Guidelines for the use of fludarabine in CLL and low grade NHL 

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Fludarabine phosphate is a fluorinated nucleotide analogue of 9--D-arabinofuranosyladeine (Ara-A). Fludarabine phosphate is rapidly dephosphorylated on injection. It is taken up by cells and is then phosphorylated intracellularly to give the active triphosphate 2-F-Ara-ATP. When 2-F-Ara-ATP is incorporated into DNA, DNA synthesis is effectively terminated due to inhibition of a number of enzymes including ribonucleotide reductase, DNA primase, DNA polymerases and DNA ligase. When incorporation of Fludarabine nucleotides into DNA reaches a critical level, programmed cell death or apoptosis is activated and the cell dies.

The prognosis for the low grade lymphoproliferative malignancies, (IWF A, B, C) and chronic lymphocytic leukaemia has essentially remained unchanged over the last 15 years with a median survival of 3 - 10 years from initial diagnosis depending on stage. No curative therapy is currently available. The finding that Fludarabine phosphate shows high activity in these conditions is encouraging and prompted a number of phase I and II studies involving investigators on both sides of the Atlantic. Two phase II trials in particular demonstrated the significant single agent activity of Fludarabine in previously treated CLL. These studies were carried out at The National Cancer Institute at Bethesda, Maryland in collaboration with the MD Anderson Cancer Centre in Houston, Texas and the Southwest Oncology Group at Ohio State University, Columbus, Ohio. High response rates were achieved in both untreated patients and in relapsed patients some of whom had become resistant to alkylating agents and in some patients 2nd line drugs such as Vincristine and Doxorubicin. In these patients Fludarabine as a single agent was able to achieve response rates comparable to those of 1st line drugs such as Chlorambucil in previously untreated patients.

In low grade lymphoma two thirds of patients will respond to Fludarabine with approximately 20% of patients achieving a complete remission. Follicular lymphomas have a higher response rate than patients with diffuse histology. The response rate was higher in patients who had received only one prior treatment regimen. The activity of Fludarabine had also been reported in the context of Waldenstrom's macroglobulinaemia and Sezary syndrome. The results of a recent multicentre prospective randomised trial of Fludarabine vs CAP for the treatment of CLL stages B and C have now been reported. Fludarabine provides an effective and well tolerated therapy for patients with advanced CLL and compare favourably with CAP. As 2nd line therapy Fludarabine induced a significantly higher rate of complete and partial remissions. No improvement in overall survival has yet been demonstrated. Multicentre randomised prospective comparisons of Fludarabine vs CVP in low grade lymphoma have yet to be reported.

Our recommendations are as follows 1) in CLL Fludarabine should be considered in patients who have relapsed after therapy with Chlorambucil or who show disease progression on Chlorambucil therapy. 2) low grade NHL all eligible patients should continue to be recruited to the EORTC/BNLI CVP vs Fludarabine study which is comparing these agents as 1st line therapy for stage III/IV NHL. While more definitive data is awaited, Fludarabine should be used as a 3rd line agent in low grade NHL after Chlorambucil and Anthracycline based regimens.

Treatment schedule

Fludarabine phosphate 25 mg/m2 iv daily for 5 days given either by 30 minute infusion or as a bolus over a few minutes repeated every 28 days.

Dose modification

Low neutrophil and platelet counts may be due to the disease. If the physician considers that a fall in counts are due to treatment the dose may be modified as indicated below. If the neutrophil count falls below 1 x 109/l or platelets below 50 x 109/l, the dose should be reduced by 50% or the full treatment may be given over 3 days. If neutrophils fall below 0.5 x 109/l or platelets below 20 x 109/l, treatment should be discontinued, and resumed as soon as the counts are to the clinicians satisfaction. Renal impairment - if the creatinine is raised, the creatinine clearance should be measured. If >70 ml/min give full dose, 30 - 70 ml/min give 50% dose and, 30 ml/min exclude.

 

Adverse Effects

The main side effect of Fludarabine phosphate is myelosuppression. Therefore cytopenia with neutropenia, thrombocytopenia and leucopenia may occur. Pulmonary infiltrates have been reported in 6 cases at the National Cancer Institute. Consideration should be given to the use of prophylactic Co-trimoxazole to prevent pneumocystis carinii infection. Irradiated blood products are recommended in view of case reports of fatal graft vs host disease in patients treated with Fludarabine. A single patient has been reported to have suffered a serious neurological disturbance causing blindness. Other possible side effects are fever, chills, nausea, emesis, malaise, fatigue, anorexia, weakness, hearing loss, numbness, pneumonia, cough, shortness of breath, diarrhoea, stomatitis, gastro intestinal bleeding, rashes, rare peripheral neuropathy, rare wrist drop.

Duration of treatment

Give 3 cycles and review. If there has been partial or complete response continue to 6 cycles. If there has been no response discontinue. Progressive disease - consider other treatment modalities.


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