Evidence-Based Choice of Conditioning Regimen for Hematopoietic Stem Cell Transplantation (HSCT) in Acute Leukemia: The Italian Cellular Therapy and Stem Cell Transplant Group (GITMO) Guidelines
Authors: Picardi Alessandra , Marchetti Monia , Castagna Luca , Algeri Mattia , Santarone Stella , Zecca Marco , Malagola Michele , Mordini Nicola , Fagioli Franca , Carella Angelo Michele , Greco Raffaella , Onida Francesco , Pastore Domenico , Troiano Michele , Mussano Anna , Tangari Federica , Guglielmi Gaspare , Balduzzi Adriana , Botti Stefano , Cannici Chiara , Pitea Martina , Ciceri Fabio , Bonifazi Francesca , Martino Massimo 
Published: December 2024

BACKGROUND
Conditioning regimens for acute myeloid (AML) and lymphoid (ALL) leukemia include a wide set of chemo-radiotherapy combinations capable of inducing a decline of bone marrow activity and thus favoring allogeneic stem cell engraftment and preventing leukemia relapse. Hematopoietic stem cell transplantation (HSCT) conditioning schedules include alkylating, non-alkylating drugs and, in some cases, total body irradiation (TBI). Drugs and/or TBI dose identify the intensity of conditioning regimen. Excessive heterogeneity of the clinical practices may limit the auditing and the correct interpretation of the outcomes. Therefore, in June 2023, GITMO started a project aimed at developing evidence-based guidelines selecting the most appropriate conditioning regimen for adult and pediatric patients receiving their first HSCT for AML or ALL in complete remission.
METHODS
The process adhered to the benchmark GRADE methodology for developing evidence-based recommendations. A methodologist and a chair leaded a nationwide panel of 12 adult hematologists, 4 pediatricians, 2 pharmacists, 1 pharmacologist, 2 transplant nurses and 2 radiotherapists. The panel broke down the target “population” into 4 subgroups: adult AML, children AML, adult ALL and children ALL. According to the EBMT Consensus (Spyridonidis 2020), a comparator was chosen for each of 3 “intensity” (TCI) classes and all the other conditioning regimens were tested as “interventions”. Critical outcomes included non-relapse-mortality (NRM), cumulative incidence of relapse (CIR) and engraftment rate. Evidence was retrieved by EMBASE and PubMed queries: relevant articles and extracted data to summary-of-evidence tables were selected. Evidence-to-decision tables were discussed and recommendations approved during 6 virtual meetings. An External Review Panel was conveyed including members of 5 scientific societies (AIRO, AIEOP, GITMO, SIFO, SIF).
RESULTS
In the first phase of the project the Panel faced high-TCI regimens for AML and completed 7 pairwise interventions comparisons versus BuCy, e.g. the standard “comparator”. The Panel agreed on 3 evidence-based statements for high-TCI conditioning in adult AML: BuCy or TreoFluMel were recommended, while TBICy was recommended against, except for specific scenarios such as extramedullary disease, dendritic cell leukemia and young people at very high risk that would be worthy of clinical trials. Overall 4 conditioning regimens were not supported by sufficient evidence in adult AML: BuFluArac and BuFLuMel were therefore judged to be better investigated by further studies, while TBICyVP16 and BuCyVP16, were not judged to be worth further research. The Panel agreed on a single evidence-based statement for high TCI in pediatric AML: patients were recommended to receive BuCyMel rather than BuCy and TBICy was recommended against. No evidence could be retrieved supporting BuFluMel in pediatric AML, but no research was deemed to be devoted to this regimen. In the second phase of the project the Panel faced high-TCI in ALL and completed 7 pairwise interventions comparisons versus TBICy, e.g. the standard “comparator”. The Panel agreed on 3 evidence-based statements for adults: both TBIVP16 and BuCy can be suggested as a valid alternative to TBICy in case of matched HSCT, while TBIFlu is preferred in case of mismatched donor because of PT-CY as GVHD prophylaxis. One evidence-based statement was elaborated for high-TCI in pediatric subset: TBIVP16 association is recommended in case of matched related or unrelated allogeneic HSCT, however TBICy represents a valid alternative option. Haploidentical pediatric HSCT was excluded because in vitro T cell depletion is used in most Italian Transplant Program (TP). Two negative statements were also included for both adult and pediatric ALL: TBI-based conditioning should not incorporate two drugs and there are no sufficient data to recommend clofarabine-treosfulfan as alternative to TBICy regimen. Recommendations for low and intermediate-TCI are in progress.
DISCUSSION
A wide variety of conditioning regimens are currently used based on clinical features, TP habits and expertise. However, GRADE method can be applied in such a complex framework and help the selection of those conditioning regimens supported by sufficient evidence that can be identified as solid backbones for the built of National Practice Guidelines.