E) NCI SR, and (F) NCI high-risk subjects. Among NCI SR patients, 5-year EFS was 85.3% ± 1.7% versus 91.8% ± 0.2% (P < .0001) and 5-year OS was 91.3% ± 1.4% versus 96.8% ± 0.2% (P < .0001). Among NCI high-risk patients, disparities in outcomes were widest, with 5-year EFS rates of 68.1% ± 3.2% versus 77.3% ± 0.6% (P = .0003) and 5-year OS rates of 78.6% ± 2.9% versus 86.0% ± 0.5% (P = .0001). DS, Down syndrome; EFS, event-free survival; NCI, National Cancer Institute; OS, overall survival; SR, standard-risk.

Outcomes by Genetic Subtype

Outcomes among the three genetic subtypes most common in DS-ALL are shown in Figure 2: CRLF2-high, CRLF2-normal (defined as normal CRLF2 expression and neutral cytogenetics), and favorable cytogenetics. When EFS and OS in CRLF2-high cases were assessed within each NCI risk group, there was no significant difference in outcomes for DS versus non-DS ALL (Data Supplement, Fig S2). However, because most DS CRLF2-high cases were NCI SR, whereas most non-DS CRLF2-high cases were NCI high-risk, the overall CRLF2-high EFS and OS were significantly better in DS versus non-DS ALL (Figs 2A and 2D; 5-year EFS, 80.6% ± 2.9% v 62.8% ± 2.9%; P < .0001; 5-year OS, 89.1% ± 2.3% v 78.1% ± 2.5%; P = .0006). Outcomes in CRLF2-normal cases did not differ significantly between DS and non-DS ALL (Figs 2B and 2E; 5-year EFS, 77.3% ± 4.1% v 80.3% ± 1.0%; P = .4118; 5-year OS, 82.6% ± 3.7% v 89.4% ± 0.8%; P = .1600). Favorable cytogenetics had a positive prognostic impact for patients with DS, but outcomes in this group were still significantly inferior to those of non-DS patients (Figs 2C and 2F; 5-year EFS, 89.7% ± 3.2% v 94.5% ± 0.3%; P < .0001; 5-year OS, 91.6% ± 2.9% v 98.1% ± 0.2%; P < .0001), and this pattern manifested in both the NCI SR and NCI high-risk subgroups (Data Supplement, Fig S3).

FIG 2.

Kaplan-Meier estimates of 5-year EFS and OS among subjects with DS and non-DS ALL. Outcomes are displayed for cases with CRLF2-high (A and D), CRLF2-normal (B and E), and favorable cytogenetics (C and F). DS, Down syndrome; EFS, event-free survival; nl, normal; OS, overall survival.

Outcomes within the DS patient population according to genetic subtype are shown in the Data Supplement (Fig S4). Among DS NCI SR patients, CRLF2-high and favorable cytogenetics groups had similar EFS (89.2% ± 2.7% and 93.0% ± 3.9%) and OS (95.7% ± 1.8% and 95.4% ± 3.3%), whereas neutral cytogenetics showed trends toward doing more poorly (EFS, 78.5% ± 5.6% and OS, 83.1% ± 5.1%; Data Supplement, Figs S4A and S4C). Among DS NCI high-risk patients, the EFS and OS were best for favorable cytogenetics, intermediate for neutral cytogenetics, and poorest for CRLF2-high (EFS, 92.3% ± 7.4%, 75.9% ± 6.1%, and 61.2% ± 6.3%, and OS, 100% ± 0%, 82.0% ± 5.5%, and 73.9% ± 5.7%, respectively; Data Supplement, Figs S4B and S4D). Among DS patients with CRLF2-high, there was no significant difference in EFS or OS according to P2RY8 versus IGH partner.

Cumulative Incidence of Relapse

The cumulative incidence of relapse (CIR) at 5 years was significantly higher in DS than in non-DS patients (11.5% ± 1.2% v 9.1% ± 0.2%; P = .0008; Fig 3A). When evaluated within NCI risk groups, NCI SR patients with DS demonstrated a significant disparity in CIR (Data Supplement, Figs S5A and S5B; 5-year CIR, 8.9% ± 1.3% v 6.6% ± 0.2%; P = .0001), whereas NCI high-risk patients with DS did not (16.2% ± 2.3% v 15.1% ± 0.5%; P = .7441). When evaluated by timing of relapse, with early defined as marrow or combined relapse <36 months from diagnosis and isolated extramedullary relapse <18 months from diagnosis, patients with DS experienced significantly more late relapses (5-year CIR, 7.1% ± 1.0% v 5.2% ± 0.2%; P = .0001), but no difference in early relapses (4.4% ± 0.8% v 3.9% ± 0.1%; P = .5576) compared with non-DS. When evaluated by site of relapse, patients with DS experienced significantly more isolated bone marrow relapses (9.0% ± 1.1% v 5.2% ± 0.2%; P < .0001; Data Supplement, Table S4) and isolated CNS relapses (1.0% ± 0.4% v 2.0% ± 0.1%; P = .0336; Data Supplement, Table S4).

FIG 3.

Cumulative incidence of (A) relapse and (B) death in remission among all subjects with DS and non-DS ALL. (C) Five-year postrelapse overall survival among SR subjects enrolled on AALL0331 with DS and non-DS ALL. DS, Down syndrome; SR, standard-risk.

Induction Deaths and Death in Remission

Death in induction was significantly more frequent in patients with DS, both overall (DS, 3.4% v non-DS, 0.8%; P < .0001) and within each of the four trials (Data Supplement, Table S5). The percentage was lower in the two recent trials, which included enhanced safety precautions throughout, compared with the two earlier trials. The 5-year cumulative incidence of death in remission was also significantly higher among DS versus non-DS patients (4.9% ± 0.8% v 1.7% ± 0.1%; P < .0001; Fig 3B), and this disparity was significant in both NCI SR patients (Data Supplement, Fig S5C) and NCI high-risk patients (Data Supplement, Fig S5D).

Postrelapse Survival

For patients enrolled on AALL0331, we evaluated the postrelapse OS among DS (N = 17) versus non-DS (N = 457) patients. DS SR patients had a dismal 5-year postrelapse OS compared with non-DS patients (18.3% ± 11.7% v 63.9% ± 2.7%; P < .0001; Fig 3C).

Univariable and Multivariable Regression Analyses

We performed Cox regression analyses for risk factors associated with inferior EFS in DS-ALL. In univariable analysis, risk factors already well established in non-DS were significantly associated with inferior EFS in the DS cohort: age ≥10 years at diagnosis, initial WBC ≥50 × 10³/µL, EOI MRD positivity, neutral cytogenetics, and Hispanic ethnicity (Data Supplement, Table S6). In multivariable analysis, our first model did not incorporate CRLF2 status to retain the whole cohort of patients (N = 702), while a second model was limited to those patients with CRLF2 status (N = 237). In the first model (Table 2), inferior EFS remained significantly associated with three factors: age, initial WBC, and EOI MRD. Similarly, in the second model (Data Supplement, Table S7), age, initial WBC, and EOI MRD remained significantly associated with inferior EFS, whereas neutral/unfavorable cytogenetics and CRLF2 status were not. In additional Cox regression analyses for the NCI SR and high-risk subgroups, EOI MRD and neutral cytogenetics were significantly associated with inferior EFS in the NCI SR subgroup (Data Supplement, Table S8), while age, initial WBC, and EOI MRD were significant in the NCI high-risk subgroup (Data Supplement, Table S9). We did not observe significant interactions between race/ethnicity and cytogenetics in the DS cohort (Data Supplement, Table S10). Multivariable analyses for EFS and OS for the full cohort of all DS and non-DS patients confirmed the significance of known risk factors, and did not demonstrate independent prognostic significance of DS status (Data Supplement, Tables S11 and S12, respectively).

TABLE 2.

Multivariable Cox Regression Analysis for Risk Factors Associated With EFS for DS-ALL

Treatment-Related Toxicity Rates Are Significantly Higher in Patients With DS

As previously reported, patients with DS experienced significantly higher frequencies of grade ≥3 mucositis, infections, and hyperglycemia (Data Supplement, Fig S6). All three toxicities were significantly increased in DS versus non-DS patients, although less frequent in NCI SR than high-risk patients. As expected, the highest frequencies of mucositis occurred in intravenous methotrexate-containing interim maintenance (IM) phases, but higher frequencies occurred in every treatment phase, including notably high frequencies during maintenance (SR DS, 9.7% v non-DS, 2.2%; P < .0001; high-risk DS, 10.6% v non-DS, 2.3%; P < .0001; Data Supplement, Table S13). Infections were also more frequent in every treatment phase, for both risk groups (Data Supplement, Table S14), with lowest frequency during IM phases and highest during maintenance. Hyperglycemia occurred more often in induction, consolidation, and delayed intensification (Data Supplement, Table S15).

An increased risk of seizures has not been previously established in DS-ALL, but has been observed in a few recent studies.^25-27 In the current cohort, Grade ≥3 seizures were significantly more frequent in patients with DS on the high-risk trials (4.1% v 1.8%; P = .005) but not on the SR trials (Data Supplement, Fig S6). Seizure incidence was evenly distributed across all phases before maintenance, with no significant association with age, sex, race or ethnicity (Data Supplement, Table S16).

DISCUSSION

To our knowledge, we present outcomes for the largest DS-ALL cohort treated in the modern era on consecutive trials with uniform diagnostic and risk stratification procedures, including a standardized centrally reviewed cytogenetic panel, standardized MRD assays, and risk-stratified postinduction therapy. Our data demonstrate that disparities in EFS, OS, and relapse have narrowed compared with earlier reports. This improvement is likely attributable to the efficacy of modern, intensified chemotherapy regimens, similar to the improvements observed in some other ALL subgroups (eg, non-Hispanic Blacks²⁸ and TCF3::PBX1+ ALL²⁹). However, despite instituting DS-specific supportive care modifications, the composite of induction deaths (3.4% v 0.8%; P < .0001; almost all due to toxicity) and postinduction TRM (4.9% v 1.7%; P < .0001) is 8.3% versus 2.5% for DS versus non-DS patients (P < .001). This comprises about 36.5% of all events in patients with DS versus 18.2% in non-DS, emphasizing the need for further DS-specific interventions to decrease the toxicity of therapy.

A large retrospective review by the Ponte di Legno group reported that relapse constituted the main cause of treatment failure in DS-ALL.² By contrast, we found a greater disparity in the risk of TRM in DS-ALL. Notably, in the NCI high-risk group, there was no evidence of an increased CIR in DS versus non-DS patients. This is particularly remarkable since most NCI high-risk DS patients were enrolled on AALL1131, which included significant treatment reductions (omission or reduction in induction anthracycline, and reduction in IV methotrexate from 5 to 2 g/m² during IM) that bore potential for increasing the risk of relapse. The size of this study provided power to assess patterns in relapse timing and site. The finding of increased risk of late relapse and isolated bone marrow and CNS relapses may have implications for development of future preventive strategies. Although the majority of relapses were late, post-relapse OS was dismal, suggesting an inability to tolerate intensive retrieval strategies. Recently, some trials in adult ALL have been using inotuzumab for reduction of bulk disease followed by multiple cycles of blinatumomab, with minimal conventional chemotherapy, particularly in elderly patients who do not tolerate intensive regimens because of TRM.^30,31 Such efforts are demonstrating promising early outcomes, and serve as an encouraging model for future trial design for the high-risk DS population.

This study provides important data on the prognostic impact of CRLF2 overexpression in DS-ALL, for which data are limited because of its more recent identification. Previous reports have suggested a lack of prognostic impact in DS-ALL.^2,3,14,32-34 Our findings, however, demonstrate that the risk differs markedly depending on NCI risk group. In a direct comparison of DS versus non-DS CRLF2-high cases, we found no significant difference in EFS or OS within each NCI risk group. Within DS-ALL, the prognostic impact of CRLF2 status differed by NCI risk group, with a significantly higher EFS in CRLF2-high versus CRLF2-neutral cases among NCI SR DS patients, and significantly poorer EFS among NCI high-risk DS patients. The lack of negative impact of CRLF2-high status among NCI SR DS patients is reminiscent of the similar finding reported in non-DS NCI SR ALL.³⁴ The differing prognostic impact of CRLF2 alterations in NCI SR and high-risk DS-ALL is an important insight, given its frequency. These data confirm that NCI SR patients should not receive treatment intensification on the basis of this alteration. The negative impact in NCI high-risk disease may be an important consideration for families and clinicians striving to balance treatment intensity with toxicity. A recently completed trial (ClinicalTrials.gov identifier: NCT02723994) will provide data on potential benefit of adding JAK inhibition to standard ALL chemotherapy in pediatric ALL with CRLF2 and JAK alterations, although the trial excluded patients with DS.

The observed increased rates of mucositis, infections, and hyperglycemia, including associations with NCI risk group and treatment phase, may inform prevention and supportive care strategies. The increased risk in SR patients and the persistent risks of mucositis and infection during maintenance are notable. The risk of seizures among high-risk patients warrants close observation on future trials. The current COG trial has implemented earlier postintrathecal leucovorin rescue for patients with DS, at 24 and 30 hours, and it will be important to see if this intervention ameliorates the seizure risk.

Limitations of this study include that genetic ancestry data were not consistently available, and that certain genetic subtypes were not determined, including Ph-like status (except for CRLF2, the most frequent Ph-like lesion) and IKZF1 alterations, which have been reported to have significant adverse prognosis in DS-ALL.^3,6,33 Last, postrelapse survival was assessed only among SR patients on AALL0331; so, although the dismal survival provides an important historical reference point, further studies are needed to assess postrelapse survival in the current era of immunotherapies.

In summary, to our knowledge, this report provides comprehensive data on genetic subtypes and outcomes in the largest DS cohort with newly diagnosed B-ALL to date. We demonstrate that although disparities in relapse have narrowed in the modern era, increased TRM persists. Our findings highlight the impact of NCI risk group on other risk factors in DS-ALL, with a greater disparity in relapse risk in NCI SR DS patients, and an inferior prognosis for CRLF2-high ALL in NCI high-risk DS patients. Novel approaches such as immunotherapies and targeted therapies hold particular promise to improve outcomes through enhanced efficacy and reduced toxicity in patients with DS.³⁶

AUTHOR CONTRIBUTIONS

Conception and design: Karen R. Rabin, Meenakshi Devidas, Zhiguo Chen, Johann K. Hitzler, Brent L. Wood, Cheryl L. Willman, Kelly W. Maloney, Eric C. Larsen, Reuven J. Schore, Michael J. Burke, Wanda L. Salzer, William L. Carroll, Elizabeth A. Raetz, Mignon L. Loh, Stephen P. Hunger, Anne L. Angiolillo

Administrative support: Cheryl L. Willman

Provision of study materials or patients: Zhiguo Chen, Julie M. Gastier-Foster, Susan R. Rheingold, Kelly W. Maloney, Michael J. Burke, William L. Carroll

Collection and assembly of data: Karen R. Rabin, Meenakshi Devidas, Zhiguo Chen, John Kairalla, Andrew J. Carroll, Nyla A. Heerema, Michael J. Borowitz, Brent L. Wood, Kathryn G. Roberts, Charles G. Mullighan, Richard C. Harvey, I-Ming Chen, Cheryl L. Willman, Shalini C. Reshmi, Julie M. Gastier-Foster, Susan R. Rheingold, Kelly W. Maloney, Leonard A. Mattano, Reuven J. Schore, Michael J. Burke, Wanda L. Salzer, William L. Carroll, Stephen P. Hunger, Anne L. Angiolillo

Data analysis and interpretation: Karen R. Rabin, Meenakshi Devidas, Zhiguo Chen, Lingyun Ji, John Kairalla, Johann K. Hitzler, Jun J. Yang, Michael J. Borowitz, Brent L. Wood, Richard C. Harvey, Cheryl L. Willman, Deepa Bhojwani, Susan R. Rheingold, Kelly W. Maloney, Leonard A. Mattano, Reuven J. Schore, Michael J. Burke, Wanda L. Salzer, Naomi J. Winick, Mignon L. Loh, Stephen P. Hunger, Anne L. Angiolillo

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Outcomes in Children, Adolescents, and Young Adults With Down Syndrome and ALL: A Report From the Children's Oncology Group

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