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Troponins in prediction of cardiotoxic effects
CORRESPONDENCE
Follow-up after HSCT
0 months 12 months 18 months 21 months
SLED ANA daily activity
24 0 16 24
1:2560 1:160 1:5120 1:10 240
Complement concentration
Authors’ reply
C3 (mg/dL)
C4 (mg/dL)
44 102 32 24
<5·0 22 5 5
Sir—We concur that extended followup of large numbers of patients will help to show whether HSCT has curative potential for SLE and other autoimmune diseases. Of our patients who received highdose chemotherapy and HSCT, extended follow-up (12–46 months) is available for seven. We have seen lowtitre-positive antinuclear antibodies and antibodies to double-stranded DNA in several of these individuals after HSCT, but only in one have serum complement concentrations declined and symptoms of active disease arisen. This patient was the only one to receive reimmunisation 1 year after transplantation. She was also the only patient who sought sun exposure after her transplant. We do not know whether either of these factors contributed to disease reactivation. As with all the transplant patients we treat, the patient’s disease was refractory to cyclophosphamide before transplantation. When her disease reactivated at 40 months after HSCT, in contrast to Rosen and colleagues’ patient, she responded to 500 mg/m2 standard intravenous cyclophosphamide. There is no current evidence of active disease and she is corticosteroid independent. In the USA, a phase III randomised study in severely affected lupus patients of standard therapy and high-dose chemotherapy and stem-cell support will soon begin. The long-term followup should answer many of the questions about the true value of HSCT.
*ELISA cut-off was 118 IU/mL. ANA=antinuclear antibodies.
Course of activity parameters
impairment of proteinuria and renal function (table). Since the treatment has failed we have decided to restart an immunoablative regimen. We agree with Traynor and colleagues’ conclusion that HSCT can be effective in selected patients, since the two other patients from our trial have been in continuous remission for 25 months and 28 months, respectively. HSCT is a novel experimental approach for treating patients with refractory autoimmune diseases. Preliminary data suggest that, especially in SLE patients, long-term remissions can be achieved. Nevertheless, disease can recur and may not respond to conventional immunosuppressive treatment. To date, factors influencing the duration of remission remain obscure. Our patient who relapsed had a very high disease activity at the onset of mobilisation. Thus, we speculate that, besides a person’s sex, disease activity could be a risk factor for relapse. Long-term follow-up is needed to distinguish transient increases of antinuclear antibodies from incipient relapses. Resetting of the immune system after HSCT and the development of tolerance might not be permanent. We speculate that autoreactive lymphocyte subpopulations will survive an immunoablative regimen. Therefore, exogenous triggers, such as sun exposure in our patient, might reactivate SLE. *Oliver Rosen, Falk Hiepe, Gero Massenkeil, Andreas Thiel, Renate Arnold University Hospital Charité (Campus Mitte), Deutsches Rheumaforschungszentrum, D-10098 Berlin, Germany 1
2
Traynor AE, Schroeder J, Rosa RM, et al. Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase I study. Lancet 2000; 356: 701–07. Rosen 0, Thiel A, Massenkeil G, et al. Autologous stem-cell transplantation in refractory autoimmune diseases after in vivo immunoablation and ex vivo depletion of mononuclear cells. Arthritis Res 2000; 2: 327–36.
808
*Ann Traynor, Richard Burt Division of Immunotherapy and Autoimmune Diseases, Northwestern University, Chicago, IL, USA
Troponins in prediction of cardiotoxic effects Sir—In their Dec 9 Commentary, Joseph Sparano and colleagues1 discuss the role of troponins in predicting cardiotoxic effects from cancer therapy. Notably anthracyclines, which are the basis of many chemotherapy regimens, might decrease left-ventricular function, which generally becomes clinically overt after a latency of various length. Therefore, early identification of individuals with an increased susceptibility to myocardial damage during treatment could prevent late cardiac complications. Raised serum concentrations of cardiac troponin T (cTnT) have already been reported to indicate early myocardial damage and to predict subsequent cardiac dysfunction in children.2,3 To assess the time course of
anthracycline-induced myocardial toxic effects in adults, we did serial measurements of serum cTnT in 41 patients with haematological malignant disorders who received a total of 85 chemotherapy courses, including anthracyclines at standard doses.4 cTnT concentrations rose in 20% of patients. By contrast with D Cardinale and colleagues5 who reported raised serum concentrations of cTnT 12–72 h after high-dose chemotherapy, we saw longterm rise of cTnT, with concentrations peaking more than 2 weeks after treatment. This finding is in accordance with those of S Lipshultz and colleagues in children and suggest that anthracyclines at standard doses cause long-term damage to the myofibrillar system. In most patients, we also measured left-ventricular ejection fraction by echocardiography. 5 months after completion of chemotherapy, we saw a significantly greater decrease in mean ejection fraction in patients with raised serum cTnT than in those without (10% vs 2%). No patient had clinically overt heart failure, however, the administered doses were lower than the commonly accepted thresholds for the development of anthracyclineassociated cardiomyopathy. These findings add further support to the notion that cTnT is a useful marker to identify individuals who are at increased risk of anthracycline-induced cardiac dysfunction. Since the time course in rises of serum troponins seems to vary depending on treatment protocols, applicability, and optimum schedule, troponin measurements will have to be determined for different regimens before routine monitoring of troponins in patients treated with anthracyclines is recommended. *Holger W Auner, Christoph Tinchon, Franz Quehenberger, Werner Linkesch, Heinz Sill Medizinische Universitäts klinik Institut für Medizinische Informatik, Karl-Franzens Universität, A-8036 Graz, Austria (e-mail: [email protected]) 1
2
3
4
5
Sparano JA, Wolff AC, Brown D. Troponins for predicting cardiotoxicity from cancer therapy. Lancet 2000; 356: 1947–48. Herman EH, Lipshultz SE, Rifai N, et al. Use of cardiac troponin T levels as an indicator of doxorubicin-induced cardiotoxicity. Cancer Res 1998; 58: 195–97. Lipshultz SE, Rifai N, Sallan SE, et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 1997; 96: 2641–48. Auner HW, Tinchon C, Linkesch W, et al. Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res 2000 (in press). Cardinale D, Sandri MT, Martinoni A, et al. Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. J Am Coll Cardiol 2000; 36: 517.
THE LANCET • Vol 357 • March 10, 2001
For personal use only. Reproduce with permission from The Lancet Publishing Group.
Follow-up after HSCT
0 months 12 months 18 months 21 months
SLED ANA daily activity
24 0 16 24
1:2560 1:160 1:5120 1:10 240
Complement concentration
Authors’ reply
C3 (mg/dL)
C4 (mg/dL)
44 102 32 24
<5·0 22 5 5
Sir—We concur that extended followup of large numbers of patients will help to show whether HSCT has curative potential for SLE and other autoimmune diseases. Of our patients who received highdose chemotherapy and HSCT, extended follow-up (12–46 months) is available for seven. We have seen lowtitre-positive antinuclear antibodies and antibodies to double-stranded DNA in several of these individuals after HSCT, but only in one have serum complement concentrations declined and symptoms of active disease arisen. This patient was the only one to receive reimmunisation 1 year after transplantation. She was also the only patient who sought sun exposure after her transplant. We do not know whether either of these factors contributed to disease reactivation. As with all the transplant patients we treat, the patient’s disease was refractory to cyclophosphamide before transplantation. When her disease reactivated at 40 months after HSCT, in contrast to Rosen and colleagues’ patient, she responded to 500 mg/m2 standard intravenous cyclophosphamide. There is no current evidence of active disease and she is corticosteroid independent. In the USA, a phase III randomised study in severely affected lupus patients of standard therapy and high-dose chemotherapy and stem-cell support will soon begin. The long-term followup should answer many of the questions about the true value of HSCT.
*ELISA cut-off was 118 IU/mL. ANA=antinuclear antibodies.
Course of activity parameters
impairment of proteinuria and renal function (table). Since the treatment has failed we have decided to restart an immunoablative regimen. We agree with Traynor and colleagues’ conclusion that HSCT can be effective in selected patients, since the two other patients from our trial have been in continuous remission for 25 months and 28 months, respectively. HSCT is a novel experimental approach for treating patients with refractory autoimmune diseases. Preliminary data suggest that, especially in SLE patients, long-term remissions can be achieved. Nevertheless, disease can recur and may not respond to conventional immunosuppressive treatment. To date, factors influencing the duration of remission remain obscure. Our patient who relapsed had a very high disease activity at the onset of mobilisation. Thus, we speculate that, besides a person’s sex, disease activity could be a risk factor for relapse. Long-term follow-up is needed to distinguish transient increases of antinuclear antibodies from incipient relapses. Resetting of the immune system after HSCT and the development of tolerance might not be permanent. We speculate that autoreactive lymphocyte subpopulations will survive an immunoablative regimen. Therefore, exogenous triggers, such as sun exposure in our patient, might reactivate SLE. *Oliver Rosen, Falk Hiepe, Gero Massenkeil, Andreas Thiel, Renate Arnold University Hospital Charité (Campus Mitte), Deutsches Rheumaforschungszentrum, D-10098 Berlin, Germany 1
2
Traynor AE, Schroeder J, Rosa RM, et al. Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase I study. Lancet 2000; 356: 701–07. Rosen 0, Thiel A, Massenkeil G, et al. Autologous stem-cell transplantation in refractory autoimmune diseases after in vivo immunoablation and ex vivo depletion of mononuclear cells. Arthritis Res 2000; 2: 327–36.
808
*Ann Traynor, Richard Burt Division of Immunotherapy and Autoimmune Diseases, Northwestern University, Chicago, IL, USA
Troponins in prediction of cardiotoxic effects Sir—In their Dec 9 Commentary, Joseph Sparano and colleagues1 discuss the role of troponins in predicting cardiotoxic effects from cancer therapy. Notably anthracyclines, which are the basis of many chemotherapy regimens, might decrease left-ventricular function, which generally becomes clinically overt after a latency of various length. Therefore, early identification of individuals with an increased susceptibility to myocardial damage during treatment could prevent late cardiac complications. Raised serum concentrations of cardiac troponin T (cTnT) have already been reported to indicate early myocardial damage and to predict subsequent cardiac dysfunction in children.2,3 To assess the time course of
anthracycline-induced myocardial toxic effects in adults, we did serial measurements of serum cTnT in 41 patients with haematological malignant disorders who received a total of 85 chemotherapy courses, including anthracyclines at standard doses.4 cTnT concentrations rose in 20% of patients. By contrast with D Cardinale and colleagues5 who reported raised serum concentrations of cTnT 12–72 h after high-dose chemotherapy, we saw longterm rise of cTnT, with concentrations peaking more than 2 weeks after treatment. This finding is in accordance with those of S Lipshultz and colleagues in children and suggest that anthracyclines at standard doses cause long-term damage to the myofibrillar system. In most patients, we also measured left-ventricular ejection fraction by echocardiography. 5 months after completion of chemotherapy, we saw a significantly greater decrease in mean ejection fraction in patients with raised serum cTnT than in those without (10% vs 2%). No patient had clinically overt heart failure, however, the administered doses were lower than the commonly accepted thresholds for the development of anthracyclineassociated cardiomyopathy. These findings add further support to the notion that cTnT is a useful marker to identify individuals who are at increased risk of anthracycline-induced cardiac dysfunction. Since the time course in rises of serum troponins seems to vary depending on treatment protocols, applicability, and optimum schedule, troponin measurements will have to be determined for different regimens before routine monitoring of troponins in patients treated with anthracyclines is recommended. *Holger W Auner, Christoph Tinchon, Franz Quehenberger, Werner Linkesch, Heinz Sill Medizinische Universitäts klinik Institut für Medizinische Informatik, Karl-Franzens Universität, A-8036 Graz, Austria (e-mail: [email protected]) 1
2
3
4
5
Sparano JA, Wolff AC, Brown D. Troponins for predicting cardiotoxicity from cancer therapy. Lancet 2000; 356: 1947–48. Herman EH, Lipshultz SE, Rifai N, et al. Use of cardiac troponin T levels as an indicator of doxorubicin-induced cardiotoxicity. Cancer Res 1998; 58: 195–97. Lipshultz SE, Rifai N, Sallan SE, et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 1997; 96: 2641–48. Auner HW, Tinchon C, Linkesch W, et al. Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res 2000 (in press). Cardinale D, Sandri MT, Martinoni A, et al. Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. J Am Coll Cardiol 2000; 36: 517.
THE LANCET • Vol 357 • March 10, 2001
For personal use only. Reproduce with permission from The Lancet Publishing Group.