A long gap between blogs for me. Someone once gave me the advice that if I wanted to be a writer, I should try and write something every day. Well I haven't been slacking. I have been doing some data manipulation to try and prepare a couple of abstracts for the IWCLL meeting in September in London.
The question I was addressing, was how mutated you have to be to be mutated. Another question is for which patients is it justified to conduct a randomized clinical trial of early treatment, because they have bad prognsostic markers. We now have about 400 patients for whom we have sequenced the IgVH genes plus another 600 for the CLL4 trial. 353 of our patients have also had CD38, ZAP-70 and FISH for del 11q and del 17p done. Our conslusion on the clinical trial is that almost all of the patients who have two of the following criteria: unmutated VH genes or if mutated, use of the V3-21 heavy chain, CD38 >20% expression, ZAP-70 >10% expression and del 11q or del 17p, will require treatment within three years of being diagnosed. But should unmutated mean >97% or >98% homology?
I looked first at whether there was a difference between different degrees of mutations and the acquisition of other adverse prognostic factors. There was. At 100% it was 96%, at 98 and 99% it was 82%, at 97% it was 59% and at less than 97% it was 31%. Then I looked at treatment-free survival curves for those without extra adverse factors. I was surprised to find that they all did equally well, no matter how many mutations they had, with a plateau of not needing treatment at about 60%. However, treatment-free survival curves of those who did acquire extra prognostic factors were different. For those with 97% or greater homology the average time to needing treatment was between 2 and 3 years, while for those with less than 97% homology, the average time to needing treatment was more than 10 years.
What this means is that IgVH genes have a double effect on CLL survival. First they represent a prognostic factor in their own right. If the homology is more than 97% they have a bad effect. But you need at least two things wrong to have a poor prognosis, and the VH gene mutation is only one of them. The second effect is to facilitated the acquisition of this second factor. With 100% it almost universal, whilc for those who are really mutated, only 3/10 will acquire another adverse factor (only for them it will be the first adverse factor). The 97% patients are about twice as likely as this to acquire a second factor, and those with 98 or 99% about 3 times as likely.
No wonder different labs have chosen different levels of mutation as the cut off.