Imatinib and Altered Bone and Mineral Metabolism
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Berman and colleagues (May 11 issue)1 report their findings regarding the development of hypophosphatemia and associated changes in bone and mineral metabolism in patients with either chronic myelogenous leukemia or gastrointestinal stromal tumors who are taking imatinib. We have reviewed the global database of clinical trials sponsored by Novartis, as well as spontaneous post-marketing reports that cover approximately 200,000 patient-years of treatment with imatinib (unpublished data). There was a low incidence of reported hypophosphatemia or potential related events, although we recognize that the observations may be underreported.
Serum phosphate levels were routinely measured in two clinical trials — in the phase 1 trial 03001 involving a total of 143 patients, including 59 patients with chronic myeloid leukemia, and in the phase 2 trial 0102 involving 260 patients with chronic myeloid leukemia in blast crisis. Hypophosphatemia of Common Toxicity Criteria grade 2 or above was observed in 50 percent of the 403 patients (33 percent had grade 2, 15 percent grade 3, and 1.5 percent grade 4). However, in these two studies, hypophosphatemia was reported as an adverse event in only 3 percent of the patients. Hypophosphatemia is listed as a possible adverse event (<1 percent) in the product labeling on the basis of adverse events reported in the overall clinical-trials program in chronic myeloid leukemia.
Novartis supports the need for further studies to elucidate the effect of imatinib on phosphate levels or bone and mineral metabolism and to determine whether clinical monitoring or any specific therapy is required. Meanwhile, it would be prudent for physicians to monitor phosphate levels in their patients who are taking imatinib. Concerned patients should talk with their health care providers to evaluate their individual treatment needs.
Samantha Owen, Ph.D.
Alan Hatfield, M.D.
Laurie Letvak, M.D.
Novartis Pharmaceuticals
East Hanover, NJ 07936-1080
samantha_jane.owen@novartis.com
References
Berman E, Nicolaides M, Maki RG, et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med 2006;354:2006-2013.
To the Editor: Berman et al. suggest that in a subgroup of patients treated with imatinib mesylate, hypophosphatemia developed as a result of the suppression of bone turnover and renal phosphate wasting. However, several aspects of the report merit comment. First, phosphate levels were measured in only four patients before treatment, rendering it uncertain that hypophosphatemia is treatment-mediated. Second, calcium levels were not corrected for albumin levels, although levels of ionized calcium seem to be similar in the two study groups. Third, 50 percent of the patients had untreated low levels of 25-hydroxyvitamin D before evaluation. Fourth, blood sampling was not standardized with respect to time and fasting status — preanalysis variables that could significantly affect measurements of bone markers.1 Finally, the correlation analysis indicated an unexpected positive association between 1,25-dihydroxyvitamin D and phosphate levels, whereas no association between parathyroid hormone (PTH) levels and phosphate excretion was reported. Thus, before one suggests that inhibition of the platelet-derived growth factor receptor by imatinib results in hypophosphatemia, other mechanisms should be investigated, such as those implicated in patients with tumor-induced osteomalacia,2 although increased levels of fibroblast growth factor 23 are reported only in patients with chronic lymphocytic leukemia and plasma-cell dyscrasias.3
Symeon Tournis, M.D.
George P. Lyritis, M.D., Ph.D.
Laboratory for Research of Musculoskeletal
System "Th. Garofalidis"
14561 Athens, Greece
stournis@med.uoa.gr
References
Hannon R, Eastell R. Preanalytical variability of biochemical markers of bone turnover. Osteoporos Int 2000;11:Suppl 6:S30-S44.
Kumar R. Tumor-induced osteomalacia and the regulation of phosphate homeostasis. Bone 2000;27:333-338.
Stewart I, Roddie C, Gill A, et al. Elevated serum FGF23 concentrations in plasma cell dyscrasias. Bone 2006;39:369-376.
To the Editor: Berman et al. diagnosed hypophosphatemia in 16 patients who were given imatinib for either leukemia or advanced gastrointestinal stromal tumors, yet the duration, reversibility, and clinical significance of imatinib-related hypophosphatemia remain unknown. Hypophosphatemia is occasionally associated with overt cancer.1,2,3
We have conducted a longitudinal follow-up of plasma phosphate and calcium levels in 11 patients who received 400 mg of imatinib daily as adjuvant treatment of gastrointestinal stromal tumors for a period of 3 to 24 months. Of these 11 patients, 9 (82 percent) had plasma phosphate levels below the normal range on at least one occasion during treatment, and most of the patients had lower mean plasma phosphate levels during treatment than at baseline (Table 1). The plasma phosphate levels had returned to the normal range in a sample obtained two to four months after the discontinuation of therapy in all but one of six patients in whom hypophosphatemia developed during treatment. None of the 11 patients had a bone fracture. These data might suggest that although hypophosphatemia is not infrequent during adjuvant treatment with imatinib, it appears to be reversible on discontinuation of the drug.
Table 1. Effect of Adjuvant Treatment with Imatinib on Plasma Phosphate Levels in Patients with Gastrointestinal Stromal Tumors.
Heikki Joensuu, M.D.
Helsinki University Central Hospital
FIN-00029 Helsinki, Finland
heikki.joensuu@hus.fi
Peter Reichardt, M.D.
Charité Campus Virchow-Klinikum
13125 Berlin, Germany
Drs. Joensuu and Reichardt report having received lecture fees and fees for service on the advisory board from Novartis, and Dr. Reichardt reports having received honoraria and research grants from Novartis.
References
Jonsson KB, Zahradnik R, Larsson T, et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 2003;348:1656-1663.
Carpenter TO. Oncogenic osteomalacia -- a complex dance of factors. N Engl J Med 2003;348:1705-1708.
Ra'anani P, Lahav M, Prokocimer R, Poles L, Theodor E. Life threatening hypophosphatemia in a patient with Philadelphia chromosome-positive chronic myelogenous leukaemia in acute blastic crisis. Postgrad Med J 1992;68:283-286.
The authors reply: We agree with the recommendation of Owen and colleagues that physicians monitor phosphate levels in patients receiving imatinib, but we would like to emphasize that high levels of urinary phosphate excretion and abnormal markers of bone formation and resorption were noted in patients with normal serum phosphate levels. Thus, serum phosphate is not a sensitive marker for detecting abnormalities of bone metabolism. Whether hypophosphatemia will ultimately develop in patients who have normal phosphate levels but urinary phosphate wasting and whether any or all such patients are at risk for osteopenia remain to be determined. We are pleased that Novartis supports the need for further research in this very important area.
Tournis and Lyritis pose several important questions related to specific metabolic measurements. We studied relatively small numbers of patients with low serum phosphate levels (low-phosphate group) or normal serum phosphate levels (normal-phosphate group), and although blood and urine samples were not obtained during a fasting state, for reasons discussed in the article, sampling was clustered around 10 a.m. The PTH levels were high in the low-phosphate group during the time of the presumed PTH nadir, which suggests that the parathyroid function was, in fact, abnormal in this group. Moreover, 4 of 12 patients in the low-phosphate group had no measurable amount of osteocalcin (documented in the Supplementary Appendix of the article); values this low would not be expected during a nadir period. It is unlikely that tumor-induced osteomalacia could account for all these metabolic changes, since similar observations were made in patients with chronic myelogenous leukemia, gastrointestinal stromal tumors, and other forms of sarcoma and would probably also be made in patients with renal-cell cancer who were taking sunitinib or sorafenib,1 groups in which hypophosphatemia has been noted as well.
Last, a direct relationship between imatinib and hypophosphatemia was illustrated in one patient (Table 1), who had a normal pretreatment serum phosphate level; hypophosphatemia with an elevated parathyroid hormone value developed while this patient was taking imatinib, and when imatinib was temporarily discontinued, the serum phosphate level increased and the PTH level decreased.
Table 1. Effect of Stopping and Resuming Imatinib Therapy in Patient 5.
Joensuu and Reichardt present data on 11 patients with gastrointestinal stromal tumors, in 9 of whom hypophosphatemia developed that resolved on discontinuation of imatinib. These data appear to confirm our findings and are consistent with the data in Table 1.
Ellin Berman, M.D.
Martin Fleisher, Ph.D.
Memorial Sloan-Kettering Cancer Center
New York, NY 10021
bermane@mskcc.org
Nicholas P. Sauter, M.D.
Novartis Pharmaceuticals
East Hanover, NJ 07936
References
Nexavar (sorafenib). West Haven, Conn.: Bayer Pharmaceuticals, December 2005 (package insert).
Serum phosphate levels were routinely measured in two clinical trials — in the phase 1 trial 03001 involving a total of 143 patients, including 59 patients with chronic myeloid leukemia, and in the phase 2 trial 0102 involving 260 patients with chronic myeloid leukemia in blast crisis. Hypophosphatemia of Common Toxicity Criteria grade 2 or above was observed in 50 percent of the 403 patients (33 percent had grade 2, 15 percent grade 3, and 1.5 percent grade 4). However, in these two studies, hypophosphatemia was reported as an adverse event in only 3 percent of the patients. Hypophosphatemia is listed as a possible adverse event (<1 percent) in the product labeling on the basis of adverse events reported in the overall clinical-trials program in chronic myeloid leukemia.
Novartis supports the need for further studies to elucidate the effect of imatinib on phosphate levels or bone and mineral metabolism and to determine whether clinical monitoring or any specific therapy is required. Meanwhile, it would be prudent for physicians to monitor phosphate levels in their patients who are taking imatinib. Concerned patients should talk with their health care providers to evaluate their individual treatment needs.
Samantha Owen, Ph.D.
Alan Hatfield, M.D.
Laurie Letvak, M.D.
Novartis Pharmaceuticals
East Hanover, NJ 07936-1080
samantha_jane.owen@novartis.com
References
Berman E, Nicolaides M, Maki RG, et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med 2006;354:2006-2013.
To the Editor: Berman et al. suggest that in a subgroup of patients treated with imatinib mesylate, hypophosphatemia developed as a result of the suppression of bone turnover and renal phosphate wasting. However, several aspects of the report merit comment. First, phosphate levels were measured in only four patients before treatment, rendering it uncertain that hypophosphatemia is treatment-mediated. Second, calcium levels were not corrected for albumin levels, although levels of ionized calcium seem to be similar in the two study groups. Third, 50 percent of the patients had untreated low levels of 25-hydroxyvitamin D before evaluation. Fourth, blood sampling was not standardized with respect to time and fasting status — preanalysis variables that could significantly affect measurements of bone markers.1 Finally, the correlation analysis indicated an unexpected positive association between 1,25-dihydroxyvitamin D and phosphate levels, whereas no association between parathyroid hormone (PTH) levels and phosphate excretion was reported. Thus, before one suggests that inhibition of the platelet-derived growth factor receptor by imatinib results in hypophosphatemia, other mechanisms should be investigated, such as those implicated in patients with tumor-induced osteomalacia,2 although increased levels of fibroblast growth factor 23 are reported only in patients with chronic lymphocytic leukemia and plasma-cell dyscrasias.3
Symeon Tournis, M.D.
George P. Lyritis, M.D., Ph.D.
Laboratory for Research of Musculoskeletal
System "Th. Garofalidis"
14561 Athens, Greece
stournis@med.uoa.gr
References
Hannon R, Eastell R. Preanalytical variability of biochemical markers of bone turnover. Osteoporos Int 2000;11:Suppl 6:S30-S44.
Kumar R. Tumor-induced osteomalacia and the regulation of phosphate homeostasis. Bone 2000;27:333-338.
Stewart I, Roddie C, Gill A, et al. Elevated serum FGF23 concentrations in plasma cell dyscrasias. Bone 2006;39:369-376.
To the Editor: Berman et al. diagnosed hypophosphatemia in 16 patients who were given imatinib for either leukemia or advanced gastrointestinal stromal tumors, yet the duration, reversibility, and clinical significance of imatinib-related hypophosphatemia remain unknown. Hypophosphatemia is occasionally associated with overt cancer.1,2,3
We have conducted a longitudinal follow-up of plasma phosphate and calcium levels in 11 patients who received 400 mg of imatinib daily as adjuvant treatment of gastrointestinal stromal tumors for a period of 3 to 24 months. Of these 11 patients, 9 (82 percent) had plasma phosphate levels below the normal range on at least one occasion during treatment, and most of the patients had lower mean plasma phosphate levels during treatment than at baseline (Table 1). The plasma phosphate levels had returned to the normal range in a sample obtained two to four months after the discontinuation of therapy in all but one of six patients in whom hypophosphatemia developed during treatment. None of the 11 patients had a bone fracture. These data might suggest that although hypophosphatemia is not infrequent during adjuvant treatment with imatinib, it appears to be reversible on discontinuation of the drug.
Table 1. Effect of Adjuvant Treatment with Imatinib on Plasma Phosphate Levels in Patients with Gastrointestinal Stromal Tumors.
Heikki Joensuu, M.D.
Helsinki University Central Hospital
FIN-00029 Helsinki, Finland
heikki.joensuu@hus.fi
Peter Reichardt, M.D.
Charité Campus Virchow-Klinikum
13125 Berlin, Germany
Drs. Joensuu and Reichardt report having received lecture fees and fees for service on the advisory board from Novartis, and Dr. Reichardt reports having received honoraria and research grants from Novartis.
References
Jonsson KB, Zahradnik R, Larsson T, et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med 2003;348:1656-1663.
Carpenter TO. Oncogenic osteomalacia -- a complex dance of factors. N Engl J Med 2003;348:1705-1708.
Ra'anani P, Lahav M, Prokocimer R, Poles L, Theodor E. Life threatening hypophosphatemia in a patient with Philadelphia chromosome-positive chronic myelogenous leukaemia in acute blastic crisis. Postgrad Med J 1992;68:283-286.
The authors reply: We agree with the recommendation of Owen and colleagues that physicians monitor phosphate levels in patients receiving imatinib, but we would like to emphasize that high levels of urinary phosphate excretion and abnormal markers of bone formation and resorption were noted in patients with normal serum phosphate levels. Thus, serum phosphate is not a sensitive marker for detecting abnormalities of bone metabolism. Whether hypophosphatemia will ultimately develop in patients who have normal phosphate levels but urinary phosphate wasting and whether any or all such patients are at risk for osteopenia remain to be determined. We are pleased that Novartis supports the need for further research in this very important area.
Tournis and Lyritis pose several important questions related to specific metabolic measurements. We studied relatively small numbers of patients with low serum phosphate levels (low-phosphate group) or normal serum phosphate levels (normal-phosphate group), and although blood and urine samples were not obtained during a fasting state, for reasons discussed in the article, sampling was clustered around 10 a.m. The PTH levels were high in the low-phosphate group during the time of the presumed PTH nadir, which suggests that the parathyroid function was, in fact, abnormal in this group. Moreover, 4 of 12 patients in the low-phosphate group had no measurable amount of osteocalcin (documented in the Supplementary Appendix of the article); values this low would not be expected during a nadir period. It is unlikely that tumor-induced osteomalacia could account for all these metabolic changes, since similar observations were made in patients with chronic myelogenous leukemia, gastrointestinal stromal tumors, and other forms of sarcoma and would probably also be made in patients with renal-cell cancer who were taking sunitinib or sorafenib,1 groups in which hypophosphatemia has been noted as well.
Last, a direct relationship between imatinib and hypophosphatemia was illustrated in one patient (Table 1), who had a normal pretreatment serum phosphate level; hypophosphatemia with an elevated parathyroid hormone value developed while this patient was taking imatinib, and when imatinib was temporarily discontinued, the serum phosphate level increased and the PTH level decreased.
Table 1. Effect of Stopping and Resuming Imatinib Therapy in Patient 5.
Joensuu and Reichardt present data on 11 patients with gastrointestinal stromal tumors, in 9 of whom hypophosphatemia developed that resolved on discontinuation of imatinib. These data appear to confirm our findings and are consistent with the data in Table 1.
Ellin Berman, M.D.
Martin Fleisher, Ph.D.
Memorial Sloan-Kettering Cancer Center
New York, NY 10021
bermane@mskcc.org
Nicholas P. Sauter, M.D.
Novartis Pharmaceuticals
East Hanover, NJ 07936
References
Nexavar (sorafenib). West Haven, Conn.: Bayer Pharmaceuticals, December 2005 (package insert).