Thiotepa–fludarabine–treosulfan conditioning for 2nd allogeneic HCT from an alternative unrelated donor for patients with AML: a prospective multicenter phase II trial

Abstract

Therapeutic options for patients with AML relapsing after allogeneic HCT range from chemotherapy or hypomethylating agents with or without donor lymphocyte infusions to a 2nd allogeneic HCT. Available data are based on retrospective single center or registry studies. The aim of this multicenter trial was to investigate prospectively intensive conditioning with Thiotepa, Fludarabine and Treosulfan (TFT) for 2nd allogeneic HCT from an alternative unrelated donor in patients with AML relapse > 6 months after a 1st allogeneic HCT. Primary endpoint was disease-free survival (DFS) at one year after 2nd HCT. 50 patients median age 53.5 years, in CR/PR (34%) or active relapse (66%) were included. 33 of 38 patients (86.8%) with available data achieved CR 100 days post transplant. 23 patients were alive and free of relapse at primary endpoint one year after 2nd HCT (DFS rate 0.46, 95%-CI (0.32–0.61). Three-year rates of DFS, relapse, non-relapse mortality, and overall survival were 0.24, 95%-CI (0.13–0.36); 0.36 (0.25–0.52); 0.40 (0.29–0.57); and 0.24 (0.13–0.37). Second HCT with TFT conditioning is feasible and has high anti-leukemic efficacy in chemosensitive or refractory AML relapse after prior allogeneic HCT. Still, relapse rates and NRM after 2nd allogeneic HCT remain a challenge. The trial is registered in the German Clinical Trials Registry (number DRKS00005126).

Continuously improving outcome over time after second allogeneic stem cell transplantation in relapsed acute myeloid leukemia - an EBMT registry analysis of 1540 patients

“…Similar ndings have been described by others 28 and are supported by data obtained both after alloSCT1 42 and in a prospective trial in alloSCT2. 43 Recent developments in the eld of conditioning have identi ed myeloablative regimen with reduced toxicity and hence improved outcome. 44 Beyond, although not validated for alloSCT2, the EBMT transplant conditioning intensity (TCI) score 12 may support the selection of less toxic, but still myeloablative regimen also for alloSCT2.…”

Comparison of fludarabine/melphalan (FluMel) with fludarabine/melphalan/BCNU or thiotepa (FBM/FTM) in patients with AML in first complete remission undergoing allogeneic hematopoietic stem cell transplantation – a registry study on behalf of the EBMT Acute Leukemia Working Party

“…With this approach, an additive/synergistic effect can be expected and several modern conditioning protocols have been developed such as thiotepa (8–15 mg/kg b.w. )/fludarabine (3–4 × 40 mg/m 2 )/treosulfan (3 × 12–14 mg/m 2 ) [TFTreo] [ 26 – 28 ] as well as thiotepa (1–2 × 5 mg/kg b.w. )/busulfan (1–3 × 3.2 mg/kg b.w.…”

Second chances – better than none

“…For example, can more effective bridging therapies that reduce disease burden pre-HSCT2 or more effective conditioning regimens for HSCT2 allow progress? 9 Also, hypomethylating agents alone or in combination with venetoclax are being used more commonly with or without donor lymphocyte infusions in patients who relapse after HSCT1. It will be interesting to study in the future how these regimens impact bridging to and results of HSCT2.…”