Oral Fludarabine for Indolent NHL: A Phase II Trial

Abstract & Commentary

By William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC and is Editor of Clinical Oncology Alert. Dr. Ershler is on the speaker’s bureau for Amgen and does research for Ortho Biotech.

Synopsis: In a phase II study conducted in Japan, oral fludarabine phosphate administered to patients with B-cell non-Hodgkin’s lymphoma was shown to have an overall response rate of 65%, but with significant, albeit manageable, hematologic toxicity. Oral administration of this drug may prove a convenient alternative to the current regimens which call for several clinic or infusion center visits in the week of therapy.

Source: Tobinai K, et al. Phase II study of oral fludarabine phosphate in relapsed indolent B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2006;24:174-180.

Fludarabine phosphate administered intravenously is effective either alone or in combination with other drugs against indolent B-cell lymphomas. However, commonly used regimens require frequent clinic or infusion center visits. Oral formulations of fludarabine phosphate offer the potential advantage of convenience if they prove to have comparable anti-tumor activity. Tobiai and colleagues in Japan conducted a Phase II study of oral fludarabine in relapsed, indolent B-cell non-Hodgkin’s lymphoma (NHL). For this, patients received fludarabine tablets (10 mg each) at doses of 40 mg/m2 daily for 5 days every 28 days for 3 to 6 cycles. The efficacy was separately analyzed in a mantle-cell lymphoma (MCL) cohort and indolent B-cell NHL (excluding MCL) cohort. The primary end point was overall response rate (ORR).

Fifty two patients with relapsed NHL were enrolled; 46 with B-NHL and 6 with MCL. Of these, 41 (79%) had received prior therapy with single-agent rituximab. The ORR and complete response (CR) rate for the B-NHL group were 65% (95% CI, 50%-79%) and 30% (95% CI, 18%-46%), respectively. For the small group with relapsed MCL, only 1 of 6 achieved a partial response. The median times to treatment failure for B-NHL patients was 8.6 months.

Hematologic toxicity was the most frequently encountered adverse event. Grade 4 neutropenia occurred in 37% of patients. No patients developed grade 4 thrombocytopenia. Granulocyte colony-stimulating factor was used in 40 (16%) of the 243 cycles. Grade 3 infections occurred in 19% but neutropenic fever requiring admission occurred in only one patient. Two patients developed herpes zoster. Nausea/vomiting and diarrhea occurred in 50% and 37% of patients, but these toxicities were graded either 1 or 2, successfully managed and no patient was withdrawn from the study because of these symptoms. One patient developed interstitial pneumonitis while on treatment and another developed myelodysplastic syndrome 7 months after receiving the fifth cycle of fludarabine.


There has been increased interest in oral chemotherapy because of its convenience and demonstrated efficacy. Capecitabine, for example, is a frequently chosen alternative to parenteral chemotherapies for colorectal and breast cancer and oncologists have become comfortable with imatinib mesylate for patients with CML and GIST tumors. Early studies have indicated reasonably good bioavailability of orally administered fludarabine.1,2 For example, in a phase I study of oral fludarabine conducted on 12 patients with relapsed, indolent B-NHL, the mean bioavailability of the drug was shown to be 63%.1 This was similar to the 55% bioavailability for oral fludarabine from a separate study conducted by Foran and colleagues.2 Upon review of the Japanese Phase I data,1 the recommended oral fludarabine dose for Phase II was 40/m2 orally days 1-5 every 28 days.

In the current study the ORR and CR rates (65% and 30%, respectively) were impressive. In fact, they measure quite well with the results from a similar clinical trial by Klasa et al3 in which patients with relapsed indolent B-NHL were treated with intravenous, single agent fludarabine and the ORR was 64% with a progression free survival of 11 months. In the Klasa study, which was a Phase III comparison of fludarabine vs. combination cyclophosphamide, vincristine and prednisone patients had received prior chemotherapy (98%) and rituximab (80%). That is a somewhat different population than the current trial in which 79% had received only rituximab as initial therapy. For those patients the oral fludarabine was their first exposure to chemotherapy. This stated, there is no question, based upon the current report, that fludarabine is active as an oral agent and perhaps further study will demonstrate it is as active as the parenteral formulation. Certainly, the convenience factor alone would warrant further investigation. For patients with indolent B-NHL, either as initial therapy or for relapsed disease, a regimen of day 1 rituximab and day 1-5 oral fludarabine would be worthy of investigational consideration.


1. Tobiai K, et al. Phase II study of oral fludarabine phosphate in relapsed indolent B-Cell non-Hodgkin’s lymphoma. J Clin Oncol. 2006;24:174-180.

2. Foran JM, et al. Pharmacokinetic study of single doses of oral fludarabine phosphate in patients with “low-grade” non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia. J Clin Oncol. 1999;17:1574-1579.

3. Klasa RJ, et al. Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin’s lymphoma previously treated with an alkylating agent or alkylator-containing regimen. J Clin Oncol. 2002;20:4649-4654.