Thiotepa-Fludarabine-Treosulfan (TFT) Conditioning for 2nd Allogeneic Peripheral Blood Hematopoietic Cell Transplantation (HCT) from a Second Unrelated Donor in Patients with Acute Myeloid Leukemia (AML) Relapsed after Prior Allogeneic HCT: A Prospective Multicenter Phase II Trial
Authors: Finke Jürgen , Schmoor Claudia , Stelljes Matthias , Burchert Andreas , Dreger Peter , Wagner Eva-Maria , Bornhäuser Martin , Sohlbach Kristina , Schub Natalie , Reicherts Christian , Kobbe Guido , Glass Bertram , Bertz Hartmut , Grishina Olga 
Published: October 2019

Abstract
Introduction: Relapse of AML after allogeneic HCT has a dismal prognosis. Long-term survival after 2nd allogeneic HCT has been described in selected patients. Here we tested a specific protocol with a fixed drug combination for myeloablative conditioning and GvHD prophylaxis for 2nd allogeneic HCT from a different unrelated donor. (EudraCT no.: 2012-005414-18, German Clinical Trials Registry no.: DRKS00005126)
Methods :
Aim of the trial was to show efficacy and safety of a 2nd alloHCT from an unrelated donor after a uniform conditioning with Treosulfan 3x12gm/m2, Fludarabin 3x30mg/m2, and Thiotepa 3x 5mg/kg (TFT), and GvHD prophylaxis with cyclosporine A (CyA) /Mycophenolate and ATG-F (Neovii) 3x10mg/kg. Eligible were adult patients with AML, ECOG ≤ 2, with sensitive or refractory hematologic relapse (≥ 20% blasts) > 6 months after a prior allogeneic HCT , including secondary (s) and/ or tAML. CR prior 2nd HCT was no prerequisite.
The primary endpoint of the study was disease-free survival (DFS) defined as being alive and free of disease at 1 year post 2nd HCT. Secondary endpoints were relapse, relapse mortality (RM), NRM, overall survival (OS), acute GvHD, chronic GvHD, engraftment, and adverse events. According to the Fleming one-stage design, 50 evaluable patients had to be included. If 16 or more patients were alive and free of disease at 1 year post 2nd SCT, the regimen could be considered as successful for evaluation in further trials. With this decision rule, it can be shown at one-sided α=0.1 that the probability of DFS at 1 year post 2nd HCT is higher than 23% with a power of 90%, when it is at least 40%. This is a first analysis of the study covering the first year after 2nd HCT of each patient. The analysis is based on the full analysis set, which includes all patients, for whom the conditioning regimen TFT and the GvHD prophylaxis regimen CyA, MPA/MMF, ATG-F has started, and for whom allogeneic HCT from an unrelated donor has been performed.
Results: Fifty-two patients were registered for the study from 25th March 2014 up to 10th March 2017 from 9 German centres. The full analysis set includes 50 patients (median age 53.5 years). ECOG was median 1. Donors for 1st allo HCT had been related (n=11 (22.0%)) or unrelated (n=39 (78.0%)) (n=48 PBSCT, n=2 bone marrow). Conditioning for 1st HCT was myeloablative in 23 (46.0%) patients. After 1st HCT, the rate of acute GvHD I-IV was 34.0%, and of chronic GvHD was 40.0%. Median time from 1st HCT to relapse was 17.2 months and from relapse after 1st HCT to 2nd HCT 2.5 months. Thirty-six (72%) patients had received induction chemotherapy for relapse prior to 2nd HCT, 11 (22.0%) patients had received azacytidine or decitabine, and 11 (22.0%) had received donor lymphocyte infusions (DLI). Remission status prior to 2nd HCT was complete remission in 16 (32.0%) patients, chemo-refractory relapse in 33 (66.0%), one patient was in partial remission.
With regard to the primary endpoint, 23 (46%, 95%-CI (31.8-60.7%) of the patients were alive and free of relapse at 1 year after 2nd SCT. With regard to the secondary endpoints at 1 year, the cumulative incidence of relapse (95%-CI) was 26 (17-42)%, 9/50 patients (18 (10-33)%) died after relapse of AML, NRM was 14/50 patients (28 (18-44)%, cause: infection n=6, infection after aGvHD n=6, PTLD n=2), OS was 54 (39-66)%. Four patients are alive after relapse. aGvHD rate was 54 (42-70)%, aGvHD III-IV 26 (16-42)%, cGvHD 26 (16-42)%, extensive cGvHD 20 (12-35)%, engraftment rate with ANC > 1.0 x 103/µl was 92 (85-100)%, with platelets > 20 x 103/µl was 80 (70-92)%, and with platelets > 100 x 103/µl was 66 (54-81)%. After 1 year, 4 patients had received DLI for prophylaxis, and 5 patients for mixed chimerism as per protocol.
Conclusion:
Second alloHCT with an ablative double alkylator containing conditioning regimen with Thiotepa, Fludarabine, and Treosulfan is feasible and can result in sustained disease control in patients with AML relapse after a first alloHCT, and therefore seems to be a valid option in this otherwise detrimental setting.

Disclosures
Finke: Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; Novartis: Honoraria; Amgen: Honoraria; JAZZ: Honoraria. Burchert:Novartis: Research Funding; Bayer: Research Funding; AOP Orphan: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Schub:Affimed: Research Funding. Kobbe:Celgene: Honoraria, Other: Travel Support, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.