Room To Grow: Bosutinib Approved for Newly Diagnosed or Relapsed/Intolerant Pediatric Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) accounts for 3% of pediatric leukemia cases in the U.S. and is driven by the fusion oncogene BCR-ABL1, created by the Philadelphia chromosome (Ph) t(9;22)(q34;q11.2) translocation.¹  Pediatric CML is primarily treated with tyrosine kinase inhibitors (TKIs) that target BCR: ABL protein. The first-generation TKI imatinib and the second-generation TKIs dasatinib and nilotinib are approved in pediatric Ph-positive CML and have significantly improved prognosis (Table).^2-5 

Prolonged TKI therapy increases patients’ risk for long-term adverse effects (AEs), including endocrinopathies and linear growth impairment from off-target kinase inhibition — particularly when TKIs are started before puberty.⁶  A preclinical animal model found limited impact on bone growth, despite continuous exposure to the dual SRC/ABL inhibitor bosutinib.⁷  The U.S. Food and Drug Administration (FDA) initially approved bosutinib for adult patients with resistant/intolerant CML,^8-10  then for newly diagnosed CML after the phase III BFORE study showed improved responses compared to imatinib.^11,12  The phase IV BYOND study also demonstrated ongoing tolerability to and response with bosutinib.¹³  The durable responses and toxicity profile, along with a potential for less growth impairment, provided rationale for the phase I/II multicenter, single-arm, open-label ITCC-054/COG AAML1921 study (NCT04258943) of bosutinib in pediatric patients with CML.¹⁴  Based on these study findings, described in more detail below, the FDA approved bosutinib for pediatric patients with newly diagnosed and resistant/intolerant CML in September 2023.¹⁵ 

In the phase I portion of the study, 28 patients (age range: 1-18 years) were treated at U.S. and European sites between November 2016 and August 2022. Eligible patients had Ph-positive CML that was resistant or intolerant to at least one previous TKI. Patients with known T315I and V299L resistance mutations were excluded. Upon bosutinib approval for adults with newly diagnosed CML in December 2017, the protocol was amended to allow newly diagnosed pediatric patients in the study’s phase II portion. The study’s primary objective was to define the recommended phase II dose (RP2D) based on tolerability and pharmacokinetic (PK) information. Tolerability was defined as a dose that resulted in dose-limiting toxicity (DLT) in none in six patients or one in 10 patients, using the 6+4 design, and PK targets were derived from population PK data for adults treated with bosutinib.

The RP2D for pediatric patients with resistant/intolerant CML was once-daily 400 mg/m² (maximum: 600 mg/m²). For patients with newly diagnosed CML, the RP2D was once-daily 300 mg/m² (maximum: 500 mg/m²). These findings were extrapolated from pediatric resistant/intolerant CML safety and PK data and adult target exposure data.

Twenty-seven patients (median age: 12 years; range: 1-17 years) with chronic-phase CML were evaluable for DLT. Patients were resistant (82%) or intolerant (18%) to prior therapy and had received one (n=16/28; 57%) or two (n=9/28; 32%) prior TKIs. The last TKI received included: imatinib (n=13), dasatinib (n=13), and nilotinib (n=2). Prior to enrollment, 16 patients (57%) had complete cytogenetic response (CCyR). Regarding molecular response (MR), four patients had ≥MR3, 10 had MR2, seven had MR1, and five had no MR.

There were no DLTs at 300 mg/m2 once daily (n=6 patients), one DLT (Grade 3 nausea/vomiting and diarrhea) at 350 mg/m2 once daily (n=11), one DLT (Grade 3 transaminase elevation and rash, grade 2 hyperbilirubinemia) at 400 mg/m2 once daily (n=10). Both patients with DLTs resumed lower dose bosutinib. Most common AEs were gastrointestinal (GI) toxicities: diarrhea (93%), abdominal pain (71%), vomiting (68%) or nausea (61%), and dermatologic toxicities: maculopapular rash (39%) or other skin disorders (43%). Most common grade 3/4 AEs were transaminase elevation (18%), maculopapular rash (11%), vomiting (11%), and diarrhea (11%). Some patients had prolonged low-grade GI toxicity, primarily diarrhea. QTC prolongation and cardiac AEs were not observed. Eleven patients had dose reduction, seven of whom stopped treatment due to intolerance (GI toxicity, neutropenia, rash); eight patients discontinued treatment due to insufficient response at the investigator’s discretion.

By six months of therapy, all patients experienced a complete hematologic response. By 12 months, nearly all attained CCyR (92.9%; 95% CI, 76.5-99.1) and nearly half attained major MR (46.4%; 95% CI, 27.5-66.1). Five patients achieved MR4/MR4.5. These response rates are comparable to other phase I/II trials of second-generation TKIs in pediatric patients with CML (Table).