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| |  Fludarabine Compared With Chlorambucil As Primary Therapy For Chronic Lymphocytic Leukemia By Lynn Haley Special to DG News
VANCOUVER, CANADA -- March 18, 2001 -- Fludarabine has a greater response rate than chlorambucil for patients with chronic lymphocytic leukemia, as well as a longer duration of remission and progression-free survival. For the past 40 years, chlorambucil has been the treatment of choice for patients with chronic lymphocytic leukemia (CLL), the most common leukemia seen in the western world. The findings of a large randomized trial were presented in Vancouver, Canada, March 8th by Dr. Kanti Rai, one of the world’s leading authorities in the management of CLL. Dr. Rai, of the Cancer and Leukemia Group B of Chicago, Illinois, and lead author of the Intergroup study, presented the findings as part of the Berlex Canada Oncology Visiting Professor Program. Between 1990 and 1994, researchers from several North American cancer institutes randomly assigned 509 previously untreated CLL patients to one of three treatments. These were intravenous fludarabine (25 mg/m2 for five days every 28 days), oral chlorambucil (40 mg/m2 every 28 days), or a combination of fludarabine (20 mg/m2 every 28 days) plus chlorambucil (20 mg/m2 every 28 days). Patients were evaluated monthly and those with an additional response continued to receive the assigned treatment for up to 12 cycles. Eligibility criteria were based on a diagnosis of CLL using National Institute of Cancer guidelines and included all high-risk patients, that is, those with stage III and IV disease, and all stage I and II patients, considered intermediate risk. Patients were enrolled if they had obvious evidence of active disease, such as weight loss, extreme fatigue, night sweats or a fever without evidence of infection. Patients had to be at least 18 years of age (median age was 64), be Coombs’ test negative, and have a performance status of 0 to 2, as well as a signed informed consent. Randomization was to one of three arms: fludarabine alone, chlorambucil alone, or the combination of the two in somewhat attenuated doses. In the first and second single treatment arm, patients were crossed over if the first randomized drug was found to be ineffective. Major oncology groups from across North America contributed significant numbers of patients. Fludarabine patients numbered 179, 193 were assigned to the chlorambucil group, and 137 patients received the combined fludarabine plus chlorambucil therapy. Each patient was evaluated monthly before the next scheduled treatment to assess the levels of toxicity and measure the clinical response to treatment. Patients in the single-arm groups who had evidence of disease progression were allowed to cross over to the other drug. At the three-and-a-half year point of the trial, planned interim analysis revealed too much toxicity in the combination arm. Researchers concluded that the combined treatment was unlikely to result in a positive treatment response. With this in mind, the decision was made to discontinue the combination arm of the study. Patients were then randomised to the remaining two single-arm regimens for the last year of the study. The purpose of the study was to determine whether or not the intravenous agent fludarabine results in a significantly greater complete response, partial response and overall response than the oral therapy chlorambucil. Researchers compared the duration of the response obtained in patients randomized to fludarabine and to chlorambucil, the progression-free survival rates with either drug, and the overall survival rates. Toxicity levels and quality of life were also considered. The results show that among the 170 patients treated with fludarabine, 20 percent had complete remission, while 43 percent had partial remission. For the 181 patients assigned to the chlorambucil arm, the values were 4 percent and 33 percent, respectively. Of the 79 patients who crossed over from chlorambucil to fludarabine, 46 percent had a complete or partial remission. Of the 29 who crossed over from fludarabine to chlorambucil, 7 percent had a response. Median duration of remission and progression-free survival in the fludarabine group were 25 months and 20 months, respectively, while in the chlorambucil, both values were 14 percent. The median overall survival among fludarabine patients was 66 months, which was not statistically different from the other two groups -- 56 months with chlorambucil and 55 months with the combination therapy. In discussing the results, Dr. Rai noted that fludarabine used as monotherapy had virtually identical incidence of complete remissions, partial remissions and overall responses as the combination arm. Therefore, by closing the third arm, the situation was not compromised. When comparing fludarabine with chlorambucil in a large number of at-risk patients in each arm, chlorambucil continues to be "mainly palliative", reducing the size of lymph nodes, and the number of lymphocytes, but without accomplishing much more than that. These findings led researchers to conclude that in the initial treatment of CLL, fludarabine is superior to chlorambucil. Patients who received this drug had better rates of complete remission and overall response (complete or partial remission), as well as duration of response and of progression-free survival. The third arm, although discontinued because of toxicity, showed response rates similar to those with fludarabine alone. Fludarabine was also superior in high-risk and intermediate risk patients, although, the researchers caution, they cannot conclude that it is preferable to start fludarabine therapy in patients with intermediate-risk CLL. The two single-drug arms of the trial showed that the drugs were well tolerated with an acceptable level of toxicity. Grade 3 and 4 neutropenia and infections were greater with fludarabine. Of note, Dr. Rai said, is the fact that increases in survival times obtained with either drug did not reach statistical significance, and this requires closer examination. "Much of it, in my view, is because we have not been successful so far in raising the incidences of complete remission (CR) high enough to make that impact, although the direction of progress with fludarabine as against chlorambucil is in the right direction -- that is from four percent CR with chlorambucil to 20 percent CR with fludarabine. But that percentage has to increase to 60, 70, or 80 percent before we can expect an impact on overall survival." The second reason for the poor survival results is the crossover, he noted. Seventy or eighty of the 180 patients in the chlorambucil group were crossed over to fludarabine, whereas only about 29 or 30 patients from the chlorambucil arm were crossed over to fludarabine. "The impact of fludarabine is, perhaps across the board, more visible or obvious than the impact of chlorambucil. Therefore, in such a randomized study, where the cross-over design is present, overall survival is not an appropriate end point to check objectively." A large majority of patients being treated for CLL are much younger today than they were two or three decades ago. During the 1970s and 80s, most CLL patients were in the 70- and 80-year age group. In that age group, chlorambucil was a reasonable choice as it was less toxic and required fewer visits to the clinic, said Dr. Rai. "Now that we are treating patients between 55 and 65 more often than older people, I feel that aiming for a complete remission makes more sense because there, with the higher incidence of complete remission, those patients will have a better likelihood of a longer life." The researchers concluded that gradually, through what they call incremental steps, the results of treatment of CLL would be improved. For over four decades, the mainstay of CLL treatment has remained chlorambucil. With the growing use of fludarabine and subsequent increased rates of remission, scientists must work to find other effective agents that, when combined with fludarabine, will lead to greater survival among CLL patients. Fludarabine is superior in that it provides a complete response rate -- a surrogate measure of disease-free survival -- that is five times greater than with chlorambucil. It offers a longer duration of response and time to disease progression, which allows CLL patients to live normal lives. Side effects are tolerable, and reported infection rates were not considered significantly greater than with chlorambucil. Significantly, although no survival benefit was demonstrated, of the 41 percent of patients who did not respond to the chlorambucil and were crossed over to fludarabine, 46 percent subsequently responded. The crossover design of the study, however, may have confounded any survival advantage related to the choice of initial therapy. "It is true that by some criteria which are not contrived, there is some evidence of superiority of survival of patients who achieve CR. I’ve come to the point where I would recommend fludarabine as the frontline treatment in the majority of patients. But because of the somewhat wishy-washy nature of the statistical analysis, the decision is still on an individual case-by-case basis." "Fludarabine is already being chosen by many practising clinicians as their frontline drug for CLL," he added. "The results of this Intergroup study will lend support to that choice." In British Columbia, Canada, provincial treatment guidelines of the B.C. Cancer Agency have endorsed fludarabine as the first-line use for treatment of patients with CLL.
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