Abstract

The prognosis of patients with systemic AL amyloidosis is mainly driven by advanced organ dysfunction, mainly heart involvement. The contribution of the underlying plasma cell clone to prognosis has not been much studied – lately the serum free light chain load has been shown to impact survival. Detailed analysis of plasma cell immunophenotype by multiparameter flow cytometry has been reported to be prognostic in myeloma as well as MGUS. We report that the plasma cell phenotype may allow us to refine prognostic assessment in patients with systemic AL amyloidosis.

48 serial patients with biopsy proven systemic AL amyloidosis had bone marrow as part of a prospective bone marrow study. Flow cytometry was done using previously published protocols (Paiva et al Blood 2010) using fluorescent labelled monoclonal antibodies to the following markers (maximum eight in one tube): CD138, CD38, CD56, CD117, CD28, CD20, CD27, CD19, CD81 and kappa and lambda light chains. Organ involvement, survival and haematological response were analysed in the context of plasma cell phenotypes. Abnormal plasma cell phenotype was defined as cells expressing CD38+CD138+CD19- and further markers were analysed on this population. Cardiac, renal and liver involvement in the cohort was 69%, 75% and 29% respectively. The median follow up was 7 months (range 0.7-18.7months).

Results

Cardiac involvement was significantly higher in patients co-expressing CD56 (spearman’s correlation coefficient = 0.342 and p=0.021) and a non-significantly greater in those with CD27 expression. 77% had achieved a haematological response on an intention to treat analysis with 65% achieving a VGPR or better. Patients with plasma cells lacking expression of CD27 or CD81 achieved a significantly higher rate of VGPR or better compared to those expressing these markers, (spearman’s correlation coefficient = -.565 and -0.394, p=0.001 and p=0.021 respectively) (Table 1).

 VGPR or better PR/NR Fisher’s exact p value 
CD27+/- 3/19 6/6 0.040 
CD28+/- 5/15 0/9 0.153 
CD56+/- 10/11 5/5 1.00 
CD81+/- 2/18 7/4 0.003 
CD117+/- 12/9 5/6 0.712 
 VGPR or better PR/NR Fisher’s exact p value 
CD27+/- 3/19 6/6 0.040 
CD28+/- 5/15 0/9 0.153 
CD56+/- 10/11 5/5 1.00 
CD81+/- 2/18 7/4 0.003 
CD117+/- 12/9 5/6 0.712 

Median OS was not reached for the whole cohort and the 2 year OS in patients with >5% normal plasma cells (defined as CD38+CD138+CD19+ plasma cells) was 74% compared to 45% in those with <5% normal plasma cells (median OS not reached (NR) vs 4.3 months respectively). Patients with cardiac involvement had a median OS of 5.2 months compared to not reached (NR) for those without cardiac involvement (p=0.017). Within the former group, those with >5% normal plasma cells had a better median OS compared to those with <5% normal plasma cells (NR vs 3.7 months, p=0.564). The median OS was not reached for those achieving a clonal response vs. 3.2 months for non responders (p<0.000). Of the patients who achieved VGPR, those with >5% normal plasma cells appear to have a better OS than those with <5% normal plasma cells with a 2 year survival of 100% and 76%, respectively.

Patients with abnormal plasma cell clone expressing CD27 phenotype had a significantly worse OS than those without CD27 (2.6 months vs median OS NR, p=0.010, figure 1). Similarly, expression of CD56 by the abnormal clones had a significantly worse OS, than CD56- plasma cells (4.3 months vs Median OS NR, p=0.052). Patients with abnormal clones expressing CD27+CD56+ had an OS of 1.5 months compared to median OS not reached in the CD27+CD56- group (p=0.003). Median OS was not reached in either CD27-CD56- or CD27-CD56+ patients, but the former group appear to have a better outcome with a 2 year survival of 90% and 67% respectively (figure 2). On a multivariate analysis, expression of CD27 and CD56 on abnormal plasma cells remained significant prognostic factors when analysed along with different variables of cardiac involvement including Mayo staging.

Conclusion

In summary, presence of >5% normal plasma cells is associated with better OS. Expression of CD56 correlated with cardiac involvement and of CD27 with a poorer haematological response. Expressions of CD27 or CD56 on CD38+CD138+CD19- plasma cells appear to be independent markers of poorer prognosis. Patients expressing both having even worse outcomes with a median OS <2 months. In summary, defining the plasma cell immunophenotype may help to refine the current staging of AL amyloidosis and response to treatment. This observation requires further validation in larger studies.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.