Picking up on Richter's Syndrome

What makes a CLL patient more prone to develop Richter's syndrome? This is an important question since early recognition and treatment are the keys to better outcomes in this dreaded complication.

A paper from Davide Rossi's group in Novara, Italy helps to address this question. A variant of the LRP4 gene affects the risk of chronic lymphocytic leukaemia transformation to Richter syndrome. Silvia Rasi, Valeria Spina, Alessio Bruscaggin, Tiziana Vaisitti, Claudio Tripodo, Francesco Forconi, Lorenzo De Paoli, Marco Fangazio, Elisa Sozzi, Emanuele Cencini, Luca Laurenti, Roberto Marasca, Carlo Visco, Zijun Y. Xu-Monette, Valter Gattei, Ken H. Young, Fabio Malavasi, Silvia Deaglio, Gianluca Gaidano, Davide Rossi British Journal of Haematology
Volume 152, Issue 3, pages 284–294, February 2011

Chief among markers for Richter's transformation is the use of the IGHV 4-39 gene, especially with a stereotyped HCDR3, and another reason why everybody with active CLL should have their V genes sequenced. A single neucleotide polymorphism (SNP) of the CD38 gene (rs6449182) has also been implicated in the development of Richter's disease, as has a TP53 deletion or mutation, or indeed the use of unmutated V genes. Rossi's group have looked at LRP4, a member of the low-density lipoprotein receptor family that acts as an antagonist of the Wnt/beta-Catenin signaling pathway. In particular they have surveyed the use of an SNP (rs2306029) in 331 cases of CLL, 21 (6.3%) of which developed Richter's syndrome.

In a multivariate analysis, the hazard ration for transformation for the use of V4-39 with the stereotyped HCDR3 was 6.13 (all of the cases transformed within 6 years), for the stereotyped HCDR3 without V4-39 it was 4.45 (38% transformed by 12 years) and for the LRP4 SNP it was 3.21 (9.5% transformed by 2and a half years). Although the CD38 polymorphism carried a significant risk in the univariant analysis, this was lost in the multivariant analysis. When the LRP4 SNP was found with the stereotyped HDR3 but without V4-39 usage, the hazard ration was 14.13 (62% transformed by 12 years).

To confirm that this was not simply a chance finding, they have validated their work in an entirely separate CLL population.