Of all the malign features of CLL, damage to the p53 pathway is the most serious. Most drugs used in CLL work by invoking the p53 pathway to destroy the CLL cells. A recent paper in Blood has examined the p53 pathway in patients entering the German CLL2H trial.
In this trial patients who required treatment but were refractory to at least one fludarabine containing regimen were treated with subcutaneous Campath. Tests were done to determine whether the patients had a loss of part of the short arm of chromosome 17 (where the p53 gene resides) or if the p53 gene was mutated or if the p53 was functionally intact by generating p21 after irradiation of the CLL cells.
The study asked two main questions: 1]what is the contribution or p53 pathway defects to fludarabine refractory CLL? and 2]what are the clinical implications of
p53 mutations in the setting of fludarabine refractory CLL treated with Campath?
The answer is that 36% of those with fludarabine refractory CLL do not have a defect in the p53 pathway. Only 32% of the patients had del 17p. 37% had mutations of the p53 gene. Most of these (68%) were in patients who had lost 17p, but the other third were in patients whose FISH test did not give any warning of fludarabine refractoriness. In other words looking for p53 mutations in patients who are refractory to fludarabine and will uncover another 12% who have a defect in the p53 pathway. Or put it another way, 18% of those who do not have del 17p will have a p53 mutation. Or if you like, 44% had a defect of p53. In addition, 19% had an 11q deletion, which leaves 36% with no obvious poor risk factor. (Note that the German CLL8 trial - which obviously came after this one - shows us that del 11q patients can be brought back into the standard risk fold by using FCR rather than FC).
So what happens to patients who are refractory to fludarabine when they are treated with Campath? Thew answer is that they don't do all that well. The average survival is about 18 months. This trial showed it to be worse for those with p53 mutations (13 months against 21 months) but this was not statistically significant - they would have needed to study more patients to be sure. Time to treatment failure was the same for both groups which tends to suggest that those without mutations will respond to something else for a while. What can be said is that despite all this, about a quarter of those with p53 mutations were still alive at 4 years.
Don't get confused; the mutations I am talking about in this article are nothing to do with the mutations of the IGHV genes that I normally write about.