It is now possible to view the ASH abstracts for 2009. Although I have already broken the news that for the first time a first line treatment has been shown to improve overall survival, we can now view the details here.
We owe a great deal to Michael Hallek and his team for doing this trial, and we ought to ought to complain to the drug company for not doing the trial at an earlier stage. Their perfidy has deprived many people of what is the best available treatment for CLL.
The German CLL8 trial was a large one, involving 817 patients with CLL that needed treating. They were randomized to either FC or FCR in standard doses. The group receiving FCR had a higher response rate (95.1 vs 88.4%) and more complete remissions (44.1 vs 21.8%; p<0.001). and a longer progression-free survival 51.8 months v 32.8 months (p<0.001). We've seen this sort of result before, but do the patients live any longer? Note that the follow up is relatively short (median just over 3 years). The Overall Survival rate was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01).
They were able to do a multivariate analysis to look for what factors predict poorer survival. Several factors acted as independent prognostic factors for both progression-free survival and overall survival, including age, sex, FCR-treatment v FC treatment, receiving fewer or more than 3 cycles of treatment, response, 17p-deletion, serum levels of thymidine kinase and ß2-microglobulin and mutational status of the IGVH genes.
Adding rituximab seems to lead to more neutropenia, but this does not lead to more infections. I presume that the neutrophils are consumed by the CD20/anti-CD20 immune complexes. In fact there were more deaths in the FC arm (86/396, 21.7% versus 65/404, 16.1%). Most commonly death was cause by progressive disease (FC 48/86, FCR 33/65), but there were also more deaths from secondary malignancies in the FC arm (13/86 v 5/65). Of course in this age group there were also deaths from unrelated causes. Treatment related mortality was just 2.0% in each arm.
One strange finding was that the benefit of FCR did not reach statistical significance for stage C patients (Rai stages III and IV). Why this was so is not clear, but it might be due to the relative immaturity of the study or it may be that these patients, with a higher tumor load, need more intensive treatment. Since platelets falling to below 100 or HB falling below 10 are indication for treatment, perhaps a higher threshold for starting treatment should be adopted.
However in another study from the German group the better efficacy of the FCR regimen in terms of response rates and progression-free survival does not yet result in an improved quality of life.