Nelarabine for T-cell acute lymphoblastic leukaemia and T-cell lymphoblastic lymphoma

Background:
Acute lymphoblastic leukaemia may involve B cells or T cells. Cancers involving the T cells are relatively rare and mainly affect children. The cancer can be considered to be a leukaemia or a lymphoma, according to the proportion of lymphoblasts found in bone marrow. Acute T-cell lymphoblastic leukaemia and lymphoma can be cured by chemotherapy, with children usually having better outcomes than adults. However, if the disease relapses it is difficult to treat and has a poor prognosis. To find better treatments for relapsed disease, there has been research into drugs targeted at T cells.

Mechanism of action:
High concentrations of deoxyguanosine triphosphate are known to be toxic to T cells. An analogue of deoxyguanosine, arabinofuranosylguanine (ara-G), is also toxic to T cells but has low water solubility. This led to the development of nelarabine which is a soluble prodrug of ara-G. After intravenous infusion, the steps in the metabolism of nelarabine lead to the intracellular production of the triphosphate form of ara-G. This accumulates in T cells, inhibiting DNA synthesis and leading to cell death.

Clinical trials:
Nelarabine was first approved in the USA in 2005; the evidence for its efficacy appears to still be based mainly on the uncontrolled phase 2 trials done around that time.^1,2 These open-label trials enrolled patients with relapsed or refractory acute T-cell lymphoblastic leukaemia or lymphoma. The response to treatment was assessed by methods such as blood counts and bone marrow biopsy.

The adult trial involved 39 patients, with a median age of 34 years (range 16 to 66 years), who had been previously treated with a median of 2 regimens. They were given an infusion of nelarabine on days 1, 3 and 5 with the response being assessed on day 22. Treatment could be repeated according to the response. Most patients received one or two courses, with the average time on treatment being 68 days. There was a complete response in 12 patients and a partial response in 4. The median overall survival was 20 weeks, and 7 patients survived for 12 months.¹

There were 153 patients enrolled in the paediatric trial of nelarabine, including 84 who were treated at the dose approved for use in Australia. The median age of the patients was 11.5 years (range 0.6 to 21 years). They were given an infusion on 5 consecutive days, repeated every 3 weeks. In the 33 assessable patients in their first relapse of lymphoblastic leukaemia there was a complete response in 16 and a partial response in 2. Among the 30 assessable patients who were in their second or subsequent relapse, there was a complete response in 7 and a partial response in one.²

Since the phase 2 trials, there have been further studies of nelarabine for the treatment of relapsed, refractory T-cell acute lymphoblastic leukaemia. A systematic review of studies up to January 2022 included 13 trials, involving 2508 adults and children. Overall, there was a complete response rate of 37% and a partial response rate of 10.2% to monotherapy.³

Adverse effects:
The doses of nelarabine used in the phase 2 trials were reduced because of emerging concerns about neurotoxicity. This has several presentations including confusion, convulsions, coma, ataxia, dizziness and peripheral neuropathy. Depending on its severity, neurotoxicity requires treatment to be stopped.

Haematological adverse effects are frequent with most patients developing anaemia, neutropenia and thrombocytopenia. Febrile neutropenia occurred in 12% of adult patients.

All patients are at risk of infection including opportunistic infections. There has been a confirmed case of progressive multifocal leukoencephalopathy.

Many other adverse events occurred during the trials, particularly in adults. Very common problems in adults included fatigue, gastrointestinal effects (e.g. nausea, vomiting, diarrhoea, constipation), headache, dyspnoea and oedema.

Use in pregnancy:
As nelarabine leads to cytotoxic effects it may impair fertility. Pregnancy should be avoided, including in women who are the partners of men undergoing treatment.

Place in therapy:
In practice, nelarabine will just be one part of the management of relapsed, refractory disease. It could be used with other chemotherapy drugs, and considered as a bridge to stem-cell transplantation.

This new drug comment was finalised on 11 February 2025.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor provided a copy of the Clinical Evaluation Report.

 

References

1. DeAngelo DJ, Yu D, Johnson JL, Coutre SE, Stone RM, Stopeck AT, et al. Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood 2007;109:5136-42.
2. Berg SL, Blaney SM, Devidas M, Lampkin TA, Murgo A, Bernstein M, et al. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol 2005;23:3376-82.
3. Kathpalia M, Mishra P, Bajpai R, Bhurani D, Agarwal N. Efficacy and safety of nelarabine in patients with relapsed or refractory T-cell acute lymphoblastic leukemia: a systematic review and meta-analysis. Ann Hematol 2022;101:1655-66.

 

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