Clonal evolution, genomic drivers and effects of therapy in CLL

[AussieNeil]

Further to the discussion on the recent posting about the carcinogenic impact of CLL therapy:

cllsupport.healthunlocked.c... , a paper has just been published by Clinical Cancer Research that reports on a comparison investigation of CLL clonal evolution in treated vs untreated patients.

Excerpts from the abstract:

"The identification of gene mutations and structural genomic aberrations that are critically involved in CLL pathogenesis is still evolving."

"We sequentially sampled a large well-characterized CLL cohort at a mean of 4 years between samplings and measured acquired copy number aberrations..."

"The paired analysis included 156 patients, of whom 114 remained untreated and 42 received intercurrent therapies, predominantly potent chemo-immunotherapy, during the sampling interval."

"Results: We identify a strong effect of intercurrent therapies on the frequency of acquisition of acquired copy number aberrations in CLL. Importantly, the spectrum of acquired genomic changes was largely similar in patients that did or did not receive intercurrent therapies; therefore, various genomic changes that become part of the dominant clones are often already present in CLL cell populations prior to therapy. Further, we provide evidence that therapy of CLL with pre-existing TP53 mutations results in outgrowth of genomically very complex clones which dominate at relapse."

Abstract:

clincancerres.aacrjournals....

The full paper is available to patients/carers if you register via RightsLink.

And there's more!

Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia

cell.com/abstract/S0092-867... (Abstract)

Quoting the summary:

"Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes."

Karl Schwartz of Lymphomation.org has recently raised the important question of whether using drugs like ibrutinib to keep a lid on CLL might give a longer life expectancy than more traditional treatments that are likely to drive clonal evolution. Hopefully more research will answer this question so that patients with TP53, etc are provided with treatment that doesn't put them at risk of developing a more aggressive form of CLL...

Neil