Januszewicz David Westerman Treatment - related myelodysplasia following fludarabine combination chemotherapy

Myelodysplasia (MDS) and secondary acute myeloid leukemia (sAML) are well-recognized complications of therapy with alkylating agents and topoisomerase II inhibitors. A recent comprehensive review of reported MDS/sAML rates concluded that up to 10% of patients treated for non-Hodgkin’s lymphoma (NHL) using either conventional dose alkylator-based regimens or high-dose therapy develop MDS or sAML within a decade of primary therapy. As the median survival of selected patients with chronic lymphocytic leukemia (CLL), follicular lymphoma and other indolent lymphoid malignancies may exceed 10 years, the risk of therapy-related MDS/sAML is an important consideration in the initial choice of therapy in these conditions. Fludarabine is a purine analog that has significant activity as a single agent in CLL and indolent NHL. In contrast to the published experience with alkylating agents, MDS and sAML are rarely reported following fludarabine monotherapy: no such cases were reported in three large cohorts of patients receiving fludarabine as initial therapy for CLL, and only a single case was recorded among 724 patients receiving fludarabine as salvage therapy for CLL. Although there is less extensive experience with the use of fludarabine monotherapy for the treatment of indolent NHL, the incidence of MDS/sAML appears similarly low, with no cases reported in the largest published series. However, the combination of fludarabine with cyclophosphamide or other DNA damaging agents may increase the risk of MDS/sAML due to synergistic effects in the induction and inhibition of DNA damage. The capacity of fludarabine to inhibit DNA repair following DNA damage is wellrecognized in malignant cells lines,11 and observations of similar effects on normal lymphocytes12 raise the possibility of cumulative genetic damage in hematopoietic stem cells. In order to define the risk of MDS/sAML following fludarabine combination therapy, we examined all such cases among consecutive cohorts of patients receiving either fludarabine-cyclophosphamide (FC), FC and rituximab (FCR) or FC-mitoxantrone and rituximab (FCMR) at the Peter MacCallum Cancer Center.