title: Multiparameter Analysis of Off-Target Effects of Dasatinib on Bone Homeostasis in Patients With Newly Diagnosed Chronic Myelogenous Leukemia.
abstract: We assessed patients with chronic myelogenous leukemia (CML) for serum calcium (Ca), phosphate (PO4), bone alkaline phosphatase, N-telopeptide (NTx), osteoprotegerin (OPG) levels, and trabecular bone area (TBA) in bone marrow (BM) specimens before and after treatment with dasatinib. We identified a significant increase in percentage of TBA in postdasatinib BM (P = .022). This suggests that dasatinib therapy can increase TBA without significant changes in bone and mineral metabolism. Interferences with bone homeostasis and mineral metabolism have been described in patients receiving imatinib for CML or gastrointestinal stromal tumors. Dasatinib is a potent second-generation tyrosine kinase inhibitor designed to inhibit ABL and SRC kinases while also interfering with the c-Kit, platelet-derived growth factor receptor, and STAT5 pathways.
  
  
  
  We used a multiparameter approach to examine the off-target effects of dasatinib in 30 patients with CML treated between 2009 and 2012. We recorded serum Ca and PO4 levels, analyzed markers of bone formation (bone alkaline phosphatase/bone-specific alkaline phosphatase [BAP]) and bone resorption (NTx), measured OPG levels, and digitally analyzed changes in TBA in paired BM biopsy specimens before and after treatment. We correlated all findings with each other and with the results of conventional cytogenetic and molecular analyses.
  
  
  
  We identified a significant increase in the percentage of TBA in postdasatinib BM biopsy specimens (P = .022) and noted a decrease in serum OPG levels in 75% of patients. Ca, PO4, BAP, and NTx levels remained steady, without significant changes. There was no correlation between biomarker levels, percentage of TBA, and/or cytogenetic or molecular response.
  
  
  
  These findings suggest that dasatinib therapy (within the therapeutic range) can increase trabecular bone, without causing significant changes in bone and mineral metabolism. Nonetheless, monitoring of bone health and skeletal integrity should be included into the long-term management of patients treated with dasatinib to further enhance our understanding of its safety profile and its potential role as a treatment modality for other bone diseases.
authors: Division of Hematopathology, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY.
authors: Daniela
authors: D
authors: Hoehn
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors: Jorge E
authors: JE
authors: Cortes
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors: L Jeffrey
authors: LJ
authors: Medeiros
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors: Elias J
authors: EJ
authors: Jabbour
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors: Juliana E
authors: JE
authors: Hidalgo
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors: Rashmi
authors: R
authors: Kanagal-Shamanna
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: cbuesora@mdanderson.org.
authors: Carlos E
authors: CE
authors: Bueso-Ramos
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D015415:Biomarkers; D001706:Biopsy; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D020732:Cytogenetic Analysis; D000069439:Dasatinib / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib
keywords: Bone marrow; Bone metabolism; Dasatinib; Digital image analysis; Trabecular bone