Establishing 'Standard Treatment' for CLL

Abstract & Commentary

By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: Fludarabine combined with cyclophosphamide was compared to fludarabine alone or chlorambucil as initial treatment for chronic lymphocytic leukemia (CLL) in a randomized multi-site trial. The combination proved superior with regard to response rate and time to progression, but overall survival was not different. Response to any of the treatments was associated with improved quality of life.

Source: Catovsky D, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukemia (the LRF CLL4 Trial): a randomized controlled trial. Lancet. 2007;370:230-239.

Since the first publication of the combination fludarabine-cyclophosphamide use in chronic lymphocytic leukemia (CLL),1 there has been considerable interest in this combination. Catovsky and colleagues present data from a randomized controlled trial (LRF CLL4 trial) in which the combination was compared with fludarabine alone or chlorambucil in previously untreated patients with CLL. There were 136 participating centers primarily in the United Kingdom but also in Argentina, Croatia, Greece, Ireland, Italy, New Zealand, and Russia. The 777 patients with CLL requiring treatment were randomly assigned to fludarabine, fludarabine plus cyclophosphamide, or chlorambucil. Those randomized to fludarabine received the drug either intravenously (25 mg/m2 per day intravenously for five days) or orally (40 mg/m2 per day given orally). Those who received the combination fludarabine and cyclophosphamide received a fludarabine dose of 25 mg/m2 per day and plus cyclophosphamide 250 mg/m2 for three days. The combination could also be administered orally and the dose of fludarabine was 24 mg/m2 per day and cyclophosphamide 450 mg/m2 per day for a five day treatment. Those that received chlorambucil were given 10 mg/m2 per day for a total of seven days. All three of the treatment schedules were repeated every four weeks. Fludarabine and fludarabine plus cyclophosphamide were given for a total of six courses and chlorambucil for a total of 12 courses.

At the time of this report, the median follow-up was three years and five months (range one year and nine months to seven years and six months). There was no significant difference in the randomization with regard to stage of disease, risk group, or age. Approximately one-third of patients were older than 70 years.

For those receiving fludarabine or fludarabine plus cyclophosphamide the oral route was given in approximately two-thirds of the cases.

Complete remission and overall response rates were significantly higher with fludarabine plus cyclophosphamide when compared with fludarabine alone or with chlorambucil. This was true for all age groups. There was no evidence that the response rates or adverse effects were different between earlier stage or more advanced stage CLL. There was no significant difference in overall survival between patients given any of the three therapies. However, in terms of treatment response, the fludarabine cyclophosphamide combination was most effective for each of the prognostic groups including those defined by immunoglobulin heavy chain (VH mutation status) and cytogenetic analyses, which were tested in 533 and 579 cases respectively.

Patients had more neutropenia and days in the hospital with the combination fludarabine cyclophosphamide or fludarabine alone when compared to chlorambucil. There was less hemolytic anemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life measures indicated a decline in all three treatment arms, but there was no significant difference between the treatments, and the quality of life improved for those who had responses.


This study marks the third large-scale investigation of the combination of fludarabine cyclophosphamide vs fludarabine alone for treatment of CLL. The German Chronic Lymphocytic Leukemia Study Group investigated 375 patients who were 65 years or younger with intravenous fludarabine and observed a higher complete remission and overall response rate with fludarabine plus cyclophosphamide, and a longer progression-free survival than when fludarabine was used alone, but no differences in overall survival were recorded.2 The second study came from US intergroup trial (E2997) which reported on 278 patients between the ages of 33 and 86, and once again a significantly higher complete remission, overall response rate and longer progression-free survival were observed in those who received fludarabine plus cyclophosphamide compared to those who received fludarabine alone.3 The current study confirms these findings in a large, well-conducted multi-site clinical trial.

Furthermore, there were some important additions. The molecular markers including immunoglobulin gene mutation status and non-random cytogenetic defects probed by fluorescence in situ hybridization (FISH) were performed and identified high risk individuals. Thus, it was determined that although fludarabine and cyclophosphamide combination was superior to the other treatments in producing remissions in patients with a 17p13 deletion, these were of short duration. Accordingly, this type of analysis may prove useful in future clinical trials to identify those warranting more aggressive treatment.

Another feature of this trial was the attention paid to quality of life. All three treatments were associated with some negative impact; however, there did not seem to be a difference among the treatments. Furthermore, for those who did respond, quality of life improved. Additionally of note, approximately one-third of the patients on the study were elderly (over the age of 70) and these patients tolerated each of the treatment arms comparably.

As with the German and North American study, there was no overall survival advantage. However, the median followup of only two to three years suggest that an additional assessment be undertaken in time. Yet, the question of overall survival is difficult because those who show evidence for disease progression are most frequently treated with additional agents in sequence, and differences in overall survival on the basis of initial therapy may be impossible to discern.


1. O'Brien SM, et al. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol. 2001;19(5):1414-1420.

2. Eichhorst BF, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006;107(3):885-891.

3. Flinn IW, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol. 2007;25(7):793-798.