title: 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.
authors.affiliation: Department of Internal Medicine, University of Milano-Bicocca, Monza, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Gambacorti-Passerini
authors.affiliation: Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Department of Hematology, Seoul St. Mary's Hospital, Seoul, South Korea.
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Division of Hematology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Hanna J
authors.initials: HJ
authors.lastname: Khoury
authors.affiliation: Hematology Research Center, Moscow, Russia.
authors.forename: Anna G
authors.initials: AG
authors.lastname: Turkina
authors.affiliation: Clinic for Oncology, Hematology, and Stem Cell Transplantation, Universitätsklinikum Aachen, RWTH Aachen, Germany.|Oncology, Hematology, and Stem Cell Transplantation, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.affiliation: Pfizer, New York, New York.
authors.forename: Ewa
authors.initials: E
authors.lastname: Matczak
authors.affiliation: Pfizer Global Research and Development, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bardy-Bouxin
authors.affiliation: Pfizer, Cambridge, Massachusetts.
authors.forename: Mark
authors.initials: M
authors.lastname: Shapiro
authors.affiliation: Pfizer, Cambridge, Massachusetts.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Turnbull
authors.affiliation: Pfizer, Cambridge, Massachusetts.
authors.forename: Eric
authors.initials: E
authors.lastname: Leip
authors.affiliation: Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects; D001752:Blast Crisis / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005334:Fever / Q000139:chemically induced / Q000473:pathology; D005500:Follow-Up Studies; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D011014:Pneumonia / Q000139:chemically induced / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; C471992:bosutinib; D000068877:Imatinib Mesylate