Wood, Brent L

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.

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.

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.

Abstract Novel treatment strategies are needed for the treatment of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in older patients. This trial evaluated the feasibility and outcomes with the anti-CD19 bispecific T-cell–engaging antibody, blinatumomab, in combination with dasatinib and steroids. Patients 65 years of age or older with Ph+ or Ph-like ALL (with dasatinib-sensitive fusions/mutations) were eligible and could be newly diagnosed or relapsed/refractory. Induction therapy consisted of dasatinib/prednisone. Patients not achieving response by day 56 proceeded to blinatumomab reinduction therapy. Patients achieving response with induction or reinduction therapy proceeded to blinatumomab/dasatinib postremission therapy for 3 cycles followed by dasatinib/prednisone maintenance. All patients received central nervous system prophylaxis with intrathecal methotrexate for a total of 8 doses. Response was assessed at days 28, 56, and 84 and at additional time points based on response parameters. Measurable residual disease was assessed centrally by 8-color flow cytometry at day 28. A total of 24 eligible patients with newly diagnosed Ph+ ALL were enrolled with a median age of 73 years (range, 65-87 years). This combination was safe and feasible. With a median of 2.7 years of follow-up, 3-year overall survival and disease-free survival were 87% (95% confidence interval [CI], 64-96) and 77% (95% CI, 54-90), respectively. Although longer follow-up is needed, these results are encouraging, and future trials are building on this backbone regimen. This trial was registered at www.clinicaltrials.gov as #NCT02143414.

PURPOSE To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Children's Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL. PATIENTS AND METHODS Children and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients. RESULTS AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, P = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, P = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% v 86.4% ± 4.0%; P = .041); and 4-year OS (78.3% ± 4.9% v 89.5% ± 3.6%; P = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS ( P = .412) and OS ( P = .600). CONCLUSION Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse.

PURPOSE Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome–negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as induction and consolidation therapy followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) maintenance chemotherapy in this patient population. PATIENTS AND METHODS Patients were treated at National Clinical Trial Network sites. Eligibility criteria included age ≥ 65 years and newly diagnosed Ph chromosome–negative B-ALL. Patients received blinatumomab as induction for one-two cycles until attainment of response (complete remission (CR) and CR with incomplete count recovery). Patients then received three cycles of consolidation with blinatumomab followed by 18 months of POMP maintenance chemotherapy. Eight doses of intrathecal methotrexate were administered as central nervous system prophylaxis. RESULTS Twenty-nine eligible patients were enrolled. The median age was 75 years, and the median bone marrow blast count at diagnosis was 87%. Cytogenetic risk was poor in 10 patients (34%), and five of 14 patients (36%) tested had the Ph-like ALL gene signature. Nineteen patients (66%; 95% CI, 46 to 82) achieved CR. Kaplan-Meier 3-year disease-free survival and overall survival estimates were 37% (95% CI, 17 to 57) and 37% (95% CI, 20 to 55), respectively. CONCLUSION Blinatumomab was well tolerated and effective in the treatment of older patients with newly diagnosed Ph chromosome–negative B-ALL, including patients with poor-risk cytogenetics. The 3-year disease-free survival and overall survival results are encouraging and suggest that this approach should be further explored.