Associations between serum asparaginase activity and asparaginase-associated toxicities in pediatric ALL patients receiving calaspargase: A report from the DFCI ALL consortium
Bibliographic record
Abstract
Abstract Background: L-asparaginase (ASP) is a universal component of acute lymphoblastic leukemia (ALL) therapy. Although highly effective, it can cause severe toxicities that may interrupt, delay, or require cessation of therapy. A serum asparaginase activity (SAA) of 0.1 IU/mL is associated with therapeutic effect; however, for several weeks after a dose of pegylated E.coli asparaginase formulations (pegaspargase or calaspargase), SAA levels exceed this threshold. With standard dosing, SAA varies between patients, with some achieving higher sustained levels than others. Some prior studies suggest that higher SAA levels may increase toxicity risk, but findings are inconsistent. Calaspargase is a relatively new formulation now standardly used in frontline therapy for childhood ALL. Whether higher SAA levels increase the risk of ASP-associated toxicities among patients receiving calaspargase has not been previously investigated. The Dana-Farber Cancer Institute (DFCI) ALL Consortium protocol 11-001 was a randomized Phase III trial comparing the efficacy and toxicity of calaspargase, given every 3-weeks x 10 doses to pegaspargase, given every 2-weeks x 15 doses during post-induction multiagent therapy. We evaluated whether higher nadir SAA levels (NSAA) obtained prior to each dose were associated with ASP-associated toxicities among patients receiving calaspargase. Methods: DFCI 11-001 enrolled patients 1 – 21 years with newly diagnosed ALL and lymphoblastic lymphoma. For the present analysis, patients who received post-induction calaspargase and had SAA levels available for evaluation were included. Patients assigned to the calaspargase arm received this formulation at a dose of 2500 IU/m2 every 3-weeks during Consolidation II therapy; NSAA levels were obtained 3-weeks after each dose. Using individual patient-level data, a mixed linear model was used to estimate the effect of week 4 SAA (collected prior to the 2nd dose) on all subsequent SAA levels collected through Consolidation II. Models indicated that NSAA levels collected prior to the 2nd dose of calaspargase using > 75th percentile cutoff highly predicted all subsequent NSAA levels; therefore, patients with high NSAA prior to 2nd dose (defined as being > 75th percentile) were considered to have high NSAA for this analysis. ASP-associated toxicity was defined as a composite endpoint, and patients were grouped as having no toxicities or ≥1 of the following: pancreatitis (mild, moderate, severe), thromboembolic event, or ≥ grade 3 hyperbilirubinemia as defined by CTCAE v 4.0. High NSAA level after 1st dose of calaspargase was evaluated as a predictive factor for composite toxicity. Additional analyses were performed to assess if patient or disease-related factors contributed to elevated SAA levels. Results: Between 2012 and 2015, N=239 patients were enrolled on DFCI 11-001, and 119 were randomized to the calaspargase arm; N=75 of these patients were included in the present analysis. The median NSAA prior to 2nd dose of calasparagase was 0.585 IU/mL, and the range was 0.025- 0.993 IU/mL. NSAA obtained prior to the 2nd dose was at or above the 75th percentile in N=19 patients (considered high NSAA) and was below the 75th percentile in N=56. There was no association between high NSAA levels and any of the following: age (p=0.53), sex (p=0.78), body mass index [BMI] (p>0.99), body surface area [BSA] (p=0.14), leukemia immunophenotype (p>0.99) or final risk group (p>0.99). There was no significant difference in the likelihood of toxicity for patients with high NSAA levels. Specifically, 37% (N=7) of patients with high NSAA levels developed at least 1 ASP-associated toxicity, vs. 29% (N=16)of patients with NSAA levels <75th percentile (p=0.57). Similarly, there was no association between ASP-associated toxicity and age (p=0.51), sex (p=0.29), BMI (p=0.21), BSA (p=0.5), or leukemia immunophenotype (p=0.85). Conclusions: Among patients receiving calaspargase for ALL, we found no association between high NSAA levels and ASP-related toxicity; NSAA levels were also not associated with demographic or disease characteristics. These results suggest that decreasing SAA via dose reduction or capping calaspargase doses may not reduce the rate of ASP-related toxicity. While our findings warrant further exploration to determine the utility of NSAA level as a predictor of toxicity risk, other potential risk factors for, and interventions to prevent, ASP-related toxicities should also be examined.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".