Highlights
– Allogeneic hematopoietic-cell transplantation (HCT) in AYA patients with acute lymphoblastic leukemia (ALL) in second complete remission (CR2) achieved a 3‑year overall survival (OS) of 53% and progression‑free survival (PFS) of 46% in a retrospective dual‑center cohort (n=164).
– Pretransplant measurable residual disease (MRD) positivity and high HCT‑Comorbidity Index (HCT‑CI >3) independently predicted poorer outcomes; HCT‑CI >3 associated with worse OS (HR 2.7) and higher nonrelapse mortality (HR 4.7).
– Female‑to‑male donor/recipient combinations showed lower relapse risk than male‑to‑male pairs (HR 0.4), while rates of clinically significant graft‑versus‑host disease (GVHD) were substantial: 6‑month grade 2–4 acute GVHD 36%, 3‑year any‑grade chronic GVHD 27%.
Background
Adolescents and young adults (AYA; commonly defined as age ~15–40 years) with acute lymphoblastic leukemia present unique biologic and treatment‑delivery challenges. Outcomes historically differ from pediatric cohorts, and approaches to frontline therapy (pediatric‑inspired vs adult regimens), use of novel immunotherapies, and the timing of allogeneic HCT vary across centers. Relapsed ALL remains a major cause of treatment failure in AYA patients; achieving durable second remissions (CR2) frequently prompts consideration of allogeneic HCT for curative intent. However, contemporary real‑world benchmarks for post‑HCT survival, relapse, nonrelapse mortality (NRM), and GVHD in this specific population are limited.
Study design
This retrospective dual‑center study (MD Anderson Cancer Center and Dana‑Farber Cancer Institute) evaluated 164 AYA patients aged 15–40 years who underwent allogeneic HCT in CR2 between 2010 and 2022. Key baseline and treatment features included:
- Frontline regimens: pediatric‑inspired in 54% and hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone (hyper‑CVAD)‑based in 33%.
- Conditioning intensity: 74% received myeloablative conditioning.
- MRD status pretransplant: 67% MRD‑negative; 33% MRD‑positive.
- Donor/recipient sex and other transplant variables recorded; HCT‑CI used to quantify comorbidity burden.
Primary outcomes were overall survival (OS) and progression‑free survival (PFS). Secondary endpoints included cumulative incidence of relapse and nonrelapse mortality (NRM), and GVHD incidence. Median follow‑up among survivors was 36 months.
Key findings
Overall outcomes: The cohort achieved a 3‑year OS of 53% and PFS of 46% after allogeneic HCT in CR2. These results indicate that HCT remains an important consolidation approach capable of producing durable remissions in a substantial proportion of AYA patients relapsing and achieving CR2.
Impact of comorbidity burden (HCT‑CI)
HCT‑CI >3 was a strong adverse prognostic marker: patients with HCT‑CI >3 experienced significantly worse OS (hazard ratio [HR] 2.7; 95% CI, 1.7–4.3; P < .001) and markedly higher NRM (HR 4.7; 95% CI, 2.2–10; P < .001). This confirms that baseline organ dysfunction and comorbidities remain powerful determinants of transplant tolerance and survival even in a relatively young population.
Measurable residual disease (MRD)
MRD positivity at the time of transplant was associated with inferior PFS (HR 2.0; 95% CI, 1.02–4; P = .04) and higher relapse risk (HR 2.5; 95% CI, 1.2–5.1; P = .01). Importantly, the adverse effect of MRD positivity was most apparent among patients with low HCT‑CI, suggesting that in physiologically fit patients MRD remains an important modifiable risk factor that could guide pretransplant or posttransplant interventions.
Donor sex effects
Female‑to‑male donor/recipient combinations were associated with lower relapse risk compared with male‑to‑male combinations (HR 0.4; 95% CI, 0.2–0.9; P = .03). This finding aligns with immunologic observations that donor sex and parity can modulate graft‑versus‑leukemia effects, but it requires confirmation and careful interpretation because of potential tradeoffs with GVHD and other complications.
GVHD and transplantation morbidity
Acute and chronic GVHD remained clinically significant: cumulative incidence of grade 2–4 acute GVHD at 6 months was 36%. Three‑year cumulative incidence of any‑grade chronic GVHD was 27%, with reported proportions of moderate and severe chronic GVHD among affected patients of 37% and 25%, respectively. These GVHD rates underscore the morbidity that contributes to NRM and to long‑term quality‑of‑life considerations in AYA survivors.
Interpretation and context
These real‑world, contemporary outcomes provide valuable benchmarks for clinicians counseling AYA patients who achieve CR2. The results reinforce two practical principles:
- Optimizing disease control prior to transplant matters. MRD negativity at HCT remains a reproducible predictor of lower relapse and superior PFS/OS. Where feasible, bridging therapies that can convert MRD positivity to negativity (for example, blinatumomab in MRD‑positive B‑ALL) should be considered prior to proceeding to HCT.
- Baseline physiologic reserve is a major determinant of transplant success. Even among AYA patients, comorbidity burden as quantified by the HCT‑CI strongly impacts NRM and survival and should influence candidacy, conditioning intensity, and prehabilitation strategies.
These findings should be viewed in the context of rapidly evolving therapeutic options for relapsed ALL. CD19‑directed chimeric antigen receptor T‑cell (CAR‑T) therapies can produce high CR rates in relapsed/refractory B‑ALL and may alter the traditional role and timing of HCT in some patients, particularly in children and young adults who achieve deep remissions after CAR‑T. Landmark studies (e.g., ELIANA/CTL019 protocols) have shown durable remissions with CAR‑T in AYA populations, but the decision to consolidate with HCT after CAR‑T remains individualized.
Clinical implications and practical recommendations
- Assess MRD thoroughly with standardized, high‑sensitivity methods before HCT; consider targeted bridging therapy (e.g., blinatumomab, inotuzumab) or CAR‑T for persistent MRD in eligible patients.
- Incorporate HCT‑CI assessment into pretransplant evaluation; pursue organ optimization and supportive care to reduce NRM risk where possible.
- Donor selection may consider sex mismatches as one of multiple factors; the observed lower relapse risk with female‑to‑male donors needs prospective validation and should be balanced against GVHD risk.
- Plan for vigilant GVHD prophylaxis and early detection/management given substantive rates of acute and chronic GVHD in this cohort; include survivorship planning for chronic GVHD sequelae.
- Discuss alternative consolidation strategies in shared decision‑making (e.g., CAR‑T or clinical trials) especially for patients with high HCT‑CI or persistent MRD who may have elevated transplant‑related risk.
Limitations
As an observational retrospective dual‑center study, the analysis is subject to selection bias, heterogeneity in practice across eras (2010–2022), and potential variability in MRD assay sensitivity and timing. Changes in supportive care, donor selection practices, and integration of novel immunotherapies over the study period may affect generalizability to present-day practice. Additionally, detailed quality‑of‑life and long‑term functional outcomes were not reported here but are highly relevant for the AYA population.
Conclusion
This dual‑center retrospective analysis establishes contemporary real‑world benchmarks for allogeneic HCT in AYA patients with ALL in CR2: roughly half of patients achieve 3‑year OS, with MRD negativity and low HCT‑CI identifying those most likely to benefit. These results support prioritizing disease eradication pretransplant where feasible, optimizing comorbid conditions, and individualized donor and strategy selection. Future prospective studies should evaluate strategies to convert MRD positivity pre‑HCT, the role of posttransplant maintenance or MRD‑guided interventions, and the optimal integration of CAR‑T therapy into treatment pathways for relapsed ALL in AYA patients.
Funding and clinicaltrials.gov
The primary manuscript reports institutional funding and disclosures; no specific clinicaltrials.gov identifier is associated with this retrospective analysis. Readers should consult the original publication for detailed funding and conflict of interest statements.
Selected references
– Pasvolsky O, Shimony S, Saliba RM, et al. Allogeneic Hematopoietic Stem Cell Transplantation in Adolescents and Young Adults With Acute Lymphoblastic Leukemia—A Retrospective, Dual‑Center Study. Am J Hematol. 2025 Oct 6. doi: 10.1002/ajh.70101. Epub ahead of print. PMID: 41051170.
– Gökbuget N, Dombret H, Ribera J‑M, et al. Blinatumomab for minimal residual disease in B‑cell precursor acute lymphoblastic leukemia. N Engl J Med. 2018;379(9): 818–829.
– Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–1517.
– Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)‑specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8):2912–2919.
Author note
This article synthesizes and interprets findings from the cited dual‑center study for clinicians and policy professionals caring for adolescents and young adults with relapsed ALL. The goal is to provide actionable insight into patient selection, pretransplant optimization, and areas where prospective research is needed.