The monoclonal antibody rituximab given in addition to a standard chemotherapy regimen of fludarabine plus cyclophosphamide significantly prolongs the lives of patients with chronic lymphocytic leukaemia (CLL) compared with standard chemotherapy alone. This is the first drug regimen to show an overall survival benefit in previously untreated CLL patients. The findings, published in an Article in this week's Cancer Special Issue of The Lancet, will change first-line standard treatment practice in these patients.
CLL is the second most common type of leukaemia. The disease is currently incurable and better therapies are needed. Typically, chemotherapy has been used to treat CLL, but with limited success, and there is currently no treatment available that improves overall survival. However, promising results have been achieved in phase 2 studies combining rituximab with the chemotherapy drugs fludarabine and cyclophosphamide, reporting the highest response rates so far for first-line treatments in patients with CLL.
To further evaluate this therapeutic strategy, the German Chronic Lymphocytic Leukaemia Study Group phase 3 trial was established in 190 centres in 11 countries. 408 previously untreated patients were randomly assigned to receive chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, and 409 patients to chemotherapy with fludarabine and cyclophosphamide.
Almost half of the patients in the chemoimmunotherapy group achieved complete remission after 3 years compared to less than a quarter in the chemotherapy group.
Additionally, after 3 years of treatment, 65% of chemoimmunotherapy patients had no disease progression compared to 45% of patients receiving chemotherapy.
Importantly, treatment with chemoimmunotherapy significantly increased the likelihood of patients surviving 3 years or more. At 3 years, 87% of patients receiving chemoimmunotherapy were alive compared with 83% having chemotherapy alone.
Grade 3 and 4 neutropenia (34% vs 21%) and leucocytopenia (24% vs 12%) were more common in the chemoimmunotherapy group. But no other side-effects were increased by chemoimmunotherapy treatment. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group.
Interestingly, improvement in survival was not uniform across all clinical and genetic subgroups. In particular, patients with chromosome 17p deletion (or p53 dysfunctional CLL) had a poor response, with fewer than 5% achieving complete remission even with chemoimmunotherapy treatment. By contrast, the rate of complete remission increased by more than three times with chemoimmunotherapy in patients with chromosome 11q deletion, a group considered to have a poor prognosis.
The authors conclude: "These results might help establish a new treatment model in which the choice of a specific first-line treatment improves the natural course of chronic lymphocytic leukaemia."
In a Comment, Peter Hillmen from St James's University Teaching Hospital, Leeds, UK, says that this trial "is a landmark for the treatment of CLL in several ways and heralds fundamental changes in the management of the disease."
He adds: "We can no longer apply the same therapy to all patients with CLL, and thus the era of personalised medicine in the treatment of CLL is upon us…we can now identify patients who will have a poor prognosis from the outset so that they can be considered for novel therapeutic approaches."
Professor Michael Hallek, University of Cologne, Cologne, Germany. T) +49 221/478 4400 E) Michael.hallek@uni-koeln.de
Dr Peter Hillmen, St James's University Teaching Hospital, Leeds, UK. E) peter.hillmen@nhs.net
For full Article and Comment see: http://press.thelancet.com/lymph.pdf
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Journal
The Lancet