A Single Dose of PEG-Asparaginase at the Beginning of Induction Not Only Accelerates MRD Clearance but Also Improves Long-Term Outcome in Children with B-Lineage ALL

Abstract

This report presents the results of the assessment of MRD response by multicolor flow cytometry (MFC) with regard to the randomized use of pegylated asparaginase (PEG). In this study, PEG was randomly administered at a dose of 1000 U/m² on day 3 of induction therapy in children with B-lineage ALL.

Methods: Conventional induction therapy consisted of dexamethasone, vincristine, and daunorubicin. MRD data was available in 502 patients who were randomized at the start of induction therapy, standard-risk (SR) patients into three (conventional induction without PEG, induction with additional PEG and with PEG but without daunorubicin) and intermediate-risk (ImR) patients into two groups (with additional PEG and without PEG).

Results: The single administration of PEG resulted in a significantly higher proportion of rapid responders, in SR patients even when no anthracyclines were used for induction. In the SR group, the event-free survival of the MFC-MRD fast responders was similar in the PEG- and PEG+ arms (92.0 ± 3.1% vs. 96.2 ± 1.5%, respectively), and the same unfavorable trend was observed for MFC-MRD slow responders (57.5 ± 12.3% vs. 66.7 ± 15.7%, respectively). Results were similar in ImR patients: (94.3 ± 3.2% vs. 95.1 ± 2.4%, for fast responders and 63.3 ± 7.6% vs. 78.1 ± 7.9%, for slow responders in PEG- and PEG+ arms, respectively). However, there is a large difference between the proportion of MFC-MRD slow responders in the PEG- and PEG+ groups (18.3% vs. 5.2% for the SR group and 44.2% vs. 25.0% for the ImR group).

Conclusions: Therefore, early use of PEG-ASP not only leads to an accelerated reduction of blasts, but also to an excellent outcome in a significantly larger proportion of patients in both risk groups.

Keywords: PEG-asparaginase; acute lymphoblastic leukemia; flow cytometry; minimal residual disease.

Figure 1

Details of the induction therapy with randomization arms in SR (A) and ImR (B) groups.

Figure 2

CONSORT diagram.

Figure 3

Distribution of MFC-MRD levels in different randomization arms in the SR group (A,B) and in the ImR group (C,D). Day 15 data is displayed in panels (A,C), while EOI data is displayed in panels (B,D).

Figure 4

Event-free survival (EFS, solid lines) and cumulative recurrence incidence (CIR, dashed lines) according to MFC-MRD values for day 15 in the SR group (A,B) and in the ImR group (C,D) with the 1% threshold. Images (A,C) show PEG− arms, images (B,D) show PEG+ arms. Standard errors are given in parentheses.

Figure 5

Event-free survival (EFS, solid lines) and cumulative recurrence incidence (CIR, dashed lines) according to MFC-MRD values for EOI in the SR group (A,B) with the 0.1% threshold and in the ImR group with the threshold of 0.01% (C,D). Images (A,C) show PEG− arms, images (B,D) show PEG+ arms. Standard errors are given in parentheses.