Azathioprine‐associated acute myeloid leukemia in a patient with Crohn's disease and thiopurine S‐methyltransferase deficiency

Abstract

Immunosuppressive thiopurines like azathioprine, 6-mercaptopurine, and thioguanine are commonly used in inflammatory and neoplastic disorders. A subset of these patients are genetically slow metabolizers due to point-mutations in enzyme thiopurine S-methyltransferase (TPMT), and are at a higher risk of hematologic toxicity and leukemogenesis. We present such a patient who was a slow metabolizer for azathioprine, and developed a rapidly lethal form acute myeloid leukemia after relatively low dose exposure to the drug. There was prominent hemophagocytic activity in the bone marrow, and cytogenetic analysis showed a complex karyotype with monosomy 7, but no involvement of chromosome 8. Am. J. Hematol. 83:80-83, 2008. V

Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study

“…A linkage between high-hyperdiploid ALL and SMN, including t-AML/MDS with Ϫ7/7q-, has not previously been reported, but thiopurine therapy has been linked to t-AML/MDS with monosomy 7 in patients with benign disorders. 41,56 It is uncertain to what extent the ALL cases with missing or normal karyotypes in reality had a highhyperdiploid clone, but it is well known that conventional chromosome analysis may fail to identify high-hyperdiploidy because of poor in vitro growth of leukemic cells in this ALL subset. 23 Because both high-hyperdiploidy and monosomy 7 represent mitotic nondisjunction, the linkage could represent an individual propensity for such mitotic errors similar to that identified in mothers of children with Down syndrome.…”

International consensus report on the investigation and management of primary immune thrombocytopenia

“…67 Although continued therapy is generally required, often a reduced dose suffices. Leukemia has only rarely been associated with azathioprine in other disorders but has not been described in ITP patients 68 (evidence level III).…”

Therapy-Related Acute Myeloid Leukemia in Crohn’s Disease

“…Here we describe a new case of acute myeloid leukemia (AML) in a Korean CD patient who was treated with mesalazine, mercaptopurine, and prednisolone. We also provide a concise review of AML cases in CD from the literature [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. …”

“…As suggested by Mullier et al [3], both regular CBC checkups and vitamin B 12 measurement are surely necessary to monitor a CD patient with an immunosuppressive agent such as azathioprine. However, recent studies have shown that a higher risk of malignancies is found when patients receiving mercaptopurine carry a defect of catabolic enzyme TPMT [16]. Patients with low TPMT activity are at a heightened risk of drug-induced bone marrow toxicity due to an accumulation of the unmetabolized drug [16,22].…”

“…However, recent studies have shown that a higher risk of malignancies is found when patients receiving mercaptopurine carry a defect of catabolic enzyme TPMT [16]. Patients with low TPMT activity are at a heightened risk of drug-induced bone marrow toxicity due to an accumulation of the unmetabolized drug [16,22]. Based on such emerging scientific evidence, and although a TPMT genetic test was not conducted in most of the previously reported AML cases in CD, we think that careful monitoring as well as a relevant genetic work-up such as TPMT genotyping would be necessary in the future monitoring of CD patients receiving immunosuppressive agents for long durations.…”