Purine Analogues

Purine analogues are metabolised to nucleotides that inhibit purine synthesis, block ribonucleotide reductase and DNA polymerase, and are incorporated into DNA. They are active in leukaemia, lymphoma and hairy cell leukaemia and are strongly immunosuppressive.

Classification. Thiopurines (mercaptopurine, thioguanine), adenosine analogues (fludarabine, cladribine, pentostatin, clofarabine) and nelarabine (guanine analogue).

Pharmacokinetics. Mercaptopurine is oxidised by xanthine oxidase (inhibited by allopurinol) and methylated by thiopurine methyltransferase and NUDT15. Fludarabine and cladribine are renally cleared.

• Mercaptopurine 50 to 75 mg/m2 orally daily at night, away from milk, for maintenance in acute lymphoblastic leukaemia; reduce to one third to one quarter when allopurinol is given.
• Thioguanine 40 mg/m2 orally daily in leukaemia regimens.
• Fludarabine 25 mg/m2 intravenously daily for 5 days every 28 days; reduce by 20 percent at creatinine clearance 30 to 70 mL/min; avoid under 30 mL/min.
• Cladribine 0.09 mg/kg daily by continuous infusion for 7 days, or 5 mg/m2 daily for 5 days for hairy cell leukaemia.
• Pentostatin 4 mg/m2 every 2 weeks.
• Clofarabine 52 mg/m2 daily for 5 days (paediatric relapsed acute lymphoblastic leukaemia).
• Nelarabine 1,500 mg/m2 on days 1, 3 and 5 (T-cell leukaemia).

Differences. Thiopurines are oral and chiefly marrow toxic; fludarabine and cladribine cause prolonged lymphopenia and neurotoxicity; nelarabine causes dose-limiting neurotoxicity.

• Acute lymphoblastic leukaemia (maintenance): mercaptopurine daily with weekly methotrexate; adjust to keep neutrophils 0.5 to 1.5 x 10^9/L.
• Chronic lymphocytic leukaemia and indolent lymphoma: fludarabine with cyclophosphamide and rituximab.
• Hairy cell leukaemia: cladribine or pentostatin.
• Before starting thiopurines: TPMT and NUDT15 genotype or activity where available; reduce the dose by 50 to 90 percent in heterozygotes and give at one tenth in deficient patients.
• Prophylaxis: co-trimoxazole for *Pneumocystis jirovecii* and antiviral cover for herpes zoster during and for months after purine analogue therapy; irradiated, leucodepleted blood products for life after fludarabine.

Selection. Choose by disease; avoid fludarabine in kidney impairment.

Contraindications. Pregnancy; creatinine clearance under 30 mL/min (fludarabine); autoimmune haemolytic anaemia (fludarabine, caution); live vaccines.

Adverse effects. Myelosuppression, profound lymphopenia, opportunistic infection, autoimmune haemolysis and thrombocytopenia (fludarabine), neurotoxicity (fludarabine, nelarabine, clofarabine), hepatotoxicity and veno-occlusive disease (thioguanine), pancreatitis, rash, secondary malignancy.

Interactions. Allopurinol and febuxostat with mercaptopurine; pentostatin with fludarabine is fatal (lung toxicity); co-trimoxazole raises marrow toxicity with mercaptopurine; warfarin interactions.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: mercaptopurine maintenance doses are titrated by neutrophil and platelet counts.
• Older adults: neurotoxicity is more common; reduce doses.
• Kidney impairment: reduce fludarabine and cladribine; avoid in severe disease.
• Liver impairment: reduce mercaptopurine and monitor.

Monitoring. Full blood count weekly at the start of maintenance then monthly, liver function, creatinine, immunoglobulins, CD4 count after fludarabine, infection surveillance, and haemolysis screening.

Referral and escalation. Neutropenic fever, new neurological signs, jaundice with ascites, severe haemolysis, and opportunistic infection need urgent care.