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Keywords | Mantle cell lymphoma | therapy | molecular risk factors | minimal residual disease (MRD) |<br />
pharmacogenomics | RNA array profi ling | proteomics |<br />
European MCL Network<br />
European Mantle Cell Lymphoma<br />
Network: Translation evaluation<br />
of molecular prognostic factors and<br />
pharmacogenomics in European<br />
interdisciplinary collaboration<br />
Summary<br />
Mantle cell lymphoma (MCL) is a subtype of malignant lymphoma<br />
with an especially poor prognosis. Recently, a European<br />
MCL Network of clinicians, basic scientists and pathologists<br />
has been established to investigate the clinical as well as<br />
molecular aspects of MCL. In previous clinical trials, the superiority<br />
of innovative treatment options (high dose therapy,<br />
combined immuno-chemotherapy) has been confi rmed, and<br />
cell proliferation has been identifi ed as the most important<br />
prognostic factor. Based on these extensive prerequisites, we<br />
have initiated a translational approach to evaluate innovative<br />
treatment options (like immuno-chemotherapy, radioimmunotherapy,<br />
high dose consolidation and molecularly targeted<br />
approaches) and molecular prognostic markers in prospective<br />
randomised studies. All study cases are subjects of<br />
innovative molecular analyses and continuous detection of<br />
minimal residual disease. This translational approach will not<br />
only lead to more eff ective therapeutic strategies based on<br />
the molecular profi ling but also pave the way to molecular<br />
targeted treatments.<br />
Problem<br />
Mantle cell lymphoma (MCL) is a distinct, clinically very<br />
aggressive subentity of malignant lymphoma with a median<br />
survival of three years. However, a small subset of patients<br />
represents long-term survivors. So far, the discriminative<br />
power of diff erent prognostic parameters has been limited<br />
and did not allow the reliable identifi cation of the individual<br />
patient’s risk profi le. Thus, a better understanding of the<br />
underlying molecular mechanisms is eagerly warranted.<br />
Aim<br />
Based on the previously established European MCL Network<br />
of clinicians, basic scientists and pathologists and the recent<br />
development of innovative molecular techniques (matrix CGH,<br />
RNA array chips, RQPCR, proteomics), we are performing<br />
TREATMENT<br />
a global approach to investigate innovative treatment options<br />
of MCL and evaluate new predictive (pharmacogenomics,<br />
minimal residual disease) and prognostic molecular markers<br />
(genomic alterations, RNA/proteome profi les) in controlled<br />
prospective studies. This translational approach of the European<br />
MCL Network will not only lead to more individualised<br />
therapeutic strategies based on the molecular risk profi le but<br />
will also fi nally elucidate the way to future molecular targeted<br />
treatment options in a subtype of malignant lymphoma with<br />
an otherwise dismal clinical outcome.<br />
Expected results<br />
• Prospective evaluation of combined immunochemotherapy<br />
and myeloablative consolidation in patients 65 years: R-CHOP vs. R-FC followed by IFN vs. Rituximab<br />
maintenance.<br />
• Regular histomorphological panel review of study cases<br />
(subtyping according to cytological criteria).<br />
• Prospective evaluation of a panel of proliferation-associated<br />
and new oncogenic markers (immuno-histochemistry).<br />
• Prospective evaluation of MRD detection (PCR, FACS,<br />
FISH) in the patient cohort of the European MCL Network.<br />
• Prospective evaluation of the proliferation-associated<br />
gene signature in the patient cohort of the European<br />
MCL Network (RNA array).<br />
Potential applications<br />
Malignant lymphoma is currently the fourth most frequent<br />
malignant disease and displays the highest increase in annual<br />
incidence of all hematological neoplasias. In this regard, the<br />
exploration of innovative treatment strategies and evaluation<br />
of prognostic markers in the rather rare disease of<br />
mantle cell lymphoma is also a model disease for much<br />
more frequent diseases which have a profound impact on<br />
the public health system as well as the general society. The<br />
prospective studies of the European MCL Network studies<br />
will enable us to gain a deeper understanding of the pathophysiological<br />
network of cell programme regulation in<br />
malignant lymphoma. In addition, applying this multivariate<br />
procedure, the critical biological players of malignant transformation<br />
will be identifi ed which may represent the suitable<br />
target genes of future treatment strategies in a disease with<br />
otherwise dismal prognosis. Moreover, this collaboration of<br />
outstanding clinical as well as molecular scientists will be<br />
a paradigm for other fi elds of biological research interlinking<br />
clinical and basic science as well as scientifi c excellence<br />
from all over Europe.<br />
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