Aim A review and summary of the evidence supporting the use of allopurinol as a treatment option to reduce side effects of 6-mercaptoprurine (6MP) during the maintenance phase of chemotherapy for children with acute lymphoblastic leukemia (ALL), and to implement this treatment option.

Method A literature search has been undertaken, and the results collated and reviewed facilitating approval for this treatment strategy through the trust’s Drugs & Therapeutics committee. The literature showed allopurinol may be a safe and effective intervention,¹ especially in 6MP related hypoglycaemia.^{2 3}

ALL patients in the ‘maintenance’ phase of treatment suffering intolerable side effects (including but not limited to abdominal pain and hypoglycaemia) were prescribed allopurinol alongside a 50% reduction in 6MP. This is based on the rationale that allopurinol shifts this metabolism of mercaptopurine in favour of production of 6-thioguanine nucleotide (6-TGN) by blocking xanthine oxidase, reducing production of 6 methyl mercaptopurine (6-MMP). 6-TGN is the active metabolite responsible for the cytotoxic effect of mercaptopurine, whereas 6-MMP is responsible for adverse effects.¹

Patient notes were reviewed to assess impact of allopurinol therapy 6 months after introduction of this treatment option.

Results 4 patients (all with’ Wild Type’ TPMT genotype) commenced allopurinol (weight-based dosing; <30 kg 50 mg once daily, >30 kg 100 mg once daily) after other non-pharmacological methods of reducing side effects failed. Metabolites monitored for patient 1 only.

Patient 1: Allopurinol was prescribed due to hypoglycaemia, stomach pain and decreased appetite. Appetite and vomiting improved, with no symptoms of hypoglycaemia. Abdominal pains initially improved but returned after an episode of illness, although less painful than before allopurinol treatment. 6-MMP levels decreased from >20,000 to 895. 6-TGN increased from 464 to 1015.

Patient 2: Commenced allopurinol due to abdominal pains. Some diarrhoea on commencing allopurinol reported. Patient’s notes state improvement in abdominal pain and generally feeling better on allopurinol.

Patient 3: Patient was suffering early morning hypoglycaemia (2 episodes requiring hospital attendance). No further episodes of hypoglycaemia upon commencement of allopurinol.

Patient 4: Symptomatic hypoglycaemia experienced with 6MP. Currently (2 weeks post commencement of allopurinol) no improvement in hypoglycaemia.

Conclusion Maintenance therapy 6MP is a well-established part of childhood ALL therapy, contributing to a reduced rate of relapse. Therefore, ensuring compliance by improving tolerability is extremely valuable. The lack of randomised controlled trials assessing the safety and efficacy of allopurinol treatment in this context is to be expected in a such a niche area of practice. The data that is available has been deemed sufficient to support the use of allopurinol when other options have been exhausted. This series of patients demonstrates allopurinol can reduce side effects some cases, although some patients may remain symptomatic.

References

1. Conneely SE, Cooper SL, Rau RE. Use of allopurinol to mitigate 6-mercaptopurine associated gastrointestinal toxicity in acute lymphoblastic leukaemia. Frontiers in Oncology 2020;10:1129.

2. Zhang M, Bostrom B. Allopurinol reverses mercaptopurine-induced hypoglycemia in patients with acute lymphoblastic leukemia. F1000Res 2019;8:176.

3. Miller MB, Brackett J, Schafer ES, et al. Prevention of mercaptopurine-induced hypoglycaemia using allopurinol to reduce methylated thiopurine metabolites. Pediatr Blood Cancer 2018;66:e27577.