Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2013
Dasatinib in children and adolescents with relapsed or refractory leukemia: results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium.
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Zwaan C Michel, Rizzari Carmelo, Mechinaud Francoise, Lancaster Donna L, Lehrnbecher Thomas, van der Velden Vincent H J, Beverloo B Berna, den Boer Monique L, Pieters Rob, Reinhardt Dirk, Dworzak Michael, Rosenberg Julie, Manos George, Agrawal Shruti, Strauss Lewis, Baruchel André, Kearns Pamela R
Аннотация
PURPOSE: Dasatinib is a potent BCR-ABL inhibitor with proven efficacy in adults with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) and in imatinib-resistant/intolerant disease. This phase I study of the Innovative Therapies for Children with Cancer Consortium assessed dasatinib safety and efficacy in pediatric patients.
PATIENTS AND METHODS: Escalating once-daily dasatinib doses (60 to 120 mg/m(2)) were administered to children (n = 58) with (i) imatinib-pretreated CML or Philadelphia chromosome (Ph)-positive acute lymhoblastic leukemia (ALL) and (ii) treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML).
RESULTS: Dasatinib safety and efficacy profiles compared favorably with those in adults. The most common drug-related nonhematologic adverse events were nausea (31%, all grades; 2%, grade 3 to 4), headache (22%, 3%), diarrhea (21%, 0%), and vomiting (17%, 2%). Of 17 patients with CML-CP, 14 (82%) achieved complete cytogenetic response (CCyR) and eight (47%) achieved major molecular response. After ≥ 24 months of follow-up, median complete hematologic response (CHR) and major cytogenetic response (MCyR) durations were not reached. Of 17 patients with advanced-phase CML or Ph-positive ALL, six (35%) achieved confirmed CHR and 11 (65%) achieved CCyR. Median MCyR duration was 4.6 months (95% CI, 2.1 to 17.4 months). No patient with Ph-negative ALL or AML responded. Dasatinib pediatric pharmacokinetic parameters were comparable with those in adult studies, showing rapid absorption (time to reach maximum concentration, 0.5 to 6.0 hours) and elimination (mean half-life, 3.0 to 4.4 hours).
CONCLUSION: Dasatinib 60 mg/m(2) and 80 mg/m(2) once-daily dosing were selected for phase II studies in children with Ph-positive leukemias.
PATIENTS AND METHODS: Escalating once-daily dasatinib doses (60 to 120 mg/m(2)) were administered to children (n = 58) with (i) imatinib-pretreated CML or Philadelphia chromosome (Ph)-positive acute lymhoblastic leukemia (ALL) and (ii) treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML).
RESULTS: Dasatinib safety and efficacy profiles compared favorably with those in adults. The most common drug-related nonhematologic adverse events were nausea (31%, all grades; 2%, grade 3 to 4), headache (22%, 3%), diarrhea (21%, 0%), and vomiting (17%, 2%). Of 17 patients with CML-CP, 14 (82%) achieved complete cytogenetic response (CCyR) and eight (47%) achieved major molecular response. After ≥ 24 months of follow-up, median complete hematologic response (CHR) and major cytogenetic response (MCyR) durations were not reached. Of 17 patients with advanced-phase CML or Ph-positive ALL, six (35%) achieved confirmed CHR and 11 (65%) achieved CCyR. Median MCyR duration was 4.6 months (95% CI, 2.1 to 17.4 months). No patient with Ph-negative ALL or AML responded. Dasatinib pediatric pharmacokinetic parameters were comparable with those in adult studies, showing rapid absorption (time to reach maximum concentration, 0.5 to 6.0 hours) and elimination (mean half-life, 3.0 to 4.4 hours).
CONCLUSION: Dasatinib 60 mg/m(2) and 80 mg/m(2) once-daily dosing were selected for phase II studies in children with Ph-positive leukemias.
Предметные рубрики MeSH
AdolescentAntineoplastic AgentsBenzamidesChildChild, PreschoolDasatinibDiarrheaDose-Response Relationship, DrugDrug Administration ScheduleFemaleHeadacheHumansImatinib MesylateInfantKaplan-Meier EstimateLeukemia, Myelogenous, Chronic, BCR-ABL PositiveLeukemia, Myeloid, AcuteMaleNauseaPiperazinesPrecursor Cell Lymphoblastic Leukemia-LymphomaProtein Kinase InhibitorsProtein-Tyrosine KinasesPyrimidinesSample SizeTherapies, InvestigationalThiazolesTreatment OutcomeVomitingYoung Adult