Expert Panel Updates NCCN Guidelines on Pediatric ALL with Focus on T-ALL

The National Comprehensive Cancer Network (NCCN) recently convened a multidisciplinary panel of experts from children’s hospitals across the US to update the NCCN Clinical Practice Guidelines in Oncology for pediatric acute lymphoblastic leukemia (ALL). Applying current evidence, the panel’s update focuses on pediatric T-cell lineage ALL (T-ALL) and was published in Journal of the National Comprehensive Cancer Network.

The panel begins the update by establishing the overall state of ALL management. This clinical area has seen significant progress in prior decades, although increases in survival benefit have been markedly greater for pediatric patients than for adults.

“Improvements are largely owed to advances in the understanding of the molecular genetics and pathogenesis of the disease, the incorporation of risk-adapted therapy, the advent of new targeted agents, the use of allogeneic hematopoietic cell transplantation (HCT), and improvements in supportive care,” according to Hiroto Inaba, MD, PhD, of St. Jude Children’s Research Hospital, Memphis, Tennessee, and colleagues.

The section on diagnosis in the updated guidelines addresses how to clinically differentiate ALL from leukemia and lymphoblastic lymphoma and T-ALL from B-cell lineage ALL (B-ALL). It encompasses patients’ presenting symptoms, blood count, laboratory biomarkers, immunophenotyping, bone marrow lymphoblast findings, central nervous system (CNS) involvement, and imaging of the head and chest. Two distinguishing features of T-ALL highlighted by the panel are that mediastinal mass is found in more than 50% of patients and that more than 50% of patients have NOTCH1 mutations.

To ascertain risk and prognoses for patients who have pediatric ALL, clinical researchers have identified patient age, white blood cell count, CNS disease, immunophenotype, and genetic features of the disease to be significant factors. However, the expert panel repeatedly stresses the importance of measurable residual disease (MRD) findings for prognosis and management decision-making in both T-ALL and B-ALL, although next-generation sequencing (NGS) to detect MRD is approved by the FDA for the latter but not the former.

Inaba and colleagues make the following point: “Collectively, studies show the high prognostic value of MRD in assessing risk for relapse in patients with ALL, and the role of MRD monitoring in identifying subgroups of patients who may benefit from further intensified therapies or alternative treatment strategies.”

As described in the update, management of pediatric T-ALL generally involves use of multiple chemotherapy agents, starting with an induction therapy regimen that usually includes vincristine, asparaginase, and corticosteroids, with or without an anthracycline. This is followed by consolidation, then interim maintenance, delayed intensification therapy, and then maintenance therapy.

“The consolidation phase is the treatment phase most affected by risk stratification, such that patients with lower-risk disease receive less intensive consolidation and patients with higher-risk disease receive consolidation that is more intensive,” as noted by Inaba and colleagues.

Regarding the induction therapy phase, the panel explains that in most protocols for pediatric T-ALL, a 4-drug regimen is used. The nucleoside metabolic inhibitor nelarabine and the proteasome inhibitor bortezomib are recommended in this setting, and in the update, the panel reviews clinical trial findings for these agents, along with findings comparing the corticosteroid types that can be used in frontline regimens. For relapsed and refractory T-ALL, nelarabine- and bortezomib-based regimens are also recommended, as are daratumumab- or venetoclax-based regimens. Revumenib may also be considered for KMT2Ar disease.

For both frontline management of T-ALL and treatment of refractory T-ALL, the panel recommends that patients be entered into a clinical trial, if one is available. Moreover, allogenic HCT remains the only curative treatment for T-ALL at this time, although it still requires induction of successful remission beforehand.

“In general, MRD positivity at the EOI [end of induction] in B-ALL and EOC [end of consolidation] in T-ALL, predicts high relapse rates and should prompt an evaluation for allogeneic HCT. When possible, therapy aimed at eliminating MRD before allogeneic HCT should be considered,” as recommended by Inaba and colleagues on the panel.

Reference

Inaba H, Teachey D, Annesley C, et al. Pediatric acute lymphoblastic leukemia, version 2.2025, NCCN Clinical Practice Guidelines In Oncology. J Natl Compr Canc Netw. 2025;23(2):41-62. doi:10.6004/jnccn.2025.0006