title: Efficacy and pharmacologic data of second-generation tyrosine kinase inhibitor nilotinib in BCR-ABL-positive leukemia patients with central nervous system relapse after allogeneic stem cell transplantation.
abstract: Central nervous system (CNS) involvement is a severe complication of BCR-ABL-positive leukemia after allogenic stem cell transplantation (alloSCT) associated with fatal outcome. Although second-generation tyrosine-kinase inhibitors (TKI) such as nilotinib have shown activity in systemic BCR-ABL(+) disease, little data exists on their penetration and efficacy within the CNS. Four patients (3 male, 1 female; age 15-49) with meningeal relapse after alloSCT and subsequent treatment with nilotinib were identified. A total of 17 cerebrospinal fluid (csf) and serum samples were assessed for nilotinib concentration and patient outcome was recorded. Nilotinib concentrations showed a low median csf/plasma ratio of 0.53% (range 0.23-1.5%), yet pronounced clinical efficacy was observed with long-lasting responses (>1 year) in three patients. Comparison with historical data showed a trend towards superior efficacy of nilotinib versus imatinib. Despite poor csf penetration, nilotinib showed significant clinical activity in CNS relapse of BCR-ABL(+) leukemias. As nilotinib has a high protein-binding affinity, the low-protein concentration in csf could translate into a relatively higher amount of free and therefore active nilotinib in csf as compared to blood, possibly explaining the observed efficacy. Thus, treatment with a 2nd generation TKI warrants further investigation and should be considered in cases of CNS relapse of BCR-ABL-positive leukemia after alloSCT.
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Reinwald
authors.affiliation: Department of Hematology and Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany ; Department of Internal Medicine, Klinikum Merseburg, Weiße Mauer 52, 06217 Merseburg, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schleyer
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kiewe
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.
authors.forename: Igor Wolfgang
authors.initials: IW
authors.lastname: Blau
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Burmeister
authors.affiliation: Department of Hematology and Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pursche
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Neumann
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Notter
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité Berlin, Hindenburgdamm 30, 12203 Berlin, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Thiel
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.affiliation: Division of Pediatric Hematology/Oncology, Department of Pediatrics, Technische Universität München, Kölner Platz 1, 80804 München, Germany.
authors.forename: Hans-Jochem
authors.initials: HJ
authors.lastname: Kolb
authors.affiliation: Division of Pediatric Hematology/Oncology, Department of Pediatrics, Technische Universität München, Kölner Platz 1, 80804 München, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Burdach
authors.affiliation: Division of Pediatric Hematology/Oncology, Department of Pediatrics, Technische Universität München, Kölner Platz 1, 80804 München, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Bender
mesh_terms: D000293:Adolescent; D000328:Adult; D001549:Benzamides / Q000008:administration & dosage; D002490:Central Nervous System / Q000473:pathology*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D053208:Kaplan-Meier Estimate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage*; D033581:Stem Cell Transplantation / Q000009:adverse effects; D014184:Transplantation, Homologous / Q000009:adverse effects
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib