Bridging two worlds: harmonizing pediatric and adult ALL

In this issue of Blood Advances, DuVall et al¹ present American Society of Hematology guidelines for frontline management of acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA). Historically, AYA ALL treatment has varied considerably, depending on whether patients were treated at a pediatric or adult center, leading to disparate care and outcomes.² This multidisciplinary panel, comprising oncologists, pharmacists, psychologists, social workers, and patient representatives, seeks to bridge this divide by harmonizing best practices for this vulnerable population, caught between the worlds of pediatric and adult oncology.

Accounting for ∼20% to 25% of newly diagnosed ALL cases, AYAs (typically defined as ages 15-39 years), have significantly worse outcomes compared to pediatric patients, whose 5-year survival exceeds 90%.³ Often termed the “survival cliff,” the reasons for this sharp decline in survival between childhood and adolescence are multifactorial, including higher risk disease biology and unique psychosocial factors. However, central to these American Society of Hematology (ASH) guidelines, is the recognition that historic differences in adult and pediatric treatment approaches have also been a major contributor. A seminal retrospective analysis in the early 2000s showed that AYAs aged 16 to 20 years treated with pediatric protocols had significantly improved overall survival compared to those receiving adult protocols (67% vs 46%).⁴ Over the past decade, accumulating evidence has confirmed that pediatric-inspired regimens (PIRs) improve outcomes compared to traditional “adult” protocols. Large prospective studies, including the landmark Cancer and Leukemia Group B (CALGB) 10403 trial, demonstrated 5-year overall survival rates of 60% to 70%, a meaningful improvement from historic controls.⁵ Despite this evidence and National Comprehensive Cancer Network (NCCN) guidelines recommending PIRs as preferred treatment, many AYAs, particularly at adult institutions, still do not receive them. Notably, of the panel's many recommendations, their only moderate-certainty guidance is to incorporate frontline PIRs for AYA patients with ALL.

PIRs are distinguished from traditional “adult” regimens by decreased reliance on myelosuppressive agents and incorporation of asparaginase, which confers unique toxicities complicating administration. A lack of familiarity with managing these toxicities likely contributes to decreased PIR implementation among adult providers prompting the panel to provide comprehensive guidance, with several recommendations representing shifts from historical practice. For hypersensitivity prevention, the panel recommended prophylactic premedication, departing from prior practice where this was avoided due to concerns about masking silent inactivation, a risk now mitigated by therapeutic drug monitoring. They also recommended against routine cryoprecipitate replacement for hypofibrinogenemia (outside active bleeding) due to potential increased venous thromboembolism (VTE) risk. However, important gaps remain. Although strongly recommending against the use of unfractionated heparin for VTE prophylaxis, heterogeneous and limited AYA-specific data prevented specific recommendations on other anticoagulants or antithrombin, which many providers increasingly use. Similarly, no recommendations were provided for rechallenging after nonhypersensitivity asparaginase toxicity, leaving an important gap in a common clinical scenario.

Beyond optimizing PIR administration, the panel also addressed the rapidly evolving landscape of novel therapies. For Philadelphia chromosome (Ph)–negative B-cell ALL (B-ALL), they suggest adding rituximab for CD20-positive disease and blinatumomab for patients achieving morphologic remission regardless of minimal residual disease (MRD) status, both based on recent data demonstrating improved outcomes.6, 7, 8 For T-cell disease, the panel’s approach reflects the complexity of interpreting data across disease subtypes and age ranges. Although many providers now incorporate nelarabine and bortezomib into frontline regimens, insufficient AYA-specific data prevented broad recommendations. The panel could only recommend against bortezomib for T-ALL and against nelarabine for T-cell lymphoblastic lymphoma. For Ph-positive ALL, the panel suggests reduced-intensity chemotherapy with tyrosine kinase inhibitors over intensive chemotherapy for remission induction, shifting from historical practice.

Representing another paradigm shift, the panel suggests against routine allogeneic hematopoietic stem cell transplantation in MRD-negative first complete remission for AYAs receiving PIRs, reflecting accumulating evidence that these patients achieve superior overall survival with continued chemotherapy, given significantly higher treatment-related mortality in transplantation.^9,10 However, specific high-risk subgroups, particularly those with MRD persistence, induction failure, or high-risk biologic subsets, may still benefit. For central nervous system (CNS) prophylaxis, with no clear differences in survival or neurotoxicity between approaches, the panel suggests using either intrathecal methotrexate alone or triple intrathecal therapy but suggests against routine cranial radiation for patients on PIRs, marking another departure from historical practice.

These guidelines, although a much-needed step in the field of AYA ALL, face several important limitations. First, except for PIR guidance, all recommendations carry very low certainty due to insufficient AYA-specific research, a consequence of historically low AYA trial enrollment,¹¹ compounded by this population spanning traditional care models. Recent multidisciplinary efforts aim to address this inequity, but filling the literature gap will take time. Second, the field is evolving rapidly. In the short time between the panel’s study inclusion cutoff and guideline publication, emerging data on novel agents such as blinatumomab, inotuzumab ozogamicin, and cellular therapies have already influenced real-world practice. Although the panel commits to updating recommendations as evidence emerges, providers must remain vigilant as new data alter best practice. Third, AYAs face complex barriers spanning equitable care access, psychosocial challenges, and financial toxicity at a formative life stage. Although “Good Practice Statements” acknowledge these issues, limited practical implementation guidance is offered, underscoring the need for providers and institutions to develop local strategies while the body of AYA-focused research grows.

Much like adolescents and young adults themselves, AYA ALL care is in rapid transition, caught between pediatric and adult oncology worlds. This ASH guideline represents an important step toward bridging this divide, providing both a roadmap for current management and a shared decision-making tool. However, substantial work remains. The field needs prospective AYA-focused trials to identify optimal treatment strategies that mitigate toxicity, alongside studies addressing AYA-specific psychosocial concerns, financial toxicity, and care access barriers. Multidisciplinary collaborations between pediatric and adult providers, such as this guideline effort, are essential to harmonize disparate approaches and ensure all AYAs receive optimal care regardless of which institutional door they enter. Despite these challenges, this is an exciting time for AYA ALL care. Novel treatment options, increased research focus, and growing awareness of this population’s unique disease biology and care needs offer unprecedented opportunities. Through continued collaboration, the field can ensure every AYA patient benefits from the best both pediatric and adult oncology have to offer. Although the journey is just beginning, this work represents an important first step in bridging two worlds that have remained too long divided.

Conflict-of-interest disclosure: E.C. declares consulting funding from Jazz Pharmaceuticals and Autolus; and research funding from Servier Pharmaceuticals. D.L. declares no competing financial interests.