Does Upfront Therapy with Fludarabine Increase the Risk of Histological Transformation In Patients with Follicular Lymphoma?

Fludarabine has been reported to increase the incidence of relapse and histological transformation in chronic lymphocytic leukemia (Thornton PD, Leukemia research, 2005) and Waldenstrom macroglobulinemia (Leleu X, J Clincal Oncology, 2009). The purpose of our study was to investigate the role of Fludarabine and the risk of transformation and relapse in follicular lymphoma (FL).

This is a retrospective single institution study. We included 50 patients consecutively diagnosed with FL Grade I and II based on WHO classification of lymphoid malignancies. Grade III patients were excluded from the study. Median follow up is 2.86 years. Patients were grouped according to the initial therapy chosen by their treating physicians: Group 1(n=14) included patients on observation and radiation therapy, Group 2 (n=6) included patients on Fludarabine based regimens, Group 3(n=13) included CVP-R and other rituximab regimens and Group 4(n=17) included R-CHOP. Data collected included time to the onset of biopsy proven transformation, time to relapse, mortality and overall survival. Level of significance was set at <0.05.

Median age of the patients was 56.5 and it was not significantly different for the various groups. High risk FLIPI score was seen in 66% of patients treated with Fludarabine regimens as compared to 61% of R-CHOP treated patients. Overall, relapse occurred in 38% patients and transformation occurred in 16% patients during the follow up period. Fludarabine treated patients had the highest relapse rate: 50% (p=0.03). R-CHOP group has lowest relapse rate: 11%. Transformation rate was highest in the Fludarabine group: 33%, as compared to 13% to 17% in other groups (p=0.10). Mortality rate was 7% in group 1, 16% in group 2, 23% for group 3 and 5% in group 4 (p=0.44). Time to relapse/progression in group 1 was 2.9 years; in group 2 was 2.1 years; in group 3 was 2.7 years and in group 4 was 5.8 years.

In our study, Fludarabine treated patients appear to be at higher risk for relapse and transformation compared to patients treated with R-CHOP. The differences can not be explained on the basis of known prognostic factors such as age or FLIPI score. The retrospective nature of the study and the small numbers of patients preclude more definitive conclusions. Further research is needed with large number of patients.

No relevant conflicts of interest to declare.