Recent advances in the treatment of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) highlight the critical role of pediatric-inspired regimens, molecular stratification, and novel immunotherapies. Historically, outcomes for AYA lagged behind children due to greater treatment resistance and toxicity. However, intensification strategies adapted from pediatric protocols have significantly improved remission and survival rates. Despite this progress, survival in AYA remains inferior to pediatric patients, underscoring the need for more refined, biology-driven approaches (Siegel et al., 2018).

One of the most important biological insights concerns the Philadelphia-like (Ph-like) ALL subtype, which is particularly prevalent in AYA (25–30%). Characterized by kinase-activating lesions, this subgroup exhibits high resistance to chemotherapy but offers opportunities for targeted therapy using tyrosine kinase inhibitors (TKIs) such as ruxolitinib or ABL-class inhibitors. Other genetic alterations, including MEF2D, ZNF384, and DUX4 fusions, also contribute to disease heterogeneity and prognosis. Identifying these lesions rapidly remains a major challenge, and the integration of genomic profiling with predictive algorithms and ex vivo drug sensitivity testing is expected to optimize individualized care (Pui et al., 2019).

Minimal residual disease (MRD) monitoring has become a cornerstone of risk stratification in AYA ALL. Early MRD levels after induction and consolidation strongly predict relapse risk and guide decisions regarding allogeneic hematopoietic stem cell transplantation (allo-HSCT). Importantly, MRD thresholds differ between pediatric and adult-inspired protocols, highlighting the need for age-specific approaches. Furthermore, MRD is increasingly employed as a primary endpoint in clinical trials and as a trigger for introducing immunotherapies (Stock et al., 2019).

Immunotherapeutic agents are transforming frontline therapy in AYA ALL. Inotuzumab ozogamicin (anti-CD22) and blinatumomab (CD3–CD19 bispecific antibody) have demonstrated superior response rates and MRD clearance compared with standard chemotherapy in relapsed/refractory settings. Both are now being evaluated earlier in therapy, particularly as consolidation strategies. Similarly, CD19-directed chimeric antigen receptor (CAR) T-cell therapy, notably tisagenlecleucel, has shown durable remissions in pediatric and AYA patients, although relapse due to antigen loss remains a challenge. Efforts are underway to improve CAR T-cell persistence and safety in this age group (Pui et al., 2019).

Beyond targeted and immune-based therapies, novel small molecules such as BCL2 inhibitors (venetoclax, navitoclax) and menin inhibitors show promise in genetically defined subgroups. These agents may further reduce chemotherapy intensity while improving efficacy.

Equally crucial is comprehensive supportive care for AYA patients. Fertility preservation, psychosocial support, and survivorship programs are essential to address long-term treatment burdens, particularly for those undergoing allo-HSCT. Late complications such as infertility, osteonecrosis, and prolonged immune dysfunction remain pressing issues that require multidisciplinary management (Siegel et al., 2018).

In conclusion, the therapeutic landscape of AYA ALL is shifting from generalized intensification to precision medicine. Advances in understanding disease biology, the incorporation of MRD into decision-making, and the integration of immunotherapy and small molecules are reshaping standards of care. Future progress will depend on broad clinical trial participation and multidisciplinary support to optimize both survival and quality of life for AYA patients with ALL.