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Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors.

ABSTRACT: Long-term efficacy and safety of bosutinib (?4 years follow-up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated-phase [AP, n = 79] chronic myeloid leukemia [CML], blast-phase [BP, n = 64] CML, acute lymphoblastic leukemia [ALL, n = 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1-88.6), 2.8 (0.03-55.9), 0.97 (0.3-89.2) months. Among AP and BP patients, 57% and 28% newly attained or maintained baseline overall hematologic response (OHR); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 years (most by 12 months). In responders at 1 versus 4 years, Kaplan-Meier (KM) probabilities of maintaining OHR were 78% versus 49% (AP) and 28% versus 19% (BP); KM probabilities of maintaining MCyR were 65% versus 49% (AP) and 21% versus 21% (BP). Most common AEs (AP, BP) were gastrointestinal (96%; 83%), primarily diarrhea (85%; 64%), which was typically low grade (maximum grade 1/2: 81%; 59%) and transient; no patient discontinued due to diarrhea. Serious AEs occurred in 44 (56%) AP and 37 (58%) BP patients, most commonly pneumonia (n = 9) for AP and pyrexia (n = 6) for BP; 11 and 13 died within 30 days of last dose (2 considered bosutinib-related [AP] per investigator). Responses were durable in ?50% AP responders at 4 years (?25% BP patients responded at year 1, suggesting possible bridge-to-transplant role in BP patients); toxicity was manageable.

SUBMITTER: Gambacorti-Passerini C

PROVIDER: S-EPMC5132035 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors.

Gambacorti-Passerini Carlo C Kantarjian Hagop M HM Kim Dong-Wook DW Khoury Hanna J HJ Turkina Anna G AG Brümmendorf Tim H TH Matczak Ewa E Bardy-Bouxin Nathalie N Shapiro Mark M Turnbull Kathleen K Leip Eric E Cortes Jorge E JE

American journal of hematology 20150601 9

Long-term efficacy and safety of bosutinib (≥4 years follow-up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated-phase [AP, n = 79] chronic myeloid leukemia [CML], blast-phase [BP, n = 64] CML, acute lymphoblastic leukemia [ALL, n = 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1-88.6), 2.8 (0.03-55.9) ...[more]

PMID: 26040495

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Project description:Purpose Bosutinib is a potent dual SRC/ABL kinase inhibitor approved for adults with Philadelphia chromosome-positive chronic myeloid leukemia (CML) resistant and /or intolerant to prior therapy. We assessed the efficacy and safety of bosutinib versus imatinib for first-line treatment of chronic-phase CML. Methods In this ongoing, multinational, phase III study, 536 patients with newly diagnosed chronic-phase CML were randomly assigned 1:1 to receive 400 mg of bosutinib once daily (n = 268) or imatinib (n = 268). Per protocol, efficacy was assessed in patients who were Philadelphia chromosome-positive with typical (e13a2/e14a2) transcripts (bosutinib, n = 246; imatinib, n = 241). Patients with Philadelphia chromosome-negative-/ BCR-ABL1-positive status and those with unknown Philadelphia chromosome status and/or atypical BCR-ABL1 transcript type were excluded from this population. Results The major molecular response (MMR) rate at 12 months (primary end point) was significantly higher with bosutinib versus imatinib (47.2% v 36.9%, respectively; P = .02), as was complete cytogenetic response (CCyR) rate by 12 months (77.2% v 66.4%, respectively; P = .0075). Cumulative incidence was favorable with bosutinib (MMR: hazard ratio, 1.34; P = .0173; CCyR: hazard ratio, 1.38; P < .001), with earlier response times. Four patients (1.6%) receiving bosutinib and six patients (2.5%) receiving imatinib experienced disease progression to accelerated/blast phase. Among treated patients, 22.0% of patients receiving bosutinib and 26.8% of patients receiving imatinib discontinued treatment, most commonly for drug-related toxicity (12.7% and 8.7%, respectively). Grade ≥ 3 diarrhea (7.8% v 0.8%) and increased ALT (19.0% v 1.5%) and AST (9.7% v 1.9%) levels were more common with bosutinib. Cardiac and vascular toxicities were uncommon. Conclusion Patients who received bosutinib had significantly higher rates of MMR and CCyR and achieved responses faster than those who received imatinib. Consistent with the known safety profile, GI events and transaminase elevations were more common with bosutinib. Results indicate bosutinib may be an effective first-line treatment for chronic-phase CML.

Dataset Information

Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors.

Publications

Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors.

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