Multiparameter Analysis of Off-Target Effects of Dasatinib on Bone Homeostasis in Patients With Newly Diagnosed Chronic Myelogenous Leukemia

Daniela Hoehn, Jorge E. Cortes, L. Jeffrey Medeiros, Elias J. Jabbour, Juliana E. Hidalgo, Rashmi Kanagal-Shamanna, Carlos E. Bueso-Ramos

Research output: Contribution to journalArticle

Abstract

We assessed patients with chronic myelogenous leukemia for serum Ca, PO4, bone alkaline phosphatase, N-telopeptide, osteoprotegerin levels and trabecular bone (TBA) in bone marrow (BM) specimens before and after treatment with dasatinib. We identified a significant increase in TBA % in post-dasatinib BM (P = .022). This suggests that dasatinib therapy can increase TBA, without significant changes in bone and mineral metabolism. Background 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. Patients and Methods 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. Results 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. Conclusion 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.

Original languageEnglish (US)
Pages (from-to)S86-S92
JournalClinical Lymphoma, Myeloma and Leukemia
Volume16
DOIs
StatePublished - Aug 1 2016
Externally publishedYes

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Homeostasis
Bone and Bones
Osteoprotegerin
Bone Marrow
Alkaline Phosphatase
Minerals
Therapeutics
Calcium
Serum
Dasatinib
Cancellous Bone
Biopsy
Platelet-Derived Growth Factor Receptors
Gastrointestinal Stromal Tumors
Cytogenetic Analysis
Bone Diseases
Bone Resorption
Osteogenesis
Cytogenetics

Keywords

  • Bone marrow
  • Bone metabolism
  • Dasatinib
  • Digital image analysis
  • Trabecular bone

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Multiparameter Analysis of Off-Target Effects of Dasatinib on Bone Homeostasis in Patients With Newly Diagnosed Chronic Myelogenous Leukemia. / Hoehn, Daniela; Cortes, Jorge E.; Medeiros, L. Jeffrey; Jabbour, Elias J.; Hidalgo, Juliana E.; Kanagal-Shamanna, Rashmi; Bueso-Ramos, Carlos E.

In: Clinical Lymphoma, Myeloma and Leukemia, Vol. 16, 01.08.2016, p. S86-S92.

Research output: Contribution to journalArticle

Hoehn, Daniela ; Cortes, Jorge E. ; Medeiros, L. Jeffrey ; Jabbour, Elias J. ; Hidalgo, Juliana E. ; Kanagal-Shamanna, Rashmi ; Bueso-Ramos, Carlos E. / Multiparameter Analysis of Off-Target Effects of Dasatinib on Bone Homeostasis in Patients With Newly Diagnosed Chronic Myelogenous Leukemia. In: Clinical Lymphoma, Myeloma and Leukemia. 2016 ; Vol. 16. pp. S86-S92.
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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 for serum Ca, PO4, bone alkaline phosphatase, N-telopeptide, osteoprotegerin levels and trabecular bone (TBA) in bone marrow (BM) specimens before and after treatment with dasatinib. We identified a significant increase in TBA {\%} in post-dasatinib BM (P = .022). This suggests that dasatinib therapy can increase TBA, without significant changes in bone and mineral metabolism. Background 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. Patients and Methods 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. Results 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. Conclusion 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.",
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T1 - Multiparameter Analysis of Off-Target Effects of Dasatinib on Bone Homeostasis in Patients With Newly Diagnosed Chronic Myelogenous Leukemia

AU - Hoehn, Daniela

AU - Cortes, Jorge E.

AU - Medeiros, L. Jeffrey

AU - Jabbour, Elias J.

AU - Hidalgo, Juliana E.

AU - Kanagal-Shamanna, Rashmi

AU - Bueso-Ramos, Carlos E.

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N2 - We assessed patients with chronic myelogenous leukemia for serum Ca, PO4, bone alkaline phosphatase, N-telopeptide, osteoprotegerin levels and trabecular bone (TBA) in bone marrow (BM) specimens before and after treatment with dasatinib. We identified a significant increase in TBA % in post-dasatinib BM (P = .022). This suggests that dasatinib therapy can increase TBA, without significant changes in bone and mineral metabolism. Background 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. Patients and Methods 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. Results 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. Conclusion 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.

AB - We assessed patients with chronic myelogenous leukemia for serum Ca, PO4, bone alkaline phosphatase, N-telopeptide, osteoprotegerin levels and trabecular bone (TBA) in bone marrow (BM) specimens before and after treatment with dasatinib. We identified a significant increase in TBA % in post-dasatinib BM (P = .022). This suggests that dasatinib therapy can increase TBA, without significant changes in bone and mineral metabolism. Background 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. Patients and Methods 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. Results 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. Conclusion 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.

KW - Bone marrow

KW - Bone metabolism

KW - Dasatinib

KW - Digital image analysis

KW - Trabecular bone

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