Safety and Management of Toxicities in the BELA Trial of Bosutinib Versus Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia

Abstract 1685

Bosutinib (BOS) is an orally active, dual competitive Src/Abl kinase inhibitor. The phase 3 BELA study compared the safety and activity of BOS 500 mg/d with imatinib (IM) 400 mg/d in patients (pts) with newly diagnosed chronic phase chronic myeloid leukemia (CP CML). This analysis summarizes the safety profile of each agent, addressing management of gastrointestinal toxicities and liver function test changes.

The median age was 48 y (range, 19–91 y) in the BOS arm and 47 y (range, 18–89 y) in the IM arm. Median treatment durations were 19.3 mo for BOS and 19.5 mo for IM; 67% and 74% of pts are still receiving therapy. The primary reason for BOS discontinuation was adverse events (AEs; 23% BOS [15/55 without prior dose adjustment] vs 6% IM). The primary reason for IM discontinuation was disease progression (4% BOS vs 13% IM). Deaths occurred in 6 (2%) BOS pts versus 13 (5%) IM pts; the majority occurred after treatment discontinuation. Non–CML-related deaths (1 pt each) included mesenteric embolia/intestinal necrosis (BOS), cardiovascular disease (IM), fatal septicemia (IM), lung embolism (IM), and pneumonia (IM).

BOS was associated with higher incidences versus IM of all grades of gastrointestinal toxicities (diarrhea [69% vs 22%], vomiting [32% vs 14%], and abdominal pain [13% vs 6%]) and pyrexia (18% vs 10%). In contrast, BOS was associated with lower incidences of edema (peripheral edema [4% vs 11%] and periorbital edema [1% vs 14%]) and musculoskeletal events (myalgia [5% vs 11%], muscle cramps [4% vs 22%], and bone pain [4% vs 10%]). Diarrhea (11% vs 1%, respectively) and vomiting (3% vs 0%) were the most common grade 3/4 AEs. Elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were reported as grade 3/4 AEs for 18% and 8% of pts on BOS, respectively, versus 2% and 2% of pts on IM.

Diarrhea typically occurred during the initial month of treatment, with the median time to first event of 3 d (range, 1–589 d) on BOS (n = 172) and 26 d (range, 1–829 d) on IM (n = 56) and median duration of a diarrhea event of 3 d (range, 1–836 d) and 5 d (range, 1–771 d), respectively. Diarrhea was managed with antidiarrheal medication in 68% of BOS pts and 43% of IM pts; 22% and 9% of pts with diarrhea required temporary dose interruption, while 8% and 0% had a reduction of their dose. Of the pts who had a temporary dose interruption due to diarrhea, 34/38 pts on BOS and 5/5 pts on IM were rechallenged without recurrence of diarrhea or permanent discontinuation due to diarrhea.

Grade 3/4 liver function test laboratory abnormalities were more common among pts receiving BOS versus IM, including elevation of ALT (23% vs 4%) and AST (12% vs 3%); the majority experienced grade 3 events. The median times to first ALT elevation were 28 d for BOS (n = 78) and 114 d for IM (n = 18); median times to first AST elevation were 28 d for BOS (n = 65) and 107 d for IM (n = 19). For BOS and IM, respectively, median durations for a grade 3/4 event to grade ≤1 severity were 21.0 versus 25.0 d for ALT elevation and 21.5 versus 25.0 d for AST elevation. Of the pts with ALT elevations, 35% versus 56% had a dose reduction and 56% versus 28% had a temporary dose interruption. Of the 40 pts who were rechallenged with BOS after dose interruption due to ALT elevation, 32 (80%) were successfully rechallenged without reoccurrence of their event or did not discontinue due to ALT elevation; all 4 pts who were rechallenged after IM interruption were successfully rechallenged. Of the pts with AST elevations, 17% versus 5% had a dose reduction and 43% versus 16% had a temporary dose interruption. All of the 26 pts who were rechallenged with BOS after dose interruption due to AST elevation were successfully rechallenged without reoccurrence of their event or discontinuation due to AST elevation; all 3 pts who were rechallenged after IM interruption were successfully rechallenged. No cases met the Hy's Law criteria. Ten pts discontinued BOS due to ALT elevation; no other discontinuations due to liver function test abnormalities were reported.

In conclusion, BOS and IM were associated with acceptable but distinct safety profiles in pts with newly diagnosed CP CML. BOS was mainly associated with gastrointestinal AEs and transient liver function test elevations, both of which were managed with dose modifications and were not life threatening. Additional experience in managing the toxicities associated with BOS treatment may reduce the overall number of pts discontinuing BOS due to toxicity.