Busulfan Fludarabine (BU-FLU) Compared to Thiotepa Busulfan Fludarabine (TBF) for Allogeneic Transplants in Acute Myeloid Leukemia (AML) or Refractory Anemia with Excess Blasts (RAEB) in Remission
Authors: Sora Federica , Sica Simona , Di Grazia Carmen , Chiusolo Patrizia , Laurenti Luca , Mordini Nicola , Olivieri Attilio , Iori Anna Paola , Angelucci Emanuele , Bacigalupo Andrea 
Published: April 2021

Abstract

INTRODUCTION The combination of Busulfan and fludarabine (BU-FLU) is considered a standard conditioning regimen for patients with acute myeloid leukemia undergoing an allogeneic hemopoietic stem cell transplant (HSCT) , especially in patient older than 40 years of age. However, in a recent prospective study, designed for patients in first or second remission (CR1 or CR2) the incidence of leukemia relapse at 3 years was 38%, both for patients receiving BU-FLU as well as for patients randomized to BU-CY (Lancet Oncol 2015;16:1525). The addition of thiotepa to a BU-FLU regimen (referred to as TBF) has shown promising control of leukemia, and has emerged as a standard regimen in cord blood (CB) transplants (BMT 2012; 47: 1287). The question is whether this holds true also for transplants other than CB grafts.
Aim of the study : to compare Bu-FLU with TBF in patients with AML or RAEB, grafted in remission from related or unrelated donors.
Methods: Eligible for this study were patients allografted between January 2008 and April 2017 with AML or RAEB in hematologic remission . Seventy-eight patients received the BU-FLU regimen (busulfan 3.2 mg/kg/day x4; and fludarabine 40 mg/m^2/day x4), and 127 received TBF( thiotepa 5mg/kgx2, busulfan 3.2 mg/kg/dayx3, fludarabine 50 mg/m^2x3). Graft-versus-host disease (GVHD) prophylaxis was as follows: in HLA identical sibling transplants , cyclosporin (CyA) and Metothrexate (MTX); in unrelated donor transplants CyA+MTX+ antithymocyte globulin (ATG) and for family haploidentical donors (HAPLO) , CyA, mycophenolate mofetil (MMF) and cyclofosphamide 50mg/kg given on day +3 and +5, after transplantation (PT-CY) . Supportive care and infectious disease prophylaxis, or pre-emptive therapy, were provided as per Institutional protocols. Clinical characteristics are shown in Table 1.
Results: With a median follow up of 481 and 551 days (range, 8-2625 and 2-2277 respectively) after transplantation, the 5-year cumulative incidence of TRM was 25% and 9% for BU-FLU and TBF (p = 0.007); the 5-year cumulative incidence of leukemia relapse related deaths (RRD) was 33% and 9% (P = 0.008). TBF showed an advantage over BU-FLU, also after exclusion of HAPLO, both in TRM (p=0.08) and RRD (p=0.04). The 5-year actuarial survival was 41% (26-56%) and 82% (74- 90%) (p=0.000) respectively for the BUFLU and the TBF group. The survival advantage was seen also when looking only at HLA identical siblings and UD, excluding HAPLO grafts (51% vs 82%,p=0.05).
In a multivariate Cox analysis, after correcting for patients age, interval diagnosis transplant, first or second remission , and donor type, the use of TBF reduced the risk of death as compared to BU-FLU (RR 0.3 , range 0.10-0.89, p=0.01) . This was true also when running a Cox model on TRM (RR 0.17 for TBF vs BU-FLU, p=0.02) . TRM was 4% vs 14% in patients receiving TBF vs Bu-FLU aged &lt; 50 years (p=0.09), and 9% vs 32% in patients receiving TBF aged &gt; 50 years (p=0.01). In a Cox analysis on RRD, TBF showed a reduced risk (RR 0.41) but this did not reach statistical significance (p=0.1)
Conclusions: Superior survival of patients receiving TBF , as compared to BU-FLU appears to be a combination of reduced toxicity and reduced relapse. The survival advantage is independent of donor type, and therefore of GvHD prophylaxis.

Disclosures
Laurenti: Roche: Other: Advisory Board; Gilead: Other: Advisory Board; Janssen: Other: Advisory Board; Abbvie: Other: Advisory Board. Angelucci: Celgene: Honoraria, Other: Advisory: research project ; Novartis Oncology Swiss: Other: Invited speakers sponsored satellite meeting during ; Novartis Oncology: Other: Advisory board: iron toxicity; Jazz: Other: Advisory board: AML; Roche: Other: Advisory board: biosimilars; Bluebird Bio: Other: Advisory board: Gene therapy in Thalassemia; Celgene: Other: protocoll ACE 536 B-Thal 001: DMC Chair; Novartis Oncology: Other: Protocol Telesto: sterring committee Chair.