Monitoring organ response in amyloidosis
http://www.100md.com
《血液学杂志》
Palladini and colleagues demonstrate that NT-proBNP can be measured serially to detect cardiac responses in patients with immunoglobulin light chain amyloidosis following therapy designed to reduce the plasma-cell burden in the bone marrow.
Evaluating responses in light chain amyloidosis (AL) is more difficult than in multiple myeloma. Historically, hematologic responses were difficult to quantify because nearly half of the patients had Bence Jones proteinemia and did not have a measurable M protein. In addition, the light chains in the urine are obscured by the albuminuria. The introduction of the immunoglobulin light chain assay allows serial measurements and assists the hematologist in assessing a therapeutic intervention.1
However, the hematologic response is no more than a surrogate for the key end point, which is improvement in organ function of an amyloid-involved tissue. Organ responses are equally difficult to evaluate because they are often delayed and difficult to quantify. With renal amyloidosis, the 24-hour urine protein is an easily assessed end point. Historically, assessment of cardiac involvement was the clinical presence of congestive heart failure with a median survival of 3 months. In the 1970s, clinical assessment was supplanted by the use of 2-dimensional echocardiography. Echocardiography is limited, however, in that reproducibility is often operator-dependent, and measurement of the thickness of the left ventricular wall can vary by 2 to 3 mm without reflecting a real change in the extent of amyloid deposition. It has been demonstrated that the NT-proBNP is a sensitive marker for cardiac amyloidosis2 (see figure). These cardiac biomarkers can now be used to predict outcomes in cardiac AL.3 In this issue of Blood, Palladini and colleagues report that the serialized measurement of NT-proBNP parallels the extent of cardiac response following chemotherapy. Moreover, these responses correlated with free light chain reduction, predictive of organ response. The correlation with traditional echocardiography was poor.
Impact of serum BNP on survival of AL patients following stem-cell transplantation at Mayo Clinic.
The ability to accurately assess cardiac improvement raises important future questions. How much free light chain reduction is really required for an organ response in amyloidosis? Does a 50% reduction in free light chain levels predict a superior outcome as it does in multiple myeloma, or does the light chain have to be completely eradicated in order to prevent further amyloid deposition in tissues? Since cardiac function can improve without a reduction in the wall thickness by echo, is the myocardial dysfunction in amyloidosis not directly related to fibril deposition but soluble intermediates that are rapidly cleared following successful chemotherapy?
The ability to accurately measure cardiac response will be of assistance in elucidating the controversial role of stem-cell transplantation in the management of amyloidosis. Although single-arm studies have suggested high response rates,4 a recent phase 3 study was unable to demonstrate a survival benefit for patients undergoing transplantation.5 The NT-proBNP will allow risk assessment in future trials to ensure that arms are balanced for cardiac involvement. What does this mean for the practicing hematologist? This represents an important practice change. Serialized measurement of NT-proBNP to assess cardiac outcomes in amyloidosis should become the new standard of care.
References
Dispenzieri A, Lacy MQ, Katzmann JA, et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplant. Blood. Prepublished on January 5, 2006, as DOI 10.1182/blood-2005-07-2922.
Palladini G, Campana C, Klersy C, et al. Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation. 2003;107: 2440-2445.
Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol. 2004;22: 3751-3757.
Leung N, Dispenzieri A, Fervenza FC, et al. Renal response after high-dose melphalan and stem cell transplantation is a favorable marker in patients with primary systemic amyloidosis. Am J Kidney Dis. 2005;46: 270-277.
Jaccard A, Moreau P, Leblond V, et al. Autologous stem cell transplantation (ASCT) versus oral melphalan and high-dose dexamethasone in patients with AL (primary)amyloidosis: results of the French Multicentric Randomized Trial (MAGandIFM Intergroup). Blood.2005;106: 127a. Abstract 421.(Morie A. Gertz)
Evaluating responses in light chain amyloidosis (AL) is more difficult than in multiple myeloma. Historically, hematologic responses were difficult to quantify because nearly half of the patients had Bence Jones proteinemia and did not have a measurable M protein. In addition, the light chains in the urine are obscured by the albuminuria. The introduction of the immunoglobulin light chain assay allows serial measurements and assists the hematologist in assessing a therapeutic intervention.1
However, the hematologic response is no more than a surrogate for the key end point, which is improvement in organ function of an amyloid-involved tissue. Organ responses are equally difficult to evaluate because they are often delayed and difficult to quantify. With renal amyloidosis, the 24-hour urine protein is an easily assessed end point. Historically, assessment of cardiac involvement was the clinical presence of congestive heart failure with a median survival of 3 months. In the 1970s, clinical assessment was supplanted by the use of 2-dimensional echocardiography. Echocardiography is limited, however, in that reproducibility is often operator-dependent, and measurement of the thickness of the left ventricular wall can vary by 2 to 3 mm without reflecting a real change in the extent of amyloid deposition. It has been demonstrated that the NT-proBNP is a sensitive marker for cardiac amyloidosis2 (see figure). These cardiac biomarkers can now be used to predict outcomes in cardiac AL.3 In this issue of Blood, Palladini and colleagues report that the serialized measurement of NT-proBNP parallels the extent of cardiac response following chemotherapy. Moreover, these responses correlated with free light chain reduction, predictive of organ response. The correlation with traditional echocardiography was poor.
Impact of serum BNP on survival of AL patients following stem-cell transplantation at Mayo Clinic.
The ability to accurately assess cardiac improvement raises important future questions. How much free light chain reduction is really required for an organ response in amyloidosis? Does a 50% reduction in free light chain levels predict a superior outcome as it does in multiple myeloma, or does the light chain have to be completely eradicated in order to prevent further amyloid deposition in tissues? Since cardiac function can improve without a reduction in the wall thickness by echo, is the myocardial dysfunction in amyloidosis not directly related to fibril deposition but soluble intermediates that are rapidly cleared following successful chemotherapy?
The ability to accurately measure cardiac response will be of assistance in elucidating the controversial role of stem-cell transplantation in the management of amyloidosis. Although single-arm studies have suggested high response rates,4 a recent phase 3 study was unable to demonstrate a survival benefit for patients undergoing transplantation.5 The NT-proBNP will allow risk assessment in future trials to ensure that arms are balanced for cardiac involvement. What does this mean for the practicing hematologist? This represents an important practice change. Serialized measurement of NT-proBNP to assess cardiac outcomes in amyloidosis should become the new standard of care.
References
Dispenzieri A, Lacy MQ, Katzmann JA, et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplant. Blood. Prepublished on January 5, 2006, as DOI 10.1182/blood-2005-07-2922.
Palladini G, Campana C, Klersy C, et al. Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation. 2003;107: 2440-2445.
Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol. 2004;22: 3751-3757.
Leung N, Dispenzieri A, Fervenza FC, et al. Renal response after high-dose melphalan and stem cell transplantation is a favorable marker in patients with primary systemic amyloidosis. Am J Kidney Dis. 2005;46: 270-277.
Jaccard A, Moreau P, Leblond V, et al. Autologous stem cell transplantation (ASCT) versus oral melphalan and high-dose dexamethasone in patients with AL (primary)amyloidosis: results of the French Multicentric Randomized Trial (MAGandIFM Intergroup). Blood.2005;106: 127a. Abstract 421.(Morie A. Gertz)