Transplant Conditioning with Treosulfan/Fludarabine with or without Total Body Irradiation: A Randomized Phase II Trial in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia

Abstract

In this prospective, randomized, phase II "pick the winner" trial we assessed the efficacy of transplant conditioning with treosulfan/fludarabine ± 2 Gy total body irradiation (TBI) in reducing post-transplant relapse in 100 patients, aged 2 to 70 years (median, 57), with myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (n = 51) or acute myeloid leukemia (AML; n = 49). Patients received i.v. treosulfan, 14 g/m/day on days -6 to -4 and i.v. fludarabine, 30 mg/m/day on days -6 to -2, alone or combined with 2 Gy TBI (day 0). Donors were related (n = 43) or unrelated (n = 57). When a planned interim analysis showed superior progression-free survival in the TBI arm (P = .04), all subsequent patients received TBI. With a follow-up of 12 to 40 months (median, 20), the 1-year overall survival was 80% for the TBI arm and 69% for the non-TBI arm. The 1-year cumulative incidence of relapse was 22% and 34%, respectively (P = .06). Among patients with low-risk disease the 1-year relapse incidence was 15% and 31% (P = .20) and for patients with high-risk disease, 26% and 36% (P = .18), respectively. Among MDS patients the 1-year relapse incidence was 27% versus 33% (P = .49) and among AML patients 16% versus 35% (P = .05), respectively. The largest difference was among patients with unfavorable cytogenetics, with 1-year relapse incidences of 31% and 63% (P = .18), respectively. Nonrelapse mortality in this high-risk patient population was 9% at 6 months and did not differ between arms. Thus, treosulfan/fludarabine/low-dose TBI provided effective conditioning for allogeneic hematopoietic cell transplantation in high-risk patients up to 70 years of age. The addition of TBI had a more profound effect in patients with AML than in those with MDS. High-risk disease features were associated with a lower overall success rate. Further studies are warranted.

Treosulfan-based conditioning is feasible and effective for cord blood recipients: a phase 2 multicenter study

“…9,10,27 Successful incorporation of low-dose radiation into the TREO/FLU regimen has been shown to decrease the relapse rates by increasing conditioning intensity without the toxicities seen in MAC regimens. 25 The 3-year OS of 67% was higher than that reported after reduced-intensity conditioning 10,16,32 and similar to that observed with high-intensity approaches. 9,27,[29][30][31]33 Furthermore, our outcomes were no different from the outcomes observed with TREO/FLU/TBI in patients receiving conventional donor HCT (no CB donors).…”

“…9,27,[29][30][31]33 Furthermore, our outcomes were no different from the outcomes observed with TREO/FLU/TBI in patients receiving conventional donor HCT (no CB donors). 25 Twenty-seven percent of patients in this study had MRD at the time of treatment and 26% had failed a prior transplant. The 3-year DFS of 43% and 48% in these 2 categories of patients, although not ideal, is superior to that reported in most other studies.…”

“…17,[21][22][23][24] Therefore, we investigated the use of the same combination regimen in patients undergoing CBT with the addition of a single dose of 200 cGy TBI as a means of better ensuring adequate immunosuppression to promote sustained donor engraftment and disease control. 25 Previous experience with nonmyeloablative (NMA) CBT suggested that patients who have had limited prior therapy are at particularly greater risk for GF. For the purposes of determining acceptable engraftment rates following TREO/FLU/TBI, patients were classified as low risk (arm 1) or high risk for GF (arm 2).…”

Acute myeloid leukemia: 2021 update on risk‐stratification and management

“… 125 Comparing seven non‐total body irradiation containing regimens they concluded patients with “acceptable” HCT‐CI scores should be conditioned with “Bu4/Cy”, “Flu/Bu4”, or Flu/Mel, with younger patients possibly also benefitting from Flu/Mel. Treosulfan in combination with fludarabine and relatively low dose TBI is another conditioning regimen that has attracted attention 126 and several studies are targeting the myeloid surface antigens CD33 and CD45 with alpha particles such as actinium‐225 and astatine‐211 127 …”

Improved Outcomes after Allogenic Hematopoietic Stem Cell Transplantation with Fludarabine/Treosulfan for Patients with Myelodysplastic Syndromes

“…Additional prognostic factors include age, HCT specific comorbidity index (HCT-CI) [2], donor HLA match, sex match, and response to induction chemotherapy [3][4][5][6]. Fibrotic bone marrow pathology and therapy-related MDS are also associated with a poor prognosis [7,8]. Complex or monosomal karyotype are predictive of a poor outcome, and several studies have shown a poor prognosis related to genetic mutations, particularly TP53 [4,[9][10][11].…”