Benzene-Induced Aplastic Anaemia

Benzene induced aplastic anaemia is bone marrow failure with pancytopenia and a hypocellular marrow, caused by benzene exposure. It can occur months to years after exposure and may progress to myelodysplastic syndrome or leukaemia.

Definition. Severe disease: marrow cellularity under 25% (or 25 to 50% with under 30% residual haematopoietic cells) with at least 2 of: neutrophils under 0.5 x 10^9/L, platelets under 20 x 10^9/L, reticulocytes under 20 x 10^9/L. Very severe: neutrophils under 0.2 x 10^9/L.

Epidemiology. Benzene is a recognised cause among workers with heavy or prolonged exposure. Risk rises with dose, but susceptibility varies.

Prognosis. Untreated severe disease has high early mortality. Immunosuppression or transplantation gives long term survival in most patients.

Clonal evolution. Myelodysplasia and leukaemia occur in a proportion, and marrow cytogenetics should be checked.

Pathophysiology.

Reactive benzene metabolites injure haematopoietic stem cells and the marrow microenvironment. This causes direct stem cell depletion and, in many patients, immune mediated destruction by activated T cells.

Reduced marrow reserve leads to pancytopenia, with fat replacement of marrow.

• Fatigue, pallor, exertional dyspnoea from anaemia.
• Bruising, petechiae, gum and nose bleeding, and menorrhagia from thrombocytopenia.
• Fever and recurrent infection from neutropenia.
• No lymphadenopathy or splenomegaly.

Red flags.

• Fever with neutropenia.
• Severe bleeding or intracranial symptoms.
• Haemoglobin under 70 g/L with heart failure features.

• Exposure history and drug and viral history.
• Full blood count with film, reticulocytes, and absence of blast cells.
• Marrow aspirate and trephine with cytogenetics: hypocellular marrow, no fibrosis, no dysplasia or blasts; flow cytometry for paroxysmal nocturnal haemoglobinuria clones.
• Exclude other causes: vitamin B12, folate, liver function, viral serology (hepatitis, HIV, parvovirus, EBV), autoimmune screen, Fanconi anaemia and telomere disorder screening in young patients.
• HLA typing of patient and siblings for transplant planning.
• Urinary benzene metabolites if exposure is recent.

Differential diagnosis. Hypoplastic myelodysplastic syndrome, paroxysmal nocturnal haemoglobinuria, inherited marrow failure syndromes, acute leukaemia, hypocellular marrow from drugs or viruses, hairy cell leukaemia, megaloblastic anaemia.

• Stop benzene exposure permanently; avoid other marrow toxic drugs; urgent haematology referral.
• Supportive care: transfuse red cells when haemoglobin is under 70 g/L (under 80 g/L with cardiovascular disease) and platelets for a count under 10 x 10^9/L, or under 20 x 10^9/L with fever or bleeding. Use leucodepleted, irradiated products; avoid family donors if transplant is planned.
• Febrile neutropenia: piperacillin with tazobactam 4.5 g intravenously every 6 hours, started within 1 hour. Maximum 18 g daily of the combined dose. Monitor creatinine, liver function and cultures. If creatinine clearance is 20 to 40 mL/min, give 2.25 g every 6 hours; under 20 mL/min, 2.25 g every 8 hours. Avoid in penicillin allergy and use an alternative by specialist advice.
• Matched sibling donor haematopoietic stem cell transplantation for severe disease in younger patients (under about 40 years) is preferred first line.
• Immunosuppressive therapy for patients without a suitable donor or older patients: horse antithymocyte globulin 40 mg/kg intravenously once daily for 4 days, with a corticosteroid course (for example methylprednisolone 1 mg/kg daily for the first 5 days, tapered over 2 weeks). Test for hypersensitivity before the first dose. Monitor serum sickness at days 7 to 14, platelets, infection and anaphylaxis. Avoid with active infection or prior equine protein reaction.
• Ciclosporin from day 1: 5 mg/kg daily orally in 2 divided doses, adjusted to a trough level of 150 to 250 micrograms/L rather than a fixed maximum, for at least 6 months then tapered slowly. Monitor creatinine, blood pressure, potassium and magnesium; reduce dose by 25 to 50% if creatinine rises by more than 30% from baseline. Check interactions (macrolides, azoles, statins).
• Eltrombopag 150 mg orally once daily on an empty stomach, 2 hours before or 4 hours after calcium, iron, antacids or dairy, for 3 to 6 months with immunosuppression. Maximum 150 mg daily. Use 75 mg daily in East Asian ancestry and in hepatic impairment. Monitor liver enzymes every 2 weeks at first, then monthly, and the full blood count. Evidence in benzene induced disease derives from idiopathic aplastic anaemia.

Monitoring. Full blood count twice weekly during induction, then monthly; marrow and cytogenetic review at 3 to 6 months and when clonal change is suspected; yearly review for late clonal disease.

Referral and escalation. Haematology and transplant centre at diagnosis; infection specialist for neutropenic sepsis; occupational physician for exposure investigation; notification and compensation where required.

Special groups. Pregnancy: immunosuppression and transplantation need specialist obstetric and haematology planning. Older adults: weigh transplant toxicity against immunosuppressive therapy.