Bosutinib Safety Profile and Management of Toxicities in Leukemia Patients with Resistance or Intolerance to Imatinib and Other Tyrosine Kinase Inhibitors
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 
Published: October 2019

Abstract
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 discontinuation in <2% of pts.
TEAEs of pleural or pericardial effusions (any grade) were relatively uncommon, occurring in 46 (8%) pts, with a median time to first onset of 11 mo and a median duration of 20 d per event. Of the pts with effusions, 15% required dose reductions, 37% had a dose interruption, and 7% discontinued bosutinib.
Grade ≥3 hematologic laboratory abnormalities (CP2L/CP3L/ADV) included thrombocytopenia (24%/25%/60%), neutropenia (17%/20%/39%), and anemia (14%/9%/34%), with median durations until decrease to grade ≤1 severity ranging from 29 to 38 d across parameters. Among pts with myelosuppression TEAEs, the median time to first onset of grade 3/4 was 29 d. Myelosuppression TEAEs (any grade) led to dose reduction in 32% of pts, dose interruption in 48% of pts, and bosutinib discontinuation in 11% of pts; events resolved in 54% of pts.
Grade ≥3 elevation of alanine aminotransferase (ALT) was reported for 10% of CP2L, 7% of CP3L, and 5% of ADV pts; grade ≥3 elevation of aspartate aminotransferase (AST) was reported for 5%, 3%, and 2% of pts, respectively. Median times to first observation of elevated ALT and AST laboratory parameters were 19 d and 28 d, respectively; median durations for a grade 3/4 event to lower to grade ≤1 severity were 28 d and 22 d. Of the pts with TEAEs of ALT and AST elevation, respectively, 14% and 13% received concomitant medication and 81% and 87% had their event resolve. TEAEs of ALT and AST elevation led to dose reduction in 22% and 10% of pts, respectively, dose interruption in 39% and 33% of pts, and permanent discontinuation in 10% and 5% of affected pts.
Bosutinib was associated with an acceptable safety profile in pts with Ph+ leukemia following resistance/intolerance to imatinib and other TKIs. Although gastrointestinal, hematologic, and liver function events were commonly observed early in the course of bosutinib therapy, they were generally well managed and controlled with dose adjustments and/or optimal medical management.

Disclosures:
Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer Inc: Research Funding; Ariad: Research Funding. Cortes:Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Kim:Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Brümmendorf:Pfizer Inc: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; BMS: Consultancy, Honoraria. Porkka:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Martinelli:Pfizer Inc: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Leip:Pfizer Inc: Employment. Besson:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment. Gambacorti-Passerini:Biodiversity: Honoraria; Novartis: Honoraria; BMS: Research Funding; Pfizer Inc: Honoraria, Research Funding.