UKMI Q&A: Is methotrexate therapy associated with an increased

Medicines Q&As
Q&A 356.1
Is methotrexate therapy associated with an increased risk of
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Date prepared: 03/12/2012
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.
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 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.
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.
There are no controlled studies exploring this question.
From the National Electronic Library for Medicines.
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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
Past enquiries
PRODIGY guidelines
DRUGDEX®System: Methotrexate Monograph In: Klasco RK (Ed): DRUGDEX® System (electronic
version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: 06/12/2012).
2 Summary of Product Characteristics – Maxtrex (methotrexate). Pharmacia Ltd. Accessed via on 06/12/12 [last
updated on the eMC: 21/06/2012].
3 Methotrexate Drug Analysis Print. Accessed via
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
From the National Electronic Library for Medicines.
Medicines Q&As
Cancer Research UK. Acute Myeloid Leuaemia Risks and Causes. Accessed via on 06/12/12
From the National Electronic Library for Medicines.