Publication Date:
2013-11-15
Description:
L- asparaginase treatment improves clinical outcomes in childhood ALL and Pegylated asparaginase (PEG-ASP) ) has become the standard of care for this patient group. By contrast, safety and efficacy data on PEG-ASP in adult ALL is limited. A key question is the impact of asparaginase associated toxicity on the delivery of multiagent chemotherapy in adult treatment regimes. UKALL14 prospectively evaluated the tolerability of PEG-ASP as part of a 5 drug induction regimen in adults with ALL between 25-65 yrs. The primary-end point of the PEG-ASP evaluation was toxicity. Here, we report on the toxicity of PEG-ASP in the first 91 subjects, after which the trial protocol was amended due to safety concerns. UKALL 14 Induction Phase 1 consisted of intravenous PEG-ASP (1000 IU/m2) on days (d) 4 and 18, Daunorubicin 60mg/m2 and Vincristine 1.4mg/m2 (2mg max) on d1,8,15 and 22, Dexamethasone 10mg/m2 d1,-4, 8-11,15-18 and a single intrathecal (IT) Methotrexate 12.5mg on d14. Patients with pre-B lineage ALL were randomized to receive Rituximab or not. Patients with Philadelphia chromosome (Ph) positive disease received continuous Imatinib 400mg escalating to 600mg daily throughout induction. Phase 2 induction comprised of cyclophosphamide 1000mg/m2 d1+ 15, Ara-C 75mg/m2 d2-5, 9-12, 16-19 + 23-26, mercaptopurine 60mg/m2 throughout and IT methotrexate d1,8,15,22. Results The median age was 47 years (25-65yrs). Overall, 80.2% (73/91) patients completed phase 1 induction. Of these 60 achieved CR, 9 did not, and 4 had missing CR data. Thirteen of the 18 patients who did not complete phase 1 induction suffered early death. The overall induction mortality was 19.8% (18/91). Sixteen deaths occurred pre phase 2 induction and 2 deaths post phase 2. The most common cause of induction death was sepsis in combination with hepatotoxicity (55.6%,10/18) followed by sepsis alone (16.7%, n= 3). Additional causes of death were bowel ischaemia in combination with hepatotoxicity (n=2), acute coronary syndrome (n=1), haemorrhage (n=1) and pancreatitis + bowel perforation (n=1). Ten of the 12 hepatotoxicity associated induction deaths had NCI Grades 3-4 hyperbilirubinaemia. The median time from last dose of PEG-ASP to induction death was 14.5 days (6-71). Taking into account the multiple risk factors contributing to hepatoxicity associated morbidity (concomitant administration of hepatotoxic drugs and sepsis itself), a PEG-ASP related cause of death was “definitely or probably” implicated in 11/18 induction deaths. Logistic regression showed that age and Ph status were independent variables predicting induction death
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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