19 December 2022

The genetic evolution that sees chronic lymphocytic leukaemia (CLL) transform into the aggressive Richter’s syndrome has been mapped for the first time.

Scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, USA, have traced the changes in unprecedented detail, revealing the molecular pathways that lead to Richter’s.

The findings, which were presented at the annual meeting of the American Society of Hematology (ASH) and published in Nature Medicine, point the way to an earlier diagnosis of the disease, when treatments may be more effective.

Study co-senior author Dr Catherine Wu, of Dana-Farber, the Broad Institute, and Brigham and Women’s Hospital, said: “The treatments for CLL and Richter’s Syndrome are very different, so it’s critical that doctors be able to determine, as early as possible, when CLL has ‘crossed over’ to become Richter’s.

“The traditional method of diagnosing Richter’s has a number of shortcomings, which can lead to delays in patients’ receiving the appropriate treatment. Our findings in this study hold the promise of an earlier, more definitive diagnosis based on the molecular makeup of the tumour cells.”

One of the biggest obstacles to diagnosing Richter’s Syndrome is that patients have a mixture of CLL or Richter’s cells. In addition, while CLL is diagnosed from a blood sample, a formal diagnosis of Richter’s requires a biopsy. However, because a biopsy collects tissue from just one area, it may find CLL cells but miss nearby Richter’s cells.

For this study, researchers gathered tissue samples from 52 patients and undertook whole exome sequencing. They used computational methods on the sequencing data to estimate the proportion of CLL and Richter’s cells in each one. The team were able to identify the genetic changes that drive the evolution from CLL to Richter’s.

Study co-senior author Dr Gad Getz of the Broad Institute and Massachusetts General Hospital, said: “We see myriad differences between CLL and Richter’s at the molecular level, with a much more complex genome in Richter’s, as well as additional driver events. In addition, we’ve found that Richter’s exists in a number of different subtypes.”

The subtypes are distinguished by their molecular signatures and these DNA-level differences suggest that the subtypes took different routes in evolving from CLL.

The team went on to explore if the disease could be detected by analysing DNA in patients’ plasma, by sequencing the DNA in 46 samples from 24 patients with Richter’s and then the DNA floating freely within the plasma. It was there that genomic features of Richter’s were indeed detectable in the plasma.

The researchers also discovered that in a significant number of patients, their Richter’s cells did not share a genetic history with their CLL cells.

Dr Getz said they now want to analyse large cohorts of Richter’s patients to obtain a comprehensive characterisation of its genomic and microenvironmental landscape. This could lead to new and robust therapies.

“Being able to trace the transition from CLL to Richter’s at a molecular level impacts not only our understanding of the disease but, potentially, our ability to treat it and improve outcomes for patients,” added Dr Wu.

Source: ASH December 2022



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