28.7. Prognostic value of sFLC response

Chapter 28

Kumar et al. [598] studied the prognostic significance of dFLC reductions in 347 patients undergoing an autologous stem cell transplant (SCT). A 50% decrease in dFLC provided poor clinical discriminatory value in predicting survival as 96% of patients in the study achieved this reduction (Figure 28.10A). In contrast, a 90% reduction in dFLC was observed in 38% of patients, providing a more useful clinical separation. Furthermore, the median overall survival post-SCT, among those patients who achieved a 90% reduction in dFLC, was not reached, compared with the 37.4 months achieved in the remaining patients (p<0.001) (Figure 28.10B). The prognostic value of achieving a 90% reduction in dFLC was confirmed in a separate cohort of 96 patients treated with melphalan and dexamethasone (Figure 28.10C) [598]. The authors concluded that assessment of the dFLC response allows clinicians to modify therapy in those patients failing to achieve a 90% reduction in dFLC. These results are supported by the findings of several other earlier studies [133][623][624][637][625]. The relative contribution of changes in monoclonal intact immunoglobulin protein and dFLC in predicting overall survival was also analysed by Kumar et al. [598]. Reductions in dFLC were shown to be superior to changes in intact immunoglobulins for predicting overall survival.

More recently, in the study used to derive the consensus agreement for response criteria (Section 28.6.2), there was a strong correlation between the haematological response category at 3 or 6 months and overall survival (Figure 28.11). Girnius and colleagues [626] noted that the studies used to produce the response criteria contained very few patients treated with high-dose melphalan and autologous stem cell transplant (HDM/ASCT). However, Girnius et al. were able to provide data indicating that the criteria did have prognostic value for 140 patients whose response was assessed 1 year after HDM/ASCT.

Cordes et al. [627] analysed survival data for 74 patients who had received HDM/ASCT and concluded that the lowest post-treatment sFLC concentration provided the best indication of those patients who were more likely to survive for >10 years. Tandon et al. [956] also studied the prognostic value of involved FLC (iFLC) concentrations, in a group of 369 AL amyloidosis patients whose κ/λ sFLC ratio had normalised after initial therapy. Patients who had persistent elevation of iFLC concentrations at two time points (n=112) had a significantly shorter overall survival compared to those whose values normalised (7.8 years vs. not reached, p<0.0001). A multivariate analysis confirmed that the prognostic value of elevated iFLCs was independent of renal function.

Palladini et al. [214] compared response to treatment as assessed by Freelite and the Siemens N Latex FLC assays. Although the results produced by both assays were prognostic, percentage reductions in FLC concentration were quite different, leading the authors to conclude that amended response criteria would be needed for the N Latex FLC assays (Chapter 8).

28.7.1. sFLC response predicting cardiac outcomes

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 cardiac-related sequelae [628]. Measurement of cardiac biomarkers, namely troponin T and B-type 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 [114][611][23].

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).

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.

28.7.2. sFLC response and renal outcome

Pinney et al. [633] assessed the value of the sFLC response in predicting long-term renal outcome in 923 patients with renal AL amyloidosis. Patients who achieved a greater sFLC response after chemotherapy demonstrated prolonged survival and superior renal outcomes. Patients who achieved more than a 90% FLC response at 6 months had an almost four-fold increase in the chance of renal response (p<0.001) and a lower rate of renal progression (p<0.001) compared with those achieving a FLC response of 0 - 50%. Among 752 patients with a baseline estimated glomerular filtration rate (eGFR) of ≥15 mL/min, those who achieved a 50 to 90% reduction or more than a 90% reduction in dFLC were less likely to experience renal progression requiring dialysis than patients achieving a <50% reduction in dFLC.

Rezk et al. [946] studied the prognostic value of the response to chemotherapy among 84 patients with AL amyloidosis who presented with advanced CKD (eGFR <20 mL/min). The median time to a composite end point of either death or dialysis was 22.9 months for patients who achieved a dFLC response of ≥90%, compared to 5.3 months among patients who achieved a lesser response (p=0.0001). The dFLC response remained prognostic in the subset of 45/84 patients who had renal amyloidosis without cardiac involvement (time to dialysis was 22.9 months compared to 6.1 months, p<0.008). The authors concluded that an early haematological response is strongly associated with outcome in patients with systemic AL amyloidosis and severe renal impairment.

It should be noted that in cases of renal insufficiency, use of a modified renal reference interval for the κ/λ sFLC ratio may be appropriate. Application of this reference interval has been demonstrated to improve the diagnostic specificity of the sFLC ratio without affecting diagnostic sensitivity in patients with renal impairment (Section 6.3).