ORLANDO, Fla.—A high combined percentage of newly diagnosed patients with Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) treated with bosutinib or imatinib achieve major molecular response (MMR), complete cytogenetic response (CCyR), and complete hematologic response (CHR), with a relatively low incidence of generally manageable grade 3 events, results of a randomized, open label, phase 3 study have found.

Bosutinib, an orally bioavailable dual Src/Abl tyrosine kinase inhibitor (TKI), with minimal inhibitory activity against PDGFR or c-kit, previously has demonstrated activity in patients with Ph+ CP-CML in second- and third-line treatment settings as well as in patients with advanced Ph+ leukemias following resistance or intolerance to imatinib and other TKIs, reported Carlo Gambacorti-Passerini, of University of Milano Bicocca, Monza, Italy.

The study enrolled adults aged ≥18 years with cytogenetic diagnosis of Ph+ CP CML within 6 months, adequate hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomized to receive oral bosutinib 500 mg/day or oral imatinib 400 mg/day. Primary efficacy end point was the rate of CCyR at 1 year; rates of hematologic response, molecular response, and progression and transformation to accelerated or blast phase were also evaluated, Dr. Gambacorti-Passerini said in an oral presentation during the 52nd American Society of Hematology Annual Meeting and Exposition.

The study randomized 502 patients. Median age was 48 years (range, 18-91 years); 56.6% were male, and median time since diagnosis was 0.7 months (range, -0.3-7.9 months; range minimum is negative due to a diagnosis of CML during the study screening period, and range maximum is >6 months because of 1 patient considered to be a major protocol violator). Median duration of treatment was 13.9 months (range, 0.03-24.8 months).

At week 48 (approximately 11 months), for both treatment arms combined, 71.5% of patients were in CCyR and 74.8% in CHR. During the study, 81.4% of patients achieved a CCyR at or before week 48, with a median time to CCyR of 24 weeks. A CHR was achieved by 82.6% of patients, with a median time to CHR of 8 weeks; and 40.6% of patients achieved a MMR, with a median time to MMR of 49-61 weeks for the 2 treatment arms.

For the combined treatment arms, common treatment-emergent adverse events (AEs) included diarrhea (43.7%), nausea (32.3%), vomiting (22.0%), rash (16.8%), pyrexia (11.6%), and fatigue (11.0%). The only grade ≥3 treatment-emergent AE observed in ≥2% of patients was diarrhea (5.2%), which was usually limited to the first weeks of treatment. Grade ≥3 hematologic laboratory abnormalities included neutropenia (14.2%), thrombocytopenia (12.4%), and anemia (5.8%). Other grade ≥3 laboratory abnormalities (≥5% of patients) included alanine aminotransferase elevation (11.6%), phosphatemia (7.6%), and aspartate aminotransferase elevation (6.4%). Overall, 22.2% patients discontinued therapy; AEs led to discontinuation or death in 12.8% of patients, and 4.2% of patients discontinued due to disease progression.

In the individual treatment arms, the rate of response at 12 months in the intent to treat population (ITT) in the bosutinib arm for CCyR was 70% versus 68% in the imatinib arm. For MMR, the bosutinib arm showed a 39% response with imatinib showing a 26% response. In this study bosutinib reduced the response time in half, versus the imatinib arm.

The most frequent side effect was diarrhea, however, this did not result in any patient discontinuations. The effect was most common in the first 30 days and most evident in grade 1/2 patients. Overall 19% of patients in the bosutinib group discontinued due to AEs, versus 6% in the imatinib group.

Treatment of bosutinib showed a superior rate of MMR at 12 months (ITT); the CCyR did not demonstrate superior rates, but did demonstrate higher rates based on the evaluable patient population. Bosutinib’s AEs were distinct, but acceptable, with an increased rate of diarrhea. All AEs were reversible and no treatment related deaths were seen. These results indicate that bosutinib may offer a new treatment option in patients with CML.