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Acute lymphoblastic leukemia (ALL) in adolescent and young adult (AYA) patients, aged between 15 and 39, accounts for approximately 20% of all ALL cases.1 While ALL is the most common childhood cancer, and pediatric patients often exhibit high cure rates (around 90%), AYA patients have historically experienced poorer outcomes, with five-year overall survival (OS) rates between 54%–74%.2 This disparity has been partly attributed to biological differences in disease subtypes, with AYA patients exhibiting a higher prevalence of high-risk cytogenetic abnormalities and T-cell ALL (T-ALL), as well as a lower prevalence of favorable features, including hyperdiploidy or ETV6-RUNX1 translocation. 2,3

The management of AYA patients with ALL

 

Treatment of this patient population poses unique challenges due to their transitional status between pediatric and adult oncology paradigms. Historically, adult treatment protocols have been used, which are generally less intensive than pediatric regimens and associated with inferior outcomes.4 However, recent studies utilizing pediatric-inspired protocols in AYA patients have demonstrated improved survival outcomes. Among these trials was the pivotal prospective CALGB 10403 trial (NCT00558519), which investigated a pediatric regimen consisting of glucocorticoids, vincristine, and pegylated asparaginase with intensive and prolonged central nervous system (CNS) prophylaxis in AYA patients up to the age of 40. This therapeutic approach demonstrated encouraging safety and efficacy, and improved survival rates compared with historical controls, suggesting that the use of pediatric treatment regimens is feasible in the AYA population.4 

 

In a real-world setting, the treatment regimen a patient receives is often determined by whether they enter into a pediatric or adult treatment center, as well as by the expertise of the treating physician and the availability of suitable clinical trials.5 Historically, the majority of AYA patients over the age of 18 have been managed in community settings by adult oncologists, resulting in limited exposure to pediatric regimens, despite their potential association with improved clinical outcomes.6,7

Unique challenges in the young adult population

 

Although the increased adoption of pediatric regimens has helped to improve the outcomes in AYA patients, challenges related to toxicity and adherence remain prominent. In an interview from the 19th International Symposium on Acute Leukemias (ISAL XIX), which took place in Munich, Germany, earlier this year, Wendy Stock, MD, University of Chicago Medical Center, Chicago, IL, provided her comments on this, noting that pediatric regimens have a ‘much more dramatic toxicity profile in a young adult population’. She also outlined some of the distinctive challenges faced by AYA patients with ALL, including fertility concerns and psychosocial burdens, highlighting that this is ‘a really unique population that requires special support’.

 

Improving outcomes for young adults with ALL: progress and challenges

 

Novel approaches are under investigation to further optimize outcomes for young adult patients with ALL further, and clinical trial enrollment, where available, is the current standard of care for AYA B-cell ALL (B-ALL). Ongoing trials are exploring the addition of targeted therapies, including bispecific antibodies and antibody-drug conjugates, to established chemotherapy backbones.8 One such study was the Phase III Alliance A041501 trial (NCT03150693), which incorporated inotuzumab ozogamicin into the CALGB 10403 regimen in newly diagnosed, young adult patients with B-ALL.9 Dr Stock shared the results of this study with VJHemOnc, stating that ‘our primary endpoint was not achieved in this trial. On the other hand, I’m happy to say that all patients, both in the randomized and non-randomized arms, did significantly better than in [CALGB] 10403, potentially because we had better adherence and because we made some minor tweaks to the protocol to make it both more effective and less toxic’.

 

 

When discussing the progress and challenges in improving outcomes for AYA patients, Dr Stock also mentioned ‘the incorporation of novel antibodies into frontline treatment‘ for B-ALL. For T-ALL, which comprises 30% of cases of young adult ALL and in which these antibodies are not yet available, she noted that there is a focus on ‘[the use of] other agents, including the BH3 mimetics, that will sort of sensitize cells to chemotherapy‘.

Additionally, CAR T-cell therapy has shown promise in the relapsed/refractory (R/R) setting, and may eventually play a role in frontline therapy, a stage at which disease burden is lower, and CAR-T may therefore demonstrate improved efficacy.8 

Although the incidence of Philadelphia chromosome–positive (Ph+) ALL in pediatric patients is low (1–2%), this entity accounts for approximately 25–30% of cases in young adults. In these patients, tyrosine kinase inhibitors (TKIs) have significantly improved survival outcomes, and investigations are currently underway to optimize the selection and intensity of TKI treatment.8 Due to the teratogenic effects of TKIs, the feasibility of TKI discontinuation may require evaluation in female patients who wish to conceive.

Advice for community oncologists when approaching AYA ALL

 

Given that ALL is considered a rare disease in AYA patients, many community oncologists may have limited experience in managing this patient population. Dr Stock indicated that ‘community physicians should feel free to reach out to people with experience in the field if they’re running into questions or problems in the management of these patients’. 

 

We also recently spoke with Marlise Luskin, MD, MSCE, of the Dana-Farber Cancer Institute, Boston, MA, as part of our coverage of the 2025 American Society of Clinical Oncology (ASCO) Meeting. Dr Luskin commented on the challenges in managing young adult ALL and provided advice to the community oncologist, reminding them that they are ‘an important partner in the care of these patients’.

In conclusion, although the outcomes for AYA patients have improved significantly with the use of pediatric and “pediatric-inspired” regimens, further work is needed to ensure this group of patients receives appropriate care and support, especially given the unique challenges they face.

References

  1. Burke MJ, Devidas M, Chen Z, et al. Outcomes in adolescent and young adult patients (16 to 30 years) compared to younger patients treated for high-risk B-lymphoblastic leukemia: report from Children’s Oncology Group Study AALL0232. Leukemia. 2022 Mar; 36(3):648-655.
  2. Janardan SK, Miller TP. Adolescents and young adults (AYAs) vs pediatric patients: survival, risks, and barriers to enrollment. Hematology Am Soc Hematol Educ Program. 2023 Dec;2023(1):581-586.
  3. Rytting ME, Jabbour EJ, O’Brien SM, et al. Acute lymphoblastic leukemia in adolescents and young adults. Cancer. 2017 Jul;123(13):2398-2403.
  4. Stock W, Luger SM, Advani AS, et al. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019 Apr;133(14):1548-1559.
  5. Curran E, Stock W. How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood. 2015 Jun;125(24):3702-10.
  6. Muffly L, Alvarez E, Lichtensztajn D, et al. Patterns of care and outcomes in adolescent and young adult acute lymphoblastic leukemia: a population-based study. Blood Adv. 2018 Apr;2(8):895-903.
  7. Siegel SE, Stock W, Johnson RH, et al. Pediatric-Inspired Treatment Regimens for Adolescents and Young Adults With Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Review. JAMA Oncol. 2018 May;4(5):725-734.
  8. Molina JC, Rotz S. Acute lymphoblastic leukemia in young adults: which up-front treatment? Hematology Am Soc Hematol Educ Program. 2023 Dec;2023(1):573-580.
  9. DeAngelo DJ, Yin J, Advani AS, et al. Addition of Inotuzumab to a Pediatric-Inspired Chemotherapy Regimen in Young Adult Patients with B-Cell Acute Lymphoblastic Leukemia: Findings from the Alliance A041501 Phase 3 Randomized Trial. Blood. 2024 Nov; 144(1):308. 
Written by Natalie Markova
Reviewed by Raffaella Facchini
Publishing date: 20/06/2025

The content of VJHemOnc is intended for healthcare professionals