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Higher Event-Free Survival with Addition of Crizotinib to a Standard Chemotherapy Backbone for Children with ALK-positive Anaplastic Large-Cell Lymphoma

An unexpected increase in the number of thromboembolic events observed in crizotinib arm of the ANHL12P1 study
18 Jan 2023
Cancer in Special Situations / Population;  Haematologic malignancies;  Personalised medicine

Crizotinib arm of the Children's Oncology Group (COG) study ANHL12P1 examined the addition of crizotinib to a standard chemotherapy backbone for children with newly diagnosed, non-localised ALK-positive, CD30-positive anaplastic large-cell lymphoma (ALCL). Adding crizotinib prevented on-treatment disease relapse and provided event-free survival (EFS) and overall survival (OS) rates at least as good as previous chemotherapy regimens. However, an unexpected increase in the number of thromboembolic events was observed. Findings show that detection of minimal disseminated disease (MDD) at the start of treatment has significant predictive value and should be incorporated into initial staging of disease and selection of treatment. This study that enrolled 69 patients from 51 different COG sites shows that conducting a clinical study to test new agents is possible in a rare disease. The findings are published by Dr. Eric J. Lowe of the Department of Pediatric Hematology-Oncology, Children's Hospital of the Kings Daughters in Norfolk, VA, US and colleagues on 19 December 2022 in the Journal of Clinical Oncology.

ALCL is a rare form of mature T cell non-Hodgkin lymphoma characterised by uniform overexpression of CD30 that accounts for 15% of all childhood lymphomas. Previous clinical studies have explored different treatment protocols for ALCL and 30% failure rate for initial treatment has persisted despite variations in medications, intensity, and length of treatment. Disease recurrence during initial treatment is difficult to treat even with an allogeneic stem-cell transplant. Interventions that prevent relapse or disease progression could therefore improve survival. The oncogenic tyrosine kinase encoded by the ALK fusion protein is critical for the pathogenesis of paediatric ALCL and majority of paediatric cases (>95%) express ALK.

The primary aim of crizotinib arm of ANHL12P1 was to determine the tolerability of critozinib administered in combination with standard chemotherapy and to estimate the EFS and OS. Between 2013 and 2019, 66 enrolled children received crizotinib with chemotherapy. Patients received a 5-day prophase followed by 6 chemotherapy cycles at 21-day intervals with crizotinib administered twice daily during each 21-day cycle. The study was temporarily closed for two periods, in total 12 months, to evaluate toxicity, during which crizotinib was discontinued. Measurements of NPM-ALK fusion transcripts in peripheral blood were performed at diagnosis for MDD.

The 2-year EFS was 76.8% (95% confidence interval [CI] 68.5 to 88.1) and the 2-year OS 95.2% (95% CI 85.7 to 98.4). In total, 15 patients relapsed, and 1 patient died. Median time to relapse was 7.4 months from diagnosis. Enrolled patients completed 384 cycles of chemotherapy.

Thirteen of the 66 patients (19.7%) experienced a grade 2+ thromboembolic adverse event. In the 25 patients who received mandated prophylactic anticoagulation, there were 2 thromboembolic events (8.0%).

Patients with negative MDD had a superior outcome, with an EFS of 85.6% (95% CI 68.6 to 93.8); positive MDD was associated with a lower EFS of 58.1% (95% CI 33.4 to 76.4).

The authors commented that brentuximab-based chemotherapy is a new standard of care in adults with ALCL based on the ECHELON-2 study. Brentuximab also improved EFS in children with ALCL. Given the increased rate of thromboembolic events associated with crizotinib, it is unlikely to be preferred over brentuximab given on the chemotherapy backbone used in this study. Crizotinib activity in ALCL warrants consideration for use in front-line ALCL potentially in combination with brentuximab alone, rather than as part of a multiagent chemotherapy regimen. They emphasized that continued collaboration to develop new treatment approaches for childhood ALCL will be critical in providing next-generation strategies using crizotinib and other targeted agents.

The study was supported by the US National Clinical Trials Network grants and the St Baldrick's Foundation.

Reference

Lowe EJ, Reilly AF, Lim MS, et al. Crizotinib in Combination With Chemotherapy for Pediatric Patients With ALK+ Anaplastic Large-Cell Lymphoma: The Results of Children's Oncology Group Trial ANHL12P1. JCO; Published online 19 December 2022. DOI: 10.1200/JCO.22.00272

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