Abstract
CALGB study 9511 used pegylated asparaginase (PEG-ASP) in lieu of the native enzyme on days 5 and 22 of the 5-drug induction course and days 15 and 43 of the first intensification of the CALGB 8811 regimen (
Blood 1995; 85:2025
). The aim of the study was to explore differences in the overall-survival (OS) and disease-free survival (DFS) profiles of those patients who did versus those who did not achieve asparagine depletion defined as enzyme levels > 0.03 units/ml for 14 consecutive days after at least one of four possible administrations of PEG-ASP (2000 U/m2, subcutaneously, capped at 3750 U). One hundred and four patients were enrolled between 7/95 and 12/97; 43F and 61M. Median age was 40 years (range, 17–71). Performance status (PS) was 0–1 in 81%. Thirty-one patients had an unfavorable [t(9;22), t(4;11), −7, +8] karyotype. Median WBC count was 86.5 x 109/L; 76/104 patients had > 30 x 109/L. PEG-ASP was tolerable (although grade 3 or 4 bilirubin occurred in 54%, hyperglycemia in 40%, and low fibrinogen in 30%). Treatment mortality was 9%. Antibodies to PEG-ASP were detected in 13/85 patients (15%). The complete remission (CR) rate was 76%. Median survival was 22 months [95% CI=13–29]. After a median follow-up of 90 months, 22 patients are alive without disease; three are alive after relapse. Samples were available from 85 eligible patients. Asparagine depletion was not significantly associated with achievement of CR (87.3% vs. 72.7%; P=0.55). Univariate analyses suggest that patients who achieved asparagine depletion (63 patients) had superior OS (two-sided P<0.0016; hazard ratio 2.4 [95%CI=1.4–4.2]) and DFS (P<0.011; hazard ratio 2.3 [95%CI=1.2–4.2]) profiles versus those who did not (22 patients). After adjusting, in the framework of an additive log-linear Cox model, for CR status (OS only), age, gender, PS, unfavorable karyotype, WBC count, detection of antibody to PEG-ASP, and transplantation, the difference between the OS profiles remained statistically significant (P<0.019; hazard ratio 2.1 [95%CI=1.1–3.9]) while the DFS profiles were borderline significant (P<0.052; hazard ratio 2.0 [95%CI=1.0–4.1]). We conclude that effective asparagine depletion with PEG-ASP as part of an intensive multi-agent therapeutic regimen in adult ALL is feasible and associated with improved outcomes.
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