research paper
Autologous stem cell transplant is an effective therapy for carefully selected patients with AL amyloidosis: experience of a single institution
Victor H. Jimenez-Zepeda,1 Norman Franke,1 Donna E. Reece,1 Suzanne Trudel,1 Christine Chen,1 Diego H. Delgado,2 Andrew Winter,1 Joseph R. Mikhael,3 Rodger Tiedemann1 and Vishal Kukreti1 1
Department of Medical Oncology and Haematology, Princess Margaret Cancer Center, 2
Division of Cardiology and Heart Transplanta-
tion, University Health Network, Toronto, ON, Canada and 3Division of Haematology and Oncology, Mayo Clinic in Arizona, Scottsdale, AZ, USA Received 16 September 2013; accepted for publication 13 October 2013 Correspondence: Vishal Kukreti, MD, Department of Medical Oncology and Haematology, Princess Margaret Cancer Center, Suite 5-100, Toronto, ON M5G 2M9, Canada.
Summary Autologous stem-cell transplant has been widely used to treat patients with AL amyloidosis. However, transplant-related mortality rates are high, and a recent randomized trial suggested that non-transplant regimens produced comparable results with less toxicity. In order to define the role of patient selection in stem cell transplantation, we evaluated 78 consecutive AL amyloidosis patients transplanted at our centre. Transplant-related mortality occurred in 115%. Complete haematological response and organ response were achieved in 56% and 60%. Median overall survival was significantly lower for patients with brain-type natriuretic peptide (BNP) >300 pg/ml (175 months vs. not-reached) (P = 00004), troponin-I >007 ng/ml (135 months vs. not-reached) (P = 000001) and those not achieving a complete haematological response (88 months vs. not-reached) (P = 00345); high BNP and troponin-I were the most important predictive factors in a multivariate analysis. Based on this study, patients with BNP 10% plasma cells in the bone marrow were carefully assessed to rule out the concomitant presence of myeloma. We excluded patients with ejection fraction 460 lmol/l, lactate dehydrogenase (LDH) >350 iu/l, C-reactive protein (CRP) >20 mg/l, albumin 200 mmol/l, BNP >300 pg/ml, troponin-I >007 ng/ml and free-light chain (FLC) difference >180 mg/l). Survival curves were constructed according to the Kaplan–Meier method and compared using the log rank test.
Results Clinical characteristics A total of 78 patients with AL amyloidosis underwent ASCT between January 2004 and March 2010. Clinical characteristics are shown in Table I. Renal involvement was the most commonly seen (718%) followed by cardiac (474%) and hepatic (231%). Twenty-percent of the patients transplanted at our centre had >3 organs affected. Most patients did not receive induction therapy (769%). Blood stem cells were mobilized in all patients using growth factors only. The median number of CD34-positive cells collected was 43 9 106/l/kg body weight. Patients received HDM at 200 mg/m2 (244%), 140 mg/m2 (564%) or 100 mg/m2 (192%), given intravenously on day 1 as per risk-adapted therapy, and stem cells were infused on day 0.(Cohen et al, 2007) The median length of hospital stay was 17 d (12–43), and the median length of time to a platelet count ≥50 9 109/l and neutrophil count ≥05 9 109/l were 17 d (15–26) and 12 d (10–15), respectively. The all-cause day-100 mortality was 115%, most commonly due to multi-organ failure, culminating in respiratory distress syndrome and ventilatory failure similar to that previously reported.(Gertz et al, 2011) Common transplantrelated complications were febrile neutropenia (66%), transient renal impairment (103%) and congestive heart failure (3%). A HR was seen in 61 out of 78 patients (78%) and included complete and partial responses in 39 (50%) and 22 (282%) patients respectively; nine died before assessment of HR (115%). OR included renal in 47 out of 69 (60%) evaluable patients and cardiac in 17 out of 33 (51%) evaluable patients. (Table II).
Survival At a mean follow-up of 122 months, sixty patients are still alive and 29 (37%) had already progressed. Median time to 723
V. H. Jimenez-Zepeda et al Table I. Clinical and laboratory characteristics of patients with AL amyloidosis undergoing autologous stem cell transplantation.
Age (years) Gender Male Female IgG kappa IgG lambda IgA lambda IgM kappa IgM lambda Free kappa Free lambda Renal involvement Cardiac involvement Hepatic involvement 3 or more organs involved by AL Gastrointestinal involvement Haemoglobin (g/l) Creatinine (lmol/l) Albumin (g/l) Alkaline phosphatase (units/l) B2-Microglobulin (lmol/l) 24-hProteinuria (g/d) Bone marrow plasma cells (%) Interventricular septal thickness (mm) Ejection fraction (%) Troponin-I (ng/ml) (normal460 lmol/l, LDH >350 iu/l, CRP >20 mg/ l, albumin 200 mmol/l, BNP >300 pg/ml and troponin-I > 007 ng/ml (P > 005 for all of them). It is clear that some patients maintain disease-progression free status for more than 8 years after ASCT, as shown in Fig 2. Furthermore, patients who achieved CHR experienced a longer PFS versus those who did not (97 months, 95% ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2014, 164, 722–728
ASCT for AL Amyloidosis confidence interval [CI], 77–116 vs. 435 months, 95% CI 31–56, P = 00001, respectively) (Fig 2). Median OS was significantly shorter for patients with BNP levels >300 pg/ml (175 months vs. NR; P = 00004) (Fig 3), troponin-I levels >007 ng/ml (135 months vs. NR; P = 000001) (Fig 4) and those who did not achieve a CHR (88 months vs. NR; P = 00345) (Fig 5). BNP >300 pg/mL and troponin-I >007 ng/mL were seen in 9/62 and 6/45 patients, where these markers were available. However, no cases with both markers elevated were seen in our group. Multivariate Cox regression analysis showed that levels of BNP >300 pg/ml and troponin-I >007 ng/ml were the most important factors predictive of OS for patients with AL amyloidosis who underwent ASCT (Hazard Ratio 174, 95% CI 027–080, P = 00002 and Hazard Ratio 171, 95% CI 016–098, P = 004, respectively). Median OS for patients who achieved CHR has not been reached versus 8817 months for those who did not achieve CHR (P = 00345). When patients with BNP >300 pg/ml and troponin-I >007 ng/ml were excluded from the analysis, the transplant-related mortality decreased to 38%.
organs.(Skinner et al, 2004) However, some contradictory data has been presented, for instance, a meta-analysis of ASCT studies concluded that stem cell transplant remains an unproven technique for the treatment of amyloidosis.(Mhaskar et al, 2009) The conclusions of the meta-analysis by Mhaskar et al (2009), which evaluated high-dose chemotherapy with
Discussion
Fig 4. Differences in overall survival between AL amyloidosis patients undergoing autologous stem cell transplantation (ASCT) according to the levels of troponin-I. Patients with abnormal troponin-I (≥007 ng/ml) exhibited a shorter median OS (135 months vs. Not Reached) (P = 000001). Cum survival, cumulative survival; Normal Trop-I, Troponin-I 300 >300-censored
0·2
40
60
80
100
Months since ASCT Number at risk BNP300
6
3
1
0
0
0
Complete Response
0·4
NOT CR NOT CR-censored
0·2
007 ng/ml (66% vs. 145%, P = 0011). The use of troponin-I and BNP as prognostication markers in patients undergoing ASCT has been explored less extensively than the more sensitive assays (cTnT and NT-Pro-BNP). Interestingly, a borderline effect of troponin-I on OS, but no effect of both troponin-I and BNP on OS and PFS when measured at 3 and 12 months post-ASCT were reported by Cohen et al (2007), the reasons for this are not clear and were felt to be associated with variability of the BNP assays. Furthermore, univariate analysis of a large series of 421 patients transplanted with AL amyloidosis showed an association of low levels of BNP with better OS, however the multivariate analysis failed to show the same impact.(Cibeira et al, 2011).
Is there any role for novel agent induction chemotherapy? Impact of cardiac biomarkers Given the dominant effect of cardiac involvement on prognosis, it is not surprising that markers of cardiac injury and dysfunction emerge as powerful prognostic factors in AL.(Dispenzieri et al, 2003; Palladini et al, 2003) Cardiac muscle injury is associated with troponin release, which provides a sensitive and specific marker of cardiac injury. Recently, Apridonidze et al (2012) reported on the role of increased troponin-I in patients with cardiac amyloidosis, using the same cut-off reported in the present study. By using a more sensitive troponin assay (cTnT), the Mayo Clinic group used a cut-off of >0025 ng/ml as part of the prognostic model in patients with AL amyloidosis in different clinical phases (i.e., stem cell transplant, conventional chemotherapy or clinical trial patients).(Kumar et al, 2012) On the other hand, BNP is a powerful predictor of outcome in CHF. (Iwanaga et al, 2006). BNP is elevated in states of increased ventricular wall stress and is most commonly used to rule out CHF in dyspneic patients. BNP levels are influenced by age, gender and body mass index.(Iwanaga et al, 2006) This variation across clinical settings has significant implications given the increasing frequency with which BNP testing is being performed. Given that BNP levels are used at 726
Whether novel agent induction chemotherapy might help to improve outcomes and transform ASCT ineligible patients into candidates for this therapy remains unknown. Data in this regard has been collected by our group showing that patients who are ineligible for upfront ASCT could be treated with bortezomib-containing induction regimens, some of whom were successfully transplanted if clinical and biochemical (BNP and troponin-I) improvement were seen without increasing risk of death (Unpublished data). ASCT after a bortezomib-based induction regimen may also improve the proportion of patients achieving complete remission. However, that remains to be shown in clinical trials. Additionally, this report describes that the achievement of a good haematological response is a feasible target for those patients receiving melphalan in a risk-adapted model. Patients receiving melphalan at 100 mg/m2 exhibited an overall response rate of 93%, while that of patients receiving melphalan at 140 mg/m2 was 77%. Nonetheless, our findings justify the use of inclusion criteria requiring preserved organ function and clinical performance status, and also highlight the importance of serum cardiac biomarkers while selecting the best group of patients to whom we can offer ASCT wisely. It also demonstrates the ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2014, 164, 722–728
ASCT for AL Amyloidosis significant selection bias that impacts most reports of ASCT for AL amyloidosis where patients have preserved performance status and normal renal, hepatic and cardiac function at the time of transplant. As reported by Dispenzieri et al (2001), eligibility for ASCT is, in itself, a favourable prognostic factor for survival. In summary, improved supportive care and refined patient selection have improved the safety of patients undergoing ASCT. We believe that ASCT is an effective therapy for some very carefully selected patients with AL amyloidosis. Prospective and randomized trials are needed to better define the role of ASCT in AL amyloidosis.
References Apridonidze, T., Steingart, R.M., Comenzo, R.L., Hoffman, J., Goldsmith, Y., Bella, J.N., Landau, H. & Liu, J.E. (2012) Clinical and echocardiographic correlates of elevated troponin in amyloid light-chain cardiac amyloidosis. American Journal of Cardiology, 110, 1180–1184. Cibeira, M.T., Sanchorawala, V., Seldin, D.C., Quillen, K., Berk, J.L., Dember, L.M., Segal, A., Ruberg, F., Meier-Ewert, H., Andrea, N.T., Sloan, J.M., Finn, K.T., Doros, G., Blade, J. & Skinner, M. (2011) Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. Blood, 118, 4346–4352. Cohen, A.D., Zhou, P., Chou, J., Teruya-Feldstein, J., Reich, L., Hassoun, H., Levine, B., Filippa, D.A., Riedel, E., Kewalramani, T., Stubblefield, M.D., Fleisher, M., Nimer, S. & Comenzo, R.L. (2007) Risk-adapted autologous stem cell transplantation with adjuvant dexamethasone +/- thalidomide for systemic light-chain amyloidosis: results of a phase II trial. British Journal of Haematology, 139, 224–233. Comenzo, R.L. (2000) Hematopoietic cell transplantation for primary systemic amyloidosis: what have we learned. Leukaemia & Lymphoma, 37, 245–258. wComenzo, R.L. (2006) Systemic immunoglobulin light-chain amyloidosis. Clin Lymphoma Myeloma, 7, 182–185. Dispenzieri, A., Lacy, M.Q., Kyle, R.A., Therneau, T.M., Larson, D.R., Rajkumar, S.V., Fonseca, R., Greipp, P.R., Witzig, T.E., Lust, J.A. & Gertz, M.A. (2001) Eligibility for hematopoietic stemcell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival. Journal of Clinical Oncology, 19, 3350–3356. Dispenzieri, A., Kyle, R.A., Gertz, M.A., Therneau, T.M., Miller, W.L., Chandrasekaran, K., McConnell, J.P., Burritt, M.F. & Jaffe, A.S. (2003) Survival in patients with primary systemic amyloidosis and raised serum cardiac troponins. Lancet, 361, 1787–1789. Dispenzieri, A., Kyle, R.A., Lacy, M.Q., Therneau, T.M., Larson, D.R., Plevak, M.F., Rajkumar, S.V., Fonseca, R., Greipp, P.R., Witzig, T.E.,
Authorship and disclosures VJZ and VK performed research, collected, analysed, interpreted data, performed statistical analysis and wrote the manuscript; NF, DD, AW and JM designed research, analysed and interpreted data and wrote the manuscript; and DR, ST, RT and CC designed research, analysed and interpreted data, performed statistical analysis and wrote the manuscript. The authors declare no competing financial interests. This manuscript was partly presented at the Amyloid Symposium 2012.
Lust, J.A., Zeldenrust, S.R., Snow, D.S., Hayman, S.R., Litzow, M.R., Gastineau, D.A., Tefferi, A., Inwards, D.J., Micallef, I.N., Ansell, S.M., Porrata, L.F., Elliott, M.A. & Gertz, M.A. (2004) Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case–control study. Blood, 103, 3960–3963. Gertz, M.A., Lacy, M.Q., Dispenzieri, A. & Hayman, S.R. (2005a) Amyloidosis: diagnosis and management. Clin Lymphoma Myeloma, 6, 208–219. Gertz, M.A., Comenzo, R., Falk, R.H., Fermand, J.P., Hazenberg, B.P., Hawkins, P.N., Merlini, G., Moreau, P., Ronco, P., Sanchorawala, V., Sezer, O., Solomon, A. & Grateau, G. (2005b) Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18–22 April 2004. American Journal of Hematology, 79, 319–328. Gertz, M.A., Lacy, M.Q., Dispenzieri, A., Hayman, S.R., Kumar, S.K., Dingli, D., Ansell, S.M., Gastineau, D.A., Inwards, D.J., Johnston, P.B., Litzow, M.R., Micallef, I.N., Porrata, L.F., Leung, N., Hogan, W.J. & Buadi, F.K. (2010) Autologous stem cell transplant for immunoglobulin light chain amyloidosis: a status report. Leukaemia & Lymphoma, 51, 2181–2187. Gertz, M.A., Lacy, M.Q., Dispenzieri, A., Kumar, S.K., Buadi, F.K., Dingli, D., Leung, N., Hogan, W.J. & Hayman, S.R. (2011) Trends in day 100 and 2-year survival after auto-SCT for AL amyloidosis: outcomes before and after 2006. Bone Marrow Transplantation, 46, 970–975. Iwanaga, Y., Nishi, I., Furuichi, S., Noguchi, T., Sase, K., Kihara, Y., Goto, Y. & Nonogi, H. (2006) B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure. Journal of the American College of Cardiology, 47, 742–748. Jaccard, A., Moreau, P., Leblond, V., Leleu, X., Benboubker, L., Hermine, O., Recher, C., Asli, B., Lioure, B., Royer, B., Jardin, F., Bridoux, F., Grosbois, B., Jaubert, J., Piette, J.C., Ronco, P., Quet, F., Cogne, M. & Fermand, J.P. (2007) High-dose melphalan versus melphalan plus
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dexamethasone for AL amyloidosis. New England Journal of Medicine, 357, 1083–1093. Kumar, S., Dispenzieri, A., Lacy, M.Q., Hayman, S.R., Buadi, F.K., Colby, C., Laumann, K., Zeldenrust, S.R., Leung, N., Dingli, D., Greipp, P.R., Lust, J.A., Russell, S.J., Kyle, R.A., Rajkumar, S.V. & Gertz, M.A. (2012) Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. Journal of Clinical Oncology, 30, 989–995. Kyle, R.A., Gertz, M.A., Greipp, P.R., Witzig, T.E., Lust, J.A., Lacy, M.Q. & Therneau, T.M. (1999) Long-term survival (10 years or more) in 30 patients with primary amyloidosis. Blood, 93, 1062–1066. Lebovic, D., Hoffman, J., Levine, B.M., Hassoun, H., Landau, H., Goldsmith, Y., Maurer, M.S., Steingart, R.M., Cohen, A.D. & Comenzo, R.L. (2008) Predictors of survival in patients with systemic light-chain amyloidosis and cardiac involvement initially ineligible for stem cell transplantation and treated with oral melphalan and dexamethasone. British Journal of Haematology, 143, 369–373. Mehta, J., Dispenzieri, A. & Gertz, M.A. (2010) High-dose chemotherapy with autotransplantation in AL amyloidosis: a flawed meta-analysis. Biol Blood Marrow Transplant, 16, 138–140; author reply 140–131. Mhaskar, R., Kumar, A., Behera, M., KharfanDabaja, M.A. & Djulbegovic, B. (2009) Role of high-dose chemotherapy and autologous hematopoietic cell transplantation in primary systemic amyloidosis: a systematic review. Biol Blood Marrow Transplant, 15, 893–902. Palladini, G., Campana, C., Klersy, C., Balduini, A., Vadacca, G., Perfetti, V., Perlini, S., Obici, L., Ascari, E., d’Eril, G.M., Moratti, R. & Merlini, G. (2003) Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation, 107, 2440–2445. Palladini, G., Perfetti, V., Obici, L., Caccialanza, R., Semino, A., Adami, F., Cavallero, G., Rustichelli, R., Virga, G. & Merlini, G. (2004) Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood, 103, 2936–2938.
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Perfetti, V., Siena, S., Palladini, G., Bregni, M., Di Nicola, M., Obici, L., Magni, M., Brunetti, L., Gianni, A.M. & Merlini, G. (2006) Long-term results of a risk-adapted approach to melphalan conditioning in autologous peripheral blood stem cell transplantation for primary (AL) amyloidosis. Haematologica, 91, 1635–1643. Skinner, M., Anderson, J., Simms, R., Falk, R., Wang, M., Libbey, C., Jones, L.A. & Cohen, A.S. (1996) Treatment of 100 patients with primary
amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only. American Journal of Medicine, 100, 290–298. Skinner, M., Sanchorawala, V., Seldin, D.C., Dember, L.M., Falk, R.H., Berk, J.L., Anderson, J.J., O’Hara, C., Finn, K.T., Libbey, C.A., Wiesman, J., Quillen, K., Swan, N. & Wright, D.G. (2004) High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Annals of Internal Medicine, 140, 85–93.
ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2014, 164, 722–728
Autologous stem cell transplant is an effective therapy for carefully selected patients with AL amyloidosis: experience of a single institution
Victor H. Jimenez-Zepeda,1 Norman Franke,1 Donna E. Reece,1 Suzanne Trudel,1 Christine Chen,1 Diego H. Delgado,2 Andrew Winter,1 Joseph R. Mikhael,3 Rodger Tiedemann1 and Vishal Kukreti1 1
Department of Medical Oncology and Haematology, Princess Margaret Cancer Center, 2
Division of Cardiology and Heart Transplanta-
tion, University Health Network, Toronto, ON, Canada and 3Division of Haematology and Oncology, Mayo Clinic in Arizona, Scottsdale, AZ, USA Received 16 September 2013; accepted for publication 13 October 2013 Correspondence: Vishal Kukreti, MD, Department of Medical Oncology and Haematology, Princess Margaret Cancer Center, Suite 5-100, Toronto, ON M5G 2M9, Canada.
Summary Autologous stem-cell transplant has been widely used to treat patients with AL amyloidosis. However, transplant-related mortality rates are high, and a recent randomized trial suggested that non-transplant regimens produced comparable results with less toxicity. In order to define the role of patient selection in stem cell transplantation, we evaluated 78 consecutive AL amyloidosis patients transplanted at our centre. Transplant-related mortality occurred in 115%. Complete haematological response and organ response were achieved in 56% and 60%. Median overall survival was significantly lower for patients with brain-type natriuretic peptide (BNP) >300 pg/ml (175 months vs. not-reached) (P = 00004), troponin-I >007 ng/ml (135 months vs. not-reached) (P = 000001) and those not achieving a complete haematological response (88 months vs. not-reached) (P = 00345); high BNP and troponin-I were the most important predictive factors in a multivariate analysis. Based on this study, patients with BNP 10% plasma cells in the bone marrow were carefully assessed to rule out the concomitant presence of myeloma. We excluded patients with ejection fraction 460 lmol/l, lactate dehydrogenase (LDH) >350 iu/l, C-reactive protein (CRP) >20 mg/l, albumin 200 mmol/l, BNP >300 pg/ml, troponin-I >007 ng/ml and free-light chain (FLC) difference >180 mg/l). Survival curves were constructed according to the Kaplan–Meier method and compared using the log rank test.
Results Clinical characteristics A total of 78 patients with AL amyloidosis underwent ASCT between January 2004 and March 2010. Clinical characteristics are shown in Table I. Renal involvement was the most commonly seen (718%) followed by cardiac (474%) and hepatic (231%). Twenty-percent of the patients transplanted at our centre had >3 organs affected. Most patients did not receive induction therapy (769%). Blood stem cells were mobilized in all patients using growth factors only. The median number of CD34-positive cells collected was 43 9 106/l/kg body weight. Patients received HDM at 200 mg/m2 (244%), 140 mg/m2 (564%) or 100 mg/m2 (192%), given intravenously on day 1 as per risk-adapted therapy, and stem cells were infused on day 0.(Cohen et al, 2007) The median length of hospital stay was 17 d (12–43), and the median length of time to a platelet count ≥50 9 109/l and neutrophil count ≥05 9 109/l were 17 d (15–26) and 12 d (10–15), respectively. The all-cause day-100 mortality was 115%, most commonly due to multi-organ failure, culminating in respiratory distress syndrome and ventilatory failure similar to that previously reported.(Gertz et al, 2011) Common transplantrelated complications were febrile neutropenia (66%), transient renal impairment (103%) and congestive heart failure (3%). A HR was seen in 61 out of 78 patients (78%) and included complete and partial responses in 39 (50%) and 22 (282%) patients respectively; nine died before assessment of HR (115%). OR included renal in 47 out of 69 (60%) evaluable patients and cardiac in 17 out of 33 (51%) evaluable patients. (Table II).
Survival At a mean follow-up of 122 months, sixty patients are still alive and 29 (37%) had already progressed. Median time to 723
V. H. Jimenez-Zepeda et al Table I. Clinical and laboratory characteristics of patients with AL amyloidosis undergoing autologous stem cell transplantation.
Age (years) Gender Male Female IgG kappa IgG lambda IgA lambda IgM kappa IgM lambda Free kappa Free lambda Renal involvement Cardiac involvement Hepatic involvement 3 or more organs involved by AL Gastrointestinal involvement Haemoglobin (g/l) Creatinine (lmol/l) Albumin (g/l) Alkaline phosphatase (units/l) B2-Microglobulin (lmol/l) 24-hProteinuria (g/d) Bone marrow plasma cells (%) Interventricular septal thickness (mm) Ejection fraction (%) Troponin-I (ng/ml) (normal460 lmol/l, LDH >350 iu/l, CRP >20 mg/ l, albumin 200 mmol/l, BNP >300 pg/ml and troponin-I > 007 ng/ml (P > 005 for all of them). It is clear that some patients maintain disease-progression free status for more than 8 years after ASCT, as shown in Fig 2. Furthermore, patients who achieved CHR experienced a longer PFS versus those who did not (97 months, 95% ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2014, 164, 722–728
ASCT for AL Amyloidosis confidence interval [CI], 77–116 vs. 435 months, 95% CI 31–56, P = 00001, respectively) (Fig 2). Median OS was significantly shorter for patients with BNP levels >300 pg/ml (175 months vs. NR; P = 00004) (Fig 3), troponin-I levels >007 ng/ml (135 months vs. NR; P = 000001) (Fig 4) and those who did not achieve a CHR (88 months vs. NR; P = 00345) (Fig 5). BNP >300 pg/mL and troponin-I >007 ng/mL were seen in 9/62 and 6/45 patients, where these markers were available. However, no cases with both markers elevated were seen in our group. Multivariate Cox regression analysis showed that levels of BNP >300 pg/ml and troponin-I >007 ng/ml were the most important factors predictive of OS for patients with AL amyloidosis who underwent ASCT (Hazard Ratio 174, 95% CI 027–080, P = 00002 and Hazard Ratio 171, 95% CI 016–098, P = 004, respectively). Median OS for patients who achieved CHR has not been reached versus 8817 months for those who did not achieve CHR (P = 00345). When patients with BNP >300 pg/ml and troponin-I >007 ng/ml were excluded from the analysis, the transplant-related mortality decreased to 38%.
organs.(Skinner et al, 2004) However, some contradictory data has been presented, for instance, a meta-analysis of ASCT studies concluded that stem cell transplant remains an unproven technique for the treatment of amyloidosis.(Mhaskar et al, 2009) The conclusions of the meta-analysis by Mhaskar et al (2009), which evaluated high-dose chemotherapy with
Discussion
Fig 4. Differences in overall survival between AL amyloidosis patients undergoing autologous stem cell transplantation (ASCT) according to the levels of troponin-I. Patients with abnormal troponin-I (≥007 ng/ml) exhibited a shorter median OS (135 months vs. Not Reached) (P = 000001). Cum survival, cumulative survival; Normal Trop-I, Troponin-I 300 >300-censored
0·2
40
60
80
100
Months since ASCT Number at risk BNP300
6
3
1
0
0
0
Complete Response
0·4
NOT CR NOT CR-censored
0·2
007 ng/ml (66% vs. 145%, P = 0011). The use of troponin-I and BNP as prognostication markers in patients undergoing ASCT has been explored less extensively than the more sensitive assays (cTnT and NT-Pro-BNP). Interestingly, a borderline effect of troponin-I on OS, but no effect of both troponin-I and BNP on OS and PFS when measured at 3 and 12 months post-ASCT were reported by Cohen et al (2007), the reasons for this are not clear and were felt to be associated with variability of the BNP assays. Furthermore, univariate analysis of a large series of 421 patients transplanted with AL amyloidosis showed an association of low levels of BNP with better OS, however the multivariate analysis failed to show the same impact.(Cibeira et al, 2011).
Is there any role for novel agent induction chemotherapy? Impact of cardiac biomarkers Given the dominant effect of cardiac involvement on prognosis, it is not surprising that markers of cardiac injury and dysfunction emerge as powerful prognostic factors in AL.(Dispenzieri et al, 2003; Palladini et al, 2003) Cardiac muscle injury is associated with troponin release, which provides a sensitive and specific marker of cardiac injury. Recently, Apridonidze et al (2012) reported on the role of increased troponin-I in patients with cardiac amyloidosis, using the same cut-off reported in the present study. By using a more sensitive troponin assay (cTnT), the Mayo Clinic group used a cut-off of >0025 ng/ml as part of the prognostic model in patients with AL amyloidosis in different clinical phases (i.e., stem cell transplant, conventional chemotherapy or clinical trial patients).(Kumar et al, 2012) On the other hand, BNP is a powerful predictor of outcome in CHF. (Iwanaga et al, 2006). BNP is elevated in states of increased ventricular wall stress and is most commonly used to rule out CHF in dyspneic patients. BNP levels are influenced by age, gender and body mass index.(Iwanaga et al, 2006) This variation across clinical settings has significant implications given the increasing frequency with which BNP testing is being performed. Given that BNP levels are used at 726
Whether novel agent induction chemotherapy might help to improve outcomes and transform ASCT ineligible patients into candidates for this therapy remains unknown. Data in this regard has been collected by our group showing that patients who are ineligible for upfront ASCT could be treated with bortezomib-containing induction regimens, some of whom were successfully transplanted if clinical and biochemical (BNP and troponin-I) improvement were seen without increasing risk of death (Unpublished data). ASCT after a bortezomib-based induction regimen may also improve the proportion of patients achieving complete remission. However, that remains to be shown in clinical trials. Additionally, this report describes that the achievement of a good haematological response is a feasible target for those patients receiving melphalan in a risk-adapted model. Patients receiving melphalan at 100 mg/m2 exhibited an overall response rate of 93%, while that of patients receiving melphalan at 140 mg/m2 was 77%. Nonetheless, our findings justify the use of inclusion criteria requiring preserved organ function and clinical performance status, and also highlight the importance of serum cardiac biomarkers while selecting the best group of patients to whom we can offer ASCT wisely. It also demonstrates the ª 2013 John Wiley & Sons Ltd British Journal of Haematology, 2014, 164, 722–728
ASCT for AL Amyloidosis significant selection bias that impacts most reports of ASCT for AL amyloidosis where patients have preserved performance status and normal renal, hepatic and cardiac function at the time of transplant. As reported by Dispenzieri et al (2001), eligibility for ASCT is, in itself, a favourable prognostic factor for survival. In summary, improved supportive care and refined patient selection have improved the safety of patients undergoing ASCT. We believe that ASCT is an effective therapy for some very carefully selected patients with AL amyloidosis. Prospective and randomized trials are needed to better define the role of ASCT in AL amyloidosis.
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Authorship and disclosures VJZ and VK performed research, collected, analysed, interpreted data, performed statistical analysis and wrote the manuscript; NF, DD, AW and JM designed research, analysed and interpreted data and wrote the manuscript; and DR, ST, RT and CC designed research, analysed and interpreted data, performed statistical analysis and wrote the manuscript. The authors declare no competing financial interests. This manuscript was partly presented at the Amyloid Symposium 2012.
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