Age-adapted chemotherapy and MRD-oriented transplant for Ph-negative acute lymphoblastic leukemia: the GRAALL-2014 trial
Boissel N, Chevret S, Huguet F, et al. Blood. 2026;147(8):821-833
Comment by Alexandros Spyridonidis, Department of Hematology, BMT and Cellular Therapy Program, University of Patras, Patras, Greece.
Unlike acute myeloid leukemia, risk stratification and transplant indications in adult acute lymphoblastic leukemia (ALL) remain incompletely defined. The central question is not whether transplantation is effective, but rather in which patients it truly provides meaningful benefit. (1)
The GRAALL-2014 trial represents a pivotal step toward answering that question. (2) In adults aged 18–59 years with Ph-negative ALL, the investigators implemented two major changes compared with GRAALL-2005. First, chemotherapy intensity was reduced in patients ≥45 years to address excessive non-relapse mortality observed in older adults. Second, and more importantly for our field, allo-HSCT in first complete remission (CR1) was restricted to very high-risk (VHR) patients defined by poor early response: late CR after salvage, MRD ≥10⁻³ after induction (TP1), or MRD ≥10⁻⁴ after consolidation (TP2). Thus, transplant indication was driven by MRD rather than by baseline biological features such as pro-B phenotype, early or mature T-ALL, KMT2A rearrangement, Ph+, or Ph-like disease.
Among 743 enrolled patients (489 B-ALL, 254 T-ALL), 89.2% achieved CR after induction. Of these, 213 (30.7%) were classified as VHR and eligible for transplantation, predominantly due to MRD positivity at TP1 (65.7%) or TP2 (20.2%), or late CR after salvage (14.1%). This VHR group was enriched in older patients and in B-ALL with high leukocyte count, KMT2A rearrangement, and IKZF1 deletion, confirming that adverse biology often translates into persistent MRD.
The MRD-driven strategy markedly reduced transplant use. Compared with GRAALL-2005, transplant indications decreased by more than half (2.5-fold in patients <45 years and 1.9-fold in those ≥45 years). Overall, 22.9% of patients underwent allo-HSCT in CR1 (66.7% of those with an indication), versus 38.5% in GRAALL-2005.
From a transplant perspective, the key observation is that the nearly 50% reduction in transplant use did not compromise outcomes. Despite a modest increase in relapse incidence (29.6% to 37.6%), likely related to the reduced transplant utilization, disease-free survival remained stable (~57%). Notably, overall survival improved significantly in both younger (65.5% to 71.7%) and older patients (49.6% to 59.5%), likely driven by a marked reduction in non-relapse mortality (11.6% to 5.3%), particularly among older patients receiving age-adapted therapy, along with improved transplant selection and advances in salvage strategies, including greater access to second transplantation and immunotherapy.
The most compelling finding for transplant physicians comes from the time-dependent Simon–Makuch analysis: after accounting for transplant timing, MRD-positive patients derived a clear survival benefit from allo-HSCT. In contrast, GRAALL-2005, which relied largely on baseline biological eligibility criteria, failed to demonstrate such a definitive transplant advantage. This distinction is crucial: transplantation is most effective when directed by biological resistance as measured by MRD.
At the same time, important questions remain. Among the 259 MRD-negative/standard-risk patients who were not transplanted, 4-year DFS was 63.7% (95% CI, 57.9–70.1), suggesting that a substantial proportion can safely avoid CR1 transplantation, although an estimated one third of MRD negative patients still experience relapse and may potentially forgo benefit by avoiding transplantation in CR1. Whether patients with high-risk genetic features who achieve MRD negativity should still undergo allo-HSCT remains unresolved. The results of the GMALL 08/13 trial, which randomizes genetically high-risk patients in molecular CR to transplantation or no transplantation, are eagerly awaited and may further refine the transplant approach. (3)
GRAALL-2014 marks an important advance in adult ALL management. Rather than diminishing the role of transplantation, it refines and more precisely defines its indication. The key message for our transplant community is clear: allo-HCT remains a potent and potentially curative therapy, with MRD now central to transplant selection. Yet the optimal integration of genetic risk and frontline immunotherapy into MRD-guided strategies remains to be defined.
References
- Spyridonidis A. To Transplant or Not To Transplant in First Remission Acute Lymphoblastic Leukemia? Study group data give some answers, but not all. Transplantation and Cellular Therapy. 2022;28(12):791–792.
- Boissel N, Chevret S, Huguet F, et al. Age adapted chemotherapy and MRD-oriented transplant for Ph-negative acute lymphoblastic leukemia: the GRAALL-2014 trial. Blood. 2026;147(8):821-833.
- Goekbuget N, Schneller F, Nachtkamp K Sr, et al. Chemotherapy or stem cell transplantation in adult high risk Ph/BCR:: ABL1-negative ALL patients with early MRD negativity: results of the randomized GMALL trial 08/2013 [abstract]. Blood. 2024; 144(suppl 1):961.