Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Evoltra (Hospira)
vials containing 20 mg/20 mL
Approved indication: paediatric acute lymphocytic leukaemia
Australian Medicines Handbook section 14.1.3

Acute lymphocytic leukaemia is the most common childhood malignancy. Although chemotherapy has improved survival, many children have a high risk of relapse. As chemotherapy can be ineffective in relapsed disease there is a need for new therapies.

Clofarabine is a purine nucleoside analogue. It has structural similarities to the purine antagonists cladribine and fludarabine.

After dilution and slow intravenous infusion, clofarabine is converted intracellularly to a metabolite which inhibits DNA synthesis and induces apoptosis. There is little hepatic metabolism with 50-60% of the dose being excreted unchanged in the urine. The terminal half-life is approximately five hours.

The approval of clofarabine is based on a phase II study of 61 people whose acute lymphocytic leukaemia was refractory or had relapsed at least twice. Their ages ranged from 1 to 20 years with a median of 12 years. Clofarabine was infused for five consecutive days every 2-6 weeks for up to 12 cycles depending on the toxicity of the treatment. As judged by blood counts and bone marrow aspirates, 20% of patients had a complete remission and 10% had a partial remission. Some of these remissions were in patients whose leukaemia had been refractory to previous treatment.1

Clofarabine is an antimetabolite so it frequently causes serious adverse effects. In the first two treatment cycles 72% of the patients had severe febrile neutropenia.1Multi-organ failure, haematemesis, hypotension, jaundice and septic shock occur commonly. A rapid reduction in leukaemia cells can cause cytokine release and tumour lysis syndrome, so intravenous fluids are recommended for the five days of each treatment cycle. Most patients experience nausea, vomiting and diarrhoea so antiemetic drugs should be considered. Skin reactions, such as palmar-plantar erythrodysaesthesia syndrome, are very common. During the phase II trial, 25% of the patients died within 30 days of treatment or as a result of a drug-related adverse effect.1

The median survival time for the patients in the trial was 13 weeks.1Survival improves in patients who respond, but this outcome may be confounded because these patients may subsequently have bone marrow transplantation. Median overall survival is 63 weeks in patients who respond and may be longer in those who have a transplant. Most of the responses to clofarabine occur in the first two treatment cycles. Patients were only able to complete a median of two cycles in the trial, so it may not be worthwhile persisting with treatment in those who do not respond by then. In view of the limited information about clofarabine, its use has been restricted to children with relapsed or refractory disease who have already received two previous treatment regimens.

manufacturer provided the product information

The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Notes on references

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).

At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).

References

  1. Jeha S, Gaynon PS, Razzouk BI, Franklin J, Kadota R, Shen V, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol 2006;24:1917-23.