Treosulfan Plus Fludarabine (TTF10) As Preparative Regimen before Haploidentical Trasplant in Elderly Patients with Acute Myeloid Leukemia
Authors: Federico Vincenzo , Matera Rosella , Salvatore Dalila , Canale Filippo Antonio , Merla Emanuela , Valente Daniela , Contento Corinne , Campagna Giulia , Messa Anna Rita , Vaddinelli Doriana , Natale Annalisa , Fina Mariapaola , Tarantino Amalia , Quarta Nadia , Seripa Davide , Grassi Tiziana , Santarone Stella , Carella Angelo Michele , Martino Massimo , Di Renzo Nicola 
Published: December 2024

Introduction: Over the past few years an increasing number of elderly patients (pts) with AML has been considered eligible for allogenic transplantation (Allo-SCT). Post-transplant cyclophosphamide (PT-CY) has been confirmed to be effective and safe as graft-versus-host disase (GVHD) prophylaxis in the setting of haploidentical SCT (Haplo-SCT). In elderly patients (³ 65 years) this potentially curative option is often precluded by toxicity of myeloablative conditioning regimens. Treosulfan, a water soluble, bifunctional alkylating drug, showed strong myelotoxic, immunosuppressive, and antileukaemic properties with favourable acute toxicity profile when combined with fludarabine in patients with AML or MDS.We report here the outcome of elderly AML pts receiving aplo-HSC with a Reduced Intensity Conditioning regimen including treosulfan and fludarabine followed by PT-CY as GVHD prophylaxis.

Methods: This is a multicentric, retrospective study involving 4 Italian Transplant Units including pts with AML aged ≥65 receiving before Haplo-SCT as preparative regimen intravenous treosulfan 10 g/m² for 3 days plus intravenous fludarabine 30 mg/m² IV for 5 days (TTF10 regimen) with PTCY, micophenolato mofetil and cyclosporine as prevention of GVHD.

Results: Between Jun 2019 and June 2024, 36 consecutive adult pts aged ≥65y received Haplo-SCT after TTF10 regimen for AML, 19 (53%) were male. Median age was 69y (range 65-74). At time of transplant 27 out 36 pts (75%) were in first CR while 9 (25%) in ≥ 2° CR.; first CR was achieved after intensive induction chemotherapy in 8 pts (30%) and after HMA-Venetoclax in 19 (70%). The median time from diagnosis or last treatment to Haplo-SCT was 6 months (range 3-10). All pts received peripheral blood stem cells as source of graft. The mean cell dose CD34+ infused was 6.4x106/Kg (range: 4.6-7.8). The median time to neutrophil engraftment &gt;0.5x109/l and platelet &gt;20x109/l was 14 days (range: 13-21) and 22 days (range: 13-48) respectively. All but one patient (pt) (3%) achieved full engraftment at day 30. One pt in CR2 had autologous reconstitution at day 90. Among the 34 (94%) pts alive at day 100, chimerism was full donor in 32 pts (94%), one pt for mixed chimerism received donor lymphocyte infusion. The Cumulative Incidence (CI) of acute GVHD was 25% (grade I-II and III-IV; 10% and 15% respectively) and CI of chronic GVHD (evaluated in 30 patients) was 35% (grade I-II and III-IV; 20% and 15% respectively). After a median follow-up of 12 months (range 2-54), 20 pts (55%) are alive, leukemia free and MRD negative. At day 100 and 1-year the estimate OS and TRM were 83% and 14%, 60% and 26% respectively. The estimate day 100 and 1-year CI of Relapse were 4% and 15%. Better estimate median OS was recorded in patients in first CR compared to those in second or more CR: 17 months (95% CI: 13.3 - 20.8) versus 5 months (95% CI: 0,1 - 10), P=0.17. Sixteen patients (44%) died., 6 (16%) of progressive disease and 10 (27%) of transplant related causes (3 infections, 1 SARS COV-2 pneumonia, 4 GVHD, 1 poor graft faction and 1 of cachesia).

Discussion: These results, although coming from a retrospective study, seems to confirm those obtained in previously published studies showing as the TTF10 regimen is safe and effective in elderly patients with AML and should be considered a standard regimen in this kind of patients. There are few published data regarding the use of TTF10 regimen before Haplo-SCT with peripheral stem cell as source of graft. In this study TTF10 regimen seems to limit the post-transplant relapse rate while more efforts should be done to reduce the TRM rate. Finally, this transplant platform allows to reduce the time between the indication of transplant and the availability of a donor when an identical HLA-related donor is laking. This aspect is extremely important for elderly AMLs, for whom repetitive treatment exposure may increase toxicity and worsen comorbidities making the patent no more eligible for transplant. However more data are needed to confirm the exact place of TTF10 regimen in the therapeutic strategy of elderly patients with AML eligible for transplant.