Bosutinib (BOS) is an oral, dual Src/Abl kinase inhibitor with minimal inhibitory activity against PDGFR or c-KIT. This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following imatinib resistance (IM-R) or intolerance (IM-I).
Pts aged ≥18 y with IM-R (n = 195) or IM-I (n = 91) CP CML received oral BOS 500 mg/d. Of 286 pts, 53% were male, median age was 53 y (range, 18–91 y), and median time from CML diagnosis was 3.7 y (range, 0.1–15.1 y). Median treatment duration was 24.6 mo (range, 0.2–72.3 mo); median BOS dose intensity was 443 mg/d (range, 61–600 mg/d); 12% of pts received dose escalation to BOS 600 mg/d. Minimum time from last enrolled pt's first dose was 38 mo; 42% of pts are still receiving BOS.
A confirmed complete hematologic response (CHR) was attained/maintained by 167/194 (86%) IM-R and 77/91 (85%) IM-I pts with a valid baseline assessment; Kaplan-Meier (KM)–estimated probabilities of maintaining a CHR at 3 y were 65% and 83%. A major cytogenetic response (MCyR) was attained/maintained by 106/182 (58%) IM-R and 49/82 (60%) IM-I pts with a valid baseline assessment. A complete cytogenetic response (CCyR) was attained/maintained by 88/182 (48%) and 42/82 (51%) evaluable pts. Among evaluable pts without a CCyR at baseline, 101/177 (57%) IM-R and 39/71 (55%) IM-I pts achieved a MCyR including 83 (47%) IM-R and 33 (47%) IM-I pts who achieved a CCyR. The KM-estimated probability of maintaining a MCyR at 3 y was 71% for IM-R and 88% for IM-I pts.
Of 210 pts with baseline mutation status assessed, 78 (37%) pts had 42 unique Bcr-Abl kinase domain mutations (P loop, 9% of pts; non-P loop, 30% of pts), including 9 (4%) pts with the T315I mutation. Responses to BOS were seen across different Bcr-Abl baseline mutations, including those associated with resistance to other TKIs, but were low (22% for both CHR and MCyR) among pts with T315I. When pts with T315I at baseline were excluded, response rates for the remaining pts with ≥1 mutation were 93% for CHR and 62% for MCyR.
Eighteen of 68 pts evaluated at baseline and treatment discontinuation had ≥1 new Bcr-Abl mutation (T315I, n = 8; V299L, n = 3; E255V, E450A, E450G, G250E, K378E, L273M, and M244V, n = 1 each); 15 of these 18 pts had discontinued due to disease progression or lack of efficacy.
On-treatment transformation to accelerated or blast phase CML occurred in 10 (5%) IM-R and 2 (2%) IM-I pts. KM-estimated on-treatment progression-free survival (PFS) at 3 y was 72% for IM-R pts and 89% for IM-I pts. KM-estimated overall survival (OS) at 2 y was 88% for IM-R and 98% for IM-I pts (3-y OS not provided as results may be unreliable since per study protocol pts were followed for OS for only 2 y after BOS discontinuation). There were 34 (12%) deaths on study, with 5 deaths occurring within 30 d of the last BOS dose. Most deaths were due to disease progression (n = 17 [6%]) or an adverse event (AE) unrelated to BOS (n = 12 [4%]); only 1 treatment-related death occurred (due to febrile neutropenia 78 d after the last BOS dose in the IM-R group). Four additional deaths were due to unknown causes ≥136 d after the last BOS dose.
The most frequent non-hematologic treatment-emergent AEs (TEAEs; all grades/grade 3/4) were diarrhea (85%/10%), nausea (46%/1%), vomiting (37%/4%), rash (36%/9%), pyrexia (26%/1%), abdominal pain (25%/1%), and fatigue (25%/1%). Diarrhea was predominantly grade 1/2 in severity, had an early onset (median time to first event of 2 d [range, 1–1,330 d]), and was typically transient (median event duration of 1 d [range, 1–830 d]). Grade 3/4 on-treatment hematologic and non-hematologic lab abnormalities in ≥10% of pts included thrombocytopenia (25%), neutropenia (18%), lymphocytopenia (16%), anemia (14%), hypermagnesemia (11%), alanine transaminase elevation (11%), and hypophosphatemia (10%). Toxicities were manageable with medications and/or BOS dose modification; 45% of IM-R and 57% of IM-I pts had ≥1 dose reduction, and 66% of IM-R and 84% of IM-I pts had ≥1 dose interruption. AEs led to BOS discontinuation in 32 (16%) IM-R and 37 (41%) IM-I pts; the most common reason was thrombocytopenia. Overall, the rates of TEAEs and BOS discontinuation due to AEs showed little increase from the prior 24-mo analysis.
In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity in pts with CP CML following IM-R or IM-I after a minimum of 36 mo of follow-up, emphasizing the therapeutic potential of BOS in this population.
Cortes:Novartis, Bristol Myer Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding. Kantarjian:Pfizer Inc: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Turkina:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brümmendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Schafhausen:Bristol Myers Squibb, Novartis, Pfizer: Consultancy, Honoraria. Porkka:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Besson:Pfizer Inc: Employment. Gambacorti-Passerini:Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy.
Asterisk with author names denotes non-ASH members.