Page 250 - Haematologica May 2020

F.A. Sharpley et al.
Figure 2. The difference in N-terminal pro b-type natriuretic peptide (NT-pro-BNP) between patients with, and without, evi- dence of cardiac involvement on cardiac magnetic resonance imaging (CMR).
multivariate model including age, autonomic nervous sys- tem involvement, NT-proBNP >152 ng/L, hsTNT >10ng/L, only NT-proBNP (P=0.008, HR: 3.180, CI: 1.349- 7.495) was an independent predictor of survival (Table 1). When cardiac involvement by MRI was added to the model, only cardiac amyloid on CMR (P=0.026, HR: 5.360, CI: 1.219-23.574) remained an independent predic- tor of outcome.
The cause of death was available for 20 of 71 patients (28.2 %). The most common cause of death was progres- sive amyloidosis (five patients), end stage renal failure (four patients), and pneumonia (three patients). Two patients died of splenic haemorrhage and two due to com- plications of treatment. One patient each died of a fall, heart failure, sepsis and a fatal arrthymia respectively. Of the 71 patients who died, 82% (n=58/71) had a repeat echocardiogram. In 12% (n=7/58) cases the echocardio- gram was clearly suggestive of cardiac amyloid progres- sion based on an interventricular septum (lVS) >12 mm and a reduced global strain pattern. In 57% (n=4/7) of these patients their baseline NT-proBNP was above our threshold of 152 ng/L suggesting that in at least a propor- tion of patients the cause of death was progressive cardiac amyloidosis.
Discussion
Patients with AL amyloidosis without cardiac involve- ment by the consensus criteria have excellent outcomes. These patients have normal cardiac biomarkers and there- fore, by definition, have Mayo (2004) stage I disease. Whilst this study confirms the excellent long-term out- comes of patients with this early disease, 22% of patients died within 5 years of diagnosis. We report here that car- diac biomarkers remain prognostic even in this group of patients at a lower threshold (NT-proBNP <152 ng/L) than previously outlined. We also show that patients with AL have CMR scans showing cardiac involvement, with adverse prognostic implications, even in patients with low biomarker levels and with echocardiogram features not suggestive of amyloidosis.
Cardiac involvement in A is currently defined by both echocardiogram criteria (>12 mm mean wall thickness in diastole by echocardiogram in absence of other causes of left ventricular hypertrophy) and by elevation of the car- diac biomarker (NT-proBNP >332 ng/L), in the absence of renal failure or atrial fibrillation. NT-proBNP is unques- tionably one of most sensitive markers of cardiac stress in AL reflecting the direct pathological activity of amyloido- genic light chains/toxic oligomers, mediated by activation of the p38-MAP kinase pathway. The importance of NT- proBNP for defining cardiac involvement is reflected in the initial Mayo staging scoring system where a threshold for NT-pro-BNP was defined using a multivariate model with a value of 332 ng/L (the upper reference limit of normal for women older than 50 years) providing the best fit and the highest HR (Table 4).4 The prognostic importance of this value has since been confirmed in a number of studies although the threshold value itself has never been system- atically re-examined. In 2011 we reported a small cohort of patients with NT-proBNP <127 ng/L had much better outcomes and those with NT-proBNP >127 ng/L had a higher risk of developing cardiac amyloidosis on longer term follow up.13 In the 2011 cohort, we had not access to MRI scanning understand the relevance of these findings. Dittick et al. have also highlighted the difficulty of using current Mayo staging scores in the setting of renal impair- ment and atrial fibrillation.14 The Mayo Clinic data, and data from the international collaborative series, were also generated in the era where highly effective novel agent- based therapies were not routinely available. The survival of patients with stage I disease in these earlier series may now be considered relatively poor compared with con- temporary survival outcomes – allowing for a potential opportunity to revisit the NT-proBNP threshold for defin- ing cardiac involvement.
This current data suggests that the extreme sensitivity of NT-proBNP in AL extends to a much a lower value of 152 ng/L and patients with a subtle increase in NT-proBNP (>152 ng/L) had poorer outcomes (HR: 3.180 [CI: 1.329- 7.495]). The “normal” range for NT-proBNP is between 100-125 ng/L for those aged less than 70 years which is lower than the prognostic threshold identified in this
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haematologica | 2020; 105(5)