Implementation of Continuous Pegasparaginase Dosing without an Asparaginase-Free Interval Reduces Hypersensitivity in Children with Newly Diagnosed Acute Lymphoblastic Leukemia: Results of the DCOG ALL11 Pegasparaginase Randomization

Background: Asparaginase is key in the treatment of pediatric acute lymphoblastic leukemia (ALL). Hypersensitivity is one of its major side effects and hamper its use. Most hypersensitivity reactions occur after an asparaginase-free interval, as neutralizing anti-drug antibodies increase during these intervals. Thus we hypothesized that a continuous PEGasparaginase dosing schedule (without an asparaginase-free interval) would result in less hypersensitivity to PEGasparaginase compared to the standard non-continuous PEGasparaginase dosing schedule. Methods: Medium risk (MR) patients (aged 1-18 yrs) with ALL enrolled in the DCOG ALL11 protocol, were randomized to receive 14 individualized PEGasparaginase doses after an asparaginase-free interval of 3 months or to continue PEGasparaginase treatment following the first 3 doses in induction (EudraCT:2012-000067-25; Dutch Trial Register NL3227). Hypersensitivity included allergies, allergic-like reactions, and silent inactivations, where inactivating hypersensitivity reactions comprised the sum of allergies and silent inactivations. Secondary endpoints included other asparaginase-related adverse event (AEs) (CTCAE >grade 3), such as febrile neutropenia, infection, a thromboembolic event, pancreatitis, and avascular necrosis, as well as antibody levels and treatment outcome. Cumulative incidence of relapse (CIR), cumulative incidence of death (CID) in CR1 and disease-free survival (DFS) were compared between both treatment arms. Results: 312 MR patients were randomized to receive PEGasparaginase in a continuous (n=155) and non-continuous (n=157) dosing schedule. Hypersensitivity reactions occurred in 4 out of 155 (2.6%) patients in the continuous treatment arm versus 17 out of 157 (10.8%) patients in the non-continuous treatment arm (P<0.01), of which 2 (1.3%) versus 13 (8.3%) were inactivating reactions (Figure 1; P<0.01). Patients in de continuous treatment arm were significantly less likely to get an inactivating hypersensitivity reaction (odds ratio: 0.15 (0.032-0.653), P=0.012). Antibody levels were significantly lower in the continuous arm compared to the non-continuous arm (P<0.01). Without the asparaginase-free interval, the antibody levels slightly increased by 1.1-fold between dose 3 and 4 whereas antibody levels in the non-continuous arm increased by 2.5-fold during the asparaginase-free interval. We did not find any significant differences in the total number of asparaginase-associated AEs between the treatment arms (Figure 1). However, the generalized Poisson model analysis revealed that the occurrence of specific AEs, such as a thromboembolic event and pancreatitis, was influenced by both treatment phase and arm. These correlations can be attributed to the timing of asparaginase administrations, since at start of randomization asparaginase treatment was interrupted in the non-continuous arm but uninterrupted in the continuous arm. Consequently, thromboembolic events and pancreatitis occurred more frequently at the beginning of randomization in the continuous arm compared to the non-continuous arm (Table 1). This pattern reversed when the non-continuous arm resumed asparaginase treatment after the asparaginase-free period, while the continuous arm concluded their treatment. The occurrence of infections was not associated with treatment phase and treatment arm. The median duration of treatment phases was comparable between the two arms, with the exception of a longer duration of protocol M in the continuous versus non-continuous arm (median 10.3 versus 9.4 weeks respectively instead of the planned 9 weeks; P<0.01) Estimated median follow-up time was 57.2 months (95%-CI 51.9-61.3). The 5-yr CIR, CID in CR1 and DFS were 5.6% (SE 2.1%), 1.9% (SE 1.1%) and 91.9% (SE 2.4%) for continuous treatment vs 4.0% (SE 1.8%), 0.6% (SE 0.6%) and 95.3% (SE 1.9%) for non-continuous treatment (P=0.710; P=0.308; P=0.289), respectively. Conclusion: A continuous dosing schedule of PEGasparaginase resulted in a 7 times lower incidence of inactivating hypersensitivity reactions and lower anti-drug antibody levels compared with a non-continuous dosing schedule with an asparaginase-free interval. The continuous schedule of asparaginase treatment did not increase toxicity but changed the timing of toxicities and did not affect the efficacy of the therapy.