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

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

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

Background

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.

Results

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.