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Donor KIR haplotype B improves progression-free and overall survival after allogeneic hematopoietic stem cell transplantation for multiple myeloma

Leukemia volume 25, pages 1657–1661 (2011)Cite this article

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Allogeneic hematopoietic stem cell transplantation from related or unrelated donor has become a standard treatment for many patients with hematological malignancies, but the role of this treatment approach in the treatment of multiple myeloma remains controversial, as high risk of relapse remains a major concern.1 In acute leukemias, especially acute myeloid leukemias, alloreactive donor-derived natural killer cells (NK cells) have been correlated with an improved survival, especially after T-cell-depleted transplant procedures such as haploidentical stem cell transplantation.2 Small reports after allogeneic stem cell transplantation for multiple myeloma as well as pre-clinical models showed that alloreactive NK cells might have a role regarding cytotoxicity and relapse prevention in multiple myeloma.3 The NK cell function is determined by several receptor families including activating and inhibitory killer cell immunoglobulin-like receptors (KIRs). For the majority, especially for the active KIRs, the correspondent ligands are unknown. Nevertheless, there is an interaction between inhibitory KIRs on donor-derived NK cells and human leukocyte antigen (HLA) class-I molecules on the recipient to determine alloreactivities on healthy and malignant cells. All HLA C allotypes have either C1 epitope, a ligand for KIR2DL2/3, or the C2 epitope, which is a ligand for KIR2DL1. Additionally, the HLA B allotypes have either BW4 or BW6 epitope, but only the BW4 epitope is a ligand for the KIR3DL1. Therefore, in allogeneic stem cell transplantation setting, it is assumed that donor NK cells attack recipient cells by recognizing HLA class-I ligands, which are not sufficiently engaged by their inhibitory receptors. As the KIR genes are located on chromosome 19, they are segregated independently from HLA, which implies that especially after unrelated allogeneic stem cell transplantation and also after HLA-identical matched transplantation, KIR genes do not consequently match between donors and recipients. The effect of KIRs on outcome after allogeneic stem cell transplantation has been investigated by several models. The KIR–ligand mismatch model that is based on the ‘missing self theory’, which explains alloreactive NK cells and is based only on HLA typing (ligand–ligand model), has not shown conclusive results. The missing KIR–ligand model (or receptor–ligand model) was proposed if the recipients are homozygous for HLA Cw group I, II or BW6 and the donor KIR genotyping included at least one KIR that lacks the corresponding ligand or the recipient (donor: 2DL2/3 and recipient lacks Cw group I; donor 2DL1 and recipient lacks Cw group II or donor 3DL1 and recipient lacks BW4 (which leads to NK alloreactive cell lysis because of inhibitory KIRs lacking corresponding HLA ligand, class-I ligand)), although all these models could not show conclusive results after allogeneic stem cell transplantation. A more attractive model is to distinguish the diverse KIR haplotypes into two biological distinguished groups—group A and B. The B haplotype has more activating receptor genes (S1) than A. B haplotype in the donor (BB or B/X) promotes disease-free survival in acute myeloid leukemia (AML), most often regardless of patient haplotype.4, 5 The role of NK alloreactivity and of donor KIR genotype in myeloma is unclear. Here we studied the impact of donor KIR genotyping, KIR–ligand mismatch and KIR haplotypes on clinical outcome in patients with multiple myeloma who underwent allogeneic stem cell transplantation.

From 1997 until 2008, a total of 118 patients with multiple myeloma who received allogeneic stem cell transplantation at the University Medical Center Hamburg were included. Patients were treated either in an auto–allo tandem protocol (n=65; NCT 00777998) or in a protocol for patients with relapse after autologous stem cell transplantation (n=46; NCT 00781170) or were refractory to conventional therapy (n=7; see Table 1).

Table 1 Patients’ characteristics (n=118)
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Acknowledgements

This work was supported by a research grant from the ‘José Carreras Foundation’ to NK.

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Authors and Affiliations

  1. Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    N Kröger, T Zabelina, E Klyuchnikov, T Stübig, Y Hilde-brandt, H Alchalby, F Ayuk, A R Zander & U Bacher

  2. Institute of Statistics, University Medical Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    J Berger

  3. Institute for Transfusion Medicine, University Medical Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    H Duske, T Binder & T Eiermann

  4. Department of Oncology/Hematology, University Medical Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    D Atanackovic

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  1. N Kröger
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Correspondence to N Kröger.

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Kröger, N., Zabelina, T., Berger, J. et al. Donor KIR haplotype B improves progression-free and overall survival after allogeneic hematopoietic stem cell transplantation for multiple myeloma. Leukemia 25, 1657–1661 (2011). https://doi.org/10.1038/leu.2011.138

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