title: Improved tolerability by a modified intermittent treatment schedule of dasatinib for patients with chronic myeloid leukemia resistant or intolerant to imatinib.
abstract: Intermittent dosing of dasatinib with a once daily regimen has been shown to reduce side effects while preserving clinical efficacy in early and advanced phase chronic myeloid leukemia (CML). Yet, hematologic toxicity and fluid retention demand a dose modification or treatment discontinuation in selected patients. Patients resistant or intolerant to imatinib were retrospectively evaluated based on the toxicity-guided administration of a dose-reduced dasatinib regimen. Patients were treated with an on/off regimen (3 to 5 days on, 2 to 4 days off) to allow regression of dasatinib-dependent off-target toxicity. Patients were followed up by routine hematologic and cytogenetic assessment and molecular monitoring to safeguard clinical response to the altered drug schedule. Thirty-three CML patients primarily in chronic phase with imatinib intolerance (n = 11) or resistance (n = 22) were investigated. Nonexclusive reasons for dose reduction were hematologic toxicity (17/33, 51%) and pleural effusions (18/33, 55%). On/off treatment with a weekend drug holiday significantly reduced pleural effusions and hematologic toxicity. Eighteen of 31 (58%) patients showed effective disease control despite reduced total weekly dasatinib doses, either demonstrated by achieving an improved response level (12/31) or keeping the response level achieved by conventional continuous dosing (6/31). Of note, 10/12 patients with subsequently improved response have been treated for a minimum of 6 months with continuous dosing dasatinib regimens without having achieved the response level achieved after allowing drug holiday. Weekend treatment interruption of dasatinib allows continuation of dasatinib treatment for patients suffering from side effects. These data mandate prospective investigation of alternative intermittent targeting regimens.
authors.affiliation: Abteilung Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, 07740 Jena, Germany. paul.larosee@med.uni-jena.de
authors.forename: Paul
authors.initials: P
authors.lastname: La Rosée
authors.forename: Philippe
authors.initials: P
authors.lastname: Martiat
authors.forename: Armin
authors.initials: A
authors.lastname: Leitner
authors.forename: Thomas
authors.initials: T
authors.lastname: Klag
authors.forename: Martin C
authors.initials: MC
authors.lastname: Müller
authors.forename: Philipp
authors.initials: P
authors.lastname: Erben
authors.forename: Thomas
authors.initials: T
authors.lastname: Schenk
authors.forename: Susanne
authors.initials: S
authors.lastname: Saussele
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000008:administration & dosage / Q000627:therapeutic use*; D000069439:Dasatinib; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000627:therapeutic use*; D012189:Retrospective Studies; D013844:Thiazoles / Q000008:administration & dosage* / Q000627:therapeutic use*
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D000069439:Dasatinib