Survival Advantage and Comparable Toxicity in Reduced-Toxicity Treosulfan-Based versus Reduced-Intensity Busulfan-Based Conditioning Regimen in Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients after Allogeneic Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) is effective in the treatment of inherited marrow failure disorders and other non-malignant diseases. Conventional myeloablative conditioning regimens have been associated with high transplant related mortality particularly in patients with co-morbid conditions. Here we report on 14 patients with marrow failure disorders (Shwachman-Diamond syndrome n=3, Diamond Blackfan anemia n=4, GATA2 deficiency n=2, paroxysmal nocturnal hemoglobinuria n=4, and an undefined marrow failure disorder n=1) who underwent HCT on a prospective phase II multi-center clinical trial. Patients were given HLA-matched related (n=2) or unrelated (n=12) grafts following conditioning with treosulfan (42 grams/m2), fludarabine (150 mg/m2), ± thymoglobulin (n=11; 6 mg/kg). All patients engrafted. At a median follow-up of 3 years, 13 patients are alive with complete correction of their underlying disease. These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with a low toxicity profile and excellent disease-free survival in patients with marrow failure disorders.

Section: Discussionsupporting

confidence: 87%

Allogeneic Hematopoietic Cell Transplantation Using Treosulfan-Based Conditioning for Treatment of Marrow Failure Disorders

Burroughs

Shimamura

Talano

et al. 2017

“…Ruutu et al [33] showed a 17% incidence of NRM and a 71% OS at 2 years in MDS patients conditioned with treosulfan. Casper et al [14] observed an NRM of 11% and an OS of 61% in a mixed cohort of patients, and Sakellari et al [34] showed, in a retrospective analysis, a survival advantage for patients with AML or MDS conditioned with a fludarabine (150 to 180 mg/m 2 )/ treosulfan (42 g/m 2 ) regimen in comparison with patients conditioned with fludarabine (150 to 180 mg/m 2 )/busulfan (6.4 mg/kg i.v.) (OS 76% versus 57%; PFS 70% versus 38%, respectively [P < .001]) without an increase in toxicity.…”

Section: Discussionmentioning

confidence: 97%

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

Deeg

Stevens

Salit

et al. 2018

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.

“…FT was associated with better relapse protection in this study. Sakellari et al [31] showed that FT14 (n = 31) was associated with better survival than FB2 (n = 26), mostly attributed to lower relapse rates.…”

Section: Discussionmentioning

confidence: 99%

Intravenous Busulfan Compared with Treosulfan-Based Conditioning for Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia: A Study on Behalf of the Acute Leukemia Working Party of European Society for Blood and Marrow Transplantation

Shimoni

Labopin

Savani

et al. 2018

Dose intensity of the conditioning regimen has significant impact on the outcomes after stem cell transplantation (SCT) for acute myeloid leukemia. Most studies have shown more relapse, less nonrelapse mortality (NRM), and similar overall survival after reduced-intensity and myeloablative conditioning. There are limited data on the dose equivalence and expected outcomes of treosulfan-based compared with busulfan-based conditioning. We compared SCT outcomes after fludarabine with either intravenous busulfan at a myeloablative dose (FB4, 12.8 mg/kg, n = 1265) or a reduced dose (FB2, 6.4 mg/kg, n = 1456) or treosulfan at 42 g/m (FT14, n = 403) or 36 g/m (FT12, n = 168). Median patient age was 48, 60, 57, and 60 years in the FB4, FB2, FT14, and FT12 groups, respectively (P < .0001). Two-year overall survival was 58%, 53%, 53%, and 51%, respectively (P = .25). Multivariate analysis identified advanced age, advanced disease status, and secondary leukemia to be associated with worse survival. Relapse rate was 30%, 35%, 34%, and 40%, respectively. Relapse was more common after FB2, advanced age and disease status, secondary leukemia, and sibling donors. NRM was 17%, 18%, 21%, and 16%, respectively. NRM was least common after FT12 and more common with advanced age and disease status and unrelated donors. Treosulfan-based regimens were associated with lower rates of graft-versus-host disease. There was no difference in any outcome among patients in first complete remission at transplantation. However, there was better survival with treosulfan-based conditioning in advanced leukemia. In conclusion, survival is determined mostly by disease biology and is similar after various regimens. Treosulfan-based conditioning is more similar to myeloablative than to reduced-intensity conditioning but can be administered safely in older patients, with lower rates of graft-versus-host disease and possibly better outcomes in patients with active leukemia.