Clinical effects of NK cells after RIC-UCBT in AML patients – a French study

The success of transplantations with Human Leukocyte Antigen (HLA) mismatches depends on donor Natural Killer (NK) cell alloreactivity which plays an important role in mediating Graft versus Leukemia (GvL) effect without Graft versus Host Disease (GvHD) in recipients. However, there is still a debate on whether Killer Immunoglobulin Receptor (KIR) ligand incompatibility between donor and recipient might favor Natural Killer (NK) cell alloreactivity after Unrelated Cord Blood Transplantation (UCBT) in Acute Myeloid Leukemia (AML) patients, hence the rationale for this study. 

Stéphanie Nguyen from AP-HP, Hôpital Pitié Salpêtrière (AP-HP), Service d'Hématologie Clinique, Paris, France and colleagues discuss results from their prospective phase II study, which assessed the impact of KIR-ligand incompatibilities and NK cell reconstitution on clinical outcomes in AML patients in Complete Remission who underwent UCBT after a Reduced Intensity Conditioning (RIC). This study was conducted by the Société Française de Greffe de Moelle Osseuse et Thérapie Cellulaire and Eurocord. The results of the study were published ahead of print in Bone Marrow Transplantation on 26^th June 2017.

In total, seventy-nine de novo AML patients (median age = 50 years) in CR were enrolled in 23 French hospitals from October 2007– September 2009 for this phase II study. Peripheral blood samples and DNA samples were collected in recipients and cords blood and analyzed in fifty-four AML patients in CR who underwent RIC-UCBT. The inhibitory KIRs, KIR2DL1, and KIR2DL2/3 bind KIR HLA ligand C2 and C1 respectively, resulting in inhibition of NK-cell mediated lysis. Recipients and Unrelated Cord Blood (UCB) were classified into C1 or C2 family depending on their HLA-C typing (C1-C1, C1-C2 or C2-C2).

The key results of the study were:

• Treatment Related Mortality (TRM) was associated with a low frequency of CD16 (Fc receptor found on the surface of NK cells) on NK cells; HR = 0.97, P = 0.043
• TRM incidence was significantly associated with a high level of HLA-DR (NK cell activation marker); HR = 1.08, P = 0.0008
• Low CD107a (NK cell degranulation marker) was significantly associated with a worse OS; HR = 0.95, P = 0.001
• Median Overall Survival (OS) in homozygous HLA-C2/C2 and heterozygous HLA- C1/C2 (C1/x) recipients; 3.8 vs 29.9 months, HR = 6.12, P = 0.001
• Compared to C1/x recipients, C2/C2 recipients had a higher Relapse Free Survival (RFS [HR = 5.04, P = 0.024]) and TRM incidence (HR = 9.44, P = 0.026)

In summation, homozygous HLA C2/C2 recipients have a worse clinical outcome after RIC-UCBT.  Moreover, low expression of CD16 and CD107a were associated with increased incidence of TRM and worse OS respectively thus indicating an “impairment in the NK licensing process in HLA-mismatched” transplantation.

Overall, the authors concluded that “HLA-dependent and independent NK-cell features may play complementary roles in clinical outcomes after RIC-UCBT”. Additionally, they suggested that “further exploration should help in the development of future strategies to select optimal UCB units and enhance immune recovery”.

Abstract

Unrelated cord blood transplantation (UCBT) after a reduced intensity conditioning regimen (RIC) has extended the use of UCB in elderly patients and those with co-morbidities without an HLA-identical donor, although post-transplant relapse remains a concern in high-risk acute myeloid leukemia (AML) patients. HLA incompatibilities between donor and recipient might enhance the alloreactivity of natural killer (NK) cells after allogeneic hematopoietic stem-cell transplantation (HSCT). We studied the reconstitution of NK cells and KIR-L mismatch in 54 patients who underwent a RIC-UCBT for AML in CR in a prospective phase II clinical trial. After RIC-UCBT, NK cells displayed phenotypic features of both activation and immaturity. Restoration of their polyfunctional capacities depended on the timing of their acquisition of phenotypic markers of maturity. The incidence of treatment-related mortality (TRM) was correlated with low CD16 expression (P=0.043) and high HLA-DR expression (P=0.0008), whereas overall survival was associated with increased frequency of NK-cell degranulation (P=0.001). These features reflect a general impairment of the NK licensing process in HLA-mismatched HSCT and may aid the development of future strategies for selecting optimal UCB units and enhancing immune recovery.