This study sought to develop selection guidelines to determine the eligibility for SCT of patients with light-chain amyloidosis. Patients with biopsy-confirmed lightchain amyloidosis who underwent SCT between 8 March 1996 and 31 December 2011 were reviewed in two cohorts by date of transplantation: between 8 March 1996 and 30 June 2009 (n=410) and between 1 July 2009 and 31 December 2011 (n=89). Also evaluated were patients who died before post-transplant day 100 to determine the features predictive of early death. After 1 July 2009, fewer transplant recipients had Mayo stage III cardiac involvement. Mortality before post-transplant day 100 was 10.5% (43/410) in the earlier group and 1.1% (1/89) in the later group. In the earlier group, one-quarter of transplant recipients with N-terminal pro-brain natriuretic peptide (NT-proBNP) >5000 pg/mL died by 10.3 months. When serum troponin T was >0.06 ng/mL, 25% died at 3.7 months. The Mayo staging system is predictive for OS but not useful for selecting transplant recipients. Patients with serum troponin T >0.06 ng/mL or NT-proBNP >5000 pg/mL (not on dialysis) should not be considered candidates for SCT because of early mortality.
Ig light-chain amyloidosis (also called primary systemic amyloidosis or amyloid light chain amyloidosis) results from the deposition of Ig fragments in visceral organs. The deposition of amyloid fibrils leads to dysfunction of the organs and death of the patients.1 Although patient survival has improved over the past 15 years,2 their prognosis remains serious. When SCT was introduced, few effective alternative treatments were available.3 At that time, combination therapy with melphalan and prednisone was the primary nontransplant option, with a median survival of only 18 months. Since that time, the introduction of melphalan and dexamethasone has seriously challenged the concept of high-dose therapy for amyloidosis.4 In a single, prospective randomized study, SCT was found not superior to conventional therapy with melphalan and dexamethasone.5 However, this study had serious patient selection issues insofar as the treatment-related mortality associated with transplant was 24%, making it nearly impossible to show any benefit from the technique. The acceptable treatment-related mortality for transplant at one point was 10–15%,6 although studies have shown mortality rates of 40%.7 A high mortality rate with SCT is no longer acceptable because lower-risk alternatives, including lenalidomide-based8, 9 and bortezomib-based10 therapies, have been introduced, with much lower immediate risk to patients. Any attempt to advance the field of SCT requires highly refined patient selection criteria so that patients can be offered SCT safely. As a consequence of this reduced acceptability of transplant-related mortality in the era of novel agent alternatives, we narrowed our criteria for transplant eligibility at the end of 2008. In this retrospective study, we reviewed the outcomes to determine whether fixed cutoffs could be recommended for eligibility. The purpose of this study was to determine the appropriate criteria for transplant centers that see small numbers of these patients to identify those patients who can receive transplants without excessive risk.
Patients and methods
This study was approved by the Mayo Clinic Institutional Review Board. In addition, in accordance with Minnesota state law, each patient considered in this study must have given written consent for medical record review. We reviewed patients with biopsy-confirmed Ig light-chain amyloidosis who underwent SCT between 8 March 1996 and 31 December 2011.
The study performed two patient comparisons. In the first, all patients who received transplants between 8 March 1996 and 30 June 2009 were compared with those who received transplants between 1 July 2009 and 31 December 2011 to determine differences between the two groups. The second study compared all transplant recipients who died from any cause before post-transplant day 100 with those who survived beyond day 100 to determine features predictive of early death.
All patients had amyloidosis confirmed histologically with Congo red tissue biopsy specimen.11 In the past 5 years of the study interval (2007–2011), every patient had mass spectroscopic analysis on the amyloid tissues to validate whether the protein subunit was Ig light chain or heavy chain.12 Before that time, the diagnosis required a serum or urine monoclonal protein in the serum or urine or clonal plasma cells in the BM, negative results from transthyretin screening of amplified DNA, and no evidence of fibrinogen amyloidosis on a renal biopsy specimen.13 No patients with light-chain amyloidosis localized to a nonvital organ, such as the skin or carpal ligament, were included for SCT.
The standard baseline evaluation of patients included immunofixation of serum and urine. An echocardiogram was performed in all patients. In 2004, Ig-free light-chain assays were introduced. PCR analysis was introduced in 1996,14 but transthyretin screening was not clinically introduced into routine clinical care at Mayo Clinic until 2005. Troponin T and N-terminal pro-brain natriuretic peptide (NT-proBNP) screening began in 2006.
All transplant recipients received at least 1.98 × 106 CD34+cells/kg. Apheresis was performed by standard techniques, processing 11–14 L of blood in a 4-h period.15 Patients were conditioned, infused and monitored on an outpatient basis, as previously reported.16 Hospitalization occurred only in the event of a fever that could not be controlled with outpatient antibiotics, mucositis or dehydration.17 Supportive care was standard for transplant after myeloablative chemotherapy and included a prophylactic fluoroquinolone antibiotic, fluconazole, acyclovir and penicillin. Growth factors were not administered after stem cell infusion.
The criteria for hematological and organ responses have been previously published.18 NT-proBNP and troponin levels were incorporated into organ response criteria, as defined by consensus,19 for patients for whom these values were available.
Patient data were entered into a continuously updated database (JMP version 9.0.1, SAS Institute, Inc., Cary, NC, USA). Differences between groups were analyzed using the Kruskal–Wallis rank sum test for continuous variables and the Fisher’s exact test for discrete variables. All probabilities reported are two-tailed. Significance was defined as P<0.05. Survival was based on the Kaplan–Meier method.
Of the 499 patients identified, none was lost to follow-up, and survival data were complete. Before 1 July 2009, 410 patients underwent auto-SCT. Forty-three of these patients died before post-transplant day 100 (10.5%). From that date onward, 89 patients underwent transplantation, with 1 death before post-transplant day 100 (1.1%). The goal sought by our transplant group was to try to create selection criteria that could make transplantation for amyloidosis as safe as it is for multiple myeloma. We set our criteria at an all-cause d+100 mortality of 2%. A logistic fit of therapy-related mortality by NT-proBNP level was performed and a receiver operating characteristic curve was generated. The 2% probability of early death fell at NT-proBNP between 4700 and 5400, and hence 5000 was selected as the cutoff for analysis. Table 1 lists the characteristics of those patients selected for transplantation in the two time periods. After 1 July 2009, there was a significant reduction in patients with Mayo stage III cardiac involvement, a slightly lower serum creatinine level, and a slightly lower pretreatment-involved free light-chain level. In the earlier group, the NT-proBNP level in the highest decile was >6537 pg/mL, whereas in the later group, the highest decile had an NT-proBNP level >4023 pg/mL, reflecting the increased reluctance of our group to perform transplants on patients with extreme elevations of NT-proBNP.
The one patient in the later group who died before post-transplant day 100 was a 54-year-old man with λ light-chain amyloid and a pretransplant-free light chain level of 63.4 mg/dL, with renal and cardiac amyloid, a pretransplant NT-proBNP level of 5408 pg/mL, and a serum troponin T level of 0.02 ng/mL. He was conditioned with melphalan 140 mg/m2, and died on post-transplant day 36 of sudden cardiac arrest, having achieved full engraftment of neutrophils 24 days before death and full engraftment of platelets (>50 × 109/L) 21 days before his death. The cardiac arrest occurred 2 weeks after hospital discharge. An autopsy was not performed.
During this 30-month period, six patients with an NT-proBNP level >5000 pg/mL received transplants. Two of these patients, however, were on dialysis, which can have a profound effect on the level of NT-proBNP,20 and one of these two was not believed to have cardiac amyloidosis. Four of the six are alive, one having died 9.6 months after transplant, from a severe upper gastrointestinal tract hemorrhage following dialysis, possibly related to heparin administration.
Table 2 provides the characteristics of the 43 patients who received their transplants before 1 July 2009 and who died before post-transplant day 100. These patients were compared with longer-term survivors who received transplants during the same period. The comparison revealed significant differences between the two groups in Mayo stage, clinically defined cardiac involvement, septal thickness, and levels of creatinine, troponin T, free light chain, albumin and BNP. The NT-proBNP level was >5000 pg/mL in 41 patients. Of the 41 patients, 7 had a serum creatinine level >1.8 mg/dL. Two had serum creatinine levels of 2.0 and 2.2 mg/dL, respectively. Five were transplanted on stable dialysis with creatinine levels of 5.9, 8.0, 10.1, 12.0, and 12.4 mg/dL, respectively. All seven survived >9 months post SCT. The median survival of the 41 patients was 27 months, but 10 (25%) of them had died by 10.3 months (Figure 1).
We reviewed the transplant recipients whose serum creatinine level was >1.8 mg/dL and who were not on chronic stable dialysis at the time of transplantation. Thirty-four patients were identified, five of whom died before post-transplant day 100. However, 21 of these patients are still alive. The median survival for the entire group has not been reached, and 60% were alive at 72 months, the longest survivor now at 170 months.
Thirty-seven patients had troponin T levels >0.06 ng/mL. Nine of these patients (25%) had died at 3.7 months, and at the time of this writing 24 of 37 patients have died. The median survival of these patients with high troponin levels was 26.1 months (Figure 2). We identified 72 Mayo stage III patients in this study, and 31 (43%) survive at 5 years (Figure 3). Of the 72, 27 had an NT proBNP >5000 pg/mL (38%). The d+100 all-cause mortality of these 27 patients, who would have been excluded from SCT using the proposed new criteria, was 4/27 (15%), considered unacceptable. Conversely, there were 24 stage III Mayo patients with both troponin level <0.06 ng/mL and NT-proBNP level <5000 pg/mL. The median survival of this cohort is 66.1 months, with 15 of the 24 alive with a median follow-up of the survivors of 39.1 months. There were 71 patients transplanted having either a troponin T >0.06 ng/mL or NT-proBNP >5000 pg/mL. Twelve died before day 100, with an all-cause mortality of 17%. Median survival of the 71 patients was 27.9 months.
The value of SCT in the treatment of amyloidosis remains controversial. Its use is more common in the United States than in Great Britain, where only 1% of amyloidosis patients receive transplants, and it is not widely used in other European countries.21 SCT in the era of novel agents, with proven high response rates, cannot be justified until the post-transplant mortality rate is reduced to levels seen in multiple myeloma patients who receive transplants.22 Investigators at Boston University23 reviewed 421 patients and demonstrated a significant decline in treatment-related mortality over time (same definition of treatment-related mortality as ours, post-transplant day 100). The mortality among 297 patients who received transplants between 1994 and 2003 was 13.8%. A similar group of 124 patients who received transplants from 2004 through 2008 had a treatment-related mortality of 5.6%. This declining mortality is in accord with what we are currently seeing, with improved supportive care and refined patient selection. They also noted that in patients who were on dialysis the treatment-related mortality was 8%, and that in patients with cardiac involvement BNP levels were predictive of mortality at 100 days.23 Combination treatment with melphalan and dexamethasone has been reported to be highly effective, with the median survival in the 5-year range and low treatment-related mortality. However, others have not had good results, with a median survival of 1 year, presumably related to the higher proportion of cardiac amyloidosis.24, 25 In the former of these two studies, patients had advanced cardiac amyloidosis as defined by NYHA class greater than stage II, systolic blood pressure <90 mm Hg or symptomatic pleural effusion.
To justify SCT, criteria need to be established so that centers that see only a few of these patients annually can select those who can receive transplants safely and then be considered for post-transplant consolidation therapy to achieve the desired state of very good PR or CR.26, 27 We believe that the criterion that would lead to exclusion of patients destined not to tolerate high-dose therapy is a serum troponin T level >0.06 ng/mL, which has been previously reported.28 However, we now add the criterion of an NT-proBNP level >5000 pg/mL. We believe the mortality rates seen with an NT-proBNP level >5000 pg/mL make SCT an unacceptable alternative unless preinduction chemotherapy were to reduce this cardiac biomarker to levels that would render transplantation a safer procedure.29 We do not believe the serum creatinine is a clear criterion for exclusion, although the risk of acute renal injury and the need for dialysis support during transplantation is sharply increased by high levels of proteinuria or elevations in serum creatinine.30, 31 We became more restrictive in 2008, selecting patients eligible for transplantation based on our analysis of predictors of early mortality. By restricting transplantation to patients with NT-pro BNP <5000, we automatically saw a population with less cardiac involvement. Moreover, as NT-proBNP is renally excreted, some patients would have an elevated NT-pro BNP owing to renal failure. There were seven such patients whose cardiac biomarkers may be directly related to renal insufficiency.
We have previously reported the number of involved organs as being a critical criterion for high risk after transplant, but we increasingly have come to believe that this criterion is unreliable.32 We believe that concordance in counting organs is poor among various medical centers. Moreover, there are those patients who have proven organ involvement but minimal organ dysfunction, which is quite different from patients who have organ involvement and advanced dysfunction. Organ counting is a somewhat subjective criterion, and the inability to distinguish mild from advanced organ involvement is a barrier to its optimal use. Patients with soft-tissue involvement, including the tongue, periarticular amyloid or claudication, are difficult to integrate into an organ-counting scheme. Therefore, we believe that use of cardiac biomarkers is a better and more reproducible method to ensure safe outcomes.
The Mayo staging system has been validated to be useful in predicting survival both in patients who receive high-dose therapy as well as in those who receive standard-dose therapy at the time of diagnosis.33, 34 However, the cutoffs for the stages are serum troponin <0.035 ng/mL and NT-proBNP <332 pg/mL. Although these criteria clearly separate patients into three groups with very significant differences in OS, this does not necessarily mean that the Mayo amyloidosis staging system is a useful tool to select patients for SCT.35 Patients with advanced cardiac amyloidosis are destined to do poorly irrespective of whether they are treated with novel agents or SCT. In fact, the early mortality rate for patients with amyloidosis seen at Mayo Clinic has not improved in nearly 40 years.2 Simply excluding patients with Mayo stage III from participation in clinical trial protocols or SCT appears to be too stringent, and many patients who have moderate cardiac involvement may benefit from high-dose therapy and SCT. In this study, we identified 72 Mayo stage III patients, and 31 (43%) survive at 5 years. Clearly, the majority of patients that we would exclude from transplant selection would be Mayo stage III, but the converse is not true. The majority of patients with Mayo stage III disease can have a very good outcome after SCT. Ten patients (11%) with Mayo stage III disease received transplants after 1 July 2009. Although the follow-up is short, the 1-year survival is 80% (8/10). In the 30 months since the changes were instituted, our transplant volumes were 2.97 transplants a month. For the 42 months before the change, we were transplanting 3.45 each month. The new criteria reduced our transplant volume by 14%, but resulted in fewer therapy-related deaths. Nonetheless, this represents a retrospective analysis of data with all the inherent biases. We believe these criteria would still be useful for transplant centers that are asked to consider intervention in amyloidosis patients if seen infrequently.
In conclusion, we believe the most rational approach is to exclude patients from transplantation based on their cardiac biomarker status, eliminating those patients whose troponin T is >0.06 ng/mL, based on our previously published criteria but validated in this larger cohort by adding NT-proBNP level >5000 pg/mL as an exclusion criterion as well. These patients should be considered for less toxic therapy, including novel agent-based treatment, alkylator-based treatment or participation in clinical trials.
Cohen AD, Comenzo RL . Systemic light-chain amyloidosis: advances in diagnosis, prognosis, and therapy. Hematology Am Soc Hematol Educ Program 2010; 2010: 287–294.
Kumar SK, Gertz MA, Lacy MQ, Dingli D, Hayman SR, Buadi FK et al. Recent improvements in survival in primary systemic amyloidosis and the importance of an early mortality risk score. Mayo Clin Proc 2011; 86: 12–18.
Comenzo RL, Vosburgh E, Simms RW, Bergethon P, Sarnacki D, Finn K et al. Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients. Blood 1996; 88: 2801–2806.
Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L et al. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood 2007; 110: 787–788.
Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O et al. Myélome Autogreffe (MAG) and Intergroupe Francophone du Myélome (IFM) Intergroup. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med 2007; 357: 1083–1093.
Seldin DC, Andrea N, Berenbaum I, Berk JL, Connors L, Dember LM et al. High-dose melphalan and autologous stem cell transplantation for AL amyloidosis: recent trends in treatment-related mortality and 1-year survival at a single institution. Amyloid 2011; 18 (Suppl 1): 122–124.
Saba N, Sutton D, Ross H, Siu S, Crump R, Keating A et al. High treatment-related mortality in cardiac amyloid patients undergoing autologous stem cell transplant. Bone Marrow Transplant 1999; 24: 853–855.
Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L et al. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol 2012; 91: 89–92.
Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F et al. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood 2010; 116: 4777–4782.
Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J et al. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood 2011; 118: 865–873.
Picken MM . Amyloidosis: where are we now and where are we heading? Arch Pathol Lab Med 2010; 134: 545–551.
Vrana JA, Gamez JD, Madden BJ, Theis JD, Bergen HR, Dogan A . Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood 2009; 114: 4957–4959.
Chee CE, Lacy MQ, Dogan A, Zeldenrust SR, Gertz MA . Pitfalls in the diagnosis of primary amyloidosis. Clin Lymphoma Myeloma Leuk 2010; 10: 177–180.
Jiménez EA, Blanco JCR, Orensanz MLM . The diagnosis of familial amyloid polyneuropathy. Neurologia 1996; 11: 310–312.
Burgstaler EA, Winters JL . Comparison of hematopoietic progenitor cell collections using the COBE Spectra version 7 and Amicus version 3.1 for patients with AL amyloidosis. J Clin Apher 2011; 26: 186–194.
Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR, Kumar SK, Dingli D et al. Autologous stem cell transplant for immunoglobulin light chain amyloidosis: a status report. Leuk Lymphoma 2010; 51: 2181–2187.
Gertz MA, Ansell SM, Dingli D, Dispenzieri A, Buadi FK, Elliott MA et al. Autologous stem cell transplant in 716 patients with multiple myeloma: low treatment-related mortality, feasibility of outpatient transplant, and effect of a multidisciplinary quality initiative. Mayo Clin Proc 2008; 83: 1131–1138.
Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN et al. 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. Am J Hematol 2005; 79: 319–328.
Palladini G, Merlini G . Uniform risk-stratification and response criteria are paving the way to evidence-based treatment of AL amyloidosis. Oncology 2011 25 7: 637–638.
Manzano-Fernández S, Januzzi JL, Boronat-García M, Pastor P, Albaladejo-Otón MD, Garrido IP et al. Impact of kidney dysfunction on plasma and urinary N-terminal pro-B-type natriuretic peptide in patients with acute heart failure. Congest Heart Fail 2010; 16: 214–220.
Thirusha L, Rannigan L, Foard D, Wechalekar A, Gibbs S, Pinney J et al. ALchemy: a large prospective ‘real word’ study of chemotherapy in AL amyloidosis [abstract]. Blood 2011; 118: 992.
Nishihori T, Alsina M . Advances in the autologous and allogeneic transplantation strategies for multiple myeloma. Cancer Control 2011; 18: 258–267.
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.
Dietrich S, Schönland SO, Benner A, Bochtler T, Kristen AV, Beimler J et al. Treatment with intravenous melphalan and dexamethasone is not able to overcome the poor prognosis of patients with newly diagnosed systemic light chain amyloidosis and severe cardiac involvement. Blood 2010; 116: 522–528.
Lebovic D, Hoffman J, Levine BM, Hassoun H, Landau H, Goldsmith Y et al. 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. Br J Haematol 2008; 143: 369–373.
Landau H, Hassoun H, Bello C, Hoover E, Riedel ER, Nimer SD et al. Consolidation with bortezomib and dexamethasone following risk-adapted melphalan and stem cell transplant in systemic AL amyloidosis. Amyloid 2011; 18 (Suppl 1): 130–131.
Cohen AD, Zhou P, Chou J, Teruya-Feldstein J, Reich L, Hassoun H et al. Risk-adapted autologous stem cell transplantation with adjuvant dexamethasone±thalidomide for systemic light-chain amyloidosis: results of a phase II trial. Br J Haematol 2007; 139: 224–233.
Gertz M, Lacy M, Dispenzieri A, Hayman S, Kumar S, Buadi F et al. Troponin T level as an exclusion criterion for stem cell transplantation in light-chain amyloidosis. Leuk Lymphoma 2008; 49: 36–41.
Perz JB, Schonland SO, Hundemer M, Kristen AV, Dengler TJ, Zeier M et al. High-dose melphalan with autologous stem cell transplantation after VAD induction chemotherapy for treatment of amyloid light chain amyloidosis: a single centre prospective phase II study. Br J Haematol 2004; 127: 543–551.
Leung N, Dispenzieri A, Lacy MQ, Kumar SK, Hayman SR, Fervenza FC et al. Severity of baseline proteinuria predicts renal response in immunoglobulin light chain-associated amyloidosis after autologous stem cell transplantation. Clin J Am Soc Nephrol 2007; 2: 440–444.
Leung N, Slezak JM, Bergstralh EJ, Dispenzieri A, Lacy MQ, Wolf RC et al. Acute renal insufficiency after high-dose melphalan in patients with primary systemic amyloidosis during stem cell transplantation. Am J Kidney Dis 2005; 45: 102–111.
Gertz MA, Lacy MQ, Dispenzieri A, Gastineau DA, Chen MG, Ansell SM et al. Stem cell transplantation for the management of primary systemic amyloidosis. Am J Med 2002; 113: 549–555.
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.
Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM et al. Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood 2004; 104: 1881–1887.
Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM et al. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood 2007; 109: 465–470.
The authors declare no conflict of interest.
All authors were involved in study conception, data analysis and acquisition.
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Leukemia & Lymphoma (2019)
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Mayo Clinic Proceedings (2019)
High-dose melphalan and autologous peripheral blood stem cell transplantation in patients with AL amyloidosis and cardiac defibrillators
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American Journal of Hematology (2019)