Medicines Q&As Q&A 356.1 Is methotrexate therapy associated with an increased risk of leukaemia? Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Date prepared: 03/12/2012 Background Methotrexate is classed as an anti-metabolite, which acts through inhibition of dihydrofolate reductase, causing disruption of the folic acid cycle and interference of DNA synthesis and repair 1. It is licensed for use as treatment in a wide range of neoplastic conditions, including acute leukaemias. It is also licensed for treatment of rheumatoid arthritis and severe, uncontrolled psoriasis 2. Answer There is no robust evidence in the literature that methotrexate therapy is associated with an increased risk of leukaemia. There have been a number of reports via the MHRA’s yellow card scheme of leukaemias following methotrexate therapy. However these data need to be interpreted with caution as the nature of the scheme means causality can not be established, nor can data be used for estimating incidence rates. It is not known if these reports involved other medicines, or if there were any other non-drug causes for the leukaemias. Up until 26th October 2012, there is one report of fatal leukaemia, one report each of acute lymphocytic leukaemia and T-cell type acute leukaemia, neither of which were fatal, 1 fatal case of acute myeloid leukaemia, 16 reports of acute myeloid leukaemia (7 of which were fatal), and one fatal case of acute myelomonocytic leukaemia. There are also reports of chronic leukaemias: one lymphocytic and one myeloid, and one report of myeloid leukaemia3. One paper, published in a low impact journal presents three case reports of acute leukaemia which the authors theorise have been caused by methotrexate. However, in two of these cases the patient was taking methotrexate for rheumatoid arthritis (see below) and one was for psoriasis, so background illness or chance cannot be excluded in these cases4. Informal press reports, such as http://www.webmd.com/rheumatoidarthritis/news/20041116/rheumatoid-arthritis-drug-linked-to-cancer appear to suggest a causal link between methotrexate and lymphoma and other cancer types. However, this appears to be based on in vitro research investigating the role of methotrexate in reactivating latent Epstein-Barr virus. The applicability of this research to clinical situations is limited. It should be noted that autoimmune disorders may be linked to an increased risk of acute myeloid leukaemia. However, it is not currently clear whether this increase in risk is due to autoimmune conditions or other drugs used to treat them5,6. Summary There is no compelling, good quality evidence to suggest an increase in leukaemia risk is associated with methotrexate therapy. Patients with autoimmune disorders may be at an increased risk due to their illness, or other medications being used to treat the disorder. Limitations There are no controlled studies exploring this question. Disclaimer From the National Electronic Library for Medicines. www.nelm.nhs.uk 1 Medicines Q&As Medicines Q&As are intended for healthcare professionals and reflect UK practice. Each Q&A relates only to the clinical scenario described. Q&As are believed to accurately reflect the medical literature at the time of writing. The authors of Medicines Q&As are not responsible for the content of external websites and links are made available solely to indicate their potential usefulness to users of NeLM. You must use your judgement to determine the accuracy and relevance of the information they contain. This document is intended for use by NHS healthcare professionals and cannot be used for commercial or marketing purposes. See NeLM for full disclaimer. Quality Assurance Prepared by Hayley Johnson, Regional Drug and Therapeutics Centre, Newcastle upon Tyne Date Prepared 3rd December 2012 Checked by Nancy Kane, Regional Drug and Therapeutics Centre, Newcastle upon Tyne Date of check 12th December 2012 Search strategy Embase Methotrexate/ae AND *Leukemia Medline Methotrexate/ae AND *Leukemia Micromedex Past enquiries eBNF PRODIGY guidelines eMC AHFS Martindale MHRA References 1 DRUGDEX®System: Methotrexate Monograph In: Klasco RK (Ed): DRUGDEX® System (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com/(cited: 06/12/2012). 2 Summary of Product Characteristics – Maxtrex (methotrexate). Pharmacia Ltd. Accessed via http://www.medicines.org.uk/EMC/medicine/6003/SPC/Maxtrex+Tablets+2.5+mg/ on 06/12/12 [last updated on the eMC: 21/06/2012]. 3 Methotrexate Drug Analysis Print. Accessed via http://www.mhra.gov.uk/home/groups/public/documents/sentineldocuments/dap_1353930696208.pdf on 06/12/12 4 Al-Anazi K, Eltayeb K, Bakr M et al. Methotrexate-induced Acute Leukaemia: Report of Three Cases and Review of the Literature. Clinical Medicine: Case Reports 2009: 2; 43-49 5 Oleinick A. Leukaemia or Lymphoma Occurring Subsequent to an Autoimmune Disease. Blood 1967 29(1)144-153 From the National Electronic Library for Medicines. www.nelm.nhs.uk 2 Medicines Q&As 6 Cancer Research UK. Acute Myeloid Leuaemia Risks and Causes. Accessed via http://www.cancerresearchuk.org/cancer-help/type/aml/about/acute-myeloid-leukaemia-risks-andcauses on 06/12/12 From the National Electronic Library for Medicines. www.nelm.nhs.uk 3