ORLANDO, Fla.—Bosutinib has therapeutic potential in the treatment of patients with Philadelphia chromosome-positive (Ph+) chronic-phase (CP) chronic myeloid leukemia (CML) with resistance to—or, particularly, intolerance to—other second-generation tyrosine kinase inhibitor (TKI) therapies, results of an open-label, phase 1/2 study has found.

The trial evaluated the safety and efficacy of bosutinib as third-line therapy in patients with Ph+ CP-CML who had previously failed imatinib (IM) and second-line therapy with dasatinib (DAS) or nilotinib (NIL), said H. Jean Khoury, of Emory University School of Medicine, Atlanta, Ga. More than one-third of patients achieved a major cytogenetic response (MCyR) with bosutinib, which had an acceptable safety profile, primarily low-grade and transient gastrointestinal treatment-emergent adverse events (TEAEs).

Bosutinib (SKI-606), an orally available, dual Src/Abl TKI with minimal inhibitory activity against PDGFR or c-kit, was administered to adults aged ≥18 years who had failed prior treatment with IM and were resistant to (n=35) or intolerant to DAS (n=51) or resistant to NIL (n=28). The starting dose of bosutinib was 500 mg/day, Dr. Khoury told those attending the 52nd American Society of Hematology Annual Meeting and Exposition.

Median age of the patients was 54 years (range, 20-79 years), and 36% were male. Median time from CML diagnosis to start of bosutinib was 7.3 years (range, 1.2-17.6 years).The median daily dose of bosutinib was 446 mg (range, 140-563 mg).

At week 24, 26% of patients achieved a MCyR, including 13% with a complete cytogenetic response (CCyR; see Table). Please click here for more study data. Cumulative response rates were 34% for MCyR and 22% for CCyR. The majority of patients (81%) who achieved a MCyR retained their response as of the data snapshot date (median follow-up duration of 23 months). Comparable rates of response were observed across BCR-ABL kinase domain mutations, with the exception of the T315I mutation.

The most frequently reported TEAEs (≥10% of patients, all grades) were diarrhea (83%), nausea (46%), vomiting (40%), rash (26%), headache (25%), and fatigue (21%). Incidence of TEAEs was generally similar for each of the three treatment groups (DAS-resistant, DAS-intolerant, and NIL-resistant). Gastrointestinal events were predominantly grade 1/2, had an early onset, and usually subsided within the first 4 weeks of treatment. The only grade 3/4 TEAE reported in ≥5% of patients was diarrhea (8%). Two grade 3 pleural effusions were observed, one in a patient with concomitant pneumonia and a history of recurrent pleural effusions on DAS. Grade 3/4 hematologic laboratory abnormalities included thrombocytopenia (26%), neutropenia (20%), and anemia (9%); all were usually transient.

Other grade 3/4 laboratory abnormalities (≥5% of patients) included elevations of magnesium (5%), alanine transaminase (ALT; 7%), and lipase (5%). Grade 3/4 transaminase elevations were observed more frequently in patients who were NIL-resistant (ALT, 18% [grade 4, n=1]; aspartate transaminase [AST], 11% [grade 4, n=1]) compared with those who were resistant or intolerant to DAS (ALT, 3%-4%; AST, 0%-3%). On-treatment QTcF interval prolongation was observed in 13 patients (11%), but was only grade 1/2 (≥500 msec) with a reported rate of arrhythmia of <1%. Adverse events led to treatment discontinuation in 31% of patients who were DAS-intolerant; 14% of those who were DAS-resistant; and 11% of those resistant to NIL. Thrombocytopenia (4%), neutropenia (3%), and increased ALT (3%) were the only events resulting in discontinuation of >2 patients.

“Bosutinib may offer a new treatment option for patients with Ph+ chronic-phase chronic myeloid leukemia who are resistant or intolerant to second-generation tyrosine kinase inhibitors,” concluded Dr. Khoury.