New from the American Society of Hematology (ASH) are 8 clinical recommendations and 1 research-only recommendations to guide management of relapsed or refractory acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYAs), emphasizing immunotherapy approaches.1
Published in Blood Advances, the 2026 Guidelines for Management of Relapsed/efractory ALL in AYAs underscore a paradigm shift toward immunotherapies, including blinatumomab and inotuzumab, over chemotherapy while reinforcing the importance of patient-informed, individualized clinical decision-making.1
AYAs sit in a unique pocket of clinical care management, especially in ALL, and are considered a high-risk population. This distinction stems from their distinct disease biology, including increased rates of T-ALL and Philadelphia-like (Ph-like) ALL compared with pediatric patients. Historically, AYAs have experienced inferior outcomes, driven in part by gaps between pediatric and adult treatment paradigms, challenges with treatment adherence, and higher rates of treatment-related toxicity.1,2,3
Although adoption of pediatric-inspired regimens has been associated with improved survival among AYAs compared with traditional adult protocols, outcomes in the relapsed or refractory setting remain suboptimal, highlighting an ongoing treatment gap.1,2,3
To address the gap in AYAs patients, a multidisciplinary panel of hematologists, AYA psychosocial care specialists, pharmacists, methodologists, and patient representatives created these guidelines. They used Grading of Recommendations Assessment, Development and Evaluation (GRADE), including GRADE Evidence-to-Decision frameworks, for evidence assessment and recommendation formation.1
The panel focused on immunotherapy, targeted therapies, allogeneic hematopoietic stem cell transplantation (allo-HSCT), and central nervous system (CNS)-directed therapy.1
In refractory or relapsed ALL, the panel recommends the use of targeted agents, such as blinatumomab and/or inotuzumab, to induce remission due to their efficacy and potentially favorable toxicity profiles. Although the evidence for survival benefits, remission rates, and reduced toxicity is of low certainty, panelists consider it relevant in guiding treatment.1
Specifically, the guidelines recommend blinatumomab over chemotherapy for patients with first relapse or refractory B-cell ALL, based on low-certainty evidence demonstrating increased remission rates, improved survival, and reduced toxicity. Inotuzumab is similarly recommended over chemotherapy in this setting. These agents are increasingly incorporated into contemporary treatment strategies and may serve as bridges to subsequent therapies, including allo-HSCT, depending on patient- and disease-specific factors.1
In contrast, while emerging therapies such as daratumumab and CD7-directed CAR T-cell approaches have demonstrated promising activity, particularly in T-ALL, the panel concluded the current evidence is insufficient to support routine use outside of clinical trials. This limitation is especially relevant for AYAs with relapsed or refractory T-ALL, including both nelarabine-naïve and nelarabine-exposed patients.1
Overall, the panel acknowledged meaningful progress in immunotherapy for relapsed or refractory T-ALL but emphasized that available data do not yet justify widespread adoption beyond the clinical trial setting. Key evidence gaps include the lack of head-to-head comparisons between immunotherapies and chemotherapy, as well as a shortage of prospective trials designed to define optimal sequencing, combinations, and treatment duration tailored specifically to AYAs.1
Accordingly, the guidelines issue a research-only recommendation that, when feasible, individuals with relapsed or refractory T-ALL be offered enrollment in clinical trials evaluating novel agents such as daratumumab, CAR T-cell therapies, BCL-2 inhibitors, tyrosine kinase inhibitors, and other emerging approaches. Further research is encouraged to assess both short- and long-term outcomes, including toxicity, fertility, and health-related quality of life.1
ReferenceDuVall AS, McNeer J, Cheung MC, et al. ASH 2026 Guidelines for Frontline Management of Acute Lymphoblastic Leukemia in Adolescents and Young Adults. Blood Advances. Published online February 11, 2026. doi:https://doi.org/10.1182/bloodadvances.2021006469Wang AY, Muffly LS, Stock W. Philadelphia Chromosome–Negative B-Cell Acute Lymphoblastic Leukemia in Adolescents and Young Adults. JCO Oncology Practice. Published online January 29, 2020:JOP.19.00197. doi:https://doi.org/10.1200/jop.19.00197Makhani S, Khalid N, Robinson K, Agarwal A, Hussain M, Goel R. Predictors of long-term survival in adolescents and young adults with acute lymphoblastic leukemia: 20 years of insight from a nationally representative database. Blood. 2025;146(Supplement 1):5098-5098. doi:https://doi.org/10.1182/blood-2025-5098