Bosutinib Safety Profile and Management of Toxicities in Leukemia Patients with Resistance or Intolerance to Imatinib and Other Tyrosine Kinase Inhibitors

• Published in: Blood 2011-11, Vol.118 (21), p.2760-2760
• Main Authors: Kantarjian, Hagop M, Cortes, Jorge E, Kim, Dong-Wook, Khoury, H. Jean, Brümmendorf, Tim H, Porkka, Kimmo, Martinelli, Giovanni, Durrant, Simon, Leip, Eric, Besson, Nadine, Kelly, Virginia, Gambacorti-Passerini, Carlo
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V118.21.2760.2760

Abstract 2760 Bosutinib is an orally active, Src/Abl tyrosine kinase inhibitor (TKI) with minimal inhibitory activity against PDGFR or c-KIT. This open-label, phase 1/2 study evaluated the clinical activity of bosutinib in 570 imatinib-treated patients (pts) with Philadelphia chromosome–positive (Ph+) leukemia. For this safety analysis, pts were grouped by disease phase and prior therapy into 3 populations: chronic phase chronic myeloid leukemia (CP CML) following prior imatinib only (CP2L; n = 288); CP CML following prior imatinib plus dasatinib and/or nilotinib (CP3L; n = 118); and advanced leukemia (ADV: accelerated/blast phase CML and acute lymphoblastic leukemia; n = 164) following prior imatinib only or with other TKIs. The current analysis summarizes the safety/tolerability of bosutinib 500 mg/d and management of key toxicities. In CP2L, CP3L, and ADV pts, respectively, 53%, 45%, and 58% were male; median times since diagnosis were 3.6 y (range, 0.1–15.1 y), 6.5 y (range, 0.6–18.3 y), and 3.7 y (range, 0.1–22.1 y). The most common reasons for discontinuation were (CP2L/CP3L/ADV) disease progression (14%/17%/45%), adverse events (AEs; 22%/20%/16%), and unsatisfactory response (7%/21%/10%). A total of 41 deaths occurred within 30 days of the last bosutinib dose due to disease progression (n = 20), AE unrelated to bosutinib (n = 17), bosutinib-related AE (n = 3; gastrointestinal bleeding, acidosis/respiratory failure, myocardial infarction), and other reasons (n = 1). The most common non-hematologic treatment-emergent AEs (TEAEs; any grade; CP2L/CP3L/ADV) were diarrhea (84%/83%/74%), nausea (45%/48%/48%), and vomiting (37%/39%/43%). The median time to first onset of diarrhea across all groups was 2 d (range, 1–594 d), and the median duration of an event of diarrhea was 2 d (range, 1–910 d). Diarrhea was the most common grade ≥3 TEAE (10%/8%/5%); median duration for a grade 3/4 event to subside to grade ≤1 severity was 5 d (range, 1–343 d). Overall, diarrhea was managed with antidiarrheal medication in 66% of pts with events (primarily loperamide [86%]); 14% of pts required a temporary dose interruption and 6% of pts had a reduction of their bosutinib dose due to diarrhea. Of the 59 pts who were rechallenged following a temporary bosutinib interruption, 57 (97%) pts were successfully rechallenged without any recurrence of diarrhea and/or permanent discontinuation of bosutinib due to diarrhea. Diarrhea events resolved in 86% of pts and led to bosutinib d