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LPL is the strongest prognostic factor in a comparative analysis of RNA-based

markers in chronic lymphocytic leukemia


Mohd Arifin Kaderi1, Meena Kanduri1, Mahmoud Mansouri1, Anne Mette Buhl2, , Marie Sevov1, Nicola Cahill1, Rebeqa Gunnarsson3, Mattias
Jansson1, Karin Ekström Smedby4, Henrik Hjalgrim5, Gunnar Juliusson3, Jesper Jurlander2, Richard Rosenquist1 
Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden, 2Department of Hematology, Leukemia Laboratory, Rigshospitalet, Copenhagen, Denmark, 3Department of Laboratory Medicine, Stem Cell Center,
1

Hematology and Transplantation, Lund University, Lund, Sweden, 4Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden, 5Department of Epidemiology Research, Statens Serum Institut,
Copenhagen, Denmark.

Conclusions Results A. LPL B. ZAP70 C. CLLU1 D. TCL1 E. MCL1


100 100 100 100 100

75 75 75

% Surviving

% Surviving
75 75

% Surviving

% Surviving
Surviving
• Among the RNA-based prognostic 1. All investigated RNA-based markers except MCL1

% Surviving
50 Low LPL , n=142 50 50 Low CLLU1 , n=134 50 Low TCL1 , n=129 50 Low MCL1 , n=126
Low ZAP70 , n=126
High LPL , n=110 High ZAP70 , n=126 High CLLU1 , n=118 High TCL1 , n=123 High MCL1 , n=122

markers, LPL was most successful in could significantly predict overall survival (Figure 1) 25 25 p < 0.01 25

%
25 p < 0.00001 25 p < 0.01 p = 0.03
Time from diagnosis (months)
0
and time to treatment (Figure 2). LPL gave the most
0 0
predicting clinical outcome in CLL and
0 0
0 24 48 72 96 120 0 24 48 72 96 120 0 24 48 72 96 120 0 24 48 72 96 120 0 24 48 72 96 120
Time (months) Time (months) Time (months) Time (months) Time (months)

remained as the strongest independent significant results in all the analyses. Figure 1. Expression status of RNA-based markers and overall survival.
marker in multivariate analysis.
• LPL expression could also further stratify 2. In multivariate analysis including the RNA markers, A. LPL B. ZAP70 D. CLLU1
Low CLLU1 , n=134
C. TCL1 E. MCL1
100 Low LPL , n=142 100 Low ZAP70, n=126 100 100 Low TCL1 , n=116 100 Low MCL1 , n=126
good-prognosis patient subgroups based on LPL expression was the only independent prognostic High LPL , n=110 High ZAP70, n=126 High CLLU1 , n=118 High TCL1 , n=103 High MCL1 , n=122

% Untreated

% Untreated
p = 0.01

% Untreated
p < 0.00001

% Untreated
p = 0.00087

% Untreated
75 75 75 75 p < 0.01 75

established markers. factor for OS and TTT (Table 1). LPL lost its 50 50 50 50 50

•Combinations of LPL and CD38 expression significance when including established markers, likely 25 25 25 25 25

could further subdivide Binet stage A CLL due to its close association to IGHV mutation status. 0
0 24 48
Time (months)
72 96 120
0
0 24
Time (months)
48 72 96 120
0
0 24
Time (months)
48 72 96 120
0
0 24 48
Time (months)
72 96 120
0
0 24 48
Time (months)
72 96 120

patients. Once the latter marker was excluded, LPL regained its
Figure 2. Expression status of the RNA-based markers and time to treatment.
• Our results suggest that LPL analysis independent prognostic strength (Table 2).
could be applied in the clinical laboratory,
Table 2. Multivariate Cox-regression analysis of LPL and established markers (excluding IGHV mutation status).
particularly in combination with established Table 1. Multivariate Cox-regression analysis of RNA-based markers.

markers. Variable
HR
Overall survival (N=248)
CI p
Time to Treatment (N=216)
HR CI P
Variable Overall survival (N = 230) Time to Treatment (N = 210)
HR CI p HR CI p
TCL1 1.38 0.86 – 2.19 0.180 1.18 0.79 – 1.75 0.415 Age at diagnosis 2.00 1.24 – 3.23 0.004 Not included
LPL 4.63 2.65 – 8.09 <0.00001 3.64 2.32 – 5.71 <0.00001
Introduction ZAP70 1.32 0.82 – 2.11 0.252945 1.25 0.84 – 1.86 0.282
Binet stage 2.60 1.57 – 4.28 0.0001 4.43 2.83 – 6.92 <0.00001
CD38 1.68 0.97 – 2.91 0.063 1.68 1.04 – 2.70 0.034
CLLU1 0.83 0.51 – 1.33 0.442747 1.16 0.77 – 1.74 0.473
Recent studies have proposed the RNA-based MCL1 1.29 0.82 – 2.04 0.275875 0.91 0.62 – 1.34 0.652
LPL 2.31 1.28 – 4.17 0.005 2.52 1.54 – 4.11 0.0002
Genomic aberrations 1.80 1.18 – 2.75 0.006 1.37 0.93 – 2.00 0.108
markers LPL, TCL1, ZAP70, CLLU1 and MCL1,
to be novel predictors of clinical outcome in CLL. The threshold values used in the analysis were determined based on ROC
curve analysis. The threshold values used in the analysis were as follows; age at diagnosis: median (63.9); Binet stage: A vs B/C;
IGHV mutation status: mutated vs unmutated; genomic aberrations: del(13q)/no aberration vs trisomy12/del(11q)
However, a comprehensive evaluation of these HR: Hazard ratio, CI: Confidence interval.
vs del(17p); CD38: 7%; LPL: threshold value based on ROC curve analysis.
RNA markers is lacking. HR: Hazard ratio, CI: Confidence interval.

Aim
To investigate the potential of the RNA-based 3. All of the RNA-based markers added further prognostic 4. We observed that LPL expression in combination with CD38
markers LPL, ZAP70, CLLU1, TCL1, and information to established markers in subgroups of patients, with expression could further subdivide Binet stage A CLL patients
MCL1 in CLL prognostication, either as single LPL expression status giving the most significant results (Table 3). (Figure 4).
markers or in combination with established Table 3. The prognostic information of RNA-based markers in subgroups of established markers.
markers. Log-rank p values A B.
Variable LPL ZAP70 CLLU1 TCL1 MCL1 .100 100

OS TTT OS TTT OS TTT OS TTT OS TTT


75
75

% Surviving
IGHV mutation status Low LPL , low CD38, n=90

Material and Methods

% Untreated
Low LPL , high CD38, n=35
Mutated NS NS NS NS NS NS NS 0.007 NS NS High LPL , low CD38, n=15
a
50 50
Unmutated 0.01 NS NS NS 0.03* NS NS NS NS NS High LPL , high CD38,n=31

• mRNA expressions levels of LPL, ZAP70, CLLU1, Low


Low
LPL
LPL
, low CD38; n=99
, high CD38; n=16
Binet Stage High LPL , low CD38; n=38 25
TCL1 and MCL1 were measured in unsorted samples A 0.00000 0.00000 0.005 NS NS 0.02 0.007 0.0001 NS NS
25
High LPL , high CD38; n=34
B/C NS NA NS NA NS NA 0.05 NA 0.03 NA
from 252 newly diagnosed CLL patients from a 0
0 24 48 72 96 120
0
0 24 48 72 96 120
Genomic aberrations
Scandinavian population-based cohort by RQ-PCR del(13q)/No aberration 0.00000 0.00002 NS NS NS NS 0.04 0.007 NS NS Time from diagnosis (months) Time to treatment (months)
Trisomy 12/ del(11q) NS NS 0.04 NS NS NS NS NS NS NS
• RNA markers were evaluated as single markers and del(17p) NA NA NA NA NA NA NA NA NA NA Figure 4. LPL and CD38 expression status subdivides overall survival and time to treatment.
in combination with established markers i.e. Binet CD38
< 7% 0.00009 0.00004 NS NS NS NS NS 0.02 NS NS
staging, IGHV mutation status, recurrent genomic ≥ 7% 0.0009 0.005 0.02 NS NS NS NS NS NS NS

aberrations and CD38 expression. a


only 3 cases with low LPL expression in this subgroup
• ROC curve analysis was applied to define the * high CLLU1 had longer OS accoding to Kaplan-Meier curve
NS not significant
threshold values for survival analyses of the RNA- NA not available; reliable log-rank test could not be performed due to very low number of cases
based markers. arifin.kaderi@genpat.uu.se

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