Asparaginase has been a critical component of acute lymphoblastic leukemia (ALL) therapy since the inception of multiagent chemotherapy regimens more than 40 years ago.1 Although pediatric ALL treatment protocols have varied widely in the timing and cumulative dosing of asparaginase, contemporary studies have reported no benefit of increased asparaginase dosing upon central nervous system relapse reduction2 and successful de-escalation of asparaginase dosing aimed at reducing toxicity while maintaining comparable overall and disease-free survival.3,4 Pegylated (peg) asparaginase induces sustained asparaginase depletion and requires less frequent dosing but is commonly complicated by hypersensitivity reactions and, less commonly, by severe thrombosis or pancreatitis adverse events (AEs). These events require alternative asparaginase product administration and/or treatment discontinuation. Defining optimal asparaginase dosing in multidrug childhood ALL regimens remains an essential task.5,6
Recent data from the Nordic Pediatric Hematology-Oncology (NOPHO) Association ALL2008 trial importantly showed no difference in relapse risk in children aged one to 17 years with standard-risk or intermediate-risk ALL randomized to eight versus 15 doses of peg-asparaginase.3 Building on these important results, Dr. Sofie Gottschalk Højfeldt and colleagues now integrate retrospective data on clinical toxicity and asparaginase enzyme activity (AEA) levels to assess the impact of inadequate asparaginase treatment upon relapse risk. Among 1,401 eligible patients, 358 (25.6%) required asparaginase therapy truncation due to hypersensitivity reactions or other toxicities. Importantly, only partial replacement of peg-asparaginase doses with shorter-acting Erwinia asparaginase was used in this trial. Patients who received truncated therapy had a relapse risk of 10.5 percent, as compared with 7.5 percent in patients who received all scheduled doses, which was not statistically significant. However, these results may be partially skewed since some patients with truncated therapy still received more asparaginase doses than those in other treatment cohorts despite similar disease characteristics due to the study design.
The NOPHO investigators further analyzed a subcohort of standard-risk and intermediate-risk patients, incorporating both therapy truncation and AEA levels for deeper characterization of patients with suboptimal asparaginase treatment. Patients were grouped into one of two categories: 1) truncated therapy or low AEA levels were grouped together (truncatedorAEA-) or 2) non-truncated therapy and normal AEA or evidence of fast metabolism (non-truncatedandAEA+). Interestingly, 186 (16.7%) of 1,115 patients had low AEA, 46 (24.7%) of whom received all asparaginase doses. Only two of 47 patients with clinical hypersensitivity had insufficient AEA. TruncatedorAEA- patients had a significantly higher relapse risk of 11.1 percent at seven years, versus 6.7 percent in non-truncatedandAEA+ patients (p<0.05), suggesting that reduced asparaginase therapy was associated with inferior outcomes. Within the truncatedorAEA- cohort, patients who received less than 10 weeks of total asparaginase therapy had the highest relapse risk (11.9%).
Additionally, there is growing evidence that reduced asparaginase therapy in the setting of toxicity or via “silent inactivation” (SI) increases relapse risk among children with ALL. A recent report from the Children’s Oncology Group demonstrated decreased event-free survival in children and adolescents/young adults with high-risk ALL who missed even one dose of peg-asparaginase therapy, although this difference appeared mitigated in patients who received full peg-asparaginase dose-equivalent replacement with shorter-acting Erwinia asparaginase.6 Development of neutralizing antibodies against asparaginase has also been described as a mechanism of asparaginase resistance, including in the absence of clinical symptoms (SI), though potential clinical impact of this phenomenon remains incompletely understood.7,8
In Brief
Optimal asparaginase dosing has yet to be defined in multi-drug childhood ALL treatment protocols, but achievement of adequate asparagine depletion over time is clearly vital for reducing relapse risk. These goals can be accomplished through routine AEA monitoring to ensure adequate drug activity and efforts to minimize clinical toxicities, which may include use of alternative asparaginase formulations. Recurrent global drug shortages in recent years, however, have hindered our ability to deliver optimal asparaginase chemotherapy and highlight an ongoing need for alternative methods of reliable and large-scale asparaginase production. To this end, the COG AALL1931 phase III trial is currently studying a new recombinant crisantaspase product in patients with peg-asparaginase hypersensitivity or SI (clinicaltrials.gov ID NCT04145531). Prospective trials using real-time AEA monitoring combined with broad availability of well-tolerated, effective peg-asparaginase alternatives for those patients with toxicity will continue to refine modern childhood ALL therapy paradigms.
Competing Interests
Dr. Conneely and Dr. Tasian indicated no relevant conflicts of interest.
