CLL: novel prognostics, and updates on therapy 1

Published on November 30, 2015   34 min

Other Talks in the Series: Topical Talks

0:00
Hello, today, I'll be presenting a lecture on Chronic Lymphocytic Leukemia, focused on novel prognostics and updates on therapy.
0:10
Specifically, this lecture has three sections. The first is focused on the new discoveries and somatic genetics of CLL and in particular how these impact on prognosis and prediction of disease response. The second section will be on frontline therapy in CLL. And the third section will be on relapse therapy in CLL which, of course, is focused on the novel targeted inhibitors of BTK, PI3-kinase delta. And we'll also speak about BCL2 inhibition.
0:39
As a brief overview, there are about 16,000 new cases of CLL per year in the United States, and it's also a very common disease in Western Europe. It's the most common adult leukemia, and although it's called a leukemia, it's really a chronic incurable mature B cell neoplasm, making it more related to mature lymphomas. Most patients present with asymptomatic increases in their lymphocyte count. And these asymptomatic patients do not require therapy initially. We typically institute therapy once symptoms, low blood counts or large lymph nodes intervene. And there are two key prognostic factors that have been identified in work over the previous 15 years and validated in many studies. And these include the mutational status of the immunoglobulin heavy chain gene and chromosomal abnormalities identified by FISH.
1:26
So in terms of the immunoglobulin variable region heavy chain gene, there is a continuum of the degree of somatic hypermutation seen in the variable gene across patients with CLL. But it was observed approximately 15 years ago that clinically, there is a cutoff in terms of the percentage of somatic hypermutation that's seen that associates with outcome. And that cutoff is approximately two percent different from the germline. Patients with less than two percent mutation are called unmutated and have a median survival of about nine years historically, while those who have more than two percent alteration from the closest germline gene have an extended median survival in excess of 24 years.
2:13
The other key prognostic factor, it turns out, are certain recurrent genetic abnormalities in CLL. These include, in particular, loss of the short arm of chromosome 17 affecting the P53 gene, which in this classic paper by Dohner in the New England Journal of Medicine was associated with an overall survival of approximately 32 months. The second worst prognostic FISH category is 11q deletion affecting the ATM gene. But that has a significantly better overall survival of 79 months. The other abnormalities trisomy 12, normal cytogenetics and 13q deletion as a sole abnormality have better prognoses.
2:54
We can actually combine the FISH abnormalities with IGHV status and we find that the two highest risk FISH abnormalities are associated with the worst prognosis and even the higher risk unmutate IGHV shown here. 17p deletion, followed by 11q deletion, followed by other on mutated IGH, whereas the mutated IGH have a better outcome.
3:17
A number of years ago, we were interested in starting to further characterize the genetics of CLL in order to better refine prognosis. And at this point, many studies have been done using SNP arrays as well as whole-exome sequencing in particular, although whole-genome sequencing is still more limited but ongoing as are RNA sequencing and methylation studies. So I'll just describe briefly some of the data on copy number from SNP arrays as well as recurrent mutations from exome sequencing.
3:49
So in this study that we published a number of years ago, you can see the data from 160 CLLs analyzed by affymetrix SNP array. And what you see is that compared to most cancers, CLL has a very stable genome. There are very few red or blue lines on this figure, red being gains and blue being losses. You do note that we see the recurrent abnormalities of 11q deletion, trisomy 12, 13q deletion and 17p deletion. We also, in this study, found three additional abnormalities. Gain of 8q24, loss of 8p and gain of 3q26.
4:29
Now although CLL has a very stable genome, it does have more copy number aberrations than normal controls or its own match germline, an average of about four additional changes as shown here.
4:44
Interestingly, copy neutral loss of heterozygosity, which is common in many cancers, is not common in CLL, and actually was not seen more frequently than in the normal germline controls.
4:58
If we look at the highest risk group of CLL, those 17p deleted cells that lack P53, you can see that there are much more common genomic aberrations and increased frequency of copy number aberrations as shown in this figure.
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CLL: novel prognostics, and updates on therapy 1

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