title: Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study.
abstract: Patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL) have a rapid disease course and a poor prognosis. Dasatinib, a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, has previously induced responses in patients with imatinib-resistant or -intolerant Ph-positive ALL. We present the interim results of a phase 2 study designed to further assess the efficacy, safety, and tolerability of dasatinib 140 mg in this patient population (n = 36). With a minimum follow-up of 8 months, treatment with dasatinib resulted in substantial hematologic and cytogenetic response rates. Major hematologic responses were achieved in 42% (15/36) of patients, 67% of whom remained progression-free. Complete cytogenetic responses were attained by 58% (21/36) of patients. The presence of BCR-ABL mutations conferring imatinib resistance did not preclude a response to dasatinib. Dasatinib was also tolerable, with 6% (2/36) of patients discontinuing therapy as a result of study-drug toxicity. Most adverse events (AEs) were grade 1 or 2; febrile neutropenia was the most frequent severe AE, but this and other cytopenias were manageable with dose reduction. Dasatinib represents a safe and effective treatment option and an important therapeutic advance for patients with Ph-positive ALL. This trial was registered at www.clinicaltrials.gov as #CA180015.
authors.affiliation: Medizinische Klinik II, Johann Wolfgang Goethe Universität, Frankfurt, Germany. ottmann@em.uni-frankfurt.de
authors.forename: Oliver
authors.initials: O
authors.lastname: Ottmann
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Bengt
authors.initials: B
authors.lastname: Simonsson
authors.forename: Francois
authors.initials: F
authors.lastname: Guilhot
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Giovanna
authors.initials: G
authors.lastname: Rege-Cambrin
authors.forename: Jerald
authors.initials: J
authors.lastname: Radich
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Apanovitch
authors.forename: Ashwin
authors.initials: A
authors.lastname: Gollerkeri
authors.forename: Steven
authors.initials: S
authors.lastname: Coutre
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D002869:Chromosome Aberrations / Q000187:drug effects*; D003582:Cytogenetics; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D004361:Drug Tolerance; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006405:Hematology; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib