Page 246 - Haematologica May 2020

F.A. Sharpley et al.
III if both biomarkers are normal, one biomarker elevated or both biomarkers elevated respectively.4 This is with progressively poorer prognosis (median survival of 27.2, 11.1 and 4.1 months respectively). Lately, with the move to high sensitivity TNT (hsTNT), the threshold for tro- ponin is <55 ng/L.
Recent studies of patients with normal NT-proBNP and hsTNT without cardiac involvement, (so called Mayo stage I disease) show excellent outcomes with median overall survival (OS) not reached at 5 years. There are still deaths in this group of patients and few have explored fac- tors predictive of poor survival. There are a number of novel prognostic variables in AL including: the number of organs involved, a high percentage of bone marrow plas- ma cells,6 raised von Willebrand factor7 and high growth differentiation factor-15 levels.8 None of the studies have focused specifically on the stage I patients. Liver involve- ment is widely believed to contribute to the poor progno- sis of such cases but in the vast majority of cases this is associated with other organ involvement.9
We designed this study to assess prognostic variables in patients with systemic AL who had no evidence of cardiac involvement by echocardiographic criteria and who had normal cardiac biomarkers (Mayo 2004 stage I).
Methods
This study included all prospectively followed up patients with AL from an ongoing prospective observational study (Alchemy) from 2009-2017, with Mayo stage I disease (defined by normal cardiac biomarkers (NT-proBNP <332 ng/L, hsTnT <55 ng/L)). A threshold of hsTNT of 55 ng/L was used (equivalent to 0.035 g/L cTNT) and this has been used by our laboratory since we moved from standard TNT measurements to using hsTNT measurements at our centre.
A diagnosis of amyloidosis was confirmed by Congo-red stain- ing of a tissue biopsy, with the demonstration of characteristic birefringence under cross polarized light, and AL typing was con- firmed by immunohistochemistry, with specific antibodies or by mass spectrometry. Hereditary amyloidosis was excluded by appropriate gene sequencing, if there was a doubt about the diag- nosis of AL. As part of the study protocol, all patients had a detailed baseline assessment of organ function, including biomark- er measurements and imaging with echocardiogram and 123I-labelled serum amyloid P (SAP) scintigraphy. Organ involve- ment was defined according to the international amyloidosis con- sensus (ISS) criteria.2 Specifically, the echocardiogram was consid- ered to show cardiac involvement if the patients had mean left ventricular (LV) wall thickness >12 mm, in the absence of any other cause of left ventricular hypertrophy. NT-proBNP was <335 ng/L and hsTNT <55 ng/L in all cases. Cardiac magnetic resonance imaging (CMR) was added to routine baseline assessments from late 2015 onwards and the result of the baseline CMR was record- ed, where available. A typical pattern of late gadolinium enhance- ment and an extracellular volume (ECV) >0.30 on an magnetic res- onance imaging (MRI) scan were used as criteria suggestive of car- diac involvement by CMR.10
OS was calculated from the date of diagnosis to death or last follow-up. Factors were analysed for their impact on survival and this included: age, sex, type and number of organ involvement, difference in serum free light chains (dFLC) and markers of car- diac, renal and liver function and treatment given. Since asympto- matic liver involvement is often detected by 123I -SAP scintigra- phy11 we assessed the prognostic significance of amyloid load by
this imaging method. Survival outcomes were analysed using the Kaplan-Meier method with comparisons done using the log rank test. All P-values were two sided with a significance level of <0.05 and median values were used to dichotomise continuous vari- ables. Any factors found to be significant on univariate analysis were further assessed in multivariate modelling by Cox’s regres- sion analysis. Statistical analysis was performed using SPSS (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY, USA) and Stata (StataCorp LLC. 2017. Stata Statistical Software: Release 15. College Station, TX, USA). Approval for analysis and publication was obtained from the National Health Service institutional review board and written consent was obtained from all patients in accordance with the Declaration of Helsinki.
Results
A total of 378 patients were included in this study. The patient baseline characteristics are outlined in Table 1. The median patient age was 69 years (range 35-92 years); 212 (56.1%) were men. The median number of organs involved was two (range: 1-7). None of the patients had cardiac involvement by standard criteria.12 The majority of patients had renal involvement (n=277, 73.3%). Thirty- nine patients (10.3%) had liver involvement by ISS crite- ria, whilst liver was abnormal by 123I-SAP scintigraphy in 111 (29.4%). By 123I-SAP scintigraphy, amyloid deposition was seen in 255 patients with the distribution: no amyloid in 122 patients (32.4%); 181 patients (48.0%) had a small or moderate amyloid load and 74 (19.6%) had a large amyloid load. The mean LV wall thickness was 10 mm (range: 6-13 mm). Six patients had a mean LV thickness of 13 mm, but none with echocardiogram appearances sug- gestive of cardiac amyloidosis based on their preserved global strain pattern. In all six patients the NT-proBNP was <335 ng/L, and co-existing hypertension was present in 5 of 6. The median NT-proBNP was 161 ng/L (range: 8- 330 ng/L) and hsTNT was 10 ng/mL (range: 3-51 ng/L). Peripheral and autonomic neuropathy were seen in 43 (11.4%) and 30 (7.9%) cases respectively.
The median follow up was 42 months (1-117 months). There were 71 deaths. Median OS was not reached (Figure 1A). The OS at 1, 3, and 5 years was 96%, 87% and 78% respectively. Liver involvement by ISS (ALP >1.5 times upper limit of normal [ULN]) was not prognostic for survival (P=0.204, HR: 1.518, CI: 0.797-2.891), neither was any abnormality in the ALP (defined by an ALP outside the ULN of 129U/L) (P=0.753, hazard ratio [HR]: 0.923, confidence interval [CI]: 0.561-1.519) (Figure 1B). Although liver involvement was detected more frequently on SAP scintigraphy, neither liver involvement by SAP (P=0.284, HR: 0.750, CI: 0.443-1.269), nor the amyloid load on SAP scans (P=0.894, HR: 0.956, CI=0.489-1.869) were prognostic for survival. Renal involvement was not predictive of outcome using the standard consensus crite- ria definition,12 (P=0.396, HR: 0.804, CI=0.486-1.330), or an estimated glomerular filtration rate (GFR) of <30 mL/min (P=0.483, HR: 2.11, CI: 0.262-17.047), but only 14 patients had an eGFR <30 mL/min and only five patients had an eGFR <20 mL/min. Patients with autonomic nerv- ous system involvement had significantly poorer out- comes on univariate analysis (P=0.018, HR: 2.177, CI: 1.144-4.142), but patient numbers were small. Age was predictive of survival on univariate analysis (P=0.005,
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