Larotrectinib in TRK fusion–positive pediatric B-cell acute lymphoblastic leukemia

Rearrangements involving neurotrophic receptor tyrosine kinase (NTRK) genes can generate fusion oncoproteins driving tumor development and survival.1 NTRK gene fusions have been identified across a range of adult and pediatric solid malignancies.2 B-cell acute lymphoblastic leukemia (ALL) can harbor an ETV6-NTRK3 gene fusion in ∼1% of the so-called “Philadelphia-like” cases.3 ETV6-NTRK3 fusion–positive B-cell ALL is characterized by rapid proliferation and infiltration of the central nervous system (CNS) in preclinical models.4 Previously published phase 1 data for larotrectinib ({"type":"clinical-trial","attrs":{"text":"NCT02637687","term_id":"NCT02637687"}}NCT02637687), a highly selective tropomyosin receptor kinase (TRK) inhibitor, has shown a 93% response rate and good tolerability in a cohort of pediatric patients with TRK-positive relapsed/refractory solid tumors, excluding leukemia patients.5 Adverse events included increased alanine and aspartate aminotransferase elevations, leucopenia, decreased neutrophil count, and vomiting, with no grade 4 or grade 5 events. Pharmacokinetics revealed that a dose of 100 mg/m2 (with a maximum dose of 100 mg) twice a day resulted in a similar exposure as in adults treated with the recommended phase 2 dose of 100 mg twice a day. Exposure in the CNS was also confirmed.5 Here, we report the successful use of larotrectinib in a child with a relapse of ETV6-NTRK3 fusion positive B-cell ALL early after hematopoietic allogeneic stem cell transplantation (HSCT).