WE know that TP53 problems are about the worst you can have with CLL, but we also know that 17p deletion is very rare in newly diagnosed patients. But what about TP53 mutations which seem to be as important?
The Swedish group run by Richard Rosenquist has looked at this.(Leuk Res 2011; 35:272) Among 268 newly diagnosed patients there were 10 who had del 17p at presentation (3.7%). Of these 7 also had TP53 mutations. 8/10 had unmutated VH genes and 5/7 with both TP53 genes affected were Binet stage B at presentation. There were only 3 (1,1%) patients with TP53 mutations and no del 17p; 2 were Binet stage B, but all three had mutated VH genes. The 3 with del 17p without TP53 mutations were all Binet stage A, but 2 had unmutated VH genes.
Even among this group with an early diagnosis and no previous treatment, time to treatment and overall survival was extremely impaired in patients whose TP53 lesion occurred on both chromosomes. Although the numbers were two small to be examined statistically among the 6 patients with only one chromosome involved three did badly. One with del 17p was treated after 5 days and died 55 months later and another with this lesion received treatment after 4 months and died 4 years after diagnosis. The other (with mutated VH genes) is alive and untreated after 9 years. Of the 3 with only mutated TP53, one was treated at 5 months and died 66 months later, while the other two were alive and well at 118 and 121 months although one was treated at 24 months.
I have been reading about p53 deletions but in multiple myeloma (MM). It seems that there may be two versions of the deletion which lead to two different median survivals. This was uncovered by looking at 70 genes identified as being the most significant in characterizing MM. I am wondering if the same might be present in CLL. The patient group you just discussed might suggest that or it could be a fluctuation due to the small sample size. TomD
ReplyDeleteYes, there are a few patients who escape the horrors associated with TP53 abnormalities. They almost always have mutated VH genes.
ReplyDeleteA new French study is looking at the functionality or p53. Determination of the functional status of p53 in CLL cells by flow cytometry was based on induction of p53 and p21 protein expression using etoposide and nutlin-3a.
ReplyDeleteBlood Cancer Journal (2011) 1, e5; doi:10.1038/bcj.2011.3
" About 80% of patients with 17p13 deletion display a mutation in the remaining TP53 allele, resulting in loss of function of the p53 protein, but mutations without a deletion are observed in 4–5% of cases.
Mutations of TP53 have been identified that are consequently associated with an unfavorable outcome, but all mutations do not predict similar consequences on the p53 pathway.
In addition, a minority of patients with 17p13 deletion have an indolent clinical course, suggesting that p53 function is preserved. Finally, it has appeared that p53 dysfunction is the result of several intricate factors that have not been clearly defined, and several questions still remain to be addressed regarding the biological consequences of TP53 deletions and the various types of mutations."
http://www.nature.com/bcj/journal/v1/n2/full/bcj20113a.html
I was about to review that Letter to the Editor which I have on my desk. They describe a flow cytometry method for measuring p53 protein. P53 protein should rapidly disappear from cells so if it can be detected there is something wrong with p53 function. I guess I don't need to bother with it now.
ReplyDeleteHi there,
ReplyDeleteWhat is your favorite option for symptomatic young / old CLL_patients with 17p(del)?
Do you think that early treatment in asymptomatic 17p(del) CLL_patients is an option?
thank's in advance + regards, HG
Asymptomatic del 17p patients should not be treated. Symptomatic patients should. Young patients should be aiming for an allograft, possibly getting in a remission first with alemtuzumab or teh alemtuzumab/methylprednisolone combination if they have nodal masses more than 5cm in diameter. Older patients are more fifficult. Possibly lenalidamide or onbe of teh new enzyme inhibitors ins a clinical trial.
ReplyDeleteDr. Hamblin,
ReplyDeleteI just started following your posts on p53 mutations.
I'm 33 years old, p53 mutated, IGHV unmutated (not 17p or 11q deleted). I'm still Binet stage A, but progressing steadily as expected.
I'm looking at a Revlimid trial and eventually a BtK trial with the expectation that I'll need a transplant.
thanks for your research on the topic