Dataset Information

Changes in bone metabolic parameters in children with chronic myeloid leukemia on imatinib treatment.

ABSTRACT:

Background

Imatinib is a highly effective drug in up-front treatment of chronic myeloid leukemia (CML). In children impaired longitudinal growth has been reported as side effect exerted by this drug under prolonged therapy. We therefore prospectively evaluated alterations of bone biochemical markers in pediatric patients with CML under ongoing imatinib exposure.

Material/methods

Bone metabolic markers (calcium, phosphate, magnesium, parathyroid hormone, vitamin D, procollagen type l N propeptide [PINP], and C-terminal cross-linking telopeptide of collagen [CTX-I], osteocalcin [OC]; pyridinoline [PYD], and desoxypyridinoline [DPD]) were determined in 17 patients with CML aged 4-17 years under imatinib treatment in three-month intervals over a 2.5 year period.

Results

Hyperparathyroidism developed in 8/17 patients and low 25-hydroxyvitamin-D3 levels were found in 15/17 patients. Increased OC levels were detected in 58% of all specimen showing a linear significant decline of -0.30 µg OC per l per week (p=0.04). Serum PINP was lowered in 25% and serum CTX-I was above the normal range in 57% of the specimen originating exclusively from prepupertal patients. Urine PYD and Urine DPD levels were above the normal range in 10% and 9%, respectively, of all specimen collected and a statistically significant linear decline of -0.16 nmol DPD/mg creatinine/week was calculated (p=0.01).

Conclusions

Bone remodeling may be dysregulated by imatinib. Data suggest that impaired bone formation exceeds that of decreased bone resorption. Regular evaluation of the skeletal actions during long-term imatinib treatment in childhood CML is warranted.

SUBMITTER: Jaeger BA

PROVIDER: S-EPMC3560809 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Publications

Changes in bone metabolic parameters in children with chronic myeloid leukemia on imatinib treatment.

Jaeger Bernadette Anna Sophia BA Tauer Josephine Tabea JT Ulmer Anna A Kuhlisch Eberhard E Roth Heinz Juergen HJ Suttorp Meinolf M

Medical science monitor : international medical journal of experimental and clinical research 20121201 12

<h4>Background</h4>Imatinib is a highly effective drug in up-front treatment of chronic myeloid leukemia (CML). In children impaired longitudinal growth has been reported as side effect exerted by this drug under prolonged therapy. We therefore prospectively evaluated alterations of bone biochemical markers in pediatric patients with CML under ongoing imatinib exposure.<h4>Material/methods</h4>Bone metabolic markers (calcium, phosphate, magnesium, parathyroid hormone, vitamin D, procollagen type ...[more]

PMID: 23197234

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Project description:Chronic myeloid leukemia (CML) in childhood and adolescence is a rare malignancy that can successfully be treated with the tyrosine kinase inhibitor (TKI) imatinib. According to the current experience, treatment is necessary for years and, in the majority of cases, a lifelong approach is required to control the malignant disease. To what extent imatinib causes immunosuppression in different age cohorts is a controversial discussion. According to general medical recommendations, live vaccines are contraindicated in individuals treated with imatinib. However, a recent increase in the number of globally reported cases of measles has been observed and continues to rise. Due to the high contagiousness of the virus, near-perfect vaccination coverage (herd immunity of 93 to 95%) is required to effectively protect against measles resurgence-a scenario that is not realistic in many countries. When four teenagers with CML (median age 13 years, range 12-15) who were enrolled into pediatric trial CML-paed II while on imatinib treatment (median treatment duration 36 months, range 11-84) were identified without protective measles and/or varicella titers, we carefully balanced the risks of a live vaccination under immunosuppressive TKI medication against the benefit of being protected. The patients underwent live vaccination with the live attenuated vaccines M-M-RVAX Pro® and Varivax® simultaneously (Patient #1), Priorix® and Varilix® consecutively (Patient #2), and Priorix® (Patients #3 and #4). While the first three patients were vaccinated while receiving TKI therapy, treatment with imatinib was interrupted in patient #4 for 1 week prior and 2 weeks after vaccination. Patients #1 and #3 reacted with stable long-term seroconversion. In Patient #2, serum titer conversion against measles and varicella could not be demonstrated and thus revaccination with Priorix® and Varilix® was performed 3 years later. However, protective titers did not develop or were lost again. Patient #4 also lost protective titers against measles when assessed 10 months after vaccination, but revaccination resulted in stable seroprotective titers over 12 months after the last vaccination during ongoing imatinib treatment. We conclude that in all patients, the safety of live vaccines could be documented, as no acute or late adverse events were observed. However, in line with observations that memory B-cells are lost under exposure to imatinib, revaccination may become necessary (two out of four patients in this small series lost their seroprotection). Considering that the number of cases is very small, we also suggest some criteria for decision-making regarding live vaccinations of CML patients treated with imatinib.

Project description:Inhibition of deregulated protein kinases by small molecule drugs has evolved into a major therapeutic strategy for the treatment of human malignancies. Imatinib mesylate has emerged as the leading compound to treat chronic myeloid leukemia (CML), through its inhibition of Bcr- Abl tyrosine kinases, and other cancers. However, resistance to imatinib develops frequently, particularly in late-stage disease and has necessitated the development of new BCR-ABL inhibitors. The synthesis of a new series of phenylaminopyrimidines, structurally related to imatinib showed large interest since the introduction of the nilotibin. To identify the cellular pathways affected by new synthesized compounds, we applied mass spectrometry together with stable isotope labeling by amino acids in cell culture (SILAC) for the comparative study of protein expression in K562 cells that were untreated or treated with imatinib and imatinib derivates. Further, the global proteome of the K562 cells treated with imatinib were quantitatively compared with the cells treated with the new compounds. This study enriched our knowledge about direct cellular targets of kinase selective drugs. Further the results offered important new knowledge for gaining insights into the structural effects of action of the new compounds. Samples were analyzed on a longer column (30cm) and a longer gradient (180min). Raw data files were processed with Mascot distiller 2.3. The mgf files were searched with Mascot daemon 2.3. The quantification was also done by Mascot Distiller. All data was stored in ms_lims. The manual validation of false peptide ratios was done with Rover (part of ms_lims). Fixed modifications: none. Variable modifications: acetylation of peptide N-terminus, pyroglutamate formation of N-terminal glutamine, methionine oxidation. Enzyme: trypsine with one missed cleavage allowed. Precursor mass tolerance: 10 ppm. Peptide fragment mass tolerance: 0.5 Da Quantitation method: SILAC arginine and lysine +6 Da. Overview of the 17 different analyses: B SK23 vs DMSO C Y22 vs DMSO D SK20 vs DMSO E Y18 vs DMSO I SK20 vs DMSO K Y18 vs DMSO O Y22 vs DMSO R Imatinib vs Water Z Imatinib vs Water J SK20 vs Imatinib M SK23 vs Imatinib N Y22 vs Imatinib P SK23 vs Imatinib Q Y18 vs Imatinib S Y22 vs Imatinib T SK20 vs Imatinib Y Y18 vs Imatinib

Project description:Imatinib has been found to substantially improve outcomes in patients with chronic myeloid leukemia (CML) compared with previously available therapies. However, its use is complicated by development of resistance or drug intolerance, prompting dose escalation or a trial of dasatinib or nilotinib, the second-generation tyrosine kinase inhibitors (TKIs).This article reviews the mechanisms of TKI resistance; discusses the tolerability and efficacy of high-dose imatinib, dasatinib, and nilotinib; and provides background for the rational use of second-line treatment options.MEDLINE (1966-December 2009) and EMBASE (1993-December 2009) were searched for pertinent English-language publications using search terms that included, but were not limited to, chronic myeloid leukemia, imatinib, dasatinib, nilotinib, and clinical trial. Abstracts from American Society of Hematology annual meetings (2005-2009) were also reviewed. There were no prespecified inclusion or exclusion criteria.Major and complete cytogenetic responses (MCyR and CCyR, respectively) to second-line treatment with high-dose (600-800 mg/d PO) imatinib were restricted to CML patients who had achieved a CyR to standard-dose imatinib: >90% of patients without a previous CyR failed to respond. The expected durability of the response to this approach remains unclear. Grade 3/4 thrombocytopenia, neutropenia, and anemia occurred in 14%, 39%, and 8%, respectively, of patients receiving high-dose imatinib. In patients who failed first-line treatment with imatinib, dasatinib (70 mg BID PO) was associated with higher rates of CCyR at 2 years compared with imatinib (44% vs 18%, respectively; P = 0.003), as well as higher estimated rates of progression-free survival at 2 years (86% vs 65%; P = 0.001). Dasatinib use was complicated by grade 3/4 thrombocytopenia and neutropenia in 57% and 63% of patients, respectively, and pleural effusion in 5%. Nilotinib treatment was effective in patients who were resistant to or unable to tolerate imatinib, with 46% and 58% achieving a CCyR and MCyR, respectively, at 2 years. Nilotinib use was complicated by grade 3/4 thrombocytopenia and neutropenia in 28% and 40% of patients, respectively, and QTc-interval prolongation in 1% to 10% of patients. Neither agent was clinically effective in patients with the common T315I mutation.Dasatinib and nilotinib were effective and generally well tolerated as second-line treatments for CML patients with a suboptimal response to standard doses of imatinib or imatinib intolerance.

Dataset Information

Changes in bone metabolic parameters in children with chronic myeloid leukemia on imatinib treatment.

Background

Material/methods

Results

Conclusions

Publications

Changes in bone metabolic parameters in children with chronic myeloid leukemia on imatinib treatment.

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