Faculty Bibliography

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).

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 to 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. 42.3% of C/EBP-activated DS-ALL also have concomitant FLT3 point mutation or indel, relative to 4.1% in other subtypes (P=7.2×10-6). CEBPD overexpression enhanced the differentiation of mouse hematopoietic progenitor cells into pro-B cells in vitro, particularly in a DS genetic background. Notably, RAG-mediated somatic genomic abnormalities were common in DS-ALL, accounting for a median of 27.5% of structural alterations, compared to 7.7% in non-DS-ALL (P=2.1×10-12). 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 (hazard ratio=5.27, P=9.3×10-8), even after adjusting for known clinical risk factors (hazard ratio=4.32; P=0.0020). These results provide important insights into the biology of DS-ALL and point to opportunities for targeted therapy and treatment individualization.

BACKGROUND:The outcome of children with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia significantly improved with the combination of imatinib and intensive chemotherapy. We aimed to investigate the efficacy of dasatinib, a second-generation ABL-class inhibitor, with intensive chemotherapy in children with newly diagnosed Ph-positive acute lymphoblastic leukaemia. METHODS:orally once daily from day 15 of induction. Patients with minimal residual disease of at least 0·05% after induction 1B or who were positive for minimal residual disease after the three consolidation blocks were classified as high risk and allocated to receive haematopoietic stem-cell transplantation (HSCT) in first complete remission. The remaining patients were considered standard risk and received chemotherapy plus dasatinib for 2 years. The primary endpoint was the 3-year event-free survival of dasatinib plus chemotherapy compared with external historical controls. The trial was considered positive if one of the following conditions was met: superiority over chemotherapy alone in the AIEOP-BFM 2000 high-risk group; or non-inferiority (with a margin of -5%) or superiority to imatinib plus chemotherapy in the EsPhALL 2010 cohort. All participants who received at least one dose of dasatinib were included in the safety and efficacy analyses. This trial was registered with ClinicalTrials.gov, NCT01460160, and recruitment is closed. FINDINGS/RESULTS:Between March 13, 2012, and May 27, 2014, 109 patients were enrolled at 69 sites (including 51 COG sites in the USA, Canada, and Australia, and 18 EsPhALL sites in Italy and the UK). Three patients were ineligible and did not receive dasatinib. 106 patients were treated and included in analyses (49 [46%] female and 57 [54%] male; 85 [80%] White, 13 [12%] Black or African American, five [5%] Asian, and three [3%] other races; 24 [23%] Hispanic or Latino ethnicity). All 106 treated patients reached complete remission; 87 (82%) were classified as standard risk and 19 (18%) met HSCT criteria and were classified as high risk, but only 15 (14%) received HSCT in first complete remission. The 3-year event-free survival of dasatinib plus chemotherapy was superior to chemotherapy alone (65·5% [90% Clopper-Pearson CI 57·7 to 73·7] vs 49·2% [38·0 to 60·4]; p=0·032), and was non-inferior to imatinib plus chemotherapy (59·1% [51·8 to 66·2], 90% CI of the treatment difference: -3·3 to 17·2), but not superior to imatinib plus chemotherapy (65·5% vs 59·1%; p=0·27). The most frequent grade 3-5 adverse events were febrile neutropenia (n=93) and bacteraemia (n=21). Nine remission deaths occurred, which were due to infections (n=5), transplantation-related (n=2), due to cardiac arrest (n=1), or had an unknown cause (n=1). No dasatinib-related deaths occurred. INTERPRETATION/CONCLUSIONS:Dasatinib plus EsPhALL chemotherapy is safe and active in paediatric Ph-positive acute lymphoblastic leukaemia. 3-year event-free survival was similar to that of previous Ph-positive acute lymphoblastic leukaemia trials despite the limited use of HSCT in first complete remission. FUNDING/BACKGROUND:Bristol Myers Squibb.

The benefit associated with the incorporation of vincristine-corticosteroid pulses into maintenance therapy for pediatric acute lymphoblastic leukemia (ALL) is unclear, particularly in the context of modern intensive therapy. This systematic review and meta-analysis examined the impact of reducing frequency of vincristine-steroid pulses during maintenance for newly diagnosed pediatric patients with B-cell ALL. Two authors reviewed all eligible studies identified through a comprehensive search, extracted data from the 25 included publications (12 513 patients), and assessed risk of bias. We created historical and contemporary subgroups; the latter included trials providing a version of Protocol III from early Berlin-Frankfurt-Munster trials and eliminating routine prophylactic cranial radiation. Meta-analysis of event-free survival data suggested no benefit between more frequent or less frequent pulses in contemporary trials (HR 0.96, 95%CI 0.85-1.09) which differs significantly from historical trials (HR 0.79, 95%CI 0.68-0.91, p=0.04). We found no significant impact of reduced pulse frequency on overall survival or relapse risk. There was however an increased odds of Grade 3+ non-hepatic toxicity in the high pulse frequency group (OR 1.31, 95%CI 1.12-1.52). This systematic review suggests that the previous benefit conferred by frequent pulses of vincristine-steroids in maintenance therapy for pediatric B-cell ALL in historical trials no longer applies in contemporary trials but is associated with toxicity. These results will help guide development of the next phase of clinical trials in the field of pediatric ALL and question the continued use of pulses in maintenance for patients not on clinical trials, particularly those experiencing toxicity.