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Ibrutinib in previously treated Waldenström´s macroglobulinemia.

Treon SP1, Tripsas CK, Meid K, Warren D, Varma G, Green R, Argyropoulos KV, Yang G, Cao Y, Xu L, Patterson CJ, Rodig S, Zehnder JL, Aster JC, Harris NL,Kanan S, Ghobrial I, Castillo JJ, Laubach JP, Hunter ZR, Salman Z, Li J, Cheng M, Clow F, Graef T, Palomba ML, Advani RH.
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Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus.

Dimopoulos MA1, Kastritis E1, Owen RG2, Kyle RA3, Landgren O4, Morra E5, Leleu X6, García-Sanz R7, Munshi N8, Anderson KC8, Terpos E1, Ghobrial IM8,Morel P9, Maloney D10, Rummel M11, Leblond V12, Advani RH13, Gertz MA3, Kyriakou C14, Thomas SK15, Barlogie B16, Gregory SA17, Kimby E18, Merlini G19,Treon SP8.
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One of the goals of the consortium is to combine clinical research with translational research focussing on our understanding of the molecular and cellular biology of WM.


Areas of research cover topics such as genetics and epigenetics, the role of non-coding RNAs, the crosstalk between WM and its microenvironment, measurement of minimal residual disease (MRD). Examples for current research projects are:


Characterizing somatic mutation signatures in Waldenstrom’s Macroglobulinemia (WM)(O. Weigert, Munich, Germany)
The clinical course of WM is highly variable, however current prognostication relies entirely on clinical parameters. The underlying biology and genetics of WM remain incompletely defined, mostly because of the rarity of the disease, the relatively low tumor cell fraction, and the presence of non-malignant bystander cells. Hybrid-capture deep-sequencing of selected genes-of-interest allows sensitive detection of low frequency variants present within malignant lymphoplasmacytic cell population. Somatic Mutation signatures will be correlated with clinicodemographic data and treatment´outcome to improve current classification and prognostic scoring schemes, and add to a comprehensive understanding of the necessary complement of alterations to confer a WM phenotype. 

Chemokines in the Waldenstrom’s Macroglobulinemia tumor microenvironment  (T. Seiler, Munich, Germany)
Cytokines and Chemokines play an important role in B- and T-cell homing, inflammation, cell growth, and differentiation. As such, they are an integral part of the tumor microenvironment in lymphoma and are secreted by tumor cells as well as non-malignant bystander cells.
Little is known about the prognostic relevance of chemokine levels or networks in WM and how they behave during therapy. A broad panel of chemokines, cytokines and soluble receptors will be analysed to characterize the chemokine milieu in WM and evaluated for prognosis and association with clincial characteristics. 


MicroRNA serum signatures in Waldenstrom’s Macroglobulinemia (F. Kuchenbauer, C. Buske, Ulm, Germany)
MicroRNAs (miRNAs) are a class of small non-coding RNA that negatively regulate gene expression by translational repression or induction of mRNA degradation. There is an increasing body of evidence that miRNAs are present in plasma in a remarkably stable form and thus have the potential to serve as novel, non-invasive biomarkers for cancer. In this project plasma miRNA signatures will be determined from  patients with newly diagnosed WM before treatment and after treatment with DRC plus/minus Bortezomib in the setting of a large randomized European trial, which will be activated this year. Signatures will be correlated to biological characteristics, clinical risk groups and treatment response and will be evaluated for their potential to serve as novel biomarker for WM.