The claim by Peter Hillmen (p 1122),1
on the basis of the CLL8 study,2
that the combination of fludarabine, cyclophosphamide, and rituximab (FCR) is now “the gold standard” for patients with chronic lymphocytic leukaemia seems premature.
First, the improved 3-year survival of 4% (87% vs 83%) is small and only has a p value of 0·01. This is a very early assessment of overall survival in a study of chronic lymphocytic leukaemia where most of the patients enrolled had Binet A and B disease, which have a known median survival of more than 150 and 84 months, respectively. Only 151 deaths in 817 patients had occurred at the time of reporting and the survival advantage of FCR will need to be maintained for significantly longer for FCR to truly be the “landmark” that Hillmen claims.
Second, although FCR caused significantly more leucocytopenia (24% vs 12%) and neutropenia (34% vs 21%) than did fludarabine plus cyclophosphamide (FC), it caused fewer deaths from infections (five vs six). This is probably because 75 of the treatment cycles of FCR also involved granulocyte colony-stimulating factor (G-CSF) compared with only 11 for FC. Nearly half the G-CSF cycles were given prophylactically in breach of the study protocol. This breach could have prevented a significant number of deaths from FCR relative to FC, which would have biased the overall survival results.
Third, it is not justifiable to terminate a study of treatment for chronic lymphocytic leukaemia early for a difference in progression-free survival, which is very subjective and has never been proven to be a reliable surrogate for overall survival in this disease.3
Finally, the findings of this study of relatively young and fit patients do not apply to most patients with chronic lymphocytic leukaemia.
We declare that we have no conflicts of interest.