Bone Marrow Transplantation (2015) 50, 868–869 © 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15 www.nature.com/bmt
LETTER TO THE EDITOR
Serum free light chain trends between orthotopic heart transplantation and auto-SCT in patients with AL amyloidosis Bone Marrow Transplantation (2015) 50, 868–869; doi:10.1038/ bmt.2015.9; published online 9 March 2015
chain (FLC) levels in the interval between planned OHT and HDM/SCT, to help guide the need for treatment. Seventeen patients were treated following collaborative protocols at the Boston Medical Center Amyloidosis Center and the Massachusetts General Hospital Heart Failure Program, between 1997 and 2013. Data were reviewed with approval of both hospitals’ Institutional Review Boards. All patients had a diagnosis of AL amyloidosis; patients with symptomatic multiple myeloma (BM plasma cell percentage 430% or hypercalcemia, anemia or lytic bone disease) were not considered OHT candidates. Of the 17 patients who underwent planned OHT followed by HDM/SCT, 12 had FLC levels available pre- and post-OHT for assessment of progression of disease before HDM/SCT (Table 1). Their median age was 57 years (range 42–60), and 8 of the patients were male. Seven of the 12 patients received chemotherapy before OHT, consisting of melphalan and dexamethasone for 3 patients, bortezomib (single agent) for 1 patient, bortezomib and dexamethasone for 1 patient, CY with bortezomib and dexamethasone for 1 patient, and dexamethasone single agent for 1 patient, at the treating physician’s discretion. Following OHT, no further antiplasma cell treatment was administered. The patients were treated with a calcineurin inhibitor (CNI), prednisone, and mycophenolate mofetil (MMF) for immunosuppression; 1 patient received azathioprine instead of MMF owing to intolerance. Once patients were on a low-prednisone dose and without sign of organ rejection, and fully recovered from OHT, they underwent
Cardiac involvement, present in about 50% of patients, is the leading cause of morbidity and mortality in immunoglobulin light chain (AL) amyloidosis. Cardiac biomarkers can risk stratify the patients, and those with advanced (stage III)1 disease, who have the poorest prognosis, regardless of treatment, with a median survival of 3.5–7 months.2 High-dose melphalan and auto-SCT (HDM/SCT), which produces a high rate of hematologic responses,3 can be used in highly selected patients with stage III disease,4 but for most stage III patients, treatment-related mortality is high. The patients with advanced cardiac involvement and preserved function of other organs have undergone orthotopic heart transplantation (OHT), but OHT alone leaves patients susceptible to rapid recurrence of AL amyloidosis in the transplanted heart and other organs.5 We have found that although mortality on the waiting list is high for AL patients, if OHT is carried out successfully and is followed by HDM/SCT, survival is similar to that of patients undergoing OHT for other indications.6,7 Comparable data have been reported from the Mayo Clinic8 and the UK National Amyloidosis Centre.9 The need for antiplasma cell therapy while awaiting HDM/SCT has not been demonstrated, although in a case series of three patients, lenalidomide or bortezomib-based chemotherapy has been employed.10 Here we evaluate the changes in serum free light
Table 1.
Patient data
Patient Age, BM PC % ΔFLC at Other Treatment # gender at diagnosis organs pre-OHT diagnosis (mg/L) involved
Time between OHT and SCT (months)
ΔFLC ΔFLC prevariation SCT between (mg/ OHT and SCT L) (%)
GI
Mel/Dex
70.1
10
83.4
↑ 19
500.6 511.6 96.6 1085.9 724.5
ST PAN, ST PAN, ST ST R, ST
None None None Bort Bort/Dex
528.6 593.4 108.9 118.8 232.5
6 5 5 6 9
400.5 353.4 130 29.5 252
↓ 24 ↓ 40 ↑ 19 ↓ 75 ↑8
5–10
356.6
R, PAN
None
420.1
7
204.9
↓ 51
10–15 10–15 10 7 10
104.5 171.7 229.7 86.5 230.1
GI, L, ST None R, PAN R R, GI, ST
CyBorD Mel/Dex Mel/Dex None Dex
130.4 29.7 93.8 100 230.1
5 6 6 5 7
23.5 19.6 73.1 166.4 67.4
↓ ↓ ↓ ↑ ↓
1
59 F
2 3 4 5 6
42 54 57 56 58
M F M M F
10–15 o5 5 20–25 30
7
59 M
8 9 10 11 12
60 59 54 54 56
F M M M M
ΔFLC preOHT (mg/L)
10
69.9
82 34 22 66 71
ΔFLC response between OHT and SCT Stable
Mel Cause of dose death (days (mg/ post-SCT) m2)
140 Multiorgan failure (D+25) Stable 200 MR 200 Stable 140 PR 200 Stable 140 Cryptococcal fungemia (D+150) PR 200 Sepsis (D+150) PR 200 MR 180 Stable 180 Progression 180 PR 140 Sepsis (D+25)
Response, 12-month post-SCT
NA PR CR VGPR CR NA NA CR CR CR PR NA
Abbreviations: Bort = bortezomib; CyBorD = CY, bortezomib, dexamethasone; CT = chemotherapy; Dex = dexamethasone; F = female; ΔFLC = difference between involved and uninvolved free light chain; GI = gastrointestinal; L = liver; M = male; Mel = melphalan; MR = minor response; NA = not available; OHT = orthotopic heart transplantation; PAN = peripheral or autonomic nervous system; PC = plasma cell; R = renal; ST = soft tissue; VGPR = very good PR.
Letter to the Editor
869 can be explored in future clinical trials, as can the potential role of alternative antiplasma cell therapies rather than HDM/SCT.
700 600
CONFLICT OF INTEREST
ΔFLC (mg/L)
500
The authors declare no conflict of interest. 400 300 200 100 0
Pre-OHT
Pre-SCT
Figure 1. Trends in serum FLC levels expressed as ΔFLC (mg/L) from time before OHT to time before high-dose melphalan chemotherapy and pre-auto-SCT. Each line represents an individual patient.
planned HDM/SCT at a median of 6 months later (range 5–10). Median follow-up of 8 surviving patients was 38.1 months (range 3–54). The ΔFLC, defined as the difference between involved and uninvolved FLC level, was used to assess the changes in the underlying plasma cell disease during the period between OHT and HDM/SCT (Figure 1). In four patients, the ΔFLC declined more than 50% during this period, consistent with a PR, two patients had a minor response (ΔFLC reduction of 25–50%) and five patients had a stable ΔFLC; only one patient had progression of disease, with an increase in ΔFLC of 450%. Responses were seen in four of seven patients who received the antiplasma cell treatment before OHT and two of five who did not; it is not clear if the pre-OHT treatment contributed to the the ΔFLC changes in subsequent months. Two patients (17%) died within 100 days of HDM/SCT, one from complications of multiorgan dysfunction from amyloidosis and the other from septic shock. At 12 months post HDM/SCT, survival was 58% (one patient not evaluable), and all evaluable patients obtained at least a hematologic PR. No statistically significant difference in survival was detected on the basis of plasma cell burden at diagnosis or on administration, or not of treatment pre-OHT. In conclusion, in this series of 12 patients, only 1 patient had evidence of hematologic progression of disease during the 5- to 10-month period between OHT and HDM/SCT, suggesting that the combination of CNI, corticosteroid and MMF may control the underlying plasma cell dyscrasia during this time. This hypothesis
© 2015 Macmillan Publishers Limited
AS Renteria1, V Sanchorawala1, ED Niehaus2, F Sun3, MJ Semigran2 and DC Seldin1 1 Amyloidosis Center, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA; 2 Heart Failure and Cardiac Transplant Program, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA and 3 Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA E-mail: [email protected] REFERENCES 1 Wechalekar AD, Schonland SO, Kastritis E, Gillmore JD, Dimopoulos MA, Lante T et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood 2013; 121: 3420–3427. 2 Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM 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. 3 Cibeira MT, Sanchorawala V, Seldin DC, Quillen K, Berk JL, Dember LM et al. Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. Blood 2011; 118: 4346–4352. 4 Girnius S, Seldin DC, Meier-Ewert HK, Sloan JM, Quillen K, Ruberg FL et al. Safety and efficacy of high-dose melphalan and auto-SCT in patients with AL amyloidosis and cardiac involvement. Bone Marrow Transplant 2014; 49: 434–439. 5 Hosenpud JD, DeMarco T, Frazier OH, Griffith BP, Uretsky BF, Menkis AH et al. Progression of systemic disease and reduced long-term survival in patients with cardiac amyloidosis undergoing heart transplantation. Follow-up results of a multicenter survey. Circulation 1991; 84(5 Suppl): III338–III343. 6 Dey BR, Chung SS, Spitzer TR, Zheng H, Macgillivray TE, Seldin DC et al. Cardiac transplantation followed by dose-intensive melphalan and autologous stem cell transplantation for light chain amyloidosis and heart failure. Transplantation 2010; 90: 905–911. 7 Gray GL, Niehaus E, Malhotra R, Ton VK, Watts J, Seldin DC et al. Predictors of survival to orthotopic heart transplant in patients with light chain amyloidosis. J Heart Lung Transplant 2014; 33: 149–156. 8 Lacy MQ, Dispenzieri A, Hayman SR, Kumar S, Kyle RA, Rajkumar SV et al. Autologous stem cell transplant after heart transplant for light chain (AL) amyloid cardiomyopathy. J Heart Lung Transplant 2008; 27: 823–829. 9 Gillmore JD, Goodman HJ, Lachmann HJ, Offer M, Wechalekar AD, Joshi J et al. Sequential heart and autologous stem cell transplantation for systemic AL amyloidosis. Blood 2006; 107: 1227–1229. 10 Varr BC, Liedtke M, Arai S, Lafayette RA, Schrier SL, Wittleles RM. Heart transplantation and cardiac amyloidosis: approach to screening and novel management strategies. J Heart Lung Transplant 2012; 31: 325–331.
Bone Marrow Transplantation (2015) 868 – 869
LETTER TO THE EDITOR
Serum free light chain trends between orthotopic heart transplantation and auto-SCT in patients with AL amyloidosis Bone Marrow Transplantation (2015) 50, 868–869; doi:10.1038/ bmt.2015.9; published online 9 March 2015
chain (FLC) levels in the interval between planned OHT and HDM/SCT, to help guide the need for treatment. Seventeen patients were treated following collaborative protocols at the Boston Medical Center Amyloidosis Center and the Massachusetts General Hospital Heart Failure Program, between 1997 and 2013. Data were reviewed with approval of both hospitals’ Institutional Review Boards. All patients had a diagnosis of AL amyloidosis; patients with symptomatic multiple myeloma (BM plasma cell percentage 430% or hypercalcemia, anemia or lytic bone disease) were not considered OHT candidates. Of the 17 patients who underwent planned OHT followed by HDM/SCT, 12 had FLC levels available pre- and post-OHT for assessment of progression of disease before HDM/SCT (Table 1). Their median age was 57 years (range 42–60), and 8 of the patients were male. Seven of the 12 patients received chemotherapy before OHT, consisting of melphalan and dexamethasone for 3 patients, bortezomib (single agent) for 1 patient, bortezomib and dexamethasone for 1 patient, CY with bortezomib and dexamethasone for 1 patient, and dexamethasone single agent for 1 patient, at the treating physician’s discretion. Following OHT, no further antiplasma cell treatment was administered. The patients were treated with a calcineurin inhibitor (CNI), prednisone, and mycophenolate mofetil (MMF) for immunosuppression; 1 patient received azathioprine instead of MMF owing to intolerance. Once patients were on a low-prednisone dose and without sign of organ rejection, and fully recovered from OHT, they underwent
Cardiac involvement, present in about 50% of patients, is the leading cause of morbidity and mortality in immunoglobulin light chain (AL) amyloidosis. Cardiac biomarkers can risk stratify the patients, and those with advanced (stage III)1 disease, who have the poorest prognosis, regardless of treatment, with a median survival of 3.5–7 months.2 High-dose melphalan and auto-SCT (HDM/SCT), which produces a high rate of hematologic responses,3 can be used in highly selected patients with stage III disease,4 but for most stage III patients, treatment-related mortality is high. The patients with advanced cardiac involvement and preserved function of other organs have undergone orthotopic heart transplantation (OHT), but OHT alone leaves patients susceptible to rapid recurrence of AL amyloidosis in the transplanted heart and other organs.5 We have found that although mortality on the waiting list is high for AL patients, if OHT is carried out successfully and is followed by HDM/SCT, survival is similar to that of patients undergoing OHT for other indications.6,7 Comparable data have been reported from the Mayo Clinic8 and the UK National Amyloidosis Centre.9 The need for antiplasma cell therapy while awaiting HDM/SCT has not been demonstrated, although in a case series of three patients, lenalidomide or bortezomib-based chemotherapy has been employed.10 Here we evaluate the changes in serum free light
Table 1.
Patient data
Patient Age, BM PC % ΔFLC at Other Treatment # gender at diagnosis organs pre-OHT diagnosis (mg/L) involved
Time between OHT and SCT (months)
ΔFLC ΔFLC prevariation SCT between (mg/ OHT and SCT L) (%)
GI
Mel/Dex
70.1
10
83.4
↑ 19
500.6 511.6 96.6 1085.9 724.5
ST PAN, ST PAN, ST ST R, ST
None None None Bort Bort/Dex
528.6 593.4 108.9 118.8 232.5
6 5 5 6 9
400.5 353.4 130 29.5 252
↓ 24 ↓ 40 ↑ 19 ↓ 75 ↑8
5–10
356.6
R, PAN
None
420.1
7
204.9
↓ 51
10–15 10–15 10 7 10
104.5 171.7 229.7 86.5 230.1
GI, L, ST None R, PAN R R, GI, ST
CyBorD Mel/Dex Mel/Dex None Dex
130.4 29.7 93.8 100 230.1
5 6 6 5 7
23.5 19.6 73.1 166.4 67.4
↓ ↓ ↓ ↑ ↓
1
59 F
2 3 4 5 6
42 54 57 56 58
M F M M F
10–15 o5 5 20–25 30
7
59 M
8 9 10 11 12
60 59 54 54 56
F M M M M
ΔFLC preOHT (mg/L)
10
69.9
82 34 22 66 71
ΔFLC response between OHT and SCT Stable
Mel Cause of dose death (days (mg/ post-SCT) m2)
140 Multiorgan failure (D+25) Stable 200 MR 200 Stable 140 PR 200 Stable 140 Cryptococcal fungemia (D+150) PR 200 Sepsis (D+150) PR 200 MR 180 Stable 180 Progression 180 PR 140 Sepsis (D+25)
Response, 12-month post-SCT
NA PR CR VGPR CR NA NA CR CR CR PR NA
Abbreviations: Bort = bortezomib; CyBorD = CY, bortezomib, dexamethasone; CT = chemotherapy; Dex = dexamethasone; F = female; ΔFLC = difference between involved and uninvolved free light chain; GI = gastrointestinal; L = liver; M = male; Mel = melphalan; MR = minor response; NA = not available; OHT = orthotopic heart transplantation; PAN = peripheral or autonomic nervous system; PC = plasma cell; R = renal; ST = soft tissue; VGPR = very good PR.
Letter to the Editor
869 can be explored in future clinical trials, as can the potential role of alternative antiplasma cell therapies rather than HDM/SCT.
700 600
CONFLICT OF INTEREST
ΔFLC (mg/L)
500
The authors declare no conflict of interest. 400 300 200 100 0
Pre-OHT
Pre-SCT
Figure 1. Trends in serum FLC levels expressed as ΔFLC (mg/L) from time before OHT to time before high-dose melphalan chemotherapy and pre-auto-SCT. Each line represents an individual patient.
planned HDM/SCT at a median of 6 months later (range 5–10). Median follow-up of 8 surviving patients was 38.1 months (range 3–54). The ΔFLC, defined as the difference between involved and uninvolved FLC level, was used to assess the changes in the underlying plasma cell disease during the period between OHT and HDM/SCT (Figure 1). In four patients, the ΔFLC declined more than 50% during this period, consistent with a PR, two patients had a minor response (ΔFLC reduction of 25–50%) and five patients had a stable ΔFLC; only one patient had progression of disease, with an increase in ΔFLC of 450%. Responses were seen in four of seven patients who received the antiplasma cell treatment before OHT and two of five who did not; it is not clear if the pre-OHT treatment contributed to the the ΔFLC changes in subsequent months. Two patients (17%) died within 100 days of HDM/SCT, one from complications of multiorgan dysfunction from amyloidosis and the other from septic shock. At 12 months post HDM/SCT, survival was 58% (one patient not evaluable), and all evaluable patients obtained at least a hematologic PR. No statistically significant difference in survival was detected on the basis of plasma cell burden at diagnosis or on administration, or not of treatment pre-OHT. In conclusion, in this series of 12 patients, only 1 patient had evidence of hematologic progression of disease during the 5- to 10-month period between OHT and HDM/SCT, suggesting that the combination of CNI, corticosteroid and MMF may control the underlying plasma cell dyscrasia during this time. This hypothesis
© 2015 Macmillan Publishers Limited
AS Renteria1, V Sanchorawala1, ED Niehaus2, F Sun3, MJ Semigran2 and DC Seldin1 1 Amyloidosis Center, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA; 2 Heart Failure and Cardiac Transplant Program, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA and 3 Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA E-mail: [email protected] REFERENCES 1 Wechalekar AD, Schonland SO, Kastritis E, Gillmore JD, Dimopoulos MA, Lante T et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood 2013; 121: 3420–3427. 2 Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM 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. 3 Cibeira MT, Sanchorawala V, Seldin DC, Quillen K, Berk JL, Dember LM et al. Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. Blood 2011; 118: 4346–4352. 4 Girnius S, Seldin DC, Meier-Ewert HK, Sloan JM, Quillen K, Ruberg FL et al. Safety and efficacy of high-dose melphalan and auto-SCT in patients with AL amyloidosis and cardiac involvement. Bone Marrow Transplant 2014; 49: 434–439. 5 Hosenpud JD, DeMarco T, Frazier OH, Griffith BP, Uretsky BF, Menkis AH et al. Progression of systemic disease and reduced long-term survival in patients with cardiac amyloidosis undergoing heart transplantation. Follow-up results of a multicenter survey. Circulation 1991; 84(5 Suppl): III338–III343. 6 Dey BR, Chung SS, Spitzer TR, Zheng H, Macgillivray TE, Seldin DC et al. Cardiac transplantation followed by dose-intensive melphalan and autologous stem cell transplantation for light chain amyloidosis and heart failure. Transplantation 2010; 90: 905–911. 7 Gray GL, Niehaus E, Malhotra R, Ton VK, Watts J, Seldin DC et al. Predictors of survival to orthotopic heart transplant in patients with light chain amyloidosis. J Heart Lung Transplant 2014; 33: 149–156. 8 Lacy MQ, Dispenzieri A, Hayman SR, Kumar S, Kyle RA, Rajkumar SV et al. Autologous stem cell transplant after heart transplant for light chain (AL) amyloid cardiomyopathy. J Heart Lung Transplant 2008; 27: 823–829. 9 Gillmore JD, Goodman HJ, Lachmann HJ, Offer M, Wechalekar AD, Joshi J et al. Sequential heart and autologous stem cell transplantation for systemic AL amyloidosis. Blood 2006; 107: 1227–1229. 10 Varr BC, Liedtke M, Arai S, Lafayette RA, Schrier SL, Wittleles RM. Heart transplantation and cardiac amyloidosis: approach to screening and novel management strategies. J Heart Lung Transplant 2012; 31: 325–331.
Bone Marrow Transplantation (2015) 868 – 869
