Oral Fludarabine phosphate as first-line treatment of chronic lymphocytic leukemia

Reviewer: Tracy d'Entremont, MD
Last Modified: December 7, 2002

Presenter: Jean-Francois Rossi
Presenter's Affiliation: CHU; Montpellier, France
Type of Session: Poster


  • Fludarabine phosphate is a nucleotide analog of arabinoside which has achieved overall response rates (ORR) of 63-70% in previously untreated patients with B-cell chronic lymphocytic leukemia (B-CLL).
  • Treatment regimens typically consist of i.v. infusion lasting 30 minutes daily for 5 days every 4 weeks.
  • An oral formulation of fludarabine phosphate has been developed to allow more convenient dosing.
  • Early pharmacokinetic data shows that the AUC after oral dosing was similar to that with i.v. dosing.
  • Bioavailability was 60%.
  • Single daily dosing of 40 mg/m2 provides similar systemic exposure to a 25 mg/m2/day i.v. dose.
  • This study was conducted to assess the ORR and safety profile of orally administered fludarabine phosphate in previously untreated patients with B-CLL.

Materials and Methods

  • A prospective, multicenter, uncontrolled, open-label, phase II clinical trial was carried out at 24 centers in Europe.
  • Patients were given oral fludarabine at a dose of 40mg/m2/day
  • Tablets were taken for 5 days each week, every 4 weeks.
  • Treatment was planned until CR was achieved for a maximum of 8 cycles.


  • Total of 82 patients were enrolled; 81 were treated.
  • ORR was 80.2% by NCI criteria (similar to that reported with i.v. fludarabine)
  • Stage at baseline had an impact on response
    80% ORR for Binet A, progressive disease
    75% ORR for Binet B 53% ORR for Binet C
  • Mean of 5.9 cycles were given with 76.5% receiving 6 or more cycles.
  • Most frequent toxicities were myelosuppression
    Gr3/4 neutropenia 32.1%
    Gr3/4 hemoglobin 9.9%
    Gr3/4 platelets 4.9%
  • 50.6% had infections with only 4.9% being severe infections.
  • Nausea/Vomiting/Diarrhea were more common with the oral formulation. However most cases were mild or moderate and did not require treatment.
  • Dose reductions were required by 14 patients mostly due to myelosuppression
  • There were 4 deaths
    1 from Septicemia
    1 from MI
    1 from Richter's Transformation
    1 from Progressive Disease
  • Quality of life questionnaires demonstrated statistically significant improvements in emotional, insomnia, and health scores after treatment.

Author's Conclusions

  • Orally administrated fludarabine has similar efficacy to that previously observed with the i.v. formulation as first-line therapy for B-CLL.
  • Treatment was generally well tolerated.
  • In this patient population, treatment with the oral formulation does not have a detrimental effect on quality of life.

Clinical/Scientific Implications

    This Phase II study of 81 patients demonstrates that oral fludarabine has a reasonable ORR in the first line setting for B-CLL and is well tolerated. Further data from a randomized trial are necessary to prove it's utility compared with other commonly utilized agents such as i.v. fludarabine and/or rituxamab.

Oncolink's ASH Coverage made possible by an unrestricted Educational Grant from Ortho Biotech.