Clinical Study 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 Mark Reinwald, 1 Eberhard Schleyer, 2,3 Philipp Kiewe, 4 Igor Wolfgang Blau, 4 Thomas Burmeister, 4 Stefan Pursche, 2 Martin Neumann, 4 Michael Notter, 4 Eckhard Thiel, 4 Wolf-Karsten Hofmann, 1 Hans-Jochem Kolb, 5 Stefan Burdach, 5 and Hans-Ulrich Bender 5 1 Department of Hematology and Oncology, University Hospital Mannheim, heodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany 2 Department of Hematology and Oncology, Medical Faculty Carl Gustav Carus, Technische Universit¨ at Dresden, Fetscherstraße 74, 01307 Dresden, Germany 3 Department of Internal Medicine, Klinikum Merseburg, Weiße Mauer 52, 06217 Merseburg, Germany 4 Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charit´ e Berlin, Hindenburgdamm 30, 12203 Berlin, Germany 5 Division of Pediatric Hematology/Oncology, Department of Pediatrics, Technische Universit¨ at M¨ unchen, K¨ olner Platz 1, 80804 M¨ unchen, Germany Correspondence should be addressed to Mark Reinwald; mark.reinwald@medma.uni-heidelberg.de Received 9 March 2014; Accepted 21 May 2014; Published 15 June 2014 Academic Editor: Carlo Visco Copyright © 2014 Mark Reinwald et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Central nervous system (CNS) involvement is a severe complication of BCR-ABL-positive leukemia ater 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 eicacy within the CNS. Four patients (3 male, 1 female; age 15–49) with meningeal relapse ater alloSCT and subsequent treatment with nilotinib were identiied. A total of 17 cerebrospinal luid (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 eicacy was observed with long-lasting responses (>1 year) in three patients. Comparison with historical data showed a trend towards superior eicacy of nilotinib versus imatinib. Despite poor csf penetration, nilotinib showed signiicant clinical activity in CNS relapse of BCR-ABL + leukemias. As nilotinib has a high protein-binding ainity, 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 eicacy. hus, treatment with a 2nd generation TKI warrants further investigation and should be considered in cases of CNS relapse of BCR-ABL-positive leukemia ater alloSCT. 1. Introduction In BCR-ABL-positive acute lymphoblastic leukemia (ALL) and advanced stages of chronic myeloid leukemia (CML; accelerated phase, blast crisis (BC)) central nervous sys- tem (CNS) involvement is a lethal complication, typically occurring late in the course of the disease, particularly ater allogeneic stem cell transplantation (alloSCT). Imatinib was the irst speciic BCR-ABL tyrosine kinase inhibitor (TKI) to be approved for the treatment of BCR-ABL + ALL and CML and has led to a major breakthrough in the treatment of these malignancies. Nonetheless, 15–20% of patients (pts) with BCR-ABL + ALL or CML-BC develop CNS relapse during ongoing imatinib therapy [1]. his may possibly be attributed Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 637059, 7 pages http://dx.doi.org/10.1155/2014/637059