Benzene-Associated Leukaemia

Benzene associated leukaemia is acute myeloid leukaemia or myelodysplastic syndrome occurring after benzene exposure. Chromosomal profile and clinical course resemble therapy related disease.

Exposure. Petrochemical, refinery and chemical workers, rubber and adhesive workers, petrol handlers and others with cumulative heavy exposure.

Epidemiology. Risk of acute myeloid leukaemia rises with cumulative dose. Other leukaemias and lymphomas are less consistently linked.

Latency. Usually 5 to 20 years or more after first exposure, and shorter after very high exposure. A prior aplastic or myelodysplastic phase may occur.

Genetic features. Loss of chromosomes 5 and 7 (including del(5q) and monosomy 7), complex karyotypes and TP53 mutation are frequent, and prognosis is often poor.

Pathophysiology.

Benzene metabolites such as hydroquinone and benzoquinone cause DNA adducts, double strand breaks, aneuploidy and epigenetic change in haematopoietic stem cells.

Clonal selection leads to myelodysplasia and transformation to acute leukaemia. Inherited variation in metabolic enzymes alters susceptibility.

• Fatigue, pallor, dyspnoea, bruising, bleeding and fever or infection.
• Bone pain, gum hypertrophy, skin infiltration and hepatosplenomegaly in some.
• Disseminated intravascular coagulation, especially in acute promyelocytic leukaemia.

Red flags.

• Bleeding with prolonged clotting times (promyelocytic leukaemia; start treatment urgently on suspicion).
• Leucostasis: dyspnoea, confusion or visual change with a very high white cell count.
• Fever with neutropenia.

• Exposure history with cumulative dose estimate, and prior chemotherapy or radiotherapy history.
• Full blood count with film, coagulation screen with fibrinogen, LDH, uric acid, urea, creatinine, electrolytes, calcium, phosphate and liver tests.
• Marrow aspirate and trephine with morphology, flow cytometry, cytogenetics and molecular testing (for example NPM1, FLT3, TP53 and related mutations).
• Lumbar puncture when neurological features or high risk features occur.
• HLA typing and assessment of fitness for intensive therapy, including echocardiography.

Differential diagnosis. Therapy related leukaemia, myelodysplastic syndrome, aplastic anaemia, acute lymphoblastic leukaemia, chronic myeloid leukaemia in blast crisis, leukaemoid reaction, viral cytopenia.

• Remove from further exposure; urgent haematology referral.
• Fit for intensive therapy: cytarabine 100 to 200 mg/m2 daily by continuous intravenous infusion for 7 days with daunorubicin 60 mg/m2 intravenously daily on days 1 to 3 (higher doses are used in some regimens). Maximum lifetime daunorubicin dose 550 mg/m2. Monitor echocardiography, blood counts, liver and renal function. Reduce daunorubicin when bilirubin is 20 to 50 micromol/L (to 75%) or over 50 micromol/L (to 50%). Reduce cytarabine when creatinine clearance is under 60 mL/min because of neurotoxicity.
• Acute myeloid leukaemia with a therapy related profile: liposomal daunorubicin with cytarabine is an alternative on specialist advice.
• Unfit for intensive therapy: azacitidine 75 mg/m2 subcutaneously or intravenously on days 1 to 7 of each 28-day cycle, with venetoclax orally with food once daily, 100 mg on day 1, 200 mg on day 2, then 400 mg daily, continuous. Maximum venetoclax 400 mg daily; reduce by at least 75% with strong CYP3A inhibitors. Monitor blood counts, tumour lysis, creatinine and bicarbonate. Specialist use only.
• Suspected acute promyelocytic leukaemia: tretinoin 45 mg/m2 orally daily in 2 divided doses started on suspicion pending confirmation, with arsenic trioxide as directed by haematology. Maximum duration until remission by specialist. Monitor coagulation, fibrinogen, and differentiation syndrome. Stop if the diagnosis is not confirmed. Avoid in pregnancy. For differentiation syndrome: dexamethasone 10 mg intravenously every 12 hours for at least 3 days and until symptoms resolve. Maximum 20 mg daily. Monitor glucose, blood pressure and infection.
• Tumour lysis prophylaxis: allopurinol 300 mg orally once daily starting 1 to 2 days before therapy. Maximum 900 mg daily. Monitor uric acid, renal function, rash and liver enzymes. If eGFR is under 20 mL/min start at 100 mg daily. Screen for HLA-B*58:01 where relevant. Rasburicase 0.2 mg/kg intravenously once daily for up to 5 days for high risk disease. Maximum 7 days. Monitor uric acid and haemolysis; contraindicated in G6PD deficiency.
• Consolidation with allogeneic stem cell transplantation for intermediate and adverse risk disease in fit patients. Supportive care: transfusion, antimicrobial prophylaxis and fertility discussion.

Monitoring. Daily blood counts and biochemistry during induction; measurable residual disease testing after remission; surveillance by haematology.

Referral and escalation. Haematology and transplant centre; intensive care for leucostasis, sepsis or coagulopathy; occupational physician for exposure and compensation assessment; notification where required.

Special groups. Pregnancy: needs specialist obstetric and haematology planning. Older adults and those with cardiac disease: adjust or avoid anthracycline dosing and consider lower intensity therapy.