FCR BETTER THAN FC FOR CLL

October 7, 2010 — Data from a pivotal phase 3 trial show that rituximab-based front-line chemoimmunotherapy can extend both overall and progression-free survival in patients with chronic lymphocytic leukemia (CLL). The study, by Michael Hallek, MD, and researchers in the German Chronic Lymphocytic Leukaemia Study Group, was published in the October 2 issue of the Lancet.

This trial "is a landmark for the treatment of CLL in several ways, and heralds fundamental changes in management of the disease" according to an accompanying editorial.

Editorialist Peter Hillmen, MD, PhD, who is chair of the CLL trials subgroup of the British National Cancer Research Institute, wrote that "a randomized phase 3 trial rarely has such a profound effect on the treatment of a disease as the German Chronic Lymphocytic Leukaemia Study Group (CLL8) trial has had on chronic lymphocytic leukemia."

Preliminary results from this trial were presented at the 2008 annual meeting of the American Society of Hematology, and were reported by Medscape Medical News at the time.

Principal investigator Dr. Hallek, who is from the Department of Internal Medicine and Centre for Integrated Oncology at the University of Cologne, Germany, told Medscape Medical News that the most important finding was that adding rituximab improves both overall and disease-free survival in CLL, and that this justifies a change in what is considered to be standard care.

"Treat physically fit patients who have CLL with fludarabine, cyclophosphamide, and rituximab," Dr. Hallek advised.

Clear Survival Difference

The CLL8 study enrolled treatment-naive, physically fit patients, 30 to 81 years of age, who had CD20-positive CLL. Patients were randomized to 6 courses of intravenous fludarabine (25 mg/m2 per day) and cyclophosphamide (260 mg/m2 per day) for the first 3 days of each 28-day treatment course with (n = 408) or without (n = 409) rituximab (375 mg/m2 on day 0 of the first course, and 500 mg/m2 on day 1 of second to sixth courses). Patients were enrolled by researchers at 190 centers in 11 countries, and neither the investigators nor the patients were masked to the treatment assignment. Progression-free survival was the primary end point, and analysis was by intention to treat.

At 3 years after randomization, progression-free survival was 65% in the rituximab group and 45% in the chemotherapy group (hazard ratio, 0.56; P < .0001). Overall survival was 87% with rituximab and 83% with chemotherapy alone. Almost half of the patients in the rituximab group achieved complete remission after 3 years, compared with less than a quarter in the chemotherapy group.

"I did not expect to see a survival difference so clear and so soon," Dr. Hallek told Medscape Medical News. "The next studies should try to maintain the remissions in patients with CLL."

Adding rituximab increased grade 3/4 neutropenia (34% vs 21%) and leukocytopenia (24% vs 12%), but did not increase other adverse effects. There were 8 (2%) treatment-related deaths in the rituximab group and 10 (3%) in the chemotherapy group.

Interestingly, survival improvement varied by genetic subgroup. Patients with a chromosome 17p deletion (or p53 dysfunctional CLL) had a poor response, with less than 5% achieving complete remission; however, complete remission rates increased by more than 3 times with rituximab in patients with a chromosome 11q deletion, a group considered to have a poor prognosis.

The authors conclude that "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 leukemia."

Dr. Hillmen writes: "We can no longer apply the same therapy to all patients with CLL. . . .The era of personalized 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."

Dr. Hallek said that the results of this trial "show that specific genetically defined subgroups of CLL patients respond to fludarabine/cyclophosphamide/rituximab therapy in different ways. For example, the prognosis of del(11q) patients (formerly believed to be a poor prognostic subgroup) is now as good as for other subgroups. The results also show clearly that achieving a good remission is of major benefit for the patient and that an efficient first-line treatment alters (improves) the natural course of CLL patients. Finally, they suggest that the addition of rituximab prevents the occurrence of treatment resistance."

Dr. Hallek reports consultancy or board membership and payment for educational presentations from Roche. Dr. Hillmen reports received speaking fees and honoraria from Roche, GlaxoSmithKline, and Genzyme.