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CLL: Phase III Studies Confirm Added Rituximab Better than Chemo Alone

Goodwin, Peter

doi: 10.1097/01.COT.0000345893.78014.42

SAN FRANCISCO—For patients with chronic lymphocytic leukemia (CLL), two Phase III studies reported at the ASH Annual Meeting here showed improved rates of complete response and progression-free survival when rituximab (R) was added to standard fludarabine/cyclophosphamide (FC) chemotherapy.



The first, presented by Michael Hallek, MD, Chairman of the German CLL Study Group and Director of the Internal Medicine Clinic at the University of Cologne, randomized 817 “physically fit,” previously untreated patients with advanced CLL from 11 countries to receive six cycles—four weeks each—of either FC, or the same regimen plus rituximab (FCR). (The doses were: fludarabine at 25 mg/m2 iv d1-3 and cyclophosphamide at 250 mg/m2 iv d1–3 for both arms; and rituximab at 375 mg/m2 iv d0 at first cycle and 500 mg/m2 d1 for all subsequent cycles in the experimental arm.)

The major endpoint was progression-free survival, which increased from 62% in the FC arm to 77% in the arm with rituximab. Dr. Hallek said that although the overall response rate increased only from an already high 88% to 95%, this gain was significant and that within it, the complete response rate nearly doubled, from 27% to 52%.

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Toxicity Increased

These gains, though, were bought at the price of increased toxicity, with severe hematologic toxicity up from 39% to 55% of patients in the immunochemotherapy arm. Neutropenia went up a third (from 21% to 34%) and leukocytopenia nearly doubled (from 12.1% to 24%) with both of these increases significant, but there was no increase in severe infections.

Thrombocytopenia and anemia both improved somewhat in the group receiving rituximab—from 7% to 10%, and from 5% to 7%—and there was little change in treatment-related mortality.

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New Standard Front-Line

“It is important to stress that patients with CLL are very often elderly,” Dr. Hallek said in an interview. “So one of the major things I should mention before coming to a conclusion is that we did this trial on physically fit patients, with selection based on a cumulative index rating scale and creatinine clearance. And in those physically fit CLL patients, I would now recommend an FCR regimen as a first-line treatment for CLL.”

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Just ‘a Little Bit’ Impressed by the Study

Asked for this article how impressed he was by the study, George Canellos, MD, the William Rosenberg Chair and Professor of Medicine at Harvard Medical School and a senior physician in the Department of Hematologic Oncology at Dana-Farber Cancer Institute, replied: “A little bit.”



But he noted that there were a number of positive factors going for Dr. Hallek's study cohort, because patients appropriate for this protocol qualified by being fit; and the median age was 61—also fairly favorable: “And so if you're fit and otherwise without serious comorbid illness, FCR does give you a better response rate, especially a better complete response rate, and a longer progression-free survival,” Dr. Canellos said.

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The second study of FCR vs FC—presented as a Late-Breaking Abstract—was in 552 patients from 17 countries who had relapsed or refractory chronic lymphocytic leukemia. The REACH (Rituximab + Chemotherapy in Relapsed/Refractory Chronic Lymphocytic Leukemia) trial reported an increase of 10 months in progression-free survival and a doubling of complete remission rates with an “excellent” safety profile.

Study presenter Tadeusz Robak, MD, PhD, Chair of the Department of Haematology at Medical University of Lodz, Poland, noted that in both arms of the study patients received fludarabine (25 mg/m2 iv, day 1–3) with cyclophosphamide (250 mg/m2 iv, day 1–3) for six cycles of four weeks. Patients in the immunochemotherapy arm additionally received rituximab (375 mg/m2 d0 in the first cycle and 500 mg/m2 d1 in cycles 2–6).

Patients of all Binet stages were included, and had received an average of one previous chemotherapy regimen per patient.

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Study Outcomes

Immunochemotherapy with FCR increased the overall response rate significantly (from 58% to nearly 70%) and nearly doubled the complete remission rate (from 13% to 24%), while prolonging progression-free survival time by a median of 10 months (from 20.6 to 30.6 months).

Dr. Robak noted a slightly higher incidence of cytopenias in the FCR arm, with no difference in infection rates. “On the basis of these two trials, we now have confirmation of our previous assumption that immunochemotherapy is better for CLL than chemotherapy alone; I believe it should be the new standard of therapy,” he said.

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‘Example of the Three 10s'

Asked for his perspective about the study, Dr. Canellos was less than enthusiastic: “Well, I call it the results of 10s. The overall response rate is 10% greater, using FCR over FC. The CR rate is 10% greater, and the response lasts 10 months longer! So it really is an example of the three 10s.”

The glaring fact is that rituximab by itself, at conventional doses, is very inactive in CLL, he said, acknowledging, though, that when added to chemotherapy, rituximab does obviously produce an enhanced effect.

But he noted: “What isn't obvious here is that overall survival is still a matter of debate in this series—whether or not there is a difference in overall survival. The median was not reached for FCR, and was 53 months for FC.”

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Three Drugs Better

The Chair of a news conference at which both CLL studies were discussed, Linda Burns, MD, Professor of Medicine and the Fellowship Director of the Hematology, Oncology, and Transplantation Division of the University of Minnesota, said afterwards, “What this tells physicians is that the three-drug regimen is better than two drugs. But you still also need to look at the patient you have in front of you. And if you're concerned about that patient being weaker with underlying illnesses, two drugs still may be better.”

© 2009 Lippincott Williams & Wilkins, Inc.
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