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

Lorenzo Lazzari, Annalisa Ruggeri, Maria Teresa Lupo Stanghellini, Sara Mastaglio, Carlo Messina, Fabio Giglio, Alessandro Lorusso, Tommaso Perini, Simona Piemontese, Magda Marcatti, Francesca Lorentino, Elisabetta Xue, Daniela Clerici, Consuelo Corti, Massimo Bernardi, Andrea Assanelli, Raffaella Greco, Fabio Ciceri, Jacopo Peccatori, Lorenzo Lazzari, Annalisa Ruggeri, Maria Teresa Lupo Stanghellini, Sara Mastaglio, Carlo Messina, Fabio Giglio, Alessandro Lorusso, Tommaso Perini, Simona Piemontese, Magda Marcatti, Francesca Lorentino, Elisabetta Xue, Daniela Clerici, Consuelo Corti, Massimo Bernardi, Andrea Assanelli, Raffaella Greco, Fabio Ciceri, Jacopo Peccatori

Abstract

Introduction: Reducing 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.

Methods: The 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://ichgcp.net/clinical-trials-registry/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%).

Results: Conditioning 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.

Conclusions: Overall, our data confirmed the myeloablative potential and safe toxicity profile of full dose Treo (42 g/m2) especially for the younger population.

Keywords: ATLG; Treosulfan; allogeneic transplant; conditioning regimen; reduced toxicity.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Lazzari, Ruggeri, Lupo Stanghellini, Mastaglio, Messina, Giglio, Lorusso, Perini, Piemontese, Marcatti, Lorentino, Xue, Clerici, Corti, Bernardi, Assanelli, Greco, Ciceri and Peccatori.

Figures

Figure 1
Figure 1
Kaplan–Meier estimates of overall survival (OS, A), progression-free survival (PFS, B), and graft-versus-host-free/relapse-free survival (GRFS, C), and cumulative incidence of relapse/progression (RI, D) and transplant-related mortality (TRM, E).
Figure 2
Figure 2
Cumulative incidence (CI) of acute graft-versus-host disease (GvHD) grade II–IV (A) and III-IV (B), and CI of chronic GvHD all grades (C) and moderate-to-severe (D).
Figure 3
Figure 3
Cumulative incidence (CI) of acute graft-versus-host disease (GvHD) grade II–IV (A) and III–IV (B) and CI of chronic GvHD all grades (C) and moderate-to-severe (D) according to anti T-lymphocyte globulin administration.
Figure 4
Figure 4
Graphic representation of the distribution of organs involved by chronic graft-versus-host disease (cGvHD) in the overall population. *Renal cGvHD.

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