28.8.1. sFLC response predicting cardiac outcomes

Chapter 28

Organ responses are typically slow to appear in patients with AL amyloidosis and are usually dependent on an adequate haematological response. The presence of cardiac amyloidosis is the major prognostic determinant in AL amyloidosis. Although cardiac involvement is present in only approximately half of patients at diagnosis (Section 28.1), virtually all AL amyloidosis patients will die from complications resulting from cardiac dysfunction; patient survival depends on the rapid suppression of monoclonal FLC synthesis and stabilisation or recovery of heart function [23]. Measurement of cardiac biomarkers, namely serum cardiac troponin T and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are useful in defining prognosis at diagnosis (Section 28.4), and should be monitored to assess response to therapy, in parallel with the assessment of haematological response [23][114][611]. However, a study by Milani et al. [1121] concluded that it was the quality of the haematological response, but not depth of NT-proBNP response, that identified cardiac responders with a significantly longer survival.

The important link between improving cardiac function in AL amyloidosis and falling sFLC concentrations was first observed by Palladini and colleagues [629]. Fifty-one AL amyloidosis patients with symptomatic myocardial involvement were given chemotherapy and monitored with sFLCs and NT-proBNP. During treatment, 22 patients had a reduction of sFLCs by more than 50%, including nine patients who had disappearance of monoclonal immunoglobulins as assessed by IFE; a corresponding reduction of NT-proBNP levels was also observed (p<0.001). Survival was superior in responders than in non-responders (p<0.001). This finding was supported by a subsequent study by Kastritis et al. [630], which confirmed by multivariate analysis that a cardiac response was associated with a haematological response (46% vs. 0% in non-haematological responders; p<0.001).

Increases in amyloidogenic sFLCs can precede cardiac progression by several months. In a study by Palladini et al. [1032], cardiac progression was observed in 20/92 patients at relapse, and at this time the median dFLC was half of its baseline value, representing a 4-fold increase from best response . In the majority of cases (15/20), the increase in dFLC preceded increases in NT-proBNP by a median of 6 months (range: 2-8 months). These results indicate that small increases in amyloidogenic FLCs may predict organ progression and should not be underestimated.

Further studies have demonstrated a direct cardiotoxic effect of amyloidogenic FLCs [631][632], and support the clinical observation that a reduction in circulating monoclonal FLCs translates into a rapid improvement in cardiac function. Therefore, it is important to reduce the concentrations of cardiotoxic FLCs promptly in AL patients with cardiomyopathy.