Highlight
This article summarizes a retrospective study on a unified transplant platform using fludarabine, cyclophosphamide, and 2 Gy total body irradiation (FluCyTBI) combined with post-transplant cyclophosphamide (PTCy). Key points include: 1) The single-platform regimen is effective and safe in elderly AML or high-risk MDS patients undergoing either haploidentical or unrelated donor allo-SCT. 2) Post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis results in low rates of severe acute and moderate/severe chronic GVHD. 3) Donor age and sex-mismatch influence GVHD incidence, highlighting the role of non-HLA donor factors. 4) Three-year overall survival was 62%, with monosomal karyotype being a negative prognostic factor.
Study Background
Allogeneic stem cell transplantation (allo-SCT) remains the only curative option for many patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), particularly those with high-risk disease features. However, elderly patients (>70 years) represent a vulnerable population with elevated procedure-related toxicity and higher relapse rates due to comorbidities and less intensive conditioning regimens. Traditional myeloablative conditioning regimens are often too toxic for these patients, necessitating the development of nonmyeloablative conditioning (NMAC) approaches that balance disease control with acceptable tolerability.
Haploidentical donor transplantation has expanded donor availability but initially carried concerns regarding graft-versus-host disease (GVHD). The use of post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis has transformed outcomes by effectively reducing GVHD rates, enabling successful haploidentical transplantations. Recently, PTCy-based prophylaxis has been extended to unrelated donor (UD) allografts, offering a potential unified GVHD prevention strategy across donor types.
Study Design
This retrospective study analyzed 203 consecutive older patients with AML or high-risk MDS who underwent allo-SCT at a single center between 2015 and 2024. Median patient age was 69 years. Conditioning consisted of fludarabine, cyclophosphamide, and low-dose (2 Gy) total body irradiation (FluCyTBI), paired with PTCy as GVHD prophylaxis. Donor sources included haploidentical donors (64%), mismatched unrelated donors (18%), and matched unrelated donors (18%). The objective was to assess safety, incidence of acute and chronic GVHD, non-relapse mortality (NRM), relapse, and overall survival (OS) following this unified platform.
Key Findings
The incidence of grade III-IV acute GVHD by day +100 was 8%, and moderate/severe chronic GVHD at 3 years was 18%, indicating favorable GVHD control with this PTCy-based regimen. Notably, donor age ≥35 years was associated with increased risk of severe acute GVHD, while female-to-male sex mismatch was linked to higher risk of moderate/severe chronic GVHD, underscoring the significance of non-HLA donor-related factors in transplant outcomes.
Three-year non-relapse mortality was 15%, reflecting acceptable transplant-related risk in this older population. Overall survival at 3 years was 62%, an encouraging outcome for this high-risk demographic. Importantly, only monosomal karyotype was an independent predictor of worse survival, highlighting the role of adverse cytogenetics over other variables.
The safety profile was favorable, with manageable toxicity owing to the nonmyeloablative conditioning and effective GVHD prophylaxis. The low-dose total body irradiation (2 Gy) likely minimized organ toxicity while providing sufficient immunomodulatory effect for engraftment.
Expert Commentary
This study supports the evolving paradigm of using PTCy not only in haploidentical but also in unrelated donor transplantation in elderly AML/MDS patients. The combination of FluCyTBI conditioning with PTCy prophylaxis represents a simplified, standardized platform that may reduce practice variability and improve outcomes.
Donor age and sex mismatch effects highlight the complexity of alloimmune responses beyond HLA compatibility and suggest that donor selection criteria should incorporate these parameters to optimize outcomes. While the retrospective design limits causal inference, the large real-world cohort and extended follow-up strengthen the clinical relevance.
Further prospective randomized studies directly comparing this unified regimen against other conditioning and GVHD prophylaxis protocols are warranted to confirm benefits and refine donor selection. Inclusion of biomarkers for immune reconstitution and GVHD prediction may also enhance individualized transplant strategies.
Conclusion
This extensive retrospective analysis demonstrates that fludarabine, cyclophosphamide, and 2 Gy TBI conditioning combined with post-transplant cyclophosphamide is a feasible, safe, and effective single-platform approach for haploidentical and unrelated donor allo-SCT in elderly patients with AML or high-risk MDS. It achieves low rates of severe GVHD and acceptable non-relapse mortality, yielding promising overall survival despite high baseline risk. Non-HLA donor factors such as age and sex mismatch emerge as critical determinants of GVHD risk and warrant consideration in donor selection. This unified platform may simplify transplant strategies and improve outcomes in older patients historically challenged by toxicity and relapse.
Funding and ClinicalTrials.gov
The study was conducted at a single center without reported external funding. No clinical trial registration information was provided, consistent with its retrospective design.
References
1. Luznik L, O’Donnell PV, Fuchs EJ. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol. 2012;39(6):683–693. doi:10.1053/j.seminoncol.2012.09.004
2. Ciurea SO, de Lima M, Giralt S, et al. Haploidentical Stem Cell Transplantation With Post-Transplant Cyclophosphamide in Adult Patients With Acute Myeloid Leukemia: A Prospective Phase II Trial. J Clin Oncol. 2020;38(25):2912-2920. doi:10.1200/JCO.19.02998
3. Solomon SR, Kasamon YL, de Lima M, et al. Haploidentical Transplantation with Post-Transplant Cyclophosphamide versus Matched Unrelated Donor Hematopoietic Stem Cell Transplantation for Acute Leukemia. J Clin Oncol. 2019;37(5):501-510. doi:10.1200/JCO.18.01280
4. McCurdy SR, Kanakry CG, Tsai HL, et al. Outcomes of matched unrelated donor hematopoietic cell transplantation following nonmyeloablative conditioning with posttransplant cyclophosphamide. Biol Blood Marrow Transplant. 2019;25(3):500-507. doi:10.1016/j.bbmt.2018.10.061
5. Devillier R, Dhedin N, Chabannon C, et al. Fludarabine, cyclophosphamide and 2 Gy TBI with PTCy as a single platform for haplo and unrelated donor allo-SCT in older AML or MDS patients. Bone Marrow Transplant. 2026 Jun 27. doi:10.1038/s41409-026-01255-2