Again, click to enlarge. For each category of patients I give the CR rate and the overall response rate. The columns headed chemotherapy refer to FC and those headed immunochemotherapy refer to FCR.
In summary FCR is significantly better at getting CRs than FC for all categories of patients except those with del 17p and those with a normal FISH. It gives a better overall response rate than FC for all patients except patients with Binet stage A (too few to be statistically significant), patients with del 11q or trisomy 12 or a normal FISH, and patients with mutated IGHV genes. Note that the CR rate in this trial was not as high as the MDACC got in their phase II trials. This is probably because MDACC treated patients who were not so severely ill. Anecdotally, it appears that entry to the phase II trials was not so stringent as in this multi-center study.
What is outstandingly different about these results is the CR rate in patients with del 11q. This is thought to be a very bad prognosis group and the CR rate for FC was only 15%. However, the CR rate for FCR was 51%. Similarly for trisomy 12 the CR rate went from 19% to 71%. Both trisomy 12 and del 11q tend to be associated with higher levels of CD20 on the surface, so this is some rationale for using rituximab in such cases.
The response rate for patients with del 17p was dismal. Although FCR pushed up the overall response rate there was only one CR, and the increased ORR was not reflected in an improvement in survival or length of emission. Rituximab may have some non-p53 dependent activity, but not enough to make a difference.
The next slides show overall survival curves according to FISH status
What they demonstrate is that rituximab takes the del 11q survival back into the pack of other karyotypes. It seems to eliminate the bad odour associated with this FISH pattern. Take home message is that if you have del 11q, your first treatment must have rituximab in it.
What is the message being conveyed about the poor outcome of those with normal FISH? We can only speculate, but this will include those with unusual karyotypes like t(14;19) and those who have mutated p53 but intact chromosome 17p.
Your comment on 'the poor outcome of those with normal FISH' reminds me of the famous quote of Rumsfeld:
ReplyDelete"We also know there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns -- the ones we don't know we don't know."
'Normal' karyotype seems hyperbole comforting the ignorant such as I. CLL would be fascinating if it didn't turn and bite you eventually.
Thank you for your light in the darkness.
Terry,
ReplyDeleteYou mentioned that 11q del had more CD20 on its surface. This is news to me. I assume this is different than whether the CD 20 is bright or dim. Can you please explain the difference? Thanks
Brian
PS I go on vacation for a week and stop reading anything about CLL, and come back to find 8 great posts by you
CD20 on the surface of CLL cells is usually moderate - at least one of the epitopes is masked by cholesterol, so that FMC7 is usually negative. Generally cases with atypical morphology also tend to have slightly brighter CD20 and this is particularly so for trisomy 12 but also in some cases of del 11q and other less typical karyotypes. But some del 11qs will still have dim CD20. I'm not entirely convinced that this is why del 11q does so well with FCR.
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