The role of fludarabine in intermediate- and high-risk chronic lymphocytic leukaemia

I. C. Yee, G. Browman, S. Wong, R. Esmail, R. Meyer, H. Abu Zahra, M. Crump, D. Dhaliwal, P. Galbraith, S. Gluck, M. Gospodarowicz, L. Huebsch, K. Imrie, L. Kaizer, J. Matthews, J. Meharchand, H. Messner, C. Sawka, A. Smith, I. Walker

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Abstract

Question: What is the role of fludarabine for previously untreated and previously treated patients with intermediate- or high-risk chronic lymphocytic leukaemia (CLL)?. Perspective: Evidence was selected, reviewed, and synthesized by a haematologist, who is a member of the Cancer Care Ontario Practice Guidelines Initiative Haematology Disease Site Group (DSG). This practice guideline report was reviewed and approved by all members of the DSG, which comprises haematologists, medical oncologists, and a radiation oncologist. No community representative participated in the development of this report, but will in future reports. Methodology: Sources of Evidence: A systematic search of MEDLINE, CANCERLIT, CARL Corporation's UnCover database, and relevant conference proceedings was conducted. Bibliographies were also reviewed. Patient Population: Patients include those with: intermediate-risk chronic lymphocytic leukaemia defined as Rai Stage II (lymphocytosis in blood and marrow with an enlarged spleen, or liver, or both [with or without enlargement of lymph nodes]), or Rai Stage III (lymphocytosis in blood and marrow with anaemia [haemoglobin < 110 g/L]); and high-risk chronic lymphocytic leukaemia defined as Rai Stage IV (lymphocytosis in blood and marrow with thrombocytopaenia [platelets < 100 x 109/L]). Outcomes of Interest: Primary outcomes of interest include overall survival and quality of life. Secondary outcomes include progression-free survival and response. Results: Search Results: Four studies examined fludarabine in previously untreated patients: 3 randomized controlled trials and 1 phase II study. Seven studies examined fludarabine in previously treated patients: 1 randomized controlled trial and 6 phase II studies. Benefits: In previously untreated patients with intermediate- or high-risk chronic lymphocytic leukaemia, the pooled analysis for response rates between fludarabine and conventional treatments from the 3 randomized controlled trials yielded an overall odds ratio of 2.44, favoring fludarabine over conventional treatments (95% confidence interval [= CI]: 1.65-3.61; p < 0.00001). Long-term survival data are lacking. For previously treated patients, preliminary results report longer progression-free survival with fludarabine compared with chlorambucil or cyclophosphamide-Adriamycin-prednisone (CAP). In previously treated patients with intermediate-or high-risk chronic lymphocytic leukaemia, the one available randomized controlled trial detected a superior response rate for fludarabine (48%; CI: 33-63; n = 48) compared with CAP (27%; CI: 15-42; n=48), but no survival advantage (median survival for fludarabine was 23.9 months and for CAP was 24 months; p-value: not significant). Long-term survival data from this trial are lacking. Harms: Fludarabine is associated with significant myelosuppression and immunosuppression, and an increased risk of opportunistic infection. Cases of transfusion-related graft-versus- host disease have been described. Therefore, patients receiving this drug should receive irradiated blood products. Auto-immune haemolytic anaemia, a condition associated with chronic lymphocytic leukaemia, may be exacerbated or precipitated by fludarabine, and is thus considered by the manufacturer as a contraindication to the use of this drug. Uncommonly reported adverse effects include neurologic and pulmonary toxicity, and tumour lysis syndrome. Practice Guideline: Previously Untreated Patients with Intermediate- or High- risk CLL: In preliminary reports of randomized controlled trials of previously untreated patients with intermediate- or high-risk chronic lymphocytic leukaemia, fludarabine has shown superior response and improved progression-free survival over conventional therapies (chlorambucil or CAP). Long-term survival data are lacking. An increased number of opportunistic infections have been reported in patients treated with fludarabine. Until long-term results on survival and quality of life are available, either fludarabine or conventional therapies are acceptable treatment options. Choice of treatment will be influenced by patient preference and clinical judgement, taking into account factors such as route of administration, risk of infection, and outcomes of interest. Previously Treated Patients with Intermediate- or High-risk CLL: The evidence in previously treated patients with intermediate- or high-risk chronic lymphocytic leukaemia is based on 1 randomized controlled trial of fludarabine versus CAP, and 6 phase II studies. The randomized trial detected superior response and a trend towards improved progression-free survival with fludarabine, but overall survival was not significantly different. Fludarabine is an acceptable treatment option after failure of first-line therapy. Choice of treatment should be influenced by previously used regimens and patient preference. Dosing and Special Considerations: Based on recommendations put forward by the Canadian Blood Services and the British Committee for Standards in Haematology Blood Transfusion Task Force, patients who have been treated with fludarabine should receive irradiated blood products because of the risk of transfusion- related graft-versus-host disease. As fludarabine is associated with an increased risk of opportunistic infections, prophylaxis against Pneumocystis carinii (trimethoprim/sulfamethoxazole) should be considered in patients at high risk for this infection (low CD4 count: 0.05 x 109/L; multiple previous treatments). Auto-immune haemolytic anaemia may be exacerbated or precipitated by fludarabine and is, therefore, considered by the manufacturer to be a contraindication to the use of this drug. A dose of 25 mg/m2 per day for 5 consecutive days intravenously every 4 weeks for a total of 6 cycles, or 2 cycles beyond maximum response is suggested.

Original languageEnglish (US)
Pages (from-to)90-102
Number of pages13
JournalCurrent Oncology
Volume6
Issue number2
StatePublished - Oct 26 1999

ASJC Scopus subject areas

  • Oncology

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    Yee, I. C., Browman, G., Wong, S., Esmail, R., Meyer, R., Abu Zahra, H., Crump, M., Dhaliwal, D., Galbraith, P., Gluck, S., Gospodarowicz, M., Huebsch, L., Imrie, K., Kaizer, L., Matthews, J., Meharchand, J., Messner, H., Sawka, C., Smith, A., & Walker, I. (1999). The role of fludarabine in intermediate- and high-risk chronic lymphocytic leukaemia. Current Oncology, 6(2), 90-102.