Faculty Bibliography

Current strategies to treat pediatric acute lymphoblastic leukemia rely on risk stratification algorithms using categorical data. We investigated whether using continuous variables assigned different weights would improve risk stratification. We developed and validated a multivariable Cox model for relapse-free survival (RFS) using information from 21199 patients. We constructed risk groups by identifying cutoffs of the COG Prognostic Index (PI_COG) that maximized discrimination of the predictive model. Patients with higher PI_COG have higher predicted relapse risk. The PI_COG reliably discriminates patients with low vs. high relapse risk. For those with moderate relapse risk using current COG risk classification, the PI_COG identifies subgroups with varying 5-year RFS. Among current COG standard-risk average patients, PI_COG identifies low and intermediate risk groups with 96% and 90% RFS, respectively. Similarly, amongst current COG high-risk patients, PI_COG identifies four groups ranging from 96% to 66% RFS, providing additional discrimination for future treatment stratification. When coupled with traditional algorithms, the novel PI_COG can more accurately risk stratify patients, identifying groups with better outcomes who may benefit from less intensive therapy, and those who have high relapse risk needing innovative approaches for cure.

Osteonecrosis is a significant toxicity of acute lymphoblastic leukemia (ALL) therapy. In retrospective analyses, superior event-free survival was noted among affected adolescents in an earlier trial. We prospectively assessed osteonecrosis incidence, characteristics, and risk factors in patients 1-30 years with newly diagnosed high-risk B-ALL on COG AALL0232. Patients were randomized to induction dexamethasone vs prednisone, and interim maintenance high-dose methotrexate vs escalating-dose Capizzi methotrexate/pegaspargase. Event-free and overall survival were compared between patients with/without imaging-confirmed osteonecrosis. Osteonecrosis developed in 322/2730 eligible, evaluable patients. The 5-year cumulative incidence was 12.2%. Risk was greater in patients ≥10 years (hazard ratio [HR], 7.23; P < 0.0001), particularly females (HR, 1.37; P = 0.0057), but lower in those with asparaginase allergy (HR, 0.60; P = 0.0077). Among rapid early responders ≥10 years, risk was greater with dexamethasone (HR, 1.84; P = 0.0003) and with prednisone/Capizzi (HR, 1.45; P = 0.044), even though neither therapy was independently associated with improved survival. Patients with osteonecrosis had higher 5-year event-free (HR, 0.51; P < 0.0001) and overall survival (HR, 0.42; P < 0.0001), and this was directly attributable to reduced relapse rates (HR, 0.57; P = 0.0014). Osteonecrosis in high-risk B-ALL patients is associated with improved survival, suggesting an important role for host factors in mediating both toxicity and enhanced efficacy of specific therapies.

Mutations in genes encoding epigenetic regulators are commonly observed at relapse in B cell acute lymphoblastic leukemia (B-ALL). Loss-of-function mutations in SETD2, an H3K36 methyltransferase, have been observed in B-ALL and other cancers. Previous studies on mutated SETD2 in solid tumors and acute myelogenous leukemia support a role in promoting resistance to DNA damaging agents. We did not observe chemoresistance, an impaired DNA damage response, nor increased mutation frequency in response to thiopurines using CRISPR-mediated knockout in wild-type B-ALL cell lines. Likewise, restoration of SETD2 in cell lines with hemizygous mutations did not increase sensitivity. SETD2 mutations affected the chromatin landscape and transcriptional output that was unique to each cell line. Collectively our data does not support a role for SETD2 mutations in driving clonal evolution and relapse in B-ALL, which is consistent with the lack of enrichment of SETD2 mutations at relapse in most studies.

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.

PURPOSE/OBJECTIVE:Historically, patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission at the end of induction (EOI) have had poor long-term survival. The goal of this study was to examine the efficacy of contemporary therapy, including allogeneic hematopoietic stem cell transplantation (HSCT) in first remission (CR1). METHODS:Induction failure (IF) was defined as the persistence of at least 5% bone marrow (BM) lymphoblasts and/or extramedullary disease after 4-6 weeks of induction chemotherapy. Disease features and clinical outcomes were reported in 325 of 6,167 (5%) patients age 21 years and younger treated in 14 cooperative study groups between 2000 and 2018. RESULTS:= .10, respectively. CONCLUSION/CONCLUSIONS:Outcomes for patients age 21 years and younger with T-ALL and IF have improved in the contemporary treatment era with a DFS benefit among those undergoing HSCT in CR1. However, outcomes still lag considerably behind those who achieve remission at EOI, warranting investigation of new treatment approaches.

BACKGROUND:Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6-cyclin D complex that regulates cell cycle progression. PROCEDURE:/dose) was administered orally once daily for 21 consecutive days, first as a single agent (Days 1-3) and subsequently combined with re-induction chemotherapy. This two-part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), followed by an expansion pharmacokinetic cohort. RESULTS:/dose orally for 21 days. No additional DLTs were observed in the dose determination or pharmacokinetic expansion cohorts, and overall rates of grade 3/4 nonhematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T-ALL and three among seven patients with B-ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. CONCLUSIONS:/day for 21 days. Complete responses were observed among heavily pretreated patients.

Chemotherapy-induced peripheral neuropathy (CIPN), a common condition in children with acute lymphoblastic leukemia, can be challenging to diagnose. Using data from Children's Oncology Group AALL0932 physical function study, we sought to determine if parent/guardian proxy-reported responses from the Pediatric Outcomes Data Collection Instrument could identify children with motor or sensory CIPN diagnosed by physical/occupational therapists (PT/OT). Four variables moderately discriminated between children with and without motor CIPN (c-index 0.76, 95% confidence interval [CI]: 0.64-0.84), but sensory and optimism-corrected models had weak discrimination (c-index sensory models 0.65, 95% CI: 0.54-0.74). New proxy-report measures are needed to identify children with PT/OT diagnosed CIPN.

Cure rates for acute lymphoblastic leukemia (ALL), the most common childhood cancer have steadily improved over the past five decades. This is due to intensifying systemic therapy, recognizing and treating the central nervous system as a sanctuary site, and implementing modern risk stratification to deliver varying intensities of therapy based on age, presenting white blood count, sentinel somatic genetics, and therapy response. Recently, numerous Children's Oncology Group trials have demonstrated the lack of benefit of intensifying traditional chemotherapy, providing evidence that new approaches are needed to cure the patients for whom cure has been elusive. Distinguishing those who require intensive or novel therapeutic approaches from others who will be cured with minimal therapy is key for future trials. Incorporating new genomic biomarkers and more sensitive measures of minimal/measurable residual disease provide opportunities to achieve these goals.

Hematologic malignancy is a risk factor for severe coronavirus disease 2019 (COVID-19) in adults; however, data specific to children with leukemia are limited. High-quality infectious adverse event data from the ongoing Children's Oncology Group (COG) standard-risk B acute lymphoblastic leukemia/lymphoma (ALL/LLy) trial, AALL1731, were analyzed to provide a disease-specific estimate of SARS-CoV-2 infection outcomes in pediatric ALL. Of 253 patients with reported infections, the majority (77.1%) were asymptomatic or mildly symptomatic (CTCAE grade 1/2) and there was a single COVID-19-related death. These data suggest SARS-CoV-2 infection does not confer substantial morbidity among young patients with B-lymphoblastic leukemia/lymphoma (B-ALL/LLy).