Bosutinib As Therapy For Chronic Phase Chronic Myeloid Leukemia Following Resistance Or Intolerance To Imatinib: 48-Month Update

Bosutinib (BOS) is an oral dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) aged ≥18 y with chronic-phase (CP) chronic myeloid leukemia (CML) following imatinib resistance (IM-R) or intolerance (IM-I).

IM-R (n=196) or IM-I (n=90) CP-CML pts received BOS as 2^nd-line TKI therapy starting at 500 mg/d. Median (range) age was 53 (18–91) y; time from CML diagnosis was 3.7 (0.1–15.1) y. Treatment duration was 24.8 (0.2-83.4) mo and follow-up duration 47.3 (0.6–90.6) mo. BOS dose was escalated to 600 mg/d in 13% of pts. For the last enrolled pt, time from first BOS dose was ≥48 mo; 40% of pts are still receiving BOS.

Confirmed complete hematologic responses (CHR) and major cytogenetic responses (MCyR, including complete cytogenetic response [CCyR]) newly attained or maintained from baseline are summarized (Table).

Of 210 pts with known mutation status at baseline, 79 (38%) had ≥1 BCR-ABL kinase domain mutation (n=42 unique), most commonly T315I (n=9), M351T (n=9), F359V (n=8), G250E (n=6), M244V (n=6), and L248V (n=5). Among pts with T315I, CHR and MCyR rates were low (22% each). Of 67 pts evaluated for mutations before and during therapy, 18 had ≥1 new BCR-ABL mutation (T315I, n=8; V299L, n=3; and E255V, E450A, E450G, G250E, K378E, L273M, and M244V, n=1 each); 17 of these 18 pts discontinued due to disease progression (n=12), lack of efficacy (n=4), or death (n=1).

The cumulative incidence of on-treatment progression (transformation to accelerated phase [AP] or blast phase [BP] CML, increasing white blood cell count [doubling over ≥1 mo with second count >20×10⁹/L and confirmed ≥1 wk later], or loss of confirmed CHR or unconfirmed MCyR) or death at 4 y was 22% for IM-R and 10% for IM-I pts; 40% of pts discontinued BOS without an event. Kaplan-Meier (KM)–estimated overall survival (OS) at 2 y was 88% for IM-R and 98% for IM-I pts (4-y OS not reliable; pts were followed for OS for only 2 y after BOS discontinuation). The cumulative incidence of on-treatment transformation to AP/BP CML at 4 y was 4%; 57% of pts discontinued treatment without transformation. No new transformations occurred after 2 y. Overall, 173 (60%) pts discontinued BOS, most common primary reasons were adverse event (AE; n=64 [22%]) and disease progression (n=51 [18%]). Forty (14%) deaths occurred on study, 7 within 30 d of last BOS dose. Most deaths were due to disease progression (n=24 [8%; 22 and 2 in IM-R and IM-I pts, respectively]) or AE unrelated to BOS (n=13 [5%; 11 and 2]). 3 deaths occurring ≥99 d after last BOS dose were due to unknown causes; no deaths were assessed as BOS-related.

The most frequent hematologic treatment-emergent AEs (TEAEs; all grades/grade 3/4) were thrombocytopenia (42%/26%) and anemia (27%/11%); the most frequent non-hematologic TEAEs were diarrhea (86%/10%), nausea (46%/1%), vomiting (37%/4%), rash (36%/9%), abdominal pain (26%/2%), fatigue (26%/1%), pyrexia (26%/1%), increased alanine aminotransferase (ALT; 22%/9%), cough (22%/0), and upper abdominal pain (20%/<1%). Cardiac events occurred in 16% of pts (7% grade 3/4). Grade 3/4 on-treatment hematologic and non-hematologic laboratory abnormalities in ≥10% of pts included thrombocytopenia (25%), neutropenia (17%), lymphopenia (15%), anemia (14%), alanine transaminase elevation (11%), and hypermagnesemia (11%). Toxicities were managed by ≥1 BOS dose reduction in 44% of IM-R and 58% of IM-I pts and by ≥1 dose delay in 66% of IM-R and 83% of IM-I pts. AEs led to BOS discontinuation in 32 (16%) IM-R and 35 (39%) IM-I pts; the most common reason was thrombocytopenia (3% of IM-R and 12% of IM-I pts).

In conclusion, BOS demonstrates durable efficacy and manageable toxicity in CP-CML pts following IM-R or IM-I after ≥48 mo of follow-up, highlighting the therapeutic potential of BOS in these pts.