Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib

Abstract

Bosutinib is an Src/Abl tyrosine kinase inhibitor (TKI) indicated for adults with Ph+ chronic myeloid leukemia (CML) resistant/intolerant to prior TKIs. This long-term update of an ongoing phase 1/2 study evaluated the efficacy and safety of third-/fourth-line bosutinib in adults with chronic phase (CP) CML. Median durations of treatment and follow-up were 8.6 (range, 0.2-87.7) months and 32.7 (0.3-93.3) months, respectively. Cumulative confirmed complete hematologic response (cCHR) and major cytogenetic response (MCyR) rates were 74% (95% CI, 65-81%) and 40% (31-50%), respectively; Kaplan-Meier (K-M) probability of maintaining cCHR or MCyR at 4 years was 63% (95% CI, 50-73%) and 69% (52-81%). Cumulative incidence of on-treatment disease progression (PD)/death at 4 years was 24% (95% CI, 17-33%); K-M 4-year overall survival was 78% (68-85%). Baseline Ph+ cells ≤35 vs. ≥95% was prognostic of MCyR and CCyR by 3 and 6 months, increased baseline basophils was prognostic of PD/death, and no prior response to second-line TKI was prognostic of death. Common adverse events included diarrhea (83%), nausea (48%), vomiting (38%), and thrombocytopenia (39%). Bosutinib demonstrates durable efficacy and a toxicity profile similar to previous bosutinib studies in CP CML patients resistant/intolerant to multiple TKIs, representing an important treatment option for patients in this setting. This trial is registered at www.clinicaltrials.gov (NCT00261846). Am. J. Hematol. 91:1206-1214, 2016. © 2016 Wiley Periodicals, Inc.

Figure 1

Cumulative incidence of response and duration of response. (A) Cumulative incidence of CHR adjusting for the competing risk of treatment discontinuation without the event; (B) duration of CHR among responders. (C) Cumulative incidence of MCyR adjusting for the competing risk of treatment discontinuation without the event; (D) duration of MCyR among responders. CHR = complete hematologic response; CI = confidence interval; D = dasatinib; I = intolerant; IM = imatinib; K–M = Kaplan–Meier; MCyR = major cytogenetic response; N = nilotinib; NE = not evaluable; R = resistant.

Figure 2

Percentage of patients with TEAEs occurring in year 1 and newly occurring in years 2, 3, and 4 in ≥10% of patients overall (any grade). AE = adverse event; ALT = alanine aminotransferase; TEAE = treatment‐emergent adverse event. Denominators are the number of patients on treatment during the specific years (note: the incidence of certain TEAEs appears higher in later years compared with previous years due to a lower number of patients on treatment: pleural effusion [year 1, n = 6/119; year 2, n = 6/50; year 3, n = 1/39; year 4, n = 5/32]; increased blood creatinine [year 1, n = 8/119; year 2, n = 2/50; year 3, n = 1/39; year 4, n = 4/32]; cardiac AEs [year 1, n = 8/119; year 2, n = 4/50; year 3, n = 1/39; year 4, n = 3/32]). 1 year = 365.25 days. Newly occurring TEAEs were defined as those MedDRA preferred terms (PTs) not experienced by the same patient previously for patients on treatment during a given year. *Includes all PTs under the high‐level group terms cardiac arrhythmias, pericardial disorders, and heart failures under the cardiac disorders system organ class (SOC) and the following PTs: cardiac death, sudden cardiac death, sudden death, decreased ejection fraction, abnormal electrocardiogram QT interval, prolonged electrocardiogram QT, congenital long QT syndrome.