KIR-Ligand Incompatibility in the Graft-Versus-Host Direction Is Associated with
Better Outcomes after Unrelated Cord Blood Stem Cell Transplantation for Acute
Leukemia in Complete Remission
Roelof Willemze, MD, PhD1, Celso arrais Rodrigues2*, Myriam Labopin, MD3*, Guillermo
Sanz, MD, PhD4, Gerard Michel, MD5*, Gerard Socié, MD, PhD6*, Bernard Rio7*, Anne
Sirvent8*, Marc Renaud9*, Luis Madero10*, Mohamad Mohty, MD, PhD11, Christelle Ferra, MD,
PhD12*, Federico Garnier13*, Juan Garcia14*, Lucilla Lecchi15*, Gesine Koegler16*, Yves
Beguin17, Cristina Navarrete18*, Timothy Devos19*, Irina Ionescu20*, Karim Boudjedir20*,
Andrée-Laure Herr, MD21*, Eliane Gluckman, MD22 and Vanderson Rocha20*
1Dept.
of Hematology, Leiden Univ. Med. Ctr., Leiden, Netherlands
France
3Hopital Saint-Antoine, Université Pierre et Marie Curie Paris 6, Paris 75571, France
4Dept. of Hematology, Hospital Universitario La Fe, Valencia, Spain
5Hopital D'Enfants de la Timone, Marseille, France
6
Hematology / Transplantation, Hopital Saint-Louis, Paris, France
7Département d'Hématologie et d'Oncologie Médicale, Hôtel Dieu, Paris, France
8Hôpital de l'Archet 1, Nice, France
9Hôpital La Miletrie, Poitiers, France
10MD, Nino Jesus Children's Hospital, Madrid, Spain
11Hematology Dept., CHU de Nantes, Nantes, France
12GETH (Grupo Español de Trasplante Hematopoyético), PETHEMA (Programa Español de
Tratamiento de Hemopatías Malignas), Barcelona, Spain
13French Network of Cord Blood Banks, Paris, France
14Cttc, Cord Blood Bank, Barcelona, Spain
15Cord Blood Bank & GRACE, Milano, Italy
16Institut für Transplantationsdiagnostik und Zelltherapeutika, Duesseldorf, Germany
17ULg, Liege, Belgium
18Cord Blood Bank, London, United Kingdom
19De Leuvense Navelstrengbloedbank, Leuven, Belgium
20Eurocord, Paris, France
21Bone Marrow Transplantation, Saint-Louis Hospital, Paris, France
22Hopital Saint-Louis, Paris, France
2Eurocord,
HLA class I, killer-cell immunoglobulin-like receptor (KIR) ligands which are missing in the
recipient may trigger cytotoxicity of donor NK cells leading to graft-versus-host disease
(GvHD) and/or graft-versus-leukemia reactions. Donor KIR(-ligand) incompatibility in the
graft-versus-host (GvH) direction is associated with decreased relapse incidence (RI) and
improved disease-free survival (DFS) in haplo-identical and HLA-mismatched unrelated
hematopoietic stem cell transplantation (HSCT). Since it is unknown whether KIR-ligand
mismatching impacts outcomes in unrelated cord blood stem cell transplantation (UCBT), we
studied patients reported to Eurocord Registry with acute leukemia in complete remission
(CR) with available high resolution typing of HLA-A, -B and -C in recipient/donor pairs who
received a single UCBT.
Patients and donors were categorized to their KIR-ligand groups by determining whether or
not they expressed: HLA-C group 1 or 2, HLA-Bw4 and HLA-A3 or -A11. A total of 218
patient-donor pairs met the eligibility criteria. The patients had ALL (n=124) or AML (n=94)
and were transplanted in 1st CR (n=105), 2nd CR (n=91) or >2nd CR (n=22). Median age was
13.4 yrs, weight 49 kg, and nucleated cell dose infused was 3.0x10E7/kg. The cord blood
was HLA identical (6/6) in 21, 5/6 in 91, 4/6 in 91 and <4/6 in 15. Conditioning was
myeloablative (84%) or reduced intensity (16%), and included ATG in 80%. Forty-one
donors were HLA-C, 12 HLA-Bw4 and 22 HLA-A3/-A11 KIR-ligand mismatched in the GvH
direction with the patient whereas fifty-one patients were HLA-C group 1 or 2, 19 HLA-Bw4
and 18 HLA-A3/-A11 KIR-ligand mismatched in the HvG direction with the donor. When
studying only donor-patient pairs in the GvH direction a total of sixty-nine patients had a
KIR-ligand mismatched (KIR+) donor and 149 had not (KIR-). There were no statistical
differences for patient-, disease- and transplantion-related factors between the KIR+ and
KIR- group, except for more cytogenetically bad risk AML patients in the KIR+ group.
HLA-C group 1 and 2, and HLA-A3/-A11, KIR-ligand incompatible UCBT showed
independently a trend to improved DFS (p=0.09 and p=0.13, respectively). Analysis of the
combined HLA-A, -B and -C KIR-ligand (mis)matches showed no statistical association with
neutrophil recovery (81±4% KIR+, 79±3% KIR- group, p=0.21), non-relapse mortality
(25±6% KIR+, 32±4% KIR-, p=0.34), acute GvHD (27±5% KIR+, 29±3% KIR-, p=0.82)
and chronic GvHD (18±4% KIR+, 14±3% KIR-, p=0.38). However, differences were shown
in RI (20±6% KIR+, 37±4% KIR-, p=0.03), DFS (55±7% KIR+, 31±4% KIR-, p=0.005) and
overall survival (57±7% KIR+, 40±4% KIR-, p=0.02). In multivariate analysis, donor KIRligand incompatibility was associated with decreased RI (HR=0.53, p=0.05), increased DFS
(HR=2.05, p=0.016) and overall survival (HR=2, p=0.004). In subgroup analysis for AML: RI
for KIR+ vs KIR- was 5±4% vs 36±7% (p=0.005) and DFS 73±10% vs 38±7% (p=0.012);
and for ALL: RI was 29±8% vs 37±6% (p=0.71) and DFS 44±9% vs 27±6% (p=0.10),
respectively.
The use of KIR-ligand incompatible donors in UCBT resulted in a lower RI and increased DFS
and overall survival, especially in AML. If these results are confirmed in a larger series of
patients KIR-ligand incompatibility in the GvH direction might be considered as a criterion of
cord blood donor choice.
Disclosures: No relevant conflicts of interest to declare.