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Combined Fludarabine, Cyclophosphamide, and Rituximab a Possible New Gold Standard in Chronic Lymphocytic Leukaemia: Presented at ICML

By Chris Berrie

LUGANO, SWITZERLAND -- June 14, 2005 -- Combined fludarabine, cyclophosphamide, and rituximab (FCR) therapy can now produce complete remission (CR) rates of 50% to 70% that can show long durations, highlighting the serious potential for curing patients with chronic lymphocytic leukaemia (CLL), researchers said here June 9^th at the 9^th International Conference on Malignant Lymphoma.

Michael J. Keating, MB, BS, principal investigator and professor of medicine and internist, Leukaemia Department, MD Anderson Cancer Centre (MDACC), University of Texas, Texas, United States, said, "Even though these drugs are both accompanied by immunosuppression and myelosuppression, there is a mechanistic rationale for their combination, as the resistance to alkylating agents occurs by excision of DNA cross links, and the purine analogues inhibit this."

Dr. Keating stressed that although rituximab showed little promise in single agent salvage studies, it has a favourable toxicity profile and increases the cytotoxicity of fludarabine and cyclophosphamide.

This evidence led Dr. Keating and colleagues at his institution to use front-line FCR extensive for patients with CLL. He presented the results of an analysis of the 300 patients treated from 1999 to 2003.

The dosing schedule was administered as follows: cycle 1 rituximab 375 mg/m² on day 1, fludarabine 25 mg/m², and cyclophosphamide 250 mg/m² on days 2 to 4; cycles 2 to 6 rituximab 500 mg/m² on day 1, fludarabine 25 mg/m², and cyclophosphamide 250 mg/m² on days 1 to 3.

This regimen produced a high complete remission (CR) of 72%, with an overall response rate of 95%, Dr. Keating said.

In a direct comparison with the 52 patients treated with FC from 1995 to 1999 at the same cancer centre, FCR achieved a significantly better CR (FC, 46%; P <.001), and median time to progression (FC, 48 months; FCR 54 months; P <.001).

An analysis of the CR rates in the FCR cohort showed significant differences between specific age groups -- 76% in patients younger than 55 years, 69% in those 55 to 69 years, and 46% in the 70-year and older group (P =.002 for all).

Similarly, patients with Rai stages of 0 to II had significantly better rates of CR than did patients in Rai III to IV (73% vs 59%; P =.002), and beta2-microglobulin levels < 3 mg/L versus 3 to 4 mg/L versus >/= 4 mg/L had significantly decreasing CRs (86%, 76%, 53%, respectively; P <.001).

Dr. Keating stressed the significant fall-off of 5-year survival both in the patients who were 70 years or older (61% vs 90% for < 70; P <.001), and in those with beta2-microglobulin levels above 4 mg/L, which was 2 times upper limit of normal, (74% vs 95% for <.001).

For time to relapse by response according to the National Cancer Institute (NCI) definitions for CLL, Dr Keating outlined that, "For the complete remission patients, two thirds of them are getting out to approximately 6 years still in clinical remission. If they had residual nodules, they do not do as well, although there is no difference in survival in these 2 groups, while the partial response was not a very good response, with a median time to relapse of approximately 2 years."

In stressing that the benefits of this FCR combination therapy suggest that CLL should now be considered potentially curable, Dr. Keating specifically emphasised the 2 main groups of patients highlighted by this analysis towards whom future efforts should be directed: those who are older than 70 years and those with high beta2-microglobulin levels.

There remain specific subsets of patients who need further attention, he said, including those with a white blood cell count above 200,000, clinical involvement of the liver and/or a very low platelet count at the initiation of therapy.


[Presentation title: Chemoimmunotherapy of CLL -- a New Gold Standard. Abstract 039]

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