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Biology and Genetics of Richter’s Transformation

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Authored by: Dr. Brian Koffman

This was a very complex basic science presentation from iwCLL 2023 by Erin Parry, MD, Ph.D., of Dana Farber Cancer Institute in Boston on the evolution of CLL (chronic lymphocytic leukemia) to Richter’s transformation (RT), also known as Richter’s syndrome (RS).

I will share only the conclusions of the important research and its clinical importance.

  1. The majority of RT evolves from CLL through the acquisition of additional genetic mutations.
    • This helps explain why the genetic instability seen in those with aberrant TP53 or 17p del and other mutations puts one at higher risk for RT as they acquire more mutations over time. TP53 has been called the guardian of the genome, and when it’s missing or not functional, genes can be altered with impunity.
  2. Clonally related RT is distinct from de novo DLBCL (diffuse large B cell lymphoma).
    • DLBCL is much easier to treat than RT. Turns out it is genetically different.
  3. Molecular subtypes of RT exist with prognostic significance.
    • Not all RT is a death sentence. Understanding the genetic drivers that better or worsen the prognosis gives us hope to find new ways to intervene.
  4. ULP-WGS (ultra-low pass-whole gene sequencing) cfDNA (cell free DNA found floating in the plasma in the peripheral blood stream) may hold promise for a simple blood test allowing early diagnosis of RT.
    • This is the most exciting result. If confirmed in larger studies, ULP-WGS cfDNA might eventually become a commercially available blood test that could detect RT many months before it is clinically apparent and, therefore, possibly allow more effective earlier therapies when the disease burden is lower. Now, RT is usually diagnosed with a biopsy, which sometimes can be a major surgical procedure depending on the location of the suspicious node. This can lead to delayed diagnosis, which is never a good thing with a rapidly growing cancer.

RT remains one of the most pressing unmet needs in the CLL community due to its generally dismal prognosis. As more and more CLL patients are living longer with better therapies developed for CLL, the risk of RT increases. Research such as this on the basic biology of its evolution is critical and is one of the research areas that the CLL Society actively funds, such as our 2022 Young Investigator Award given to Dr. Christine Ryan for her work on drivers of apoptosis (cell death) in RT.

Watch my monologue on the abstract:

Biology and Genetics of Richter’s Transformation

Stay strong. We are all in this together.

Brian Koffman MDCM (retired), MS Ed
Co-Founder, Executive VP, and Chief Medical Officer
CLL Society