Dr. Stephan Stilgenbauer on the Evolution of CLL to Richter’s Syndrome from ASH 2022

Medically reviewed and interview by Dr. Brian Koffman.

The Bottom Line:

This new research identifies some of the genetic changes that drive the evolution of CLL to Richter’s syndrome. Researchers hope this information can be used to develop better treatments for Richter’s syndrome.

Who Performed the Research and Where Was it Presented:

Dr. Stephen Stilgenbauer from Ulm University and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2022.

Background:

Richter’s syndrome (a.k.a. Richter’s transformation) is a rare complication of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), where the cancer cells transform into a much more aggressive lymphoma. It currently has no approved therapies and is associated with an extremely poor prognosis. One way of identifying potential therapeutic targets is to study the biology and mechanisms contributing to the development of Richter’s syndrome. The hope is that it would help scientists to identify better approaches for treating Richter’s syndrome.

Dr. Brian Koffman interviewed Dr. Stephan Stilgenbauer, Professor of Medicine and Medical Director of the Comprehensive Cancer Center at Ulm University in Germany. They discussed new research looking at the genetic changes that drive the evolution of CLL into Richter’s syndrome. Much of this is very technical information that will help inform new therapies.

Methods and Participants:

Researchers analyzed all the DNA in matched Richter’s syndrome and CLL samples from 52 patients. They also analyzed DNA on a validation cohort of 43 independent Richter’s syndrome cases. They used this information to trace the evolution of CLL to Richter’s syndrome.

Results:

• Researchers identified several genes that they think are drivers of Richter’s syndrome (including IRF2BP2, SRSF1, B2M, DNMT3A, CCND3) and other alterations in patients’ genomes.
• Some alterations in key signaling pathways are pre-existing in CLL, such as changes in DNA damage response, NOTCH signaling, and MAPK signaling.
• However, changes in other signaling pathways appear to newly occur with the transformation to Richter’s syndrome, such as changes in inflammatory signaling, cell cycle regulation, immune evasion, and MYC signaling.
• Increasing massive chromosomal rearrangement (chromothripsis) was identified as one of the hallmarks of Richter’s syndrome.
• Richter’s syndrome is genetically distinct from diffuse large B cell lymphoma (DLBCL).
• Though none of the pathways identified in this research have drugs available in the clinic yet, researchers are hopeful that this new information will help to drive the development of new solutions for Richter’s syndrome.

Conclusions:

This new research identifies some of the genetic changes that drive the evolution of CLL to Richter’s syndrome. Researchers hope this information can be used to develop better treatments for Richter’s syndrome.

Links and Resources:

Watch the interview on the abstract here:

ASH 2022: Dr. Stephan Stilgenbauer on the Evolution of CLL to Richter Syndrome

Here is the actual ASH abstract: Evolutionary History of Transformation from Chronic Lymphocytic Leukemia to Richter Syndrome

Ann Liu PhD