Page 252 - Haematologica May 2020

F.A. Sharpley et al.
cohort. Other factors can influence NT-proBNP levels such as age. There was a correlation of NT-proBNP with age (P=0.002) but there was no significant difference in the numbers of patients over or below 75 years with NT- proBNP < or > 152 ng/L. Additionally, age was not signif- icant in the multivariable analysis.
The exquisite prognostic sensitivity of NT-proBNP in AL may suggest either early cardiac involvement or light chain proteotoxicity. The structurally established echocar- diographic criteria for AL cardiac involvement is an LV wall of >12 mm (in the absence of other causes). It is con- ceivably possible for a patient with baseline 8-10 mm LV wall could have substantial amyloid deposition before the threshold of 12 mm is reached. The opportunity to track changes in NT-proBNP during development of cardiac AL is rare. The kinetics of NT-proBNP increase as well as its correlation with LV wall thickness at early stage of the dis- ease process remain largely unknown.
CMR is an alternative method of monitoring patients with cardiac amyloidosis. In this current cohort, a third of all patients who had a CMR showed features of cardiac amyloidosis. Moreover, the presence of amyloid deposi- tion on CMR was an independent prognostic marker. CMR, with late gadolinium enhancement (LGE) and T1 mapping, is emerging as a highly sensitive and specific tool for diagnosis and characterisation of cardiac amyloi- dosis in AL (Figure 3).15 Transmural LGE with phase-sensi- tive inversion recovery (PSIR) is associated with the bur- den of cardiac amyloid and predicts death independent of NT-pro-BNP and other known prognostic factors.10 In this cohort, it clearly identified cardiac involvement in patients where the echocardiogram was not suggestive of cardiac amyloidosis but not all patients with NT-proBNP >152 ng/L had abnormal CMR (31% had abnormal CMR) and not all patients with NT-proBNP <152 ng/L had normal CMR (22% had abnormal CMR). This suggests that CMR provided complementary information on patients’ cardiac damage. NT-proBNP may be detecting cardiac damage by light chain proteotoxicity before structural amyloid depo- sition is apparent on CMR, conversely, some patients may have non-proteotoxic light chains (analogous to cardiac amyloid deposition in transthyretin amyloidosis [ATTR]) where the structural changes are apparent on CMR before biomarkers become abnormal. In this early stage of the disease, NT-proBNP and CMR findings should be used together for defining cardiac involvement.
In this study, liver involvement, a previously reported poor prognostic marker,9,16 did not significantly impact sur- vival. Relatively few patients had significant liver involve- ment - only 10% by consensus criteria (although a third had asymptomatic liver involvement on 123I-SAP scintigra- phy). The strict exclusion of cardiac involvement by con- sensus criteria may have excluded patients with advanced
liver involvement since the latter patients often have multi-organ amyloidosis. Likewise, although the majority of patients had renal involvement, 277 (73.3%) the medi- an presenting creatinine was low (76 mmol/L), with only a small proportion (n=14/375, 3.7%) with an eGFR <30 mL/min, which may explain why neither the presence of renal involvement nor proteinuria was a predictor of sur- vival. Autonomic involvement (ANS) was significant on univariate but not multivariate analysis, but the number of patients was small.
This study has limitations and needs to be interpreted in this context. This is single centre data but we are planning validation in an international collaborative data set. One major limitation is that the exact cause of death was only available in a small proportion of patients and when the cause was recorded as “amyloidosis” this does not elucidate whether cardiac amyloidosis was the real cause of death. Progressive cardiac amyloidosis does appear to be the cause of death in at least a proportion of patients in this study, based on serial echocardiogram imaging. The use of a very sensitive marker of cardiac disease like NT-proBNP at a low level is also challenging as other unrelated factors can impact upon NT-proBNP (such as age, renal function, sex, body mass index as evidenced by the Framingham study from 2011, and a more recent study by Dittrick et al.14,17 Finally, only a proportion of patients had CMR scans. Larger studies are needed to address these limitations.
In conclusion, this study demonstrates that in patients with AL with no cardiac involvement by consensus crite- ria even small elevations of NT-proBNP as well as cardiac involvement by CMR are factors highly prognostic for sur- vival. This novel finding offers some insight into the het- erogeneity in survival of Mayo stage I patients. There find- ings have implications for clinical practice. We suggest that a baseline cardiac MRI scan should be considered at diagnosis for stage I AL patients, if possible. Better out- comes for patients in a CR and those with decrease in NT- proBNP, suggest that in “high risk” stage I patients (those with NT-proBNP >152 ng/L) the goal of therapy should be similar to those with cardiac AL i.e. a complete haemato- logical response. The follow up of such patients should include routine NT-proBNP measurement including assessment of response (as patients with presenting NT- proBNP >152 ng/L and NT-proBNP progression [>30% increase] had poorer outcomes); those with NT-proBNP progression should be considered for further treatment. The “high risk relapse criteria” defined by the Italian amy- loidosis group, should be applied for treatment at relapse for patients with NT-proBNP >152 ng/L (high risk stage I).18 Serial CMR data is needed to assess cardiac structure and functional changes to delineate the natural history of ‘high risk’ patients and to help identify interventions to prevent progressive cardiac involvement.
References
1. Kyle RA, Greipp PR, O'Fallon WM. Primary systemic amyloidosis: multivariate analysis for prognostic factors in 168 cases. Blood. 1986;68(1):220-224.
2. Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treat- ment response in immunoglobulin light chain amyloidosis (AL): a consensus opin- ion from the 10th International Symposium
on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Haematol. 2005;79(4):319-328.
3. Palladini G, Dispenzieri A, Gertz MA, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival out- comes. J Clin Oncol. 2012;30(36):4541- 4549.
4. Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal
pro-brain natriuretic peptide: a staging sys- tem for primary systemic amyloidosis. J Clin Oncol. 2004;22(18):3751-3757.
5. Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012; 30(9):989-995.
6. Moreau P, Leblond V, Bourquelot P, et al. Prognostic factors for survival and response
1412
haematologica | 2020; 105(5)