Daratumumab in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma: DELPHINUS Study.

Patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) have poor outcomes compared with newly diagnosed, treatment-naïve patients. The phase 2, open-label DELPHINUS study evaluated daratumumab (16 mg/kg intravenously) plus backbone chemotherapy in children with relapsed/refractory B-cell ALL (n=7) after ≥2 relapses and children and young adults with T-cell ALL (children, n=24; young adults, n=5) or LL (n=10) after first relapse. The primary endpoint was complete response (CR) in the B-cell ALL (end of Cycle 2) and T-cell ALL (end of Cycle 1) cohorts, after which patients could proceed off study to allogeneic hematopoietic stem cell transplant (HSCT). Seven patients with advanced B-cell ALL received daratumumab with no CRs achieved; this cohort was closed due to futility. For the childhood T-cell ALL, young adult T-cell ALL, and T-cell LL cohorts, the CR (end of Cycle 1) rates were 41.7%, 60.0%, and 30.0%, respectively; overall response rates (any time point) were 83.3% (CR+CR with incomplete count recovery [CRi]), 80.0% (CR+CRi), and 50.0% (CR+partial response); minimal residual disease-negativity (<0.01%) rates were 45.8%, 20.0%, and 50.0%; observed 24-month event-free survival rates were 36.1%, 20.0%, and 20.0%; observed 24-month overall survival rates were 41.3%, 25.0%, and 20.0%; and allogeneic HSCT rates were 75.0%, 60.0%, and 30.0%. No new safety concerns with daratumumab were observed. In conclusion, daratumumab was safely combined with backbone chemotherapy in children and young adults with T-cell ALL/LL and contributed to successful bridging to HSCT. This trial was registered at www.ClinicalTrials.gov as NCT03384654.

Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia.

PURPOSE: Although cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk (SR) disease. MATERIALS AND METHODS: To identify genomic determinants of relapse in children with SR ALL, we performed genome and transcriptome sequencing of diagnostic and remission samples of children with SR (n = 1,381) or high-risk B-ALL with favorable cytogenetic features (n = 115) enrolled on Children's Oncology Group trials. We used a case-control study design analyzing 439 patients who relapsed and 1,057 who remained in complete remission for at least 5 years. RESULTS: Genomic subtype was associated with relapse, which occurred in approximately 50% of cases of PAX5-altered ALL (odds ratio [OR], 3.31 [95% CI, 2.17 to 5.03]; P = 3.18 × 10-8). Within high-hyperdiploid ALL, gain of chromosome 10 with disomy of chromosome 7 was associated with favorable outcome (OR, 0.27 [95% CI, 0.17 to 0.42]; P = 8.02 × 10-10; St Jude Children's Research Hospital validation cohort: OR, 0.22 [95% CI, 0.05 to 0.80]; P = .009), and disomy of chromosomes 10 and 17 with gain of chromosome 6 was associated with relapse (OR, 7.16 [95% CI, 2.63 to 21.51]; P = 2.19 × 10-5; validation cohort: OR, 21.32 [95% CI, 3.62 to 119.30]; P = .0004). Genomic alterations were associated with relapse in a subtype-dependent manner, including alterations of INO80 in ETV6::RUNX1 ALL, IKZF1, and CREBBP in high-hyperdiploid ALL and FHIT in BCR::ABL1-like ALL. Genomic alterations were also associated with the presence of minimal residual disease, including NRAS and CREBBP in high-hyperdiploid ALL. CONCLUSION: Genetic subtype, patterns of aneuploidy, and secondary genomic alterations determine risk of relapse in childhood ALL. Comprehensive genomic analysis is required for optimal risk stratification.

The genomic basis of childhood T-lineage acute lymphoblastic leukaemia.

T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour1 that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation2,3. Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes. Analyses of chromatin topology revealed multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific manner, thereby demonstrating widespread involvement of the noncoding genome. We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of 'early T cell precursor-like' leukaemia. This category has a variable immunophenotype and diverse genomic alterations of a core set of genes that encode regulators of hematopoietic stem cell development. Using multivariable outcome models, we show that genetic subtypes, driver and concomitant genetic alterations independently predict treatment failure and survival. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.

Anti-CD7 allogeneic WU-CART-007 in patients with relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma: a phase 1/2 trial.

Relapsed/refractory T-cell acute lymphoblastic leukemia (ALL)/lymphoma (LBL) represent a significant unmet medical need. WU-CART-007 is a CD7-targeting, allogeneic, fratricide-resistant chimeric antigen receptor T cell product generated from healthy donor T cells. WU-CART-007 was evaluated in a phase 1/2 study with a 3 + 3 dose-escalation design followed by cohort expansion in relapsed/refractory T-ALL/LBL. Patients received one infusion of WU-CART-007 after standard or enhanced lymphodepleting chemotherapy. The primary objectives, to characterize safety and assess the composite complete remission rate, were met. Of 26 patients enrolled, 13 received the recommended phase 2 dose (RP2D) of 900 million cells of WU-CART-007 with enhanced lymphodepletion. The most common treatment-related adverse event was cytokine release syndrome (88.5%; 19.2% grade 3-4). Biochemical abnormalities consistent with grade 2 hemophagocytic lymphohistiocytosis were seen in one patient (3.8%). Grade 1 immune effector cell-associated neurotoxicity syndrome events (7.7%) and one grade 2 acute graft-vs-host disease event occurred. Grade 5 events (11.5%) were due to fungal infection and multi-organ failure. The composite complete remission rate was 81.8% among 11/13 patients evaluable for response at the RP2D. WU-CART-007 at the RP2D demonstrated a high response rate in patients with relapsed/refractory T-ALL/LBL and has the potential to provide a new treatment option. ClinicalTrials.gov registration: NCT04984356.

Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults.

BACKGROUND: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission. METHODS: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point. RESULTS: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P = 0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group. CONCLUSIONS: The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.).

A de novo germline RUNX1 variant preceding development of concurrent T-lymphoblastic leukemia and myelodysplastic syndrome.

Germline variants of the RUNX1 gene are associated with RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies (RUNX1-FPDMM), which is characterized by an increased risk of developing myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. Patients with FPDMM have also been described to develop B- or T-cell acute lymphoblastic leukemia. We present a pediatric patient with RUNX1-FPDMM that evolved into concurrent MDS and T-cell acute lymphoblastic leukemia after a decade of monitoring with serial blood counts. We aim to highlight the treatment challenges and clinical decision-making that may be anticipated in this unique disorder, as well as the potentially curative role for allogenic hematopoietic stem cell transplant in the first complete remission.

MRD at the end of induction and EFS in T-cell lymphoblastic lymphoma: Children's Oncology Group trial AALL1231.

ABSTRACT: Defining prognostic variables in T-lymphoblastic lymphoma (T-LL) remains a challenge. AALL1231 was a Children's Oncology Group phase 3 clinical trial for newly diagnosed patients with T acute lymphoblastic leukemia or T-LL, randomizing children and young adults to a modified augmented Berlin-Frankfurt-Münster backbone to receive standard therapy (arm A) or with addition of bortezomib (arm B). Optional bone marrow samples to assess minimal residual disease (MRD) at the end of induction (EOI) were collected in T-LL analyzed to assess the correlation of MRD at the EOI to event-free survival (EFS). Eighty-six (41%) of the 209 patients with T-LL accrued to this trial submitted samples for MRD assessment. Patients with MRD <0.1% (n = 75) at EOI had a superior 4-year EFS vs those with MRD ≥0.1% (n = 11) (89.0% ± 4.4% vs 63.6% ± 17.2%; P = .025). Overall survival did not significantly differ between the 2 groups. Cox regression for EFS using arm A as a reference demonstrated that MRD EOI ≥0.1% was associated with a greater risk of inferior outcome (hazard ratio, 3.73; 95% confidence interval, 1.12-12.40; P = .032), which was independent of treatment arm assignment. Consideration to incorporate MRD at EOI into future trials will help establish its value in defining risk groups. CT# NCT02112916.

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

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.

Quantification of measurable residual disease using duplex sequencing in adults with acute myeloid leukemia.

The presence of measurable residual disease (MRD) is strongly associated with treatment outcomes in acute myeloid leukemia (AML). Despite the correlation with clinical outcomes, MRD assessment has yet to be standardized or routinely incorporated into clinical trials and discrepancies have been observed between different techniques for MRD assessment. In 62 patients with AML, aged 18-60 years, in first complete remission after intensive induction therapy on the randomized phase III SWOG-S0106 clinical trial (clinicaltrials gov. Identifier: NCT00085709), MRD detection by centralized, high-quality multiparametric flow cytometry was compared with a 29-gene panel utilizing duplex sequencing (DS), an ultrasensitive next-generation sequencing method that generates double-stranded consensus sequences to reduce false positive errors. MRD as defined by DS was observed in 22 (35%) patients and was strongly associated with higher rates of relapse (68% vs. 13%; hazard ratio [HR] =8.8; 95% confidence interval [CI]: 3.2-24.5; P<0.001) and decreased survival (32% vs. 82%; HR=5.6; 95% CI: 2.3-13.8; P<0.001) at 5 years. DS MRD strongly outperformed multiparametric flow cytometry MRD, which was observed in ten (16%) patients and marginally associated with higher rates of relapse (50% vs. 30%; HR=2.4; 95% CI: 0.9-6.7; P=0.087) and decreased survival (40% vs. 68%; HR=2.5; 95% CI: 1.0-6.3; P=0.059) at 5 years. Furthermore, the prognostic significance of DS MRD status at the time of remission for subsequent relapse was similar on both randomized arms of the trial. These findings suggest that next-generation sequencing-based AML MRD testing is a powerful tool that could be developed for use in patient management and for early anti-leukemic treatment assessment in clinical trials.

Identification and targeting of treatment resistant progenitor populations in T-cell Acute Lymphoblastic Leukemia.

Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to cure in T-cell Acute Lymphoblastic Leukemia (T-ALL). Biomarker guided risk stratification and targeted therapy have the potential to improve outcomes in high-risk T-ALL; however, cellular and genetic factors contributing to treatment resistance remain unknown. Previous bulk genomic studies in T-ALL have implicated tumor heterogeneity as an unexplored mechanism for treatment failure. To link tumor subpopulations with clinical outcome, we created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic (CITE-seq/snATAC-seq) analysis to a cohort of 40 cases of T-ALL treated on the Children's Oncology Group AALL0434 clinical trial. The cohort was carefully selected to capture the immunophenotypic diversity of T-ALL, with early T-cell precursor (ETP) and Near/Non-ETP subtypes represented, as well as enriched with both relapsed and treatment refractory cases. Integrated analyses of T-ALL blasts and normal T-cell precursors identified a bone-marrow progenitor-like (BMP-like) leukemia sub-population associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL within two independent patient cohorts using bulk RNA-sequencing data from over 1300 patients. We defined the mutational landscape of BMP-like T-ALL, finding that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. We transcriptionally matched BMP-like blasts to early thymic seeding progenitors that have low NR3C1 expression and high stem cell gene expression, corresponding to a corticosteroid and conventional cytotoxic resistant phenotype we observed in ex vivo drug screening. To identify novel targets for BMP-like blasts, we performed in silico and in vitro drug screening against the BMP-like signature and prioritized BMP-like overexpressed cell-surface (CD44, ITGA4, LGALS1) and intracellular proteins (BCL-2, MCL-1, BTK, NF-κB) as candidates for precision targeted therapy. We established patient derived xenograft models of BMP-high and BMP-low leukemias, which revealed vulnerability of BMP-like blasts to apoptosis-inducing agents, TEC-kinase inhibitors, and proteasome inhibitors. Our study establishes the first multi-omic signatures for rapid risk-stratification and targeted treatment of high-risk T-ALL.

Updates on lymphoblastic leukemia/lymphoma classification and minimal/measurable residual disease analysis.

Lymphoblastic leukemia/lymphoma (ALL/LBL), especially certain subtypes, continues to confer morbidity and mortality despite significant therapeutic advances. The pathologic classification of ALL/LBL, especially that of B-ALL, has recently substantially expanded with the identification of several distinct and prognostically important genetic drivers. These discoveries are reflected in both current classification systems, the World Health Organization (WHO) 5th edition and the new International Consensus Classification (ICC). In this article, novel subtypes of B-ALL are reviewed, including DUX4, MEF2D and ZNF384-rearranged B-ALL; the rare pediatric entity B-ALL with TLF3::HLF, now added to the classifications, is discussed; updates to the category of B-ALL with BCR::ABL1-like features (Ph-like B-ALL) are summarized; and emerging genetic subtypes of T-ALL are presented. The second half of the article details current approaches to minimal/measurable residual disease (MRD) detection in B-ALL and T-ALL and presents anticipated challenges to current approaches in the burgeoning era of antigen-directed immunotherapy.

Prognostic significance of ETP phenotype and minimal residual disease in T-ALL: a Children's Oncology Group study.

The early thymic precursor (ETP) immunophenotype was previously reported to confer poor outcome in T-cell acute lymphoblastic leukemia (T-ALL). Between 2009 and 2014, 1256 newly diagnosed children and young adults enrolled in Children's Oncology Group (COG) AALL0434 were assessed for ETP status and minimal residual disease (MRD) using flow cytometry at a central reference laboratory. The subject phenotypes were categorized as ETP (n = 145; 11.5%), near-ETP (n = 209; 16.7%), or non-ETP (n = 902; 71.8%). Despite higher rates of induction failure for ETP (6.2%) and near-ETP (6.2%) than non-ETP (1.2%; P < .0001), all 3 groups showed excellent 5-year event-free survival (EFS) and overall survival (OS): ETP (80.4% ± 3.9% and 86.8 ± 3.4%, respectively), near-ETP (81.1% ± 3.3% and 89.6% ± 2.6%, respectively), and non-ETP (85.3% ± 1.4% and 90.0% ± 1.2%, respectively; P = .1679 and P = .3297, respectively). There was no difference in EFS or OS for subjects with a day-29 MRD <0.01% vs 0.01% to 0.1%. However, day-29 MRD ≥0.1% was associated with inferior EFS and OS for patients with near-ETP and non-ETP, but not for those with ETP. For subjects with day-29 MRD ≥1%, end-consolidation MRD ≥0.01% was a striking predictor of inferior EFS (80.9% ± 4.1% vs 52.4% ± 8.1%, respectively; P = .0001). When considered as a single variable, subjects with all 3 T-ALL phenotypes had similar outcomes and subjects with persistent postinduction disease had inferior outcomes, regardless of their ETP phenotype. This clinical trial was registered at AALL0434 as #NCT00408005.

γ-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial.

BACKGROUND: γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma. METHODS: We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0-2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 106 CAR T cells, 150 × 106 CAR T cells, 300 × 106 CAR T cells, and 450 × 106 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals. FINDINGS: 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 106 CAR+ cells, and the recommended phase 2 dose was not reached. INTERPRETATIONS: Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials. FUNDING: Juno Therapeutics-a Bristol Myers Squibb company and the National Institutes of Health.

Quantification of measurable residual disease using duplex sequencing in adults with acute myeloid leukemia.

The presence of measurable residual disease (MRD) is strongly associated with treatment outcomes in acute myeloid leukemia (AML). Despite the correlation with clinical outcomes, MRD assessment has yet to be standardized or routinely incorporated into clinical trials. Discrepancies have been observed between different techniques for MRD assessment and there remains a need to compare centralized, high-quality multiparametric flow cytometry (MFC) and ultrasensitive next-generation sequencing (NGS) in AML patients with diverse mutational profiles. In 62 patients with AML, aged 18-60, in first complete remission after intensive induction therapy on the randomized phase 3 SWOG-S0106 clinical trial, MRD detection by MFC was compared with a 29 gene panel utilizing duplex sequencing (DS), an NGS method that generates double-stranded consensus sequences to reduce false positive errors. Using DS, detection of a persistent mutation utilizing defined criteria was seen in 22 (35%) patients and was strongly associated with higher rates of relapse (68% vs 13% at year 5; HR, 8.8; 95% CI, 3.2-24.5; P<0.001) and decreased survival (32% vs 82% at year 5; HR, 5.6; 95% CI, 2.3-13.8; P<0.001). MRD as defined by DS strongly outperformed MFC, which was observed in 10 (16%) patients and marginally associated with higher rates of relapse (50% vs 30% at year 5; HR, 2.4; 95% CI, 0.9-6.7; P=0.087) and decreased survival (40% vs 68% at year 5; HR, 2.5; 95% CI, 1.0-6.3; P=0.059). Furthermore, the prognostic significance of DS MRD status at the time of remission was similar on both randomized arms of the trial, predicting S0106 clinical trial outcomes. These findings suggest that DS is a powerful tool that could be used in patient management and for early treatment assessment in clinical trials.

Genomic landscape of Down syndrome-associated acute lymphoblastic leukemia.

Trisomy 21, the genetic cause of Down syndrome (DS), is the most common congenital chromosomal anomaly. It is associated with a 20-fold increased risk of acute lymphoblastic leukemia (ALL) during childhood and results in distinctive leukemia biology. To comprehensively define the genomic landscape of DS-ALL, we performed whole-genome sequencing and whole-transcriptome sequencing (RNA-Seq) on 295 cases. Our integrated genomic analyses identified 15 molecular subtypes of DS-ALL, with marked enrichment of CRLF2-r, IGH::IGF2BP1, and C/EBP altered (C/EBPalt) subtypes compared with 2257 non-DS-ALL cases. We observed abnormal activation of the CEBPD, CEBPA, and CEBPE genes in 10.5% of DS-ALL cases via a variety of genomic mechanisms, including chromosomal rearrangements and noncoding mutations leading to enhancer hijacking. A total of 42.3% of C/EBP-activated DS-ALL also have concomitant FLT3 point mutations or insertions/deletions, compared with 4.1% in other subtypes. CEBPD overexpression enhanced the differentiation of mouse hematopoietic progenitor cells into pro-B cells in vitro, particularly in a DS genetic background. Notably, recombination-activating gene-mediated somatic genomic abnormalities were common in DS-ALL, accounting for a median of 27.5% of structural alterations, compared with 7.7% in non-DS-ALL. Unsupervised hierarchical clustering analyses of CRLF2-rearranged DS-ALL identified substantial heterogeneity within this group, with the BCR::ABL1-like subset linked to an inferior event-free survival, even after adjusting for known clinical risk factors. These results provide important insights into the biology of DS-ALL and point to opportunities for targeted therapy and treatment individualization.

Racial and ethnic disparities in childhood and young adult acute lymphocytic leukaemia: secondary analyses of eight Children's Oncology Group cohort trials.

BACKGROUND: Previous studies have identified racial and ethnic disparities in childhood acute lymphocytic leukaemia survival. We aimed to establish whether disparities persist in contemporaneous cohorts and, if present, are attributable to differences in leukaemia biology or insurance status. METHODS: Patients with newly diagnosed acute lymphocytic leukaemia in inpatient and outpatient centres in the USA, Canada, Australia, and New Zealand, aged 0-30 years, who had race or ethnicity data available, enrolled on eight completed Children's Oncology Group trials (NCT00103285, NCT00075725, NCT00408005, NCT01190930, NCT02883049, NCT02112916, NCT02828358, and NCT00557193) were included in this secondary analysis. Race and ethnicity were categorised as non-Hispanic White, Hispanic, non-Hispanic Black, non-Hispanic Asian, and non-Hispanic other. Event-free survival and overall survival were compared across race and ethnicity groups. The relative contribution of clinical and biological disease prognosticators and insurance status was examined through multivariable regression models, both among the entire cohort and among those with B-cell lineage versus T-cell lineage disease. FINDINGS: Between Jan 1, 2004, and Dec 31, 2019, 24 979 eligible children, adolescents, and young adults with acute lymphocytic leukaemia were enrolled, of which 21 152 had race or ethnicity data available. 11 849 (56·0%) were male and 9303 (44·0%) were female. Non-Hispanic White patients comprised the largest racial or ethnic group (13 872 [65·6%]), followed by Hispanic patients (4354 [20·6%]), non-Hispanic Black patients (1517 [7·2%]), non-Hispanic Asian (n=1071 [5·1%]), and non-Hispanic other (n=338 [1·6%]). 5-year event-free survival was 87·4% (95% CI 86·7-88·0%) among non-Hispanic White patients compared with 82·8% (81·4-84·1%; hazard ratio [HR] 1·37, 95% CI 1·26-1·49; p<0·0001) among Hispanic patients and 81·8% (79·3-84·0; HR 1·45, 1·28-1·65; p<0·0001) among non-Hispanic Black patients. Non-hispanic Asian patients had a 5-year event-free survival of 88·1% (95% CI 85·5-90·3%) and non-Hispanic other patients had a survival of 82·8% (76·4-87·6%). Inferior event-free survival among Hispanic patients was substantially attenuated by disease prognosticators and insurance status (HR decreased from 1·37 [1·26-1·49; p<0·0001] to 1·11 [1·00-1·22; p=0·045]). The increased risk among non-Hispanic Black patients was minimally attenuated (HR 1·45 [1·28-1·65; p<0·0001] to 1·32 [1·14-1·52; p<0·0001]). 5-year overall survival was 93·6% (91·5-95·1%) in non-Hispanic Asian patients, 93·3% (92·8-93·7%) in non-Hispanic White patients, 89·9% (88·7-90·9%) in Hispanic, 89·7% (87·6-91·4%) in non-Hispanic Black patients, 88·9% (83·2-92·7%) in non-Hispanic other patients. Disparities in overall survival were wider than event-free survival (eg, among non-Hispanic other patients, the HR for event-free survival was 1·43 [1·10-1·85] compared with 1·74 [1·27-2·40] for overall survival). Disparities were restricted to patients with B-cell acute lymphocytic leukaemia, no differences in event-free survival or overall survival were seen in the T-cell acute lymphocytic leukaemia group. INTERPRETATION: Substantial disparities in outcome for B-cell acute lymphocytic leukaemia persist by race and ethnicity, but are not observed in T-cell acute lymphocytic leukaemia. Future studies of relapsed patients, access to and quality of care, and other potential aspects of structural racism are warranted to inform interventions aimed at dismantling racial and ethnic disparities. FUNDING: National Cancer Institute and St Baldrick's Foundation.