Abstract
Background
Asparaginase is an important component of induction and consolidation chemotherapy for acute lymphoblastic leukemia (ALL). Effective asparagine depletion in adult patients with ALL results in a longer duration of overall survival and disease free survival. Variation in asparaginase activity is in part due to the formation of anti-asparaginase antibodies that inactivate asparaginase and result in inadequate asparagine depletion. In addition, the presence of anti-asparaginase antibodies influences dexamethasone pharmacokinetics by increasing dexamethasone clearance, which has been shown to correlate with a higher risk of relapse. Hypoalbuminemia is a recognized side effect of asparaginase, and has been studied as a measure of asparaginase inhibition of liver protein synthesis. The purpose of this retrospective study was to evaluate the effect of asparaginase activity during induction, using serum albumin as a surrogate marker, on overall outcomes. We hypothesized that patients with lower albumin levels, and thus increased asparaginase activity, would have improved survival.
Methods
A retrospective electronic chart review was performed on 108 adult patients with newly diagnosed ALL who underwent induction chemotherapy treatment with Cancer and Leukemia Group B (CALGB) 9511 protocol at Stanford Hospital and Clinics between 2004 and 2012. PEG-asparaginase (2000 units per m2, capped at 3750 units) administration on day 5 of induction was confirmed on the electronic medical administration record. Patients also received therapy per protocol including prednisone (60mg per m2 per day) from days 1 through 21, with the exception of patients >60 years old who received prednisone from days 1 through 7. The primary outcomes measured were median overall survival and disease free survival. Patients were divided based on percent change in albumin level at day 14 of induction, using 20% decrease from pre-treatment baseline as a cut-off. The log rank test was used to calculate differences in survival and the Cox proportional hazards model was used to calculate hazard ratios. Baseline characteristics between the two groups were compared using chi-square or t-test analysis.
Results
A total of 104 patients with newly diagnosed ALL were included in the final analysis (1 patient did not receive PEG-asparaginase and 3 were lost early to follow-up). Of these, 52% were male. The median age was 49 years, and 20% of patients were 60 or older. The majority had B cell ALL (88%). Cytogenetics were normal in 28% of patients; t(9;22) was observed in 28% and t(4;11) in 4%. The induction mortality was 9% and 88% achieved complete remission (CR). In the entire patient population, the median overall survival was 27.4 months, and the median disease free survival was 25.0 months. For the patients who achieved at least a 20% decrease in albumin at day 14 of induction (57 patients), there was a statistically significant difference in median overall survival compared to those who had less than a 20% decrease in albumin, with an overall survival duration of 47.4 months and 15.8 months, respectively (HR = 2.23, P = 0.007). The median duration of disease free survival in those who achieved at least a 20% decrease in albumin at day 14 was 39 months compared to 13 months in those with less than a 20% decrease (HR = 1.93, P = 0.039). There was no statistically significant difference in the rate of CR between the two groups (P = 0.503). There was also no statistically significant difference in the baseline characteristics (age, WBC at diagnosis, presence of Philadelphia chromosome, and proportion of patients who eventually underwent BMT) between the two groups.
Conclusion
This study found a correlation between a decrease in albumin levels during induction, which was used as a surrogate measure of asparaginase activity, and duration of overall survival and disease free survival. This suggests that lower albumin levels associated with higher asparaginase activity and adequate asparagine depletion are important predictors of outcomes. Further studies assessing the effect of optimal individualized dosing of asparaginase based on albumin levels and/or asparagine depletion might be helpful to improve outcomes of adult patients with ALL.
Disclosures:
No relevant conflicts of interest to declare.
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