Missing HLA C group 1 ligand in patients with AML and MDS is associated with reduced risk of relapse and better survival after allogeneic stem cell transplantation with fludarabine and treosulfan reduced toxicity conditioning

Abstract

Reduced-toxicity conditioning with fludarabine and treosulfan is a dose-intensive regimen with enhanced anti-leukemia effect and acceptable toxicity in AML/MDS. HLA-C regulates natural-killer (NK) cell function by inhibiting Killer immunoglobulin-like receptors (KIR) and is divided into C1 and C2 epitopes. The missing-ligand theory suggests that missing recipient KIR ligands drives NK-alloreactivity after SCT, in the absence of HLA-mismatch by activating unlicensed donor NK cells. We analyzed SCT outcomes in 203 patients with AML/MDS, median age 58 years, given SCT from matched-siblings (n = 97) or matched-unrelated donors (n = 106), using two treosulfan doses (total 36 or 42 g/m ). 34% expressed one HLA-C group 1 allele (C1C1), 19% one HLA-C group 2 allele (C2C2), and 48% both KIR ligands (C1C2). Median follow-up was 48 months. 5-year relapse, nonrelapse mortality (NRM) and leukemia-free survival (LFS) rates were 38%, 27%, and 36%, respectively. Relapse rates were 43%, 45%, and 26% in patients expressing C1C1, C1C2, and C2C2 ligands, respectively (P = .03). Multivariate-analysis identified chemo-refractory disease (HR 3.1, P = .003), poor cytogenetics (HR 1.7, P = .08), female donor to male recipient (HR 0.4, P = .01) and C2C2 ligands (HR 0.4, P = .04) as independent factors predicting relapse. HLA-C ligands were not associated with GVHD or NRM. LFS was 33%, 30%, and 46%, respectively (P = .07). Chemorefractory disease (HR 3.1, P = .0004) and C2C2 group ligand (HR 0.6, P = .06) independently predicted LFS. Treosulfan dose did not predict any SCT outcome. In conclusion, missing HLA-C group 1 ligand is associated with reduced relapse risk, similar NRM and improved LFS, after HLA-matched SCT with treosulfan conditioning in AML/MDS.

Treosulfan-Based Conditioning Regimen Prior to Allogeneic Stem Cell Transplantation: Long-Term Results From a Phase 2 Clinical Trial

“…Thereafter, Treo was approved by the European Medicines Agency (EMA) at a total dose of 30 g/ m 2 according to the results of a multicenter randomized phase 3 trial in older and comorbid patients. 15 Although potentially limited by the presence of single-center data, our long-term analysis confirms that a full-dose Treo-based conditioning regimen displays a strong myeloablative and immunosuppressive potential coupled with a good safety profile, in line with other recent studies (9,15,(20)(21)(22)(23)(27)(28)(29). A fast and stable full donor engraftment was achieved by most of our patients, toxicities were limited, and no case of SOS was reported.…”

Intravenous Busulfan Compared with Treosulfan-Based Conditioning for Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia: A Study on Behalf of the Acute Leukemia Working Party of European Society for Blood and Marrow Transplantation

“…In all, FT14 was associated with better outcomes in patients with active disease at SCT, but this conclusion must be taken with caution because of the retrospective nature of this study and heterogeneity of the patient groups. Several prior studies found no significant differences between the various treosulfan doses [11,18,19,21]. Most found similar NRM, whereas some showed higher relapse rates in the lower dose [11].…”

“…The combination of fludarabine and treosulfan (FT) has been introduced over the last few years [10][11][12][13][14][15][16][17][18][19][20][21]. It was reported mostly in patients with AML and MDS [10][11][12][13][14][15][16][17][18][19] but also in lymphoid malignancies [20], acute lymphoblastic leukemia, and in pediatric patients [21]. The Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) has recently reported the outcome of treosulfan-based conditioning in a relatively large group of 520 adult patients with AML [19].…”

BSHI guideline: HLA matching and donor selection for haematopoietic progenitor cell transplantation

“…Worldwide, the evidence base is building to show that recipients who are homozygous for HLA C1 or C2 group alleles are disadvantaged in the HPCT setting compared with those who are heterozygous (Cook et al, 2004; Cooley et al., 2014; Neuchel et al., 2017; Shimoni et al., 2017; Sobecks et al., 2015). Moreover, the evidence highlighting worse outcomes for HLA C2/C2 group recipients (approximately 20% of the population) is reproducible for all donor categories (related, unrelated, haploidentical, UCB).…”