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Clinical Trial
. 2017 Jan;31(1):58-64.
doi: 10.1038/leu.2016.219. Epub 2016 Aug 2.

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

B Patel  1 , A A Kirkwood  2 , A Dey  3 , D I Marks  4 , A K McMillan  5 , T F Menne  6 , L Micklewright  2 , P Patrick  2 , S Purnell  2 , C J Rowntree  7 , P Smith  2 , A K Fielding  3
Affiliations
Clinical Trial

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

B Patel et al. Leukemia. 2017 Jan.

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.

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Conflict of interest statement

Fielding received lab funding from Medac GmBH to carry out part of this work and that company were the supplier of PEG-ASP at the time of this work. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic of UKALL14 treatment protocol. High risk features: karyotypes: t(9;22) t(4;11), low hypodiploidy near triploidy or complex, age >40 years, WBC ⩾30 × 109/l (precursor B lineage ALL), ⩾100 × 109/l (T-cell-ALL), molecular minimal residual disease positivity (>1 × 10−4) after induction phase 2.
Figure 2
Figure 2
Flow chart of progress of the 91 patients enrolled. Grade 4 sepsis n=4, grade IV organ toxicity n=4 (hepatotoxicity n=1, pancreatitis n=1, hepatotoxicity plus neurological event n=1, hepatotoxicity plus thromboembolism together with sepsis n=1 and wrong diagnosis n=1, withdrawal of consent, n=1.
See this image and copyright information in PMC

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