Treosulfan-Based Conditioning Regimen Prior to Allogeneic Stem Cell Transplantation: Long-Term Results From a Phase 2 Clinical Trial

Abstract

IntroductionReducing toxicities while preserving efficacy in allogeneic stem cell transplant (allo-HCT) remains a particularly challenging problem. Different strategies to enhance the antitumor activity without increasing early and late adverse toxicities of the conditioning regimens have been investigated.MethodsThe aim of “AlloTreo” prospective phase 2 clinical trial was to evaluate the efficacy and safety of a conditioning regimen based on Treosulfan (42 g/m2) and fludarabine (https://clinicaltrials.gov/ct2/show/NCT00598624). We enrolled 108 patients with hematological diseases who received a first allo-HCT between June 2005 and January 2011, inside the frame of this trial at our center. Median age at allo-HCT was 49 (21–69) years. Disease Risk Index was low in 14 (13%) patients, intermediate in 73 (67.7%), high in 17 (15.7%), and very high in 4 (3.7%). Donors were human leukocyte antigen (HLA)-matched related in 50 cases, 10/10-matched unrelated in 36, and 9/10-mismatched unrelated in 22. Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporine-A and methotrexate. Anti-T-lymphocyte globulin (ATLG) was administered in patients receiving unrelated allo-HCT. Stem cell source was mainly peripheral blood stem cells (95%).ResultsConditioning regimen was well tolerated. Full donor chimerism was documented for most patients (88%) at day +30. At 12 years, overall survival (OS) was 41.7% (32.2%–50.9%), progression-free survival (PFS) was 31.7% (23%–40.7%), GvHD-free/relapse-free survival was 20.9% (13.7%–29.1%), cumulative incidence (CI) of relapse was 44.5% (34.9%–53.6%), and transplant-related mortality (TRM) was 22.5% (15.1%–30.9%). CI of acute GvHD grades II–IV was 27.8% (19.7%–36.5%) at 100 days; 12-year CI of chronic GvHD was 40.7% (31.3%–49.9%). Relevant long-term adverse effects were 10 secondary malignancy, 3 fatal cardiovascular events, and 1 late-onset transplant-associated thrombotic microangiopathy. Ten successful pregnancies were reported after allo-HCT. In multivariate analysis, older age (≥60 years) at transplant [hazard ratio (HR), 2.157; p = 0.004] and a high/very high disease risk index (HR, 1.913; p = 0.026) were significantly associated with a lower OS.ConclusionsOverall, our data confirmed the myeloablative potential and safe toxicity profile of full dose Treo (42 g/m2) especially for the younger population.

Thiotepa-busulfan-fludarabine Compared to Treosulfan-based Conditioning for Haploidentical Transplant With Posttransplant Cyclophosphamide in Patients With Acute Myeloid Leukemia in Remission: A Study From the Acute Leukemia Working Party of the EBMT

“…It is noteworthy that the only cases of fatal SOS/VOD were in patients who received TBF; this finding confirms previous reports of low incidence of SOS/VOD-related deaths in patient receiving treosulfan as part of the conditioning regimen. 17 , 32 , 35 This could be particularly relevant when selecting a conditioning for patients at very high risk of developing SOS/VOD, considering that the haplo-HSCT with PTCy platform provides for a built-in alkylator (cyclophosphamide) with known toxicity to sinusoidal endothelial cells. 36 Importantly, reduced toxicity should not come at the expense of increased relapse.…”

“…GRFS at 2 years did not differ as well, 54% (95% CI, 46-63) in TBF and 53% (95% CI, 43-63) in Treo group, respectively (HR, 1.04 [95% CI, 0.73-1.49]; P = 0.83). CRFS at 2 years was 28% (95% CI, [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] and 39% (95% CI, 29-49) in TBF and Treo, respectively (HR, 0.81 [95% CI, 0.58-1.14]; P = 0.23).…”

New drugs before, during, and after hematopoietic stem cell transplantation for patients with acute myeloid leukemia

“…This could be explained by the higher disease risk of patients included in the study. 94 To confirm these findings, a phase III, open-label, non-inferiority trial (MC-FludT.14/L) was conducted comparing treosulfan/fludarabine (FT10) to RIC fludarabine/busulfan in patients ≥50 years or with comorbidities. Treosulfan was given at a dose of 10 mg/m 2 for 3 days.…”

Hematopoietic stem cell transplantation and cellular therapies for autoimmune diseases: overview and future considerations from the Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT)

“…During the last decade major changes have occurred in the field of allogeneic HSCT [ 88 – 90 ], including the introduction of less aggressive conditioning regimens [ 91 , 92 ], improved patient selection, and better supportive care, with a substantial progress in reducing GvHD because of more accurate HLA-typing and better GvHD prevention drugs, opening this procedure also to nonmalignant disorders [ 93 – 96 ]. Progressively the choice of donors and the sources of HSCs have enlarged, extending transplant indications to more patients [ 97 ].…”