Lymphoma - nelarabine
Although they are fairly rare, lymphoid malignancies that involve T-cells are usually aggressive, and the prognosis is poor in patients who do not respond to standard treatment or who have relapsed.
Although they are fairly rare, lymphoid malignancies that involve T-cells are usually aggressive, and the prognosis is poor in patients who do not respond to standard treatment or who have relapsed.
Purine nucleoside phosphorylase deficiency is associated with T-cell lymphopoenia, and as a result a number of nucleoside analogues were developed to treat such malignancies.
The deoxyguanosine analogue 9-ß-D-arabinofuranosylguanine was found to accumulate in the T-cells, inhibiting DNA synthesis, but its water solubility was too low to be of clinical use. Now, GlaxoSmithKline has developed a prodrug version, nelarabine, whose water solubility is ten times greater and which is converted to the active form in vivo.1,2
Many trials have been carried out. These include a study in 53 heavily pretreated adult patients with relapsed T-cell acute lymphoblastic leukaemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL).3 They were given 1.5g/m2 of the drug on days 1, 3 and 5. Twenty-five of the subjects achieved a complete response, and a further seven experienced partial responses. The probability of survival was 27% in those who achieved a complete response, and 16% overall.
It was also given, in a similar dosing regime, to a further 15 heavily pretreated adult patients, plus one adolescent at a lower dose.4 More than half the patients achieved a complete response, eight of which then received allogeneic stem cell transplants.
A longer term trial was carried out in 23 adults with relapsed or refractory peripheral T-cell lymphoma or indolent B-cell non-Hodgkin's lymphoma.5 Doses were similar to the previous two studies, but the regimen was repeated every 28 days for a maximum of six cycles. Nineteen patients were evaluable, overall response rates were 44% for the T-cell disease and 33% for the B-cell form, and median time to progression in those who responded was eight months.
The drug has recently been licensed by the US FDA, where it had been granted orphan drug status, under the trade name Arranon to treat unresponsive or relapsing T-ALL or T-LBL which has failed with at least two other regimens.