UAE Congress 2012

1. Primary Central Nervous System Lymphoma maybe associated with an
Activated B-cell Phenotype and BCL6 Translocation
K Tay1 , J Hoe4 , LP Khoo1 , Y Lee 1,2 , E Kalaw3 , J Ha1 , L Tan3, R Quek1 , M Tao1 , SY Tan3, ST Lim1
1Dept of Medical Oncology, National Cancer Centre Singapore. 2Biostatistics Unit, Clinical Trials and Epidemiology, National Cancer Centre Singapore
3Department of Pathology, Singapore General Hospital. 4Yong Loo-lin School of Medicine, National University of Singapore.
INTRODUCTION
Primary Central Nervous System Lymphoma (PCNSL) is a rare and
aggressive extra-nodal form of diffuse large B-cell lymphoma (DLBCL)
with unique clinical and biological features.
Methotrexate (MTX) has been established as one of the most efficient
treatment for PCNSL whether as a single agent or in a regimen or with
whole-brain radiotherapy (WBRT).
However, these patients still have a dismal outcome despite combined
modality treatment (CMT) of chemotherapy and whole-brain
radiotherapy. This is largely due to morbidity as a result of CNS
involvement and the development of neurotoxicity post-treatment.
The aim of this study was to identify clinical and pathological defining
characteristics of PCNSL as well as the survival trends in patients with
PCNSL.
METHODS
This is a retrospective study of 77 patients newly diagnosed with PCNSL
from 1998–2011 that were treated at the National Cancer Centre
Singapore (NCCS).
All cases were investigated by immunohistochemistry (IHC) and
Fluorescence in-situ hybridization (FISH), using break-apart FISH probes
targeting BCL2, BCL6, MYC, CCND1, PAX5, MALT1 and IgH genes.
PATIENT CHARACTERISTICS
RESULTS
•The median overall survival (OS) and progression-free survival (PFS) of all 77 patients were 27.2
months and 14.9 months respectively. Among the 53 patients treated with curative intent, the
median OS and median PFS were 35.9 months and 19.0 months respectively. The corresponding
3 year OS in the curative group of 53 patients is 46.3% and 3 yr PFS is 28% (graphs not shown).
•FISH analysis revealed BCL6 translocation as the only translocation seen in our cohort of
patients, with 11 of 27 (40.7%) patients expressing it.
•The use of CMT was the only significant prognostic factor identified by univariate cox regression
analysis.
•The presence of BCL6 translocation, the addition of Rituximab to methotrexate-based
chemotherapy regimen, the presence of leptomeningeal or intraocular involvement, ECOG at
diagnosis, IPI score and none of the IHC markers (results not shown) appeared to show any
impact on survival in our cohort of patients.
• Our patients treated with curative intent had a median overall
survival of 35.9 months which is comparable to most published
clinical studies.
• Majority of the PCNSL patients in our study expressed the ABC
phenotype by the Han’s classification.
• Only BCL6 translocation was detected and seen in 11 patients, with
no other associations with MYC translocation or double-hit
phenomenon.
• Patients who received CMT was associated with a better outcome
and remains the standard of care but this needs to be balanced
with the potential long term complication of neurotoxicity from
therapy.
CONCLUSION
REFERENCES
OS
ACKNOWLEDGEMENTS: This study was funded by the National Medical Research Council of Singapore as well as a grant from HSBC Trustee (Singapore) Limited as trustees of the Major John Long Trust Fund and the Chew Woon Poh Trust Fund. *All the authors listed above have no relevant conflicts of interest to disclose.
IMMUNOSTAINING
1. Rubenstein J. et al. Primary lymphoma of the central nervous system: epidemiology,
pathology and current approaches to diagnosis, prognosis and treatment. Leukemia &
Lymphoma 2008; 49(S1): 43-51.
2. Gavrilovic IT. et al. Long-Term follow-Up of high-dose methotrexate-based therapy with
and without whole brain irradiation for newly diagnosed Primary CNS Lymphoma. J Clin
Oncol 2006;24:4570-4574.
3. Ferreri AJM. et al. High-dose cytarabine plus high-dose methotrexate versus high-dose
methotrexate alone in patients with primary CNS lymphoma: a randomized phase 2 trial.
Lancet 2009;374:1512-1520.
PFS
Immunostaining
Evaluable
cases %
Ki67 % (median, range) N = 49
< 70 13 26.5
> 70 36 73.5
CD10 N = 43
Positive 10 23.3
Negative 33 76.7
CD20 N = 63
Positive 63 80.8
Negative 0
BCL6 N = 34
Positive 29 85.3
Negative 5 14.7
MUM1 N = 36
Positive 31 86.1
Negative 5 13.9
Characteristics N = 77 %
Age (median = 58, range = 25-79)
< 60 49 63.6
> 60 28 36.4
Gender
Female 30 39
Male 47 61.0
HIV status
Positive 6 7.8
Negative 57 74.0
Other CNS involvement
None 57 74.0
Leptomeningeal 11 14.3
Intraocular 8 10.4
Leptomeningeal + Intraocular 1 1.3
IPI score
Low (0-1) 31 40.3
Low intermediate (2) 19 24.7
High intermediate (3) 7 9.1
Treatment modality
Chemotherapy 14 18.2
Chemotherapy & radiotherapy 39 50.6
Whole brain radiotherapy 14 18.2
Steroids 5 6.5
None 5 6.5
Remission
Complete response 26 33.8
Partial response 11 14.3
Stable disease 11 14.3
Progressive disease 13 16.9
Characteristics
Overall survival, curative intent (n=53)
HR (95% CI) p-value
Age 0.58
< 60 1.00
> 60 0.79 (0.36-1.78)
Gender 0.84
Female 1.00
Male 0.93 (0.43-2.00)
Other CNS involvement 0.11
None 1.00
Leptomeningeal or intraocular 0.49 (0.20-1.20)
ECOG 0.25
0-1 1.00
2-4 0.50 (0.15-1.68)
IPI score 0.082
Low (0-1) 1.00
Low intermediate (2) 0.33 (0.12-0.91)
High intermediate (3) 0.58 (0.15-2.29)
Regimen 0.23
De-Angelis 1.00
De-Angelis rituximab 2.19 (0.60-8.02)
Treatment modality 0.02
Chemotherapy 1.00
Chemotherapy & radiotherapy 0.41 (0.19-0.89)
BCL6 translocation 0.29
Normal 1.00
Translocation 2.37 (0.45-12.32)
Univariate Cox Regression Analysis
Evaluable
cases %
Han’s Classification N = 21
ABC 18 85.7
GCB 3 14.3
Molecular cytogenetic N %
BCL6 N = 27
Normal 16 59.3
Translocation 11 40.7
HAN’S & FISH
Median OS: 27.2 months
Median FU: 14.0 months
Median PFS: 14.9 months
Median FU : 9.4 months