Efficacy and Safety Following Bosutinib Dose Reduction in Patients with Philadelphia Chromosome‒Positive Chronic Myeloid Leukemia

Objectives: Bosutinib (BOS), an oral dual Src/Abl tyrosine kinase inhibitor for adult patients with Philadelphia chromosome−positive chronic myeloid leukemia (Ph+ CML), has a recommended starting dose of 500 mg/d. This analysis evaluates efficacy and safety following BOS dose reduction due to intolerance in patients with Ph+ CML.

Methods: Data from 2 studies were analyzed: a phase 1/2 study (NCT00261846) that included patients with chronic phase (CP) CML following resistance/intolerance to imatinib (IM; CP2L) or to IM plus dasatinib and/or nilotinib (CP3L), and those with accelerated/blast phase CML or acute lymphoblastic leukemia after at least IM (advanced [ADV]); and a phase 3 study (NCT00574873) in CP CML patients treated with BOS or IM as first-line therapy (CP1L).

Results: Of 570 CP2L/CP3L/ADV patients receiving BOS (median treatment duration 11 months [range: 0.03−96]), 257 (45%) experienced ≥1 dose reduction (236 patients to 400 mg/d and 95 to 300 mg/d). Median time to dose reduction to 400 and 300 mg/d was 54.5 (range: 4-1875) and 146 days (8-2166), respectively; median duration of dose reduction was 3.6 (0.03-87.7) and 4.2 months (0.03-60.5), respectively. In CP1L, 248 patients received BOS (median treatment duration: 55.4 months [0.03−76]), of whom 111 (45%) experienced ≥1 dose reduction (103 to 400 mg/d and 56 to 300 mg/d). Median time to dose reduction to 400 and 300 mg/d was 64.0 (2-1714) and 139 days (20-1778), respectively; median duration of dose reduction was 2.6 (0.03-66.1) and 8.9 months (0.03-71.2), respectively. Patients achieved anew or maintained a previously achieved complete cytogenetic response following BOS dose reduction to 400 mg/d (achieved: 29% [CP2L/CP3L/ADV], 40% [CP1L]; maintained: 13% [CP2L/CP3L/ADV], 26% [CP1L]) and to 300 mg/d (achieved: 14% [CP2L/CP3L/ADV], 18% [CP1L]; maintained: 24% [CP2L/CP3L/ADV], 45% [CP1L]; Table 1). Treatment-emergent adverse events (TEAEs) were generally similar in incidence, type, and severity before vs after BOS dose reduction. However, incidences of certain gastrointestinal TEAEs were lower and of similar severity following BOS dose reduction to 400 mg/d (diarrhea: 84% vs 50% [CP2L/CP3L/ADV], 70% vs 41% [CP1L]; nausea: 45% vs 23% [CP2L/CP3L/ADV], 34% vs 21% [CP1L]; vomiting: 33% vs 21% [CP2L/CP3L/ADV], 28% vs 22% [CP1L]) or to 300 mg/d (diarrhea: 85% vs 31% [CP2L/CP3L/ADV], 75% vs 38% [CP1L]; nausea: 43% vs 14% [CP2L/CP3L/ADV], 43% vs 21% [CP1L]; vomiting: 34% vs 11% [CP2L/CP3L/ADV], 34% vs 18% [CP1L]).

Conclusions: CP2L/CP3L/ADV and CP1L CML patients who required BOS dose reduction due to AEs were still able to achieve or maintain cytogenetic responses and appeared to experience fewer gastrointestinal AEs.

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