Immunosuppressive treatments in Crohn's disease induce myelodysplasia and leukaemia
Authors: Andrea Piccin, Sergio Cortelazzo, Ugo Rovigatti, Billy Bourke, Owen P. Smith
Journal: American Journal of Hematology (2010)

We report on a pediatric and an adult patient suffering from Crohn's disease (CD), treated with mercaptopurine (6-MP) and anti-TNF-α therapy, who respectively subsequently developed MDS with monosomy-7 and acute myeloid leukemia (AML). Although a link between exposure to 6-MP and anti-TNF-α and malignant lymphomas has been documented [1], the risk of developing leukemia or myelodysplasia (MDS) has not been clearly ascertained. Recent studies have shown that a higher risk of malignancies is found when patients on 6-MP, have an associated deficit of its catabolic enzyme thiopurine methyltransferase (TMPT) [2]. Heterozygousity or absence of TPMT gene is associated with myelosuppression, while anti-TNF-α therapy may favor malignancies possibly increasing the risk of developing MDS/leukemia. Case#1: A 14-years-old male with CD since the age of 8 years (January 2001). Blood count on presentation: Hb 8.8 g/dL, Wcc 21.3 × 109/μL, Platelet 873 × 109/μL. He was commenced on prednisolone (25 mg PO OD). In June 2001 after presenting with new bloody-diarrhea, oral prednisolone was discontinued and 6-MP (50 mg PO OD) was commenced. In April 2003 due to persistent diarrhea weekly anti-TNF-α was started (100 mg IV). In May 2003 he became transfusion-dependent and bone marrow studies showed MDS-erythrodisplasia with monosomy-7. Enzymatic study documented TPMT heterozygousity. In November 2004, a HLA-matched sibling transplant was performed. The patient is currently well 5 years and 8 Months post-HSCT; his last chimerism-study showed 100% donor-chimera. Case#2: A 21-year-old girl, suffering from CD since November 2006. She was initially treated with prednisone (1 mg/Kg PO OD), then in July 2007 she was started on mesalazine (1200 mg PO BD) and budesonide (Entocort®) (4.5 mg TDS). In September she was commenced on 6-MP (50 mg once a day PO) up until December 2008 when she complained of severe diarrhea. Anti-TNFα was started and continued up to May 2009, when she developed thrombocytopenia and leukocytosis (WBC 15800/μl, Hb 10g/dl, Plts 88000/μl) high fever and laterocervical lymphoadenopaties. A diagnosis of AML M5a was made. She was started on induction chemotherapy with idarubicine 12 mg/m2 (days 1,3,5), cytarabin (100 mg/m2 days 1–7), and etoposide (100 mg/m2 days 1–3), followed by consolidation, with CR. She is currently well, 100% donor-chimera 8 months post allogeneic sibling HSCT. The presence of heterozygosity for TPMT in case#1 is in keeping with previous studies on intermediate or absent TPMT activity and hematopoietic malignancies. Moreover, CD incidence has shown a constant increase over the past 20–30 years in Western Countries, a pattern mirrored by epidemiological studies of childhood-leukemia [3, 4]. Therefore, the existence of a common pathogenic-agent involved in CD and MDS/leukemia, cannot be out ruled. Whorwell et al. identified a virus from CD patients causing cytopathic effects in vitro [6] and similar isolates were demonstrated by Rovigatti et al. from childhood leukemia/lymphoma samples [5]. Additional studies are warranted to clarify the role of immunosuppressive drugs in CD progression toward MDS/leukemia and the hypothesis of a common pathogenic agent between these conditions. Andrea Piccin* , Sergio Cortelazzo*, Ugo Rovigatti?, Billy Bourke?, Owen P. Smith , * Haematology Department, San Maurizio Regional Hospital, Bolzano, Italy, Haematology Department, Our Lady's Children's Hospital, Dublin, Ireland, Department of Hematology, Trinity College University, Dublin, Ireland, ? Department of Oncology, University of Medicine, Pisa, Italy, ? Gastroenterology Department, Our Lady's Children's Hospital, Dublin, Ireland.