Relapse Risk and Outcome of Discontinuing Asparaginase in Children with Acute Lymphoblastic Leukemia

Objection: Truncation of asparaginase treatment due to asparaginase related toxicities is common and may increase relapse risk in ALL. In the present study, we aimed to explore the impact of discontinuing asparaginase on children with ALL.

Methods: We conducted a retrospective analysis of 1072 pediatric patients with ALL diagnosed from May 2015 to Oct 2020. Patients were completed their last administered asparaginase treatment and followed until relapse, death, secondary malignancy (SMN), or end of follow-up. Compared cumulative incidence of relapse (CRI), event-free survival (EFS) and overall survival (OS) among those receiving all prescribed asparaginase doses versus not receiving all asparaginase doses.

Results: A total of 1072 patients were included in the Chinese Children’s Cancer Group-ALL-2015 protocol (CCCG-ALL 2015 ) study cohort and eligible for inclusion in this study. Following exclusion of patients with an event prior to completed asparaginase treatment, we investigated relapse risk following asparaginase exposure among 1013 children aged 1–17 years, diagnosed with ALL , and treated according to the CCCG-ALL 2015.There was an equal distribution of males (60%) and females (40%), median age at diagnosis was 5.3 years (range: 0.5–17), median white blood cell (WBC) was 10.3 ×10⁹/L (range: 0.7– 846.5), and 52% were intermediate-risk and high-risk patients. The majority of patients (90%) did not have CNS disease at time of diagnosis (CNS1). Of the 1013 patients, 40 (4.0%) had their asparaginase treatment truncated. In the truncated group, there were 24 males and 16 females, with a median age of 6.6 years (range: 2.3-14.3). Among the 40 children, 8 were low risk and 32 were intermediate risk. The median WBC was 8.74×10⁹/L (range: 0.66– 494.72), hemoglobin was 88g/L(range: 44-143), platelet was 58×10⁹/L (range: 10-372). Median number of asparaginase doses given in the truncated group was 3 (range: 1-8) versus 8 (range: 3-9) in the nontruncated group. The most frequent reasons for truncation were clinical hypersensitivity (55%), pancreatitis (47.5%) and thromboembolism (7.5%). With a median follow-up time of 5.6 years (range: 0.5–10.8), 57 patients died, 3 had developed a SMN, and 156 had developed a relapse with a 8-year cumulative incidence of relapse of 16.4% (95% CI: 9.3–9.7). The 5-year EFS and OS rates were 84% and 94.5%, respectively, for all patients included in this analysis. The 5-year EFS and OS rates were 72.5% and 90% in truncated group. Survival was apparently lower for truncated patients compared with those non-truncated, but this finding was not statistically significant (HR, 2.0; 95% CI, 0.73-5.53 ; P=0.18), with corresponding 5-year OS rates of 90% and 94.6%, respectively.The 8-year CRI for the non-truncated group was 15.6% (95% CI: 7.9-8.2) and for the truncated group 27.6% (95% CI: 6.0–7.8). Comparing patients with (n=40) and without (n=973) truncated asparaginase treatment due to clinical toxicity, the relapse-specific hazard ratio (HR) was 1.95 (95% confidence interval [CI]: 1.06–3.60, P=0.033). Of the 157 relapses in the study, 120 were bone marrow relapses, 10 were testicular relapses, 14 were CNS relapses, and the remaining 13 were composite relapses. The 8-year cumulative incidence of bone marrow relapse for the truncated patients versus the non-truncated patients was 23.1% (95% CI: 8.1–8.4) and 13.2% (95% CI: 3.6–7.2), respectively, and the relapse-specific HR was 1.91 (95% CI: 0.972–3.763, P=0.61). Of the 40 truncated patients, the median asparaginase exposure intensity was 33% (range: 11-89), and the cut off was 29%. The 8-year CRI for receiving <29% of asparaginase doses patients was 46.2% (95% CI: 4.19–7.55), for receiving >29% of asparaginase doses patients was 18.5% (95% CI: 6.36-8.36). Comparing patients who received <29% doses of asparaginase with those who received >29% doses of asparaginase, relapse-specific HR was 2.69 (95% CI: 0.82–8.82, P=0.102) .

Conclusion: We found that patients with truncated asparaginase treatment had a significantly increased risk of relapse compared to those with non-truncated therapy. Children who received <29% doses of asparaginase had a higher risk of relapse, although the difference was not statistically significant. Therefore, it is necessary to administer the full dosage of asparaginase, including using Erwinia chrysanthemiASNase (Erwinia) as substitutes.