4 missed opportunities for boosting survival rates in pediatric ALL patients

Childhood acute lymphoblastic leukemia (ALL) has seen dramatic improvements in survival over the past few decades. Five-year survival rates for children under 15 now exceed 90%.^[]

However, these gains risk being undermined by missed opportunities; critical areas where current treatment practices fail to optimize outcomes.

1. Failure to strictly stick to pediatric treatment protocols

Even within pediatric settings, deviations from standard ALL treatment protocols, particularly during oral maintenance therapy, are linked to worse outcomes. While formal prospective trials on protocol adherence during early intensification are limited, real-world data show that nonadherence to maintenance-phase chemotherapy significantly increases the risk of relapse.

A multicenter study found that children with <90% adherence to 6-mercaptopurine (6-MP) had a 3.9-fold increased risk of relapse, regardless of race or ethnicity.^[] Another meta-analysis confirmed that adherence to maintenance therapy is critical for sustaining remission in pediatric ALL.^[]

David Dickens, MD, FAAP, clinical professor of Pediatrics–Hematology/Oncology at the University of Iowa Carver College of Medicine, elaborates, “Any patient diagnosed with ALL should be receiving treatment according to guidelines set by the National Comprehensive Cancer Network.” (Read the guidelines here.)

2. Underdetection of asparaginase hypersensitivity and silent inactivation

Failure to detect asparaginase hypersensitivity, especially silent inactivation, remains a major gap in ALL treatment, often leading to premature discontinuation and increased relapse risk.

Ibrahim T. Aldoss, MD, board-certified medical oncologist, hematologist, and internist from City of Hope in Orange County, CA, says, “Despite its known importance, therapeutic drug monitoring (TDM) for ASNase activity is rarely performed in patients.” 

In a recent study using the ALLTogether protocol, researchers analyzed 1,631 asparaginase enzyme activity (AEA) samples from 253 patients (ages 1–45).^[] They found that 18.2% experienced inactivation—50% with severe allergy, 28.3% mild allergy, and 21.7% silent inactivation. A pharmacokinetic model revealed that 93% of inactivated patients had elevated ASNase clearance beforehand, while 86% of those without hypersensitivity had stable clearance. This suggests rising clearance is an early predictor of inactivation and a missed intervention point.^[]

3. Pharmacogenomic-guided therapy personalization

For example, TPMT and NUDT15 gene variants significantly affect thiopurine metabolism.^[] Patients with these variants are at higher risk for myelosuppression when given standard doses of 6-mercaptopurine, requiring dose reduction; this is reflected in current NCCN guidelines.

In contrast, while MTHFR polymorphisms have been associated with increased methotrexate toxicity and prolonged need for leucovorin rescue, they are not currently included in NCCN, ESMO, or FDA recommendations for dose adjustment in ALL.^[] Clinicians typically identify methotrexate toxicity risk through post-administration drug level monitoring, rather than preemptive genotyping. Beyond pharmacogenetics, mutational profiling of leukemia at diagnosis can also guide targeted therapy decisions.

For instance, BCR-ABL fusion-positive ALL is associated with poor prognosis but responds well to tyrosine kinase inhibitors like imatinib, improving outcomes. Conversely, patients with the ETV6-RUNX1 fusion tend to have a favorable prognosis, and this may influence decisions about treatment intensity.^[] (Current recommendations, however, don’t include an alternate treatment strategy for these patients.) These genetic insights are critical for risk stratification and individualized therapy, and should be integrated into routine clinical practice.

4. Access to newer medications

Seth Karol, MD, a pediatric oncologist at St. Jude Children's Research Hospital, says, “Newer therapies such as bispecific antibodies, antibody drug conjugates, and chimeric antigen receptor T-cell therapy all appear to have significant promise in higher-risk ALL patients.” 

Dr. Karol's observation regarding newer therapies for high-risk ALL is substantiated by recent clinical advancements:

• Tisagenlecleucel, a CD19-directed CAR T-cell therapy, has demonstrated significant efficacy in relapsed/refractory B-cell ALL. In a real-world study, the best overall response rate was 93%, with 1-year overall survival and event-free survival rates of 82% and 56%, respectively.^[]

• Other examples include blinatumomab, a bispecific antibody, which has improved survival in relapsed/refractory B-ALL,^[] and inotuzumab ozogamicin, a CD22-targeting antibody-drug conjugate, which is now approved for pediatric and adult use.^[]

With the availability of newer medications, access and supportive care for their use remains critical. As Dr. Karol concludes, “Ensure patients have the support they need to receive timely treatment, and supportive care is also critical. While we have very effective treatments for ALL, they work best when patients can access them and are supported well throughout their cancer journey.”