Fludarabine-Associated Acute Promyelocytic Leukemia

Abstract 4383

Here we describe a case of acute promyelocytic leukemia (APL) (M3 leukemia) which developed in a patient treated with single-agent fludarabine for lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia [WM]).

This 69-year-old male was diagnosed with WM in 2003. He received single-agent therapy with 4 cycles of fludarabine, after having an adverse reaction to his first and only dose of rituximab. Therapy was completed in 2007, with the patient in a complete remission. Two years later, he presented with leukocytosis and a consumptive coagulopathy. A bone marrow biopsy showed 90% abnormal promyelocytes with prominent Auer rods. PML/RARA fusion was positive by FISH. PCR was positive for t(15;17) (PML/RAR long (bcr1 and bcr2) and short (bcr3) form translocations. Cytogenetic studies showed abnormal 3q, monosomy 15 and 17, 2 unidentified marker chromosomes and a complex insertional translocation of chromosomes 15 and 17, with a PML/RARA fusion. The patient's APL was treated with ATRA and 7+ 3 chemotherapy because of a rising number of blasts in his peripheral blood. His subsequent clinical course was complicated by refractory atrial fibrillation, renal failure, a catheter-related upper-extremity deep venous thrombosis, and severe deconditioning. The patient died four months later from probable sepsis. A marrow performed two weeks prior to his death showed a complete hematologic remission, and no evidence of either Waldenstrom's or acute promyelocytic leukemia.

There are forty-eight cases published of hematologic malignancies which occurred after single-agent nucleoside-analog treatment: none were APL. Twenty-four of these cases consisted of a lymphoid transformation to a more aggressive histology and twenty-four cases described development of a myeloid leukemia or myelodysplastic syndrome. In these patients, a variety of chromosomal changes were demonstrated with abnormalities of chromosome 7 being the most frequently observed (exclusively in those with myeloid disorders). There were no cases of a t(15;17) reported. We then reviewed all documented cases of therapy-related APL. No cases implicating nucleoside analogs were found. Topoisomerase inhibitors were the most common agents implicated as were radiation, anthracyclines, and alkylating agents.

Because fludarabine was the only chemotherapy agent to which the patient was exposed, and the patient developed APL within the time frame expected for therapy-related leukemogenesis, we conclude that this is the first reported case of fludarabine-associated APL.