Radiation-Induced Leukaemia

Radiation induced leukaemia is leukaemia or myelodysplastic syndrome attributable to ionising radiation from medical, occupational, accidental or environmental sources. Acute myeloid leukaemia, acute lymphoblastic leukaemia and chronic myeloid leukaemia are linked to radiation. Chronic lymphocytic leukaemia is not.

Epidemiology. Evidence comes from atomic bomb survivors, radiotherapy cohorts, early radiologists and nuclear workers. Excess risk is detectable from about 0.1 to 0.2 Gy and rises with dose. The relative effect is larger after childhood exposure.

Latency. The earliest cases appear about 2 years after exposure and the peak is at 5 to 10 years. Excess risk wanes over decades. Myelodysplasia may precede acute leukaemia.

Attribution. A single case cannot be proven to be radiation caused. Causation is judged by dose, latency and exclusion of other causes, and compensation schemes use probability-of-causation estimates.

Genetic features. Loss of chromosomes 5 and 7, complex karyotypes and TP53 mutation resemble therapy related disease. BCR::ABL1 is present in chronic myeloid leukaemia.

Pathophysiology.

Radiation causes double strand DNA breaks in haematopoietic stem and progenitor cells. Misrepair produces deletions and translocations.

Genomic instability and clonal selection lead to myelodysplasia or leukaemia.

• Fatigue, pallor, bruising, bleeding, fever and recurrent infection.
• Chronic myeloid leukaemia: often found on a blood count, with splenomegaly, sweats and weight loss.
• Bone pain, gum hypertrophy and skin infiltration in some acute cases.

Red flags.

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

• Exposure history with dose records, dosimeter data and radiotherapy fields; dose reconstruction by the occupational physician.
• 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; BCR::ABL1 PCR when chronic myeloid leukaemia is suspected.
• HLA typing and fitness assessment including echocardiography.
• The dicentric chromosome assay reflects recent exposure only and is not useful years later.

Differential diagnosis. Therapy related myeloid neoplasm after chemotherapy, de novo acute myeloid leukaemia, myelodysplastic syndrome, aplastic anaemia, leukaemoid reaction, viral cytopenia.

• Stop further exposure and refer urgently to haematology.
• Acute myeloid leukaemia, 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. 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.
• 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. 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.
• Chronic myeloid leukaemia, chronic phase: imatinib 400 mg orally once daily with food and a large glass of water, long term. Maximum 400 mg daily in chronic phase (600 mg in accelerated phase and 800 mg in divided doses in blast crisis). Monitor full blood count weekly for the first month, then BCR::ABL1 PCR every 3 months, plus liver enzymes, fluid retention and weight. Reduce to 300 mg daily in severe hepatic impairment and monitor closely when eGFR is under 60. Avoid in pregnancy. Check interactions with CYP3A4 inducers and inhibitors, and avoid warfarin.
• 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.
• 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.
• Allogeneic stem cell transplantation for intermediate and adverse risk disease in fit patients.

Monitoring. Daily blood counts and biochemistry during induction; measurable residual disease testing after remission; lifelong haematology follow up.

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