Background: Quality of life (QOL) is impacted in children treated for leukemia. AALL0932 randomized reduction in vincristine/dexamethasone (VCR/DEX) pulses every 4 vs. 12 weeks during maintenance in the average-risk subset of NCI standard risk B-ALL (NCI-SR AR B-ALL). We longitudinally assessed physical and emotional QOL, behavioral health, and school services by randomization. Procedure: NCI-SR AR B-ALL English-speaking patients aged ≥4 years were evaluated at T1-T5 (~2, 9, 18, 26 [girls treatment end], and 38 [boys only] months from diagnosis) with parent-report. The Pediatric Quality of Life Inventory-4.0 and school services survey were administered longitudinally and the Behavior Assessment Scale for Children-2 at therapy end. Results: Data were obtained from 420 consented and randomized participants (mean 6.0±1.6 years, 45.7% female). Impairment among randomized participants at T2 and T4, respectively, was 11.3% and 12.5% for physical, and 12.2% and 9.8% for emotional function. In longitudinal models adjusting for race/ethnicity, time, and baseline impairment, pulse frequency was not associated with impairment (physical OR=0.9, 95%CI=0.5-1.8; emotional OR=0.9, 95%CI=0.5-1.7). T2 impairment was associated with increased risk of post-randomization impairment for physical (OR=4.3, 95% CI 1.9-9.9) and emotional (OR=4.9, CI 2.3-10.5) function. 73.8% reported ≥1 school-based service during treatment: special education/accommodations (67.6%) and physical/occupational therapy (8.8%). Depression (20%) and anxiety (19%) did not differ by pulse frequency. Discussion: Children with NCI-SR AR B-ALL experience diminished QOL, despite reduced frequency of VCR/DEX maintenance pulses. Impairment begins early during ALL therapy and persists; interventions should commence early and continue throughout and after therapy.

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 The Children’s Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four-drug reinduction chemotherapy in children and young adults with relapsed/refractory B- and T-cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m 2/dose) was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently combined with reinduction 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 (PK) cohort. Results Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose-limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m 2/dose orally for 21 days. No additional DLTs were observed in the dose determination or PK expansion cohorts and overall rates of grade 3/4 non-hematologic 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 Palbociclib in combination with reinduction chemotherapy was well tolerated with a RP2D of 50 mg/m 2/day for 21 days. Complete responses were observed among heavily pretreated patients.

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 (WBC), 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 (MRD) provide opportunities to achieve these goals.