How to manage azathioprine-induced mild leucopenia (low white blood cell count)?

From the Guidelines

Azathioprine-induced mild leucopenia should be managed by reducing the azathioprine dose by 25-50% and continuing to monitor blood counts weekly until stabilization occurs, as recommended by the most recent guidelines 1.

Management Strategies

• Reduce azathioprine dose by 25-50% for mild leucopenia (white blood cell count between 3,000-4,000/mm³) and monitor blood counts weekly until stabilization occurs
• Temporarily discontinue azathioprine if leucopenia is more significant or worsening, and reintroduce at a lower dose once counts recover
• Consider adding allopurinol (100mg daily) to a reduced azathioprine dose (25-50% of original) in some cases, as it inhibits xanthine oxidase and increases azathioprine's active metabolites while reducing toxic metabolites
• Monitor patients for signs of infection, such as fever, sore throat, or unusual fatigue, during this period
• Ensure adequate hydration and avoid other myelosuppressive medications to minimize bone marrow suppression

Rationale

• Leucopenia occurs because azathioprine's metabolites interfere with DNA synthesis and cell proliferation, particularly affecting rapidly dividing cells like white blood cells
• Genetic variations in thiopurine methyltransferase (TPMT) enzyme activity can increase susceptibility to myelosuppression, so TPMT testing before initiating therapy may help identify patients at higher risk
• Regular monitoring of blood counts is essential to detect early changes in hematologic parameters and adjust treatment accordingly, as recommended by guidelines 1 and supported by earlier studies 1

From the FDA Drug Label

The incidence of hematologic toxicities and neoplasia encountered in groups of renal homograft recipients is significantly higher than that in studies employing AZASAN for rheumatoid arthritis. Leukopenia and/or thrombocytopenia are dose-dependent and may occur late in the course of therapy with AZASAN. Dose reduction or temporary withdrawal may result in reversal of these toxicities Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in or persistently low leukocyte count, or other evidence of bone marrow depression.

Management of Azathioprine-Induced Mild Leucopenia:

• Dose Reduction: Reduce the dose of azathioprine to minimize the risk of further leukopenia.
• Temporary Withdrawal: Temporarily withdraw azathioprine if the leukopenia is severe or persistent.
• Monitoring: Closely monitor the patient's complete blood count (CBC) to assess the severity of leukopenia and adjust the treatment plan accordingly.
• Alternative Therapies: Consider alternative therapies if the patient has a history of severe myelosuppression or if the leukopenia is recurrent. 2

From the Research

Management of Azathioprine-Induced Mild Leucopenia

• Azathioprine-induced leucopenia is a potentially severe complication of treatment, with leucopenia being the most common and important haematological complication 3.
• Regular monitoring of the full blood count is recommended during treatment to detect leucopenia early 3.
• In cases of mild leucopenia, the dose of azathioprine may be reduced or the drug withdrawn 3.
• NUDT15 genotyping may be useful in predicting the risk of azathioprine-induced leucopenia, particularly in patients of Asian descent 4.
• Treatment of azathioprine-induced leucopenia may involve discontinuation of the drug and initiation of granulocyte-colony stimulating factor administration 4.

Assessment and Treatment of Leucopenia

• Leucopenia is typically characterized by a significant reduction in neutrophils, and neutropenia is defined as an absolute neutrophil count (ANC) of less than 1,500/mcL 5.
• Assessment of patients with neutropenia should be guided by the severity of presentation, duration of leucopenia, and clinical status of the patient 5.
• Patients with neutropenia are at risk of developing life-threatening bacterial infections, and treatment with antibiotics may be necessary in cases of febrile neutropenia 5.
• Other treatments for neutropenia are aimed at managing the underlying cause of the condition 5.

Azathioprine Dosage and Monitoring

• Azathioprine is typically administered at a dose of 1-2 mg/kg/day, and the dose may be adjusted based on response and adverse effects 6, 7.
• Regular monitoring of the full blood count is essential to detect leucopenia and other haematological complications early 3, 6, 7.
• Patients with a history of leucopenia or other haematological complications may require more frequent monitoring and dose adjustments 6, 7.