New combo treatment for chronic lymphocytic leukaemia increases survival

The combination treatment of fludarabine plus cyclophosphamide for chronic lymphocytic leukaemia (CLL) greatly increases progression-free survival and response rates, compared with single treatment with either fludarabine or chlorambucil alone.

The findings are reported in an Article in this week’s edition of The Lancet, and the authors claim this combination treatment should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.

Chronic lymphocytic leukaemia is the most common leukaemia in the developed world. The disease is currently incurable and the best treatment continues to be defined.

Professor Daniel Catovsky, Institute of Cancer Research, Sutton, UK and colleagues did a study of 777 patients with CLL, funded by Leukaemia Research (LRF). The patients were divided into three groups, with 196 receiving fludarabine plus chlorambucil, 194 receiving fludarabine only, and 386 receiving chlorambucil.

The researchers found that although there was no significant difference in overall survival rates, progression free survival at five years for the combination treatment was significantly better with the combination treatment (36%) than with fludarabine or chlorambucil (both 10%). Complete response rates were also much improved with the fludarabine/cyclophosphamide combination (38%) as compared with fludarabine (15%) and chlorambucil (7%), as were overall response rates, which were 94% for the combination treatment, 80% for fludarabine and 72% for cyclophosphamide. The combined treatment was found to be the best for all age groups, including those over 70-years. Quality of life was better for those that responded to treatment, but analyses showed no significant difference between treatment regimens.

Some side effects were worse for the combined treatment, while others were worse for the single treatments. Patients who received the combined treatment or fludarabine alone had more neutropenia (low numbers of neutrophils, a type of white blood cell), and days in hospital, than those receiving the chlorambucil alone. There was less haemolytic anaemia (the abnormal breakdown of red blood cells) with the combined treatment (5%) than with fludarabine alone (11%) or chlorambucil (12%).

The authors conclude: “We have shown that the combination treatment of fludarabine plus cyclophosphamide produces a substantial improvement in both response rates and progression-free survival compared with either single-agent chlorambucil or fludarabine.

“Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.”

In an accompanying Comment, Dr Tait Shanafelt and Dr Neil Kay, Mayo Clinic College of Medicine, Rochester, Minnesota, USA, say: “These findings are consistent with the results of similar studies recently reported by the German CLL Study Group and the North American Intergroup (NAIG), which also found superior progression free survival in patients with fludarabine/cyclophosphamide.”

Further, the comment authors emphasise the importance of the trial providing information on efficacy and tolerability of these treatment regiments for elderly patients, whereas in many trials older patients (those over 65-years) are typically under-represented or excluded.