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Editorials
Predicting survival in light chain amyloidosis
Giovanni Palladini, Paolo Milani and Giampaolo Merlini
Amyloidosis Research and Treatment Center, Foundation “Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo”, and Department of Molecular Medicine, University of Pavia, Italy
E-mail: GIOVANNI PALLADINI - giovanni.palladini@unipv.it doi:10.3324/haematol.2019.218859
In this issue of the Journal, Dittrich and coworkers report their systematic analysis of the performance of the three currently used staging systems for AL amyloidosis in a large population of 1,224 patients.1 Their aim was to estab- lish whether one of the available models had better dis- criminating ability and was preferable in the overall popu- lation and in subgroups of patients with potential interfer- ing factors, such as renal failure and atrial arrhythmias.
In systemic AL amyloidosis a plasma cell clone produces light chains that misfold, aggregate and form deposits in tis- sues, causing dysfunction of the involved organs.2 While the bone marrow clone is usually indolent and small, the amy- loid light chains often give rise to rapidly progressive dys- function and damage of one or more organs. The pattern of organ involvement determines the clinical presentation of the disease, which is fatal if recognized late or unsuccessful- ly treated. The heart and the kidneys are the most com- monly involved organs. Cardiac and renal dysfunction also limit the access to intensive treatment. Survival is largely dependent on the presence and severity of heart involve- ment. Amyloid light chains cause direct toxicity to the myocardium, inducing p38 mitogen-activated protein kinase (MAPK) signaling and resulting in oxidative stress, impaired excitation-contraction coupling and cardiomy- ocyte death. Notably, MAPK signaling mediates transcrip- tion of the cardiac biomarker natriuretic peptide type-B (BNP), supporting a direct connection between light chain cardiotoxicity and BNP levels.3 Indeed, the level of the amino-terminal portion of pro-BNP (NT-proBNP) can indi- cate clinically relevant heart involvement in 100% of cases and is a powerful prognostic marker in AL amyloidosis.4,5 After chemotherapy targeting the plasma cell clone, the reduction of the concentration of the amyloid free light chain (FLC) results in decreased NT-proBNP levels that pre- dict longer survival.6 Validated criteria for cardiac response are based on the decrease of NT-proBNP level.7 However, the clearance and, consequently, the serum concentration of natriuretic peptides are influenced by renal function. While BNP is also actively removed from the bloodstream, follow- ing binding with natriuretic peptide receptors and through protease hydrolysis, NT-proBNP appears to lack active clearance mechanisms and is almost exclusively removed through glomerular filtration. Thus, renal failure is a poten- tial confounding factor when assessing cardiac dysfunction by natriuretic peptide levels. In AL amyloidosis, BNP is pre- ferred over NT-proBNP in prognosticating survival of patients with an estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2 (end-stage renal disease).8 In addition, increased concentrations of natriuretic peptides are sensi- tive but not specific markers of heart dysfunction in AL amyloidosis, and certain common cardiac conditions, par- ticularly atrial fibrillation, can contribute to their elevation.
Cardiac troponin (cTn) is another powerful predictor of
survival in AL amyloidosis.9 As well as NT-proBNP, cTn can be used to identify patients at higher risk of transplant-relat- ed mortality (those with NT-proBNP >5,000 ng/L and/or cTnT >0.06 ng/mL) who should not be considered candi- dates for autologous stem cell transplantation.10 Levels of cardiac troponins and NT-proBNP can be combined to gen- erate simple, yet accurate staging systems that sharply dif- ferentiate groups of patients with different survival (Table 1). Initially, a three-stage system was designed by Mayo Clinic investigators (Mayo2004).11 Subsequently, two four- stage systems were devised. One of them, proposed by European collaborative studies, uses very high NT-proBNP levels to identify high-risk patients (Mayo2004/European).12,13 The other was proposed by the Mayo Clinic group and included the difference between involved and uninvolved FLC (dFLC) as an indicator of clonal burden together with cardiac biomarkers (Mayo2012).14 The use of BNP, cTnT, cTnI, and high-sensi- tivity troponin assays in these staging systems is now vali- dated.15-17
Until now, there was no indication on which of the avail- able staging systems performed better and should be pre- ferred in different settings. This can be particularly relevant in determining eligibility for clinical trials and in specific patient populations with confounding factors, such as renal failure and atrial arrhythmia, which can interfere with the assessment of cardiac dysfunction. Dittrich and coworkers adopted a 50 mL/min/1.73 m2 cutoff to discriminate patients with reduced eGFR based on the current stratifica- tion of renal involvement in AL amyloidosis.18 In the overall population all the staging systems provided a sharp discrim- ination of survival between subgroups. However, the Mayo2004/European system was superior in identifying low-risk and very high-risk patients. Notably, reduced eGFR and atrial arrhythmia predicted poorer survival per se, besides being associated with higher concentrations of car- diac biomarkers. Thus, patients with impaired eGFR and atrial arrhythmia were correctly assigned to higher stages. Importantly, the impact of low eGFR on prognosis appeared to be associated with heart involvement, mainly because of prerenal kidney injury. At multivariate analysis, decreased eGFR retained an independent prognostic value with the Mayo2004 and Mayo 2012 staging systems, but not with the Mayo2004/European system. Atrial arrhyth- mia reduced the discriminating ability of all three staging systems, with a more pronounced impact on the Mayo2012 system. Moreover, the very high levels of NT- proBNP (>8,500 ng/L) used in the Mayo2004/European model to identify high-risk patients portended a very poor outcome irrespective of decreased renal function and atrial arrhythmia.
A similar study in 1,005 patients was recently published by the Mayo Clinic investigators.19 Overall, they did not
haematologica | 2019; 104(7)