Treosulfan, Fludarabine, and 2-Gy Total Body Irradiation Followed by Allogeneic Hematopoietic Cell Transplantation in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia

Abstract

Allogeneic hematopoietic cell transplantation (HCT) offers curative therapy for many patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics. In this prospective phase II trial we assessed the efficacy and toxicity of treosulfan, fludarabine and 2 Gy total body irradiation (TBI) as conditioning for allogeneic HCT in patients with MDS or AML. Ninety-six patients with MDS (n=36; 15 RMCD; 10 RAEB-1; 10 RAEB-2; 1 CMML-1) or AML (n=60; 35 CR1; 18 CR2; 3 advanced CR; 4 refractory relapse) were enrolled; median age was 51 (range: 1–60) years. Twelve patients had undergone a prior HCT with high intensity conditioning. Patients received intravenous (IV) treosulfan, 14 g/m2/day on days −6 to −4, IV fludarabine, 30 mg/m2/day on days −6 to −2, and 2 Gy TBI on day 0, followed by infusion of hematopoietic cells from related (n=27) or unrelated (n=69) donors. Graft-vs.-host disease prophylaxis consisted of tacrolimus and methotrexate. With a median follow-up of 30 months, the 2-year overall survival (OS), relapse incidence and non-relapse mortality were 73%, 27% and 8%, respectively. The incidences of grades II–IV (III–IV) acute and chronic graft-versus-host disease were 59% (10%) and 47%, respectively. Two-year OS was not significantly different between MDS patients with poor risk and good/intermediate risk cytogenetics (69% and 85%, respectively), or between AML patients with unfavorable and favorable/intermediate risk cytogenetics (64% and 76%, respectively). In AML patients, minimal residual disease (MRD; n=10) at the time of HCT predicted higher relapse incidence (70% vs. 18%) and lower OS (41% vs. 79%) at 2 years, when compared to patients without MRD. In conclusion, treosulfan, fludarabine and low-dose TBI provided effective conditioning for allogeneic HCT in patients with MDS or AML, and resulted in low relapse incidence, regardless of cytogenetic risk. In patients with AML, MRD at the time of HCT remained a risk factor for post-HCT relapse.

Impact of Donor Type in Patients with AML Given Allogeneic Hematopoietic Cell Transplantation After Low-Dose TBI-Based Regimen

“…Approaches to decrease the incidence of disease relapse might consist of increasing the intensity of the conditioning regimen (for example with the addition of treosulfan (49) or with radiolabeled antibodies (50, 51)) or adding diseasetargeted therapies after transplantation (52,53). Furthermore, recent studies have demonstrated that triple postgrafting immunosuppression with cyclosporine, MMF and sirolimus improved outcomes in MUD patients conditioned with fludarabine þ 2 Gy TBI (54), while administration MMF at the dose of 3g/day (instead of 2 g/day) decreased the incidence of grade II-IV acute GVHD without affecting infection-related mortality of other transplantation outcomes in the double CBT setting (55).…”

Reduced-intensity conditioned allogeneic SCT in adults with AML

“…Treosulfan, a novel alkylating agent, has shown promise in single-arm clinical trials of younger patients. 36,37 Another myeloablative regimen with reduced toxicity uses a combination of fludarabine and high-dose BU (Flu/Bu4). [38][39][40] The Flu/Bu4 regimen has been compared with BU/CY in patients with leukemia or MDS, showing increased relapse and no benefit in terms of NRM for Flu/Bu4.…”

Stem cell comparison: what can we learn clinically from unrelated cord blood transplantation as an alternative stem cell source?

“…Slower recovery of naive CD45RAþ T cells and T-cell receptor excision circle levels and more diverse T-cell repertoire have been also associated with the use of high-dose total body irradiation as part of conditioning regimen for UCBT recipients, especially in adults [52,55,56]. Novel ATG-free, reduced-intensity regimens [57,58], alternative to either high-dose myelo-ablatives or NMA, have been shown to be highly effective in adult patients with hematologic malignancies. Whether or not these new preparative regimens will have less impact on immune reconstitution still must be determined, although the preliminary results are encouraging and might contribute to further improving the outcomes of UCBT.…”