"CLL is a well-defined lymphoid neoplasm with very heterogeneous biological and clinical behavior. The last decade has been remarkably fruitful in novel findings elucidating multiple aspects of the pathogenesis of the disease. These include mechanisms of genetic susceptibility, insights into the relevance of immunogenetic factors driving the disease, profiling of genomic alterations, epigenetic subtypes, global epigenomic tumor cell reprogramming, modulation of tumor cell and microenvironment interactions, and dynamics of clonal evolution from early steps in monoclonal B cell lymphocytosis to progression and transformation into diffuse large B-cell lymphoma.
All this knowledge has offered new perspectives that are being exploited therapeutically with novel target agents and management strategies.
In this review they provide an overview of these novel advances and highlight questions and perspectives that need further progress to translate into the clinics the biological knowledge and improve the outcome of the patients."
Thank you Jackie, for drawing our attention to this very interesting paper. Some highlights for me, particularly given my recent post on the importance of IGHV mutation status and the unexpectedly common number of stereotypes: healthunlocked.com/cllsuppo... (and no, I hadn't read this paper beforehand).
- The B-cell receptor (BCR) is crucial for CLL pathogenesis and is composed of immunoglobulin (IG) molecules plus CD79a/b subunits. From an immunogenetic point of view, two major molecular subgroups have been identified: those harboring unmutated IG heavy-chain variable region (IGHV) genes (U-CLL, ≥98% identity with the germline) and those with mutated IGHV genes (MCLL). 17,18 U-CLL originates from B cells that have not experienced the germinal center, whereas M-CLL originates from post-germinal center B cells.19 In addition, around 30% of patients have highly homologous amino acid sequences derived from almost identical IG rearrangements, known as stereotypes.20 Several hundred stereotypes have been identified, of which 19 are considered major due to their frequency. The prognostic importance of several stereotypes has been prospectively validated.21 The presence of stereotypes and the remarkable bias in the use of certain IGHV genes highlight the relevance of antigen selection in CLL clonal expansion.
- Epigenetic studies have shown that, although both CLL subtypes are antigen-experienced, M-CLL keeps a methylation signature of germinal center-experienced cells (memory-like B cells), whereas U-CLL has a pre-germinal center, naïve-like methylation signature.5,26 Of note, these epigenetic studies also identified a third subtype with an intermediate profile made of cases with moderate IGHV mutation levels. All three epigenetic subsets have different usage of IGHV genes, stereotypes, genomic aberrations and clinical outcome (Table 1).2 Some members have previously asked about the significance of their borderline IGHV mutation status.
- CLL cells are highly dependent on signals coming from the microenvironment for proliferation and survival. The description of Figure 2 is a must read.
The interesting discussion on complex karyotype CLL.
Ditto the discussion on clonal evolution.
- Yearly, 1% of cases of high-count MBL evolve into CLL requiring therapy,79 and 2-10% of patients with symptomatic CLL eventually develop Richter transformation.80 At the other end of the spectrum, around 30% of patients with CLL never require any CLL-specific therapy and die of other causes, and 1-2% of them even experience spontaneous regression of their disease.81 It is therefore evident that the rate and pattern of growth (or even decline) of the disease can vary greatly among patients. Good to see the lower limit of 2% for Richter's Transformation. I've always felt the risk was historically overstated. Oops, they missed the duplicated paragraph in their proof reading!
Confirmation in the Frontline Therapy section that even with the new non Chemoimmunotherapy (CIT) treatments, watch and wait appears to still be appropriate, but watch this space!
As has been stated many times in this community, Googling about CLL needs to be done carefully, due to all the incorrect and outdated information out there. Hence I found the following words in the Conclusions and Perspectives section very encouraging for our members in watch and wait.
Most studies have been performed in pretreated patients and it is not fully understood how the genome and epigenomic alterations and microenvironmental interactions influence the evolution of the disease. Translating new knowledge into clinical practice will require an effort to obtain an integrated view of all these factors in order to understand the disease better and design effective treatments and management strategies.
We do live in exciting times with lots of promise.
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