Highlight
- Fludarabine combined with treosulfan (FluTreo) and fludarabine with total body irradiation (FluTBI) were compared as conditioning regimens before allogeneic HSCT in adult acute lymphoblastic leukemia (ALL).
- No significant differences were found in the incidences of acute/chronic graft-versus-host disease (GVHD), relapse, or non-relapse mortality between the two groups.
- Leukemia-free survival and overall survival rates showed a nonsignificant trend favoring FluTBI, but outcomes were generally comparable.
- This study supports FluTreo as a valid conditioning alternative for patients in complete remission prior to alloHSCT in ALL.
Study Background
Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy that often requires allogeneic hematopoietic stem cell transplantation (alloHSCT) to achieve long-term remission, especially in adults. Conditioning regimens administered prior to alloHSCT are critical to eliminate residual leukemic cells and immunosuppress the host to allow engraftment. Historically, total body irradiation (TBI) combined with chemotherapy, such as fludarabine, has been a standard conditioning approach due to its myeloablative and anti-leukemic effects.
However, TBI carries risks of long-term toxicities and may be contraindicated in older patients or those with comorbidities. Treosulfan, a bifunctional alkylating agent with favorable toxicity profiles, has emerged as a promising alternative conditioning agent. Data on treosulfan-based regimens in ALL remain limited, motivating comparative studies to evaluate their safety and efficacy relative to conventional TBI-based conditioning strategies.
Study Design
This retrospective matched-pair analysis utilized data from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). Patients with ALL who underwent alloHSCT in complete remission after conditioning with fludarabine combined with either treosulfan (FluTreo, n=153) or total body irradiation (FluTBI, n=431) were included.
Median patient ages were 56.5 years in the FluTreo group and 54.1 years in the FluTBI group. Donor sources included unrelated donors (~53%), matched siblings (~31%), and haploidentical donors (~15%) in both groups. Primary endpoints assessed were incidences of acute (grade II–IV) and chronic GVHD, relapse, non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS), and GVHD-free/relapse-free survival (GRFS).
Key Findings
The analysis demonstrated no statistically significant differences in key transplant outcomes between the FluTreo and FluTBI conditioning regimens:
- Acute GVHD (grade II–IV): 26.6% in FluTreo vs. 30% in FluTBI (p=0.43)
- Chronic GVHD (2-year incidence): 33.5% in FluTreo vs. 40.7% in FluTBI (p=0.23)
- Relapse (2-year incidence): 28.1% in FluTreo vs. 25.1% in FluTBI (p=0.15)
- Non-relapse mortality (2-year incidence): 25.6% in FluTreo vs. 20.4% in FluTBI (p=0.38)
- Leukemia-free survival: 46.2% for FluTreo vs. 54.5% for FluTBI (p=0.1)
- Overall survival: 55% for FluTreo vs. 61.3% for FluTBI (p=0.22)
- GVHD-free, relapse-free survival: 33.7% in FluTreo vs. 40.8% in FluTBI (p=0.06)
Though the FluTBI group showed numerically higher survival and GRFS rates, these differences did not reach conventional statistical significance. The comparable rates of GVHD and non-relapse mortality indicate that treosulfan-based conditioning does not increase transplant-related toxicity risk.
Expert Commentary
Conditioning regimen selection in alloHSCT balances the goals of achieving sufficient anti-leukemic efficacy while minimizing toxicity. TBI offers robust myeloablation but is linked to significant long-term organ toxicity and secondary malignancies. Treosulfan has gained attention as a less toxic conditioning agent offering effective myeloablation with reduced non-hematologic adverse effects.
This large registry-based matched-pair study provides important evidence supporting the non-inferiority of FluTreo regimens compared to FluTBI in adult ALL patients in remission. The findings align with earlier smaller studies suggesting that treosulfan-based conditioning may be especially attractive for older patients or those with comorbidities where TBI is less feasible.
Limitations include the retrospective design, potential unmeasured confounders, and lack of subgroup analyses by ALL subtype or minimal residual disease status. Randomized prospective trials would further clarify the comparative effectiveness. Incorporating biological markers and patient-reported outcomes could refine conditioning regimen personalization.
Conclusion
This retrospective matched-pair analysis from the EBMT ALWP demonstrated that conditioning with fludarabine combined with treosulfan achieves transplant outcomes comparable to fludarabine with total body irradiation in adult patients undergoing alloHSCT for ALL in complete remission. There were no significant differences in acute or chronic GVHD, relapse incidence, non-relapse mortality, or survival endpoints. These data support the use of treosulfan as a viable alternative to TBI-based conditioning, particularly in settings where TBI-related toxicities are a concern.
Future prospective studies and tailored conditioning regimens considering patient age, comorbidities, and leukemia biology are needed to optimize alloHSCT results for adult ALL.
Funding and Clinical Trials
Funding details were not specified in the report. No clinical trial registration was referenced as the study was retrospective and registry-based.
References
- Swoboda R, Labopin M, Kröger N, et al. Fludarabine combined with treosulfan or total body irradiation as a conditioning therapy before allogeneic hematopoietic stem cell transplantation in acute lymphoblastic leukemia. Bone Marrow Transplant. 2026 Jul 8. PMID: 42420467.
- Locatelli F, Schrappe M, Bernardo ME, et al. How I treat relapsed childhood acute lymphoblastic leukemia. Blood. 2012;120(14):2807-2816.
- Mohty M, Szydlo R, Bouabdallah R, et al. Reduced-intensity conditioning using Treosulfan in lymphoid malignancies. Biol Blood Marrow Transplant. 2010;16(1):109-113.
- Wolschke C, Finke J, Ensinger C. Current status of conditioning regimens for allogeneic hematopoietic cell transplantation in adults with acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2019;2019(1):462-468.