Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial

B Patel,P Patrick,L Micklewright,A Dey,S Purnell,A K Fielding,T F Menne,D I Marks,A K Mcmillan,P Smith,C J Rowntree,A A Kirkwood

doi:10.1038/leu.2016.219

Abstract

Safety and efficacy data on pegylated asparaginase (PEG-ASP) in adult acute lymphoblastic leukaemia (ALL) induction regimens are limited. The UK National Cancer Research Institute UKALL14 trial NCT01085617 prospectively evaluated the tolerability of 1000 IU/m2 PEG-ASP administered on days 4 and 18 as part of a five-drug induction regimen in adults aged 25–65 years with de novo ALL. Median age was 46.5 years. Sixteen of the 90 patients (median age 56 years) suffered treatment-related mortality during initial induction therapy. Eight of the 16 died of sepsis in combination with hepatotoxicity. Age and Philadelphia (Ph) status were independent variables predicting induction death >40 versus ⩽40 years, odds ratio (OR) 18.5 (2.02–169.0), P=0.01; Ph− versus Ph+ disease, OR 13.60 (3.52–52.36), P<0.001. Of the 74 patients who did not die, 37 (50.0%) experienced at least one grade 3/4 PEG-ASP-related adverse event, most commonly hepatotoxicity (36.5%, n=27). A single dose of PEG-ASP achieved trough therapeutic enzyme levels in 42/49 (86%) of the patients tested. Although PEG-ASP delivered prolonged asparaginase activity in adults, it was difficult to administer safely as part of the UKALL14 intensive multiagent regimen to those aged >40 years. It proved extremely toxic in patients with Ph+ ALL, possibly owing to interaction with imatinib.

Highlights

Depletion of extracellular asparagine by parenteral administration of the enzyme L-asparaginase is a key component of most current therapeutic strategies in acute lymphoblastic leukaemia (ALL)
A major study aim is to evaluate the addition of two doses of 1000 IU/m2 pegylated Escherichia coli-derived L-asparaginase (PEG-ASP) to the standard induction regimen that had been evaluated in our previous study, UKALL12,12 in which non-pegylated E. coli L-asparaginase was given at 10 000 IU daily on days 17–28 of phase 1 induction
One patient died before starting any treatment and has been excluded from all analyses

Summary

INTRODUCTION

Depletion of extracellular asparagine by parenteral administration of the enzyme L-asparaginase is a key component of most current therapeutic strategies in acute lymphoblastic leukaemia (ALL). The only other change to the ‘backbone’ induction regimen between the two consecutive national trials was the addition of a steroid prephase and the substitution of pulsed dexamethasone for prednisolone. The aim of these changes was to make our regimen more compatible with a 'paediatric-inspired' intensive approach. We report on the outcome of PEG-ASP administered during induction in the first consecutive 91 trial subjects At this point, it was judged by the trial management group that a toxicity end point had been reached and a change was made to the PEG-ASP trial therapy

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONFLICT OF INTEREST