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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, 2 Department 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, 5 Department 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 L o w L P L, n = 1 4 2 50 50 L o w C L L U 1, n = 1 3 4 50 Low TC L1, n=129 50 Low M C L1, n=126
L o w Z A P 7 0, n = 1 2 6
H ig h L P L , n = 1 1 0 H ig h Z A P 7 0 , n = 1 2 6 H ig h C L L U 1 , n = 1 1 8 H ig h T C L 1 , n = 1 2 3 H ig h M C L 1 , n = 1 2 2

markers, LPL was most successful in could significantly predict overall survival (Figure 1) 25 25 p < 0 .0 1 25

%
25 p < 0 .0 0 0 0 1 25 p < 0 .0 1 p = 0 .0 3
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 C LLU 1, n= 134
C. TCL1 E. MCL1
100 L o w L P L, n = 1 4 2 100 Low ZAP70, n=126 100 100 Low TC L1, n=116 100 Low M C L1, n=126
good-prognosis patient subgroups based on LPL expression was the only independent prognostic H ig h L P L , n = 1 1 0 H ig h Z A P 7 0 , n = 1 2 6 H ig h C L L U 1 , n = 1 1 8 H ig h T C L 1 , n = 1 0 3 H ig h M C L 1 , n = 1 2 2

% Untreated

% Untreated
p = 0 .0 1

% Untreated
p < 0 .0 0 0 0 1

% Untreated
p = 0 .0 0 0 8 7

% Untreated
75 75 75 75 p < 0 .0 1 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 48
Time (months)
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.

Introduction
Recent studies have proposed the RNA-based
Variable Variable
Overall survival (N=248)
HR CI p
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
markers LPL, ZAP70, CLLU1, TCL1, and
TCL1 1.38 0.86 – 2.19
Age at diagnosis 0.180
3. All of the RNA-based markers added further prognostic
information to established markers in subgroups of patients, with
4. We observed that LPL expression in combination with CD38
expression could further subdivide Binet stage A CLL patients
MCL1 in CLL prognostication, either as single
markers or in combination with established
markers.
LPL 4.63 2.65 –
Binet stage8.09 <0.0000
LPL expression status giving the most significant results (Table 3).
Table 3. The prognostic information of RNA-based markers in subgroups of established markers.
(Figure 4).

A B.

ZAP70 1.32 0.82 – 2.11 0.25294


.1 0 0 100

CD38
75
75

% Surviving
Low L P L , lo w C D 3 8 , n = 9 0

Material and Methods

% Untreated
Low L P L , h ig h C D 3 8 , n = 3 5
H ig h L P L , lo w C D 3 8 , n = 1 5
50 50 H ig h L P L , h ig h C D 3 8 , n = 3 1

• mRNA expressions levels of LPL, ZAP70, CLLU1, Low L P L , lo w C D 3 8 ; n = 9 9

Variable LPL
Low L P L , h ig h C D 3 8 ; n = 1 6

CLLU1 0.83 0.51 – 1.33 0.44274


H ig h L P L , lo w C D 3 8 ; n = 3 8 25
TCL1 and MCL1 were measured in unsorted samples 25
H ig h L P L , h ig h C D 3 8 ; n = 3 4

from 252 newly diagnosed CLL patients from a

LPL
0 0
0 24 48 72 96 120
0 24 48 72 96 120
Scandinavian population-based cohort by RQ-PCR Time from diagnosis (months) Time to treatment (months)

• RNA markers were evaluated as single markers and


OS TTT O Figure 4. LPL and CD38 expression status subdivides overall survival and time to treatment.

MCL1 1.29 0.82 – 2.04 0.27587


in combination with established markers i.e. Binet
staging, IGHV mutation status, recurrent genomic

Genomic aberrations
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