Sajitha Sachchithanantham
Use of plasma cell immunophenotype as prognostic markers in patients with
systemic AL amyloidosis.
Sajitha Sachchithanantham 1*, Anna Baginska1*, Dorota Rowczenio1, Shameem A Mahmood1, Rabya
Sayed1, Ketna Patel1 ,Julian D Gillmore1, Helen J Lachmann1, Thirusha Lane1, Darren Foard1, Lisa
Rannigan1, Philip N Hawkins1 and Ashutosh D Wechalekar1
1Center
for Amyloidosis and Acute Phase Proteins, University College London Medical School, UK
*Co-authors
– Authors had equal contribution to the study
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).
CD27+/CD28+/CD56+/CD81+/CD117+/-
VGPR or better
3/19
5/15
10/11
2/18
12/9
PR/NR
6/6
0/9
5/5
7/4
5/6
Fisher’s exact p value
0.040
0.153
1.00
0.003
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 (figure2). 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.
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.
Figure 1:
Figure 2: