General AML

Missing HLA-C group 1 ligand is associated with improved outcomes of AML & MDS patients after HLA-matched SCT with treosulfan conditioning

Natural Killer (NK) cells are regulated by interactions between Killer-Immunoglobulin-Like Receptors (KIRs) and their corresponding Human Leukocyte Antigen (HLA) ligands. KIRs can be grouped into either inhibitory (KIR A) or activating and inhibitory receptors (KIR B). The major ligand for inhibitory KIRs belong to the HLA C ligand and include group C2 and C1.

 On 19th July 2017, in the American Journal of Hematology, Avichai Shimoni from the Chaim Sheba Medical Center, Tel Aviv, and colleagues reported results from their study, which investigated the role of KIRs ligand grouping on Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) patients who underwent allogenic Stem Cell Transplantation (SCT) with a fludarabine and treosulfan (FT) reduced toxicity conditioning.1

In this retrospective study, 203 patients (median age = 58 years) with AML (n = 129) and MDS (n = 74) who were administered FT conditioning and underwent allogenic SCT at two institutions (the Chaim Sheba Medical Center [NCT00491634)] and San Raffaele Scientific Institute) were analyzed. Patients were either transplanted using matched-siblings (n = 97) or matched unrelated (n = 106) grafts. HLA-C group 1 allele (C1C1), HLA-C group 2 allele (C2C2), and both KIR ligands (C1C2) were seen in 34%, 48%, and 19% of patients, respectively.

The key results of the study were:
  • 5-year Non Relapse Mortality (NRM) in patients with C2C2, C1C1, and C1C2 KIR ligand group; 25% vs 24% vs 28%, P = 0.70
  • 5-year relapse rate in patients with C2C2, C1C1, and C1C2 KIR ligand group; 26% vs 43% vs 45%, P = 0.03
  • 5-year Leukemia-Free Survival (LFS) in patients with C2C2, C1C1 and C1C2 KIR ligand; 46% vs 33% vs 30%, P = 0.07
  • C2C2 KIR ligand (HR = 0.6, P = 0.06) and chemo-refractory disease (HR = 3.1, P = 0.0005) were independent predictors of LFS

In summary, “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” patients.

The results of this study is in contrast with the results obtained by Nguyen et al., which the AGP reported on here. In this study, homozygous HLA C2/C2 recipients had a worse clinical outcome after Reduced Intensity Conditioning-Unrelated Cord Blood Transplant.2 This suggests that the impact of HLA matching on the outcomes of AML patients who underwent allogenic SCT is still debatable.

The authors concluded by proposing that a clinical study incorporating genetic, phenotypic, and functional NK cell reconstitution after SCT with different conditioning regimens should be carried out in order to confirm the findings of their study.

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/m2). 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.

References
  1. Shimoni A. et al. 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. Am J Hematol. 2017 Jul 19. DOI: 10.1002/ajh.24827. [Epub ahead of print].
  2. Nguyen S. et al. Clinical impact of NK-cell reconstitution after reduced intensity conditioned unrelated cord blood transplantation in patients with acute myeloid leukemia: analysis of a prospective phase II multicenter trial on behalf of the Société Française de Greffe de Moelle Osseuse et Thérapie Cellulaire and Eurocord. Bone Marrow Transplantation. 2017 Jun 26. DOI: 10.1038/bmt.2017.122. [Epub ahead of print].