Bosutinib As Therapy For Chronic Phase Chronic Myeloid Leukemia Following Failure With Imatinib Plus Dasatinib and/Or Nilotinib: 36-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) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure.

Pts (n=118) aged ≥18 y with prior imatinib (IM) failure plus dasatinib (D) resistance (D-R; n=38) or intolerance (D-I; n=50), nilotinib (N) resistance (N-R; n=26), or N-I or D-R/I + N-R/I (n=4) received BOS starting at 500 mg/d. Median (range) age was 56 (20–79) y; time from CML diagnosis was 6.6 (0.6–18.3) y; follow-up duration was 33.1 (0.3–84.8) mo; BOS treatment duration was 8.5 (0.2–78.1) mo. Escalation to BOS 600 mg/d occurred in 21 (18%) pts. For the last enrolled pt, time from first dose was ≥36 mo; 19% are still receiving BOS.

Confirmed complete hematologic response (CHR) was newly attained or maintained from baseline by 73% of pts (Table ). Major cytogenetic response (MCyR) was attained/maintained by 40% of pts (32% with complete cytogenetic response [CCyR]). Kaplan-Meier probability of maintaining CHR or MCyR at 3 y was 65%.

Of 85 pts with known baseline mutation status, 19 unique BCR-ABL mutations occurred in 39 (46%) pts, including 7 (8%) with T315I. Responses were seen across mutations, but were low in pts with T315I (29% CHR; 14% MCyR). In pts with ≥1 mutation, excluding T315I, 75% had CHR and 40% had MCyR.

38 pts had known baseline and end of treatment mutation status; 8/38 had ≥1 new mutation (V299L, n=4; T315I, n=2; F359C, G250E, L248V, n=1 each); 7/8 discontinued BOS due to disease progression or lack of efficacy.

Cumulative incidence of on-treatment transformation to accelerated-phase (AP) CML at 3 y was 4%; 77% discontinued without transformation. No pt transformed to blast-phase (BP); no transformations occurred after 2 y. Cumulative incidence of on-treatment progression (transformation to AP/BP CML, increasing white blood cell count [doubling over ≥1 mo with 2nd count >20×10⁹/L and confirmed ≥1 wk later], or loss of confirmed CHR or unconfirmed MCyR) or death at 3 y was 25%; 55% of pts discontinued without an event. Overall survival (OS) at 2 y was 84% (Table ; 3-y OS estimates unreliable; pts followed for OS for only 2 y after BOS discontinuation]).

Overall, 96 (81%) pts discontinued treatment, the most common primary reasons were adverse event (AE; n=29 [25%]), disease progression (n=25 [21%]), or unsatisfactory efficacy (n=23 [19%]). 26 (22%) deaths occurred on study, 5 within 30 d of last BOS dose. Most deaths were due to disease progression (n=11 [9%]) or AE (n=11 [9%], including 1 death reported as treatment-related due to lower gastrointestinal bleeding). 4 deaths had unknown cause 33–615 d after the last BOS dose.

Non-hematologic treatment-emergent AEs in ≥20% of pts (all grades; grade 3/4) were diarrhea (83%; 9%), nausea (48%; 1%), vomiting (38%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (23%; 2%), and abdominal pain (24%; 1%); common hematologic toxicities included thrombocytopenia (38%; 26%), neutropenia (20%; 15%), and anemia (19%; 7%). Cardiac events occurred in 15% of pts (8% grade 3/4). Grade 3/4 laboratory abnormalities in ≥10% of pts were thrombocytopenia (26%), neutropenia (20%), lymphopenia (16%), and hypermagnesemia (12%). 78 (66%) pts had ≥1 dose delay; 59 (50%) had ≥1 dose reduction. 31 (26%) pts discontinued BOS due to AE, most commonly thrombocytopenia (7%).

BOS continues to demonstrate durable efficacy and manageable toxicity after ≥36 mo follow-up in CP-CML pts following resistance or intolerance to multiple TKIs.