Abstract
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.
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<40yrs vs ≥40yrs, odds ratio (OR) 5.27 (95% CI 1.13-24.7), p =0.035; age <55yrs vs ≥55yrs OR 4.47 (1.51-13.18), p =0.007 and Ph pos vs Ph neg disease, OR 6.08 (2.01 – 18.34), p =0.001. The trial steering committee confirmed that there was no relationship to Rituximab randomization.
The incidence of non-fatal PEG-ASP toxicity during induction was 36.7% (n=33).The most common toxicity was abnormal liver function test (24.5%,n=22) followed by coagulopathy (7.7%,n=7) and thrombosis (5.6%,n=5). Grade 3-4 PEG-ASP related liver dysfunction was significantly associated with older age (<40 vs >40, p= 0.031).
Enzyme activity, assessed by MAAT, after the first PEG-ASP dose in phase 1 induction was available for a subset of patients (n=27). Nearly all patients (88.9%) achieved a therapeutic level of enzyme activity of >100IU/ml 14 days after the first PEG-ASP.
Significant levels of treatment associated mortality occurred in adults treated with a PEG-ASP containing induction regimen on UKALL 14 which was strongly associated with older age and Ph pos disease. As a consequence of the toxicity the protocol was amended to omit d4 PEG-ASP for those over 40yrs. PEG-ASP was completely removed from induction treatment for Ph positive patients. Furthermore, due to the high level of sepsis related to profound myelosuppression, the daunorubicin dose was halved to 30mg /m2 on d1,8,15 and 22. One year following the amendment 123 further patients have been recruited and 8 (6.5%) induction deaths recorded. Our data indicate that whilst PEG-ASP achieves effective asparagine depletion in adult patients it is difficult to deliver safely to those over the age of 40yrs with particularly pronounced toxicity in the over 55s, and should not be started early during induction. Caution should be exercised in co-administration with Imatinib.
Fielding:Medac: Research Funding.
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