A New Staging System for AL Amyloidosis Incorporating Serum Free Light Chains, cardiac Troponin-T and NT-ProBNP.
Authors: Wechalekar Ashutosh D , Wassef Nancy L , Gibbs Simon DJ , Gillmore Julian , Dike Felicia , Lachmann Helen , Sattianayagam Prayman , Bradwell Arthur , Hawkins Philip N 
Published: October 2019

Abstract
Abstract 2796
Poster Board II-772

Background:
Risk stratification for patients with AL amyloidosis remains difficult. The Mayo staging system (Dispenzieri et al JCO 2004), based on cardiac biomarkers, is a widely accepted staging method. The Mayo staging cohort was diagnosed over a 21 year period during which the treatment for AL amyloidosis has completely changed. It also does not take into account the underlying clonal disease biology which is emerging as an independent prognostic factor. We propose a new staging for AL amyloidosis incorporating serum free light chains into the Mayo staging system using a much more uniformly treated cohort of patients.

Methods:
212 patients with systemic AL amyloidosis attending the UK National Amyloidosis Centre between Jan 2001 and March 2008 with complete data sets (or stored sampled for retrospective testing) for FLC, NT-ProBNP and cardiac Troponin-T prior to any treatment were identified from the database. Patients with overt symptomatic myeloma were excluded from the analysis.

Results:
Median age was 64 years (range 26-88), male: female ratio was 1.3:1. Median serum creatinine was 149 μmol/L (37-1079), and 24 hour proteinuria 3.9g (<0.1- 20g) with renal involvement being the commonest followed by cardiac. The FLC ratio was abnormal in 180 (85%) patients, with a lambda bias in 136 (64%) cases and a kappa bias in 44 (21%). The concentration of the abnormal class of FLC (iFLC) exceeded 500mg/L in 71 (33%) cases. The median overall survival (OS) of the cohort was 1.8 years with no significant difference in OS for patients with either kappa or lambda as the abnormal component.
The cut-off for NT-ProBNP and troponin-T were based on the Mayo staging system (35 pMol/L and 0.03 ng/ml respectively) and iFLC cut-off was selected as 500 mg/L. The median overall survival for patients with values above and below the cut-off were: troponin-T – 0.4 yrs vs. 4.7 yrs (p<0.0001), NT-ProBNP – 1.2 yrs vs. median not reached (p <0.0001) and FLC – 0.9 yrs vs. 3.2 yrs (p=0.02). All patients with a high troponin-T had high NT-ProBNP. For patients with high troponin-T, serum free light chain level at presentation did not significantly affect OS (0.34 vs. 0.48 yrs). When this group was excluded, serum free light chains further stratified patients with a normal or abnormal NT-ProBNP. For the group with normal NT-ProBNP, the median OS was not reached for patients with iFLC <500 mg/L vs. 3.1 yrs for those with iFLC >500mg/L; those with abnormal NT-ProBNP – median OS was 4.6 yrs vs. 1.2 yrs (p=0.015) respectively for low and high FLC. iFLC >500 mg/L independently predicted for poorer OS in a multivariate model (p =0.016). A new staging system is proposed incorporating iFLC using the above mentioned cut-off values for NT-ProBNP, troponin-T and iFLC: Stage I - normal NT-ProBNP/troponin-T with low iFLC (median OS not reached); Stage II - high NT-ProBNP and low iFLC (median OS 4.6 yrs); Stage III - high iFLC (median OS 2 yrs); and Stage IV - abnormal troponin (median OS 0.4 yrs). At 18 months from diagnosis, 8% of stage I, 25% of stage II, 45% of stage III and 76% of stage IV patients had died. Stage IV patients were more likely to have not completed a full course of treatment (42%) compared to other groups (23% stage, 18% and 24% for the other three stages). 6% and 7% of stage I and II patients underwent an autologous stem cell transplant compared to none in the other stages.

Conclusion:
This new staging system for AL amyloidosis brings clonal markers in the stratification process. Patients with high troponin-T at presentation have a dismal outcome even with recent treatment advances which is unaffected by clonal parameters and need novel rapidly effective approach to treatment. In the other groups, the free light chains at presentation – a surrogate for the clonal burden – are prognostically important. This system offers better stratification of patients over the current system – it upstaged 14% Mayo stage I and 32% stage II patients. Adding the clonal markers may make this useful for addressing new questions in clinical trials. Given the low clonal burden in the good risk stage I patients, is the highest intensity treatment (i.e. ASCT) really needed and could they conceivably achieve the same outcome with less toxic short course treatment? This new staging system needs to be validated in independent patient groups and if validated should be adopted as a new amyloidosis staging system.

Disclosures:
Bradwell: The Binding Site: Equity Ownership.