Low Dose Oral Chemotherapy for Indolent NHL in Elderly Patients

Abstract & Commentary

By William B. Ershler, MD, Editor

Synopsis: Oral fludarabine and cyclophosphamide were used in combination for initial treatment of non-Hodgkin lymphoma in 25 elderly patients. During an observation period of just over 3 years, 84% were responsive to treatment and there was an overall survival rate of 70%. Hematological and non-hematological toxicity were generally mild and manageable.

Source: Fabbri A, et al. Br J Haematol. 2007;139:90-93.

Fludarabine (Flu) and cyclophosphamide (Cy) are each active in the treatment of indolent lymphoma, and when administered together have a demonstrable synergistic effect.1 For example, in vitro studies demonstrated that Flu inhibits DNA repair of interstrand cross-links induced after exposure of neoplastic B-lymphocytes to activated Cy. In turn, the incorporation of the F-ara-A (the nucleoside derived from Flu) into lymphocyte DNA was markedly increased by Cy.2 Thus, Flu-Cy combinations have been tested extensively with excellent anti-neoplastic effects, but at considerable risk for myelosuppression and infectious complications.3 Attempts at reduction of toxicity have included lower dose regimens, some of which have demonstrated a retention of excellent response rates.4

Another feature of this combination is that both drugs have been formulated for oral administration. This convenience, in combination with a reduced dosing strategy was the basis of the current phase II clinical trial in elderly patients with indolent non-Hodgkin lymphoma (NHL). The study, conducted by Fabbri and colleagues at the University of Siena and the University of Genova included 25 elderly (median age 74 years, range 66-85 years) patients with previously untreated NHL. Both Flu (25 mg/m2) and Cy (150 mg/m2) were administered orally for four days, repeated every 28 days for a total of four cycles. Twenty-one (84%) responded favorably to treatment; 10 achieved a complete remission, and 11 met criteria for partial remission. During an observation period of 37 months, there was an overall survival rate of 70% and a median event-free survival of 20 months. Eighteen patients received the entire planned treatment and there were no delays or dose reductions required. In total, only four patients were considered non-responders; two of these had stable disease and two had evidence for disease progression. Thirteen of 21 responding patients had maintained their response after a median observation period of 19 months and the median overall survival (OS) had not been reached at 37 months. As noted, median event free survival was 20 months.

Myelosuppression was the main side effect, although grade 3-4 hematological toxicity was documented in only seven cases (28%) and these patients were treated successfully with growth factor (G-CSF and/or erythropoietin). Infectious complications occurred in five patients. Extrahematological toxicity was mild, consisting of grade 1-2 nausea/vomiting in 24% and one patient who experienced grade 3 peripheral neuropathy.


Like most cancer, NHL is a disease of the elderly. While moderately aggressive regimens, such as R-CHOP have proven safe and effective,5 for those with indolent disease, such may be more than required to maintain excellent disease control. Furthermore, the convenience of oral therapy with the associated reduced need for clinic visits may be particularly advantageous for patients in this age group. However, as with oral therapy in general, this advantage must be balanced by the concern regarding compliance to dose and schedule.6

Recently, rituximab has been shown to be highly effective and well tolerated in the treatment of NHL. It is likely that the addition of rituximab to this regimen would favorably increase results including event free and overall survival. However, this may come at an increased risk for infection, a concern that warrants further investigation before widespread application in the community setting.


1. Bellosillo B, et al. Blood. 1999;94(8):2836-2843.

2. Yamauchi T, et al. Clin Cancer Res. 2001;7(11):3580-3589.

3. O’Brien SM, et al. J Clin Oncol. 2001;19(5):1414-1420.

4. Tam CS, et al. Cancer. 2004;100(10):2181-2189.

5. Coiffier B, et al. N Engl J Med. 2002;346(4):235-242.

6. Lonardi S, et al. Drugs Aging. 2007;24(5):395-410.