Acute myelogenous leukaemia following etanercept therapy

G. Bakland1 and H. Nossent1,2,

1 Department of Rheumatology, University Hospital Tromsø and
2 Institute for Clinical Medicine, University of Tromsø, Norway

SIR, Tumour necrosis factor-{alpha} (TNF-{alpha}) blocking agents have become increasingly popular in the treatment of chronic polyarthritis. While approved for patients with severe (juvenile) rheumatoid arthritis (RA) that is resistant to disease-modifying anti-rheumatic drugs (DMARDs), they are under investigation in seronegative spondylarthritis and vasculitis [14]. They increase infectious complications, especially extrapulmonary tuberculosis, but no increases in the occurrence of malignancies have been described so far [58]. We report the development of acute myelogenous leukaemia 4 months after the initiation of etanercept therapy for complicated ankylosing spondylitis (AS). A now 31-yr-old female, diagnosed with AS in 1988 (inflammatory back pain and grade II radiological bilateral sacroileitis) subsequently developed progressive spine involvement and uveitis despite various non-steroidal anti-inflammatory drug (NSAID) regimens, exercise programmes and 18 months treatment with Salazopyrin at 2 g/day. Endometriosis was diagnosed in 1998 during an infertility work-up and treated with gonadotrophin-releasing hormone (GnRH) analogue. In 1999, incapacitating arthritis of the shoulders and ankles appeared and was unresponsive to intra-articular steroids and reintroduction of salazopyrin. Expansion of the arthritis to wrists and left elbow as well as several episodes of uveitis followed. Laboratory findings are shown in Table 1Go. Despite her poor condition, she declined cytotoxic therapy as deleterious to her fertility and was administered three doses of 1000 mg of i.v. methylprednisolone, followed by a tapering dose of oral corticosteroids, azathioprine at 100 mg daily and NSAID use.


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TABLE 1. Course of laboratory variables in a patient prior to and after initating Etanercept therapy in October 2000, diagnosed with acute myeloid leukaemia in March 2001

 
After a short-lived improvement, polyarthritis returned and based on preliminary data in the literature, anti-TNF-{alpha} therapy was initiated in September 2000. Owing to the distance from her house to the hospital, she preferred the self-administration of 25 mg of etanercept twice weekly to the infusions of infliximab. Soon a rapid and dramatic improvement in her general clinical condition occurred with disappearance of morning stiffness, malaise and clearing of the peripheral arthritis; laboratory tests paralleled this improvement (Table 1Go). After 4 months in remission, she began to report reduced well-being, increased tiredness, upper respiratory symptoms and increasing joint pain while acute-phase reactants increased again (Table 1Go). Chest radiography was normal and treatment with antibiotics for a presumed airway infection did not lead to improvement. She was advised to stop the Etanercept injections, but soon after she developed erythema nodosum-like lesions and was admitted for a diagnostic work-up. Aside from the skin lesions, no other abnormalities were found upon physical examination. Laboratory findings showed a severe leucopenia, where bone marrow investigations showed acute myelogenous leukaemia (AML; M2), confirmed by cytogenetic analysis. She received induction chemotherapy with Cytosar and Cerubidin and despite transfusion dependency and severe bone and joint pains, she attained remission after the second course and completed a full course of consolidation therapy. As of writing, 1 yr after AML diagnosis, she remains in remission of her AML, has few joint symptoms, takes no prescription drugs and finally become pregnant and gave birth to a healthy baby girl in January 2003.

This case history is the first description of the development of AML after initiating successful etanercept therapy in a patient with complicated spondylarthritis. While a cause and effect relationship between the AML and etanercept cannot be proven, we were unable to find any other explanation for this patient's disease course. No references in the literature indicate an AML predilection connected to salazopyrin or GnRH analogue therapy, which is even used in gonadal protection during chemotherapy. While earlier radiotherapy is a known risk factor for leukaemia development in AS patients [9], there is no evidence of increased leukaemia risk with AS itself. A recent report suggests that HLA-B27 carriers may be at increased risk for acute leukaemia, but the four AS patients described there developed lymphocytic leukaemia [10]. In addition, at the time AML manifested itself, there was virtually no sign of activity in the underlying AS.

On the other hand, various haematological side-effects after Etanercept therapy have been reported to the US Food and Drug Administration including pancytopenia and aplastic anaemia (http://www.fda.gov/medwatch/safety/2000/enbrel2.htm), and the chronology points to an etanercept-mediated effect in this patient; it has therefore been reported to health authorities as a possible side-effect of etanercept therapy. In retrospect, earlier action should have been undertaken for the slight, but persistent, leucopenia before instituting etanercept therapy. At the time it was attributed to either a protracted salazopyrin or azathioprine effect or to the developmental stage of a connective tissue disease (with ANA and anti-dsDNA antibody positivity). A protracted course of AML-M2 over 1 yr seems an unlikely explanation for this early leucopenia, but existence of a pre-leukaemic situation cannot be excluded and its earlier detection would have prohibited the administration of an anti-TNF agent. This case history thus indicates the importance of addressing an even slight leucopenia before the initiation of TNF blocking therapy.

Notes

Correspondence to: H. Nossent, Department of Rheumatology, University Hospital Tromsø, N-9038 Tromsø, Norway. E-mail: hans.nossent{at}unn.no Back

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Accepted 19 September 2002