Highlights
– In a real-world Campus ALL analysis of adults with Philadelphia chromosome–negative ALL treated with the pediatric-inspired GIMEMA LAL1913 protocol, pre-transplant measurable residual disease (MRD) was the dominant predictor of post–alloHSCT success.
– Three‑year overall survival (OS) and disease-free survival (DFS) were 80% and 70% for MRD‑negative patients versus 47% and 41% for MRD‑positive patients.
– MRD negativity conferred benefit even for patients transplanted in second complete remission (CR2): 3‑year OS/DFS 60%/56% versus 13%/13% when MRD positive.
– Patients older than 55 years experienced similar long-term survival to younger patients, with non-relapse mortality (NRM) below 20% at three years, supporting careful use of alloHSCT in selected older adults.
Background: clinical context and unmet need
Adult acute lymphoblastic leukemia (ALL) remains a high-risk hematologic malignancy where long-term cure often requires consolidation with allogeneic hematopoietic stem cell transplantation (alloHSCT) for patients with adverse disease features or inadequate early response. Over the past two decades, ‘pediatric-inspired’ intensive chemotherapy regimens applied to adults have improved remission rates and survival, but optimal post-remission allocation—particularly the decision and timing of alloHSCT—continues to rely on early risk stratifiers, notably measurable residual disease (MRD).
MRD quantification by molecular or multi‑parameter flow cytometry is now an established prognostic marker in ALL. MRD positivity pre-transplant has been associated with higher relapse rates and worse survival in multiple cohorts, motivating strategies to reduce disease burden prior to transplantation, including targeted immunotherapies and intensified cytoreduction. However, data originating from real-world use of contemporary pediatric-inspired protocols combined with MRD-guided transplant strategies are still needed to inform practical decisions across age groups and remission statuses.
Study design: Campus ALL analysis of GIMEMA LAL1913-treated patients
The Campus ALL collaborative group performed a multicenter, real-world analysis of adult Philadelphia chromosome–negative ALL patients treated according to the pediatric-inspired, MRD‑oriented GIMEMA LAL1913 protocol who subsequently underwent alloHSCT. The study sought to evaluate long-term transplant outcomes and identify key pre-transplant factors linked to survival and relapse, with particular focus on MRD status and remission number (first complete remission, CR1, versus second complete remission, CR2).
Patients were selected from routine clinical practice across participating centers and managed according to the protocol’s MRD-directed workflow. MRD assessment methodologies and thresholds used for clinical decisions were those adopted locally within the GIMEMA framework; transplant conditioning, donor selection, and graft-versus-host disease (GVHD) prophylaxis followed center-specific standards. Primary endpoints included overall survival (OS) and disease-free survival (DFS) at three years post-transplant; secondary analyses examined non-relapse mortality (NRM) and outcomes stratified by age and remission status.
Key findings and results
MRD is the dominant predictor of post-transplant survival
The Campus ALL analysis demonstrates a pronounced difference in long-term outcomes according to pre-transplant MRD. Patients who were MRD negative at the time of alloHSCT achieved markedly superior survival: 3‑year OS of approximately 80% and DFS of 70%. By contrast, MRD‑positive patients had substantially worse outcomes, with 3‑year OS of 47% and DFS of 41%.
These effect sizes are clinically meaningful and consistent with the established concept that residual disease immediately before transplant represents biologic chemo-resistance and an increased likelihood of post-transplant relapse despite graft-versus-leukemia effects. The observed absolute differences in survival emphasize the importance of achieving MRD negativity whenever feasible before proceeding to alloHSCT.
Impact in patients transplanted in CR2
Importantly, the benefit of MRD negativity extended to patients transplanted in CR2. In this subgroup, MRD‑negative patients had 3‑year OS and DFS of 60% and 56%, respectively. Conversely, MRD-positive CR2 patients had dismal outcomes—3‑year OS and DFS around 13%—indicating that MRD positivity portends very high risk even after achieving a subsequent morphologic remission.
This finding has significant practical implications: for patients relapsing and achieving a second remission, MRD status should be assessed and considered pivotal for transplant timing and adjunctive therapy decisions. In many cases, attempting MRD reduction prior to alloHSCT (for example with immunotherapy) may be warranted to improve transplant efficacy.
Age does not eliminate transplant benefit but modifies risk
In contrast to older historic series that discouraged transplant in older adults because of high NRM, the Campus ALL data show that patients aged >55 years attained overall survival comparable to younger cohorts. Although NRM was slightly higher in older patients, it remained under 20% at three years—an acceptable level in many transplant programs when weighed against relapse risk in high-risk ALL.
These findings support a more individualized approach in older adults: with careful patient selection, optimized conditioning (including reduced-intensity approaches where appropriate), and contemporary supportive care, alloHSCT remains a viable curative option for fit older patients with high-risk Ph‑negative ALL.
Safety and non-relapse mortality
Non-relapse mortality in the entire cohort remained below 20% at three years for older patients and was acceptable in the population as a whole. The analysis suggests that modern transplant platforms and center expertise can limit transplant-related mortality, thereby preserving the potential benefit of alloHSCT even in populations historically considered higher risk.
Expert commentary: interpretation, mechanistic rationale, and clinical implications
The Campus ALL analysis aligns with a robust body of evidence that places MRD at the center of treatment decision-making in adult ALL. Biological plausibility for the observed effect is straightforward: detectable residual leukemic cells reflect resistant clones that can evade conditioning and immune-mediated graft-versus-leukemia effects, seeding early relapse after transplant. Achieving MRD negativity prior to transplant therefore both lowers disease burden and improves the chance that the allograft will eradicate remaining malignant cells.
Clinically, this argues for systematic MRD monitoring during induction and consolidation, standardized MRD methodologies across centers, and pathways to intervene when MRD persists. Available strategies to convert MRD‑positive status to negative prior to transplant include targeted immunotherapies (e.g., bispecific T‑cell engager antibodies or antibody–drug conjugates), salvage chemotherapy, and chimeric antigen receptor T (CAR‑T) cell therapy where appropriate. The Campus ALL authors conclude that early pre-transplant immunotherapy should be considered whenever feasible for MRD‑positive patients, a recommendation consistent with evolving practice patterns.
For CR2 patients, the extremely poor outcomes when MRD positive highlight an urgent need for intensification or alternative strategies before transplant. When MRD eradication cannot be achieved, clinicians should weigh the limited benefit of proceeding directly to alloHSCT against the potential to use experimental or newer targeted approaches to deepen response first.
Limitations and generalizability
As a real-world multicenter analysis, the Campus ALL study captures pragmatic outcomes but also inherits limitations common to observational datasets. These include heterogeneity in MRD assays and thresholds, variation in conditioning regimens and supportive care practices, and potential selection biases for who proceeds to transplant. The observational design cannot definitively attribute causality to MRD status beyond well-recognized associations, nor can it specify the optimal interventions to convert MRD‑positive to MRD‑negative status.
Despite these caveats, the magnitude and consistency of the observed MRD effect make a convincing case for integrating MRD into transplant decision algorithms. The findings are most directly generalizable to adult Ph‑negative ALL treated under the pediatric-inspired GIMEMA LAL1913 approach but likely apply broadly where similar induction intensity and MRD monitoring are used.
Practical recommendations for clinicians
– Systematic MRD assessment should be performed before transplant and used as a key determinant of transplant timing and pre-transplant interventions.
– For MRD-negative patients, proceeding to alloHSCT when otherwise indicated is supported by favorable 3‑year OS and DFS.
– For MRD-positive patients—particularly those in CR2—consideration should be given to MRD-reduction strategies (e.g., immunotherapy or clinical trial enrollment) before alloHSCT when clinically feasible.
– Older but fit patients should not be excluded from transplant solely based on chronological age; individualized assessment and optimization of conditioning and supportive care can yield acceptable NRM and comparable long-term survival.
Research and policy implications
Key unanswered questions include the optimal MRD threshold and assay standardization across centers, the best sequence and choice of MRD‑eradicating agents before transplant, and prospective evidence that pre-transplant MRD eradication improves post-transplant survival. Randomized or prospective trials evaluating MRD-directed pre-transplant interventions and standardized MRD-driven transplant algorithms are needed to move from association to evidence-based practice change.
Conclusion
The Campus ALL real-world analysis of adult Ph‑negative ALL patients treated with the pediatric‑inspired GIMEMA LAL1913 protocol confirms that alloHSCT remains a cornerstone consolidative therapy for high-risk disease. Crucially, pre-transplant MRD status is the dominant predictor of post-transplant outcome: MRD negativity is associated with substantially higher 3‑year OS and DFS, including in patients transplanted in CR2, whereas MRD positivity predicts high relapse risk and poor survival.
These data support routine MRD-guided pathways for transplant decisions, proactive efforts to achieve MRD negativity—potentially with immunotherapies—and thoughtful consideration of transplant for selected older adults. Future prospective studies should focus on standardized MRD assessment and testing pre-transplant interventions aimed at converting MRD‑positive patients to negative to improve long-term survival.
Funding and clinicaltrials.gov
The Campus ALL study is reported as published in Bone Marrow Transplantation (Cavallaro et al. 2025). Funding sources and trial registrations are those declared in the primary publication.
References
1. Cavallaro G, Lazzarotto D, Pavoni C, Valsecchi F, Grassi A, Papayannidis C, Cerrano M, Fracchiolla N, Giglio F, Dargenio M, Lunghi M, Imbergamo S, Del Principe MI, Trappolini S, Fumagalli M, Zappasodi P, Salutari P, Delia M, Pasciolla C, Mosna F, Scappini B, Forghieri F, Chiusolo P, Skert C, Cambò B, Defina M, Lanzarone G, Mauro E, Bonifacio M, Mazzone C, Santoro L, Mulè A, Mancini V, Minetto P, Battipaglia G, Cignetti A, Aprile L, Chiaretti S, Foà R, Candoni A, Lussana F. Outcomes of allogeneic stem cell transplant in adult Philadelphia negative acute lymphoblastic leukemia patients treated with the pediatric-inspired GIMEMA 1913 protocol. A Campus ALL study. Bone Marrow Transplant. 2025 Sep;60(9):1228-1235. doi: 10.1038/s41409-025-02632-z. Epub 2025 Jun 2. PMID: 40456937; PMCID: PMC12401717.
Note: Readers are encouraged to consult the full publication for detailed methods, cohort sizes, and center-specific practices underlying the summary presented here.
