General AML

Treosulfan-based conditioning regimen in AML patients receiving allo-HCT

Standard conditioning regimens for Allogenic Hematopoietic Cell Transplantation (allo-HCT) including busulfan-based and Total Body Irradiation (TBI)-based regimens are characterized by toxicity and high mortality rate in patients with Acute Myeloid Leukemia (AML). Treosulfan is an alkylating agent with immunosuppressive and anti-leukemic properties and a low toxicity profile and it may be a possible alternative for allo-HCT conditioning.

In an article published ahead of print on 22nd March 2017 in Cancer, Arnon Nagler from the European Society for Blood and Marrow Transplantation Paris Study Office, Paris, France, and colleagues discuss results from their retrospective study which investigated the safety and efficacy of treosulfan-based conditioning regimen in patients with AML who undergone allo-HCT.

520 AML patients (median age = 57) who received treosulfan-based conditioning regimen followed by allo-HSCT from either a related donor (n = 285) or an Unrelated Donor (URD, n = 235) between 2000­–2012 and reported to the European Society for Blood and Marrow Transplantation (EMBT) Acute Leukemia Working Party were included in this study. Patients received treosulfan at a dose of 42 g/m2 (n =396), 36 g/m2 (n = 109) or 30 g/m2 (n = 15) over 3 days. 94% of patients (n = 484) received treosulfan and fludarabine-based conditioning regimen. Median follow-up length of the study was 61 months.

The key results of the study were:
  • 5-year Cumulative Incidence (CI) of grade II–IV and grade III–IV acute Graft versus Host Disease (GvHD); 24% and 11% respectively
  • 5-year CI of chronic GvHD; 38%
  • 5-year CI of Non Relapse Mortality (NRM); 25%
  • Active disease (HR = 1.66, P = 0.015) and poor cytogenetics (HR = 1.52, P = 0.044) were associated with increased risk of acute GvHD and chronic GvHD respectively
  • 5-year cumulative Relapse Incidence (RI); 42%
  • 5-year Overall Survival (OS) and Leukemia Free Survival (LFS) were 38% and 33% respectively
  • 11 patients (2%) developed veno-occlusive disease with death occurring in 2

In summation, this is the largest study of treosulfan-based conditioning regimen in AML patients demonstrating comparable long-outcomes with low risk of acute GvHD and organ toxicity compared to historic data using ablative regimens in AML. The authors suggested that prospective studies are required in order to optimize treosulfan-based conditioning regimen in AML patients.

The authors concluded by stating “treosulfan is an effective conditioning regimen for HCT in patients who have AML” and provides “an acceptable long-term survival with favorable non-relapse mortality and a very low risk of veno-occlusive disease”.

Abstract
BACKGROUND

Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for patients with acute myeloid leukemia (AML). However, post-HCT relapse and regimen-related toxicity remain significant barriers to long-term survival. In recent years, new conditioning regimens have been explored to improve transplantation outcomes in patients with AML. Treosulfan combines a potent immunosuppressive and antileukemic effect with a low toxicity profile.

METHODS

To investigate the role of treosulfan-based conditioning, the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party performed a registry analysis of 520 adult patients with AML who received treosulfan-based conditioning and underwent HCT between 2000 and 2012, including 225 patients in first complete remission, 107 in second or later complete remission, and 188 with active/advanced disease 188 (88 with primary refractory disease). The median patient age was 57 years (range, 20-73 years). Donors were human leukocyte antigen-identical siblings (n = 187), unrelated donors (n = 235), or mismatched related donors (n = 98). Conditioning regimens included treosulfan (42 g/m2 [n = 396], 36 g/m2 [n = 109], or 30 g/ m2 [n = 15]) with fludarabine or alkylating agents followed by infusion of hematopoietic stem cells (bone marrow, n = 52; peripheral blood, n = 468).

RESULTS

At a median follow-up of 61 months, the 5-year overall survival, leukemia-free survival, relapse incidence, and nonrelapse mortality rates were 38%, 33%, 42%, and 25%, respectively. The incidence of grade II-IV acute and chronic graft-versus-host disease was 24% (grade III-V, 11%) and 38%, respectively. Only 11 patients (2%) developed veno-occlusive disease, with two deaths (0.4%) from veno-occlusive disease.

CONCLUSIONS

Treosulfan-based conditioning regimens provide an acceptable long-term survival with favorable nonrelapse mortality and a very low risk of veno-occlusive disease. Further studies are needed to optimize the treosulfan-based conditioning regimen for patients with AML.

References
  1. Nagler A. et al. Long-term outcome after a treosulfan-based conditioning regimen for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Cancer. 2017 Mar 22. DOI: 1002/cncr.30646. [Epub ahead of print].