ASH Releases Clinical Practice Guidelines for ALL in Adolescents and Young Adults

The American Society of Hematology (ASH) has released new guidelines on the treatment of adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL). Guidelines are available for both treatment-naïve and relapsed/refractory disease. The ASH president said in a statement that caring for these individuals is complex given the unique challenges associated with their age group, which doesn’t align neatly with standard pediatric or adult treatment regimens, and that the guidelines aim to address this gap by outlining best treatment practices and providing vital standardization to clinical approaches.

For AYAs with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL) or T-cell acute lymphoblastic lymphoma, the ASH guideline panel recommends frontline pediatric-inspired (asparaginase-containing) regimens (strong recommendation based on moderate certainty in the evidence of effects). For patients receiving these regimens, the panel also suggests that empiric dose capping and dose reductions are reasonable strategies to mitigate asparaginase-induced toxicities without evidence that they have an adverse effect on disease outcomes. The panel defines dose capping as a maximum peg-asparaginase dose of 3750 international units (IU); reduced dosing of pegaspargase is defined as any weight-based dose below the dose of 2500 IU/m2 for those younger than 22 years or below 2000 IU/m2 for those 22 years and older.

The panel also strongly recommends using prophylactic premedication to prevent hypersensitivity reactions, based on very low certainty in the evidence of effects. The panel does not recommend the routine use of cryoprecipitate replacement or fibrinogen concentrate absent active bleeding, and recommends against the routine use of unfractionated heparin for venous thromboembolism prophylaxis. For AYAs with ALL receiving frontline therapy who are in first complete remission (CR1), the panel makes a conditional recommendation against routinely proceeding with allogeneic hematopoietic stem cell transplantation (allo-HSCT) as consolidation, though there may be a benefit for specific high-risk groups, such as patients with minimal residual disease persistence, induction failure, and high-risk biologic subsets.

In relapsed/refractory B-ALL, the panel strongly recommends using blinatumomab over chemotherapy despite low certainty in the evidence of effects. In individuals with high blast counts at relapse, debulking before proceeding with blinatumomab may be necessary. The panel also makes a strong recommendation in favor of inotuzumab over chemotherapy; the risk of veno-occlusive disease should be considered in individuals intended to proceed with allo-HSCT following inotuzumab ozogamicin.

In HSCT-naïve AYAs with relapsed B-ALL who achieve a second or greater remission with autologous CD19 CAR-T products approved by the US Food and Drug Administration, tisagenlecleucel and brexucabtagene autoleucel, the panel suggests further consolidation with allo-HSCT. For those with relapsed B-ALL who achieve a second or greater remission, the panel suggests allo-HSCT over chemotherapy alone as definitive consolidation treatment. For patients with relapsed/refractory ALL proceeding with allo-HSCT, the panel suggests myeloablative conditioning regimens that include total body irradiation, rather than chemotherapy only.

The panel suggests a nelarabine-based regimen for patients with relapsed/refractory T-ALL. The panel noted that there is limited available evidence for novel therapies in relapsed/refractory T-ALL and is currently unable to issue a formal recommendation regarding these treatment approaches, despite recognizing that early phase data appear promising. The panel has issued a “Research-only Recommendation” that individuals with relapsed/refractory T-ALL should be offered participation in clinical trials of novel therapies, including CAR-T cell therapy, if such trials are available and feasible.

Acute lymphoblastic leukemia is a rapidly progressing cancer characterized by the uncontrolled proliferation of lymphoblasts. Originating from B-cell or T-cell lineages, these cells lose the ability to mature into functional lymphocytes while simultaneously acquiring a survival and proliferative advantage. Approximately 50-60% of ALL cases occur in children, and about 60% are diagnosed before age 20; only 25% of cases are diagnosed between ages 20-60, while adults aged 60 years and older account for ~11% of new diagnoses.

ALL is broadly divided into B-cell ALL and T-cell ALL, with modern classification further separating it according to cytogenetic and molecular lesions, such as Philadelphia chromosome (BCR::ABL1-positive), Ph-like ALL, ETV6::RUNX1 fusion, KMT2A rearrangements, IKZF1 alterations/deletions, and hyperdiploidy/hypodiploidy. In children, especially 1-10 years of age, ALL more often carries genetic subtypes associated with high treatment sensitivity, such as ETV6-RUNX1 fusion and high hyperdiploidy. Adults have higher rates of Philadelphia chromosome-positive ALL, Ph-like ALL, IKZF1, TP53 alterations, and complex cytogenetics, meaning adult ALL is often biologically distinct with its own patterns of resistance, vulnerability, and relapse risk.

Age affects the patient’s capacity to tolerate treatment; bone marrow reserve, hepatic metabolism, renal function, vascular integrity, and immune resilience generally decline over time, alongside higher rates of comorbidities. As a result, therapies tolerated in childhood may cause greater toxicity in adults, leading to dose reductions, treatment delays, or failure to deliver curative-intent therapy. Outcome differences arise from the interaction of leukemia biology and host biology.