Reconstitution of NK cells expressing KIR3DL1 is associated with reduced NK cell activity and relapse of CML after allogeneic hematopoietic stem cell transplantation.

Although the prognosis of chronic myeloid leukemia (CML) in blastic crisis remains poor, some patients achieve long-term remission after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This may be attributable to graft-versus-leukemia (GVL) effects by donor lymphocytes, but their regulating mechanisms are unclear. Antitumor natural killer (NK) cell immunity is assumed to be important in CML, and we have previously shown that allelic polymorphisms of killer immunoglobulin-like receptors (KIRs) and histocompatibility leukocyte antigens (HLAs) are associated with the response of CML to tyrosine kinase inhibitors. Here, we report a case of CML in blastic phase who received HLA-matched but KIR3DL1 allelic-mismatched allo-HSCT. After transplant, decreased BCR-ABL transcript levels and enhanced NK cell activity were transiently observed. However, reconstitution of KIR3DL1-expressing NK cells occurred, which was associated with diminished NK cell activity and increased BCR-ABL. This case indicates the potential significance of KIR3DL1 in NK cell-mediated GVL activity following allo-HSCT. To the best of our knowledge, this is the first report to analyze the association between sequential KIR3DL1 expression and activity of NK cells after allo-HSCT. Selecting donors with KIR3DL1-null alleles may maintain competent GVL effects and provide improved outcomes in allo-HSCT for CML.

Allelic Polymorphisms of KIRs and HLAs Predict Favorable Responses to Tyrosine Kinase Inhibitors in CML.

Response to tyrosine kinase inhibitors (TKIs) is variable in chronic myeloid leukemia (CML), and elevated natural killer (NK) cells during TKI therapy are positively correlated with superior outcomes. NK cell function involves interactions of their killer immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I on target cells, and the avidity of KIR-HLA interactions depends on the combination of KIR and HLA alleles. We hypothesized that KIR and HLA polymorphisms may influence response to TKIs. KIR and HLA allele genotyping was performed by next-generation sequencing for 76 CML cases, and association with clinical outcome was analyzed. Second-generation TKIs as first-line therapy and patients' sex (female) were strongly associated with achievement of complete molecular response (CMR: MR4.0) after 2 years (P < 0.001 and P = 0.002, respectively). After adjustment for these two characteristics, several KIR alleles remained associated with achievement of MR4.0: KIR2DL4*005/011 or *008 (HR = 1.797, P = 0.032); KIR2DS4*003 or *007/010 (HR = 3.348, P < 0.001); KIR3DL1*005 (HR = 2.746, P = 0.003); and KIR3DL2*009 or *010 [HR = 1.980 (1.109-3.524), P = 0.021]. Strong linkage among these alleles exists, implying that they comprise favorable KIR allele haplotypes. Allelic polymorphisms of KIR3DL1 and HLA-B determine their differential avidity into strong/weak or no interaction. Patients carrying noninteracting KIR3DL1 and HLA-B allele pairs achieved better outcomes than those with strongly interacting pairs, and KIR3DL1*005 associated with a positive outcome among patients with weak-interacting pairs. Thus, KIR3DL1*005 and its associated haplotypes associated with superior TKI therapeutic effects. The combinations of these KIR and HLA alleles may correlate with potent NK cell immunity against CML. Cancer Immunol Res; 6(6); 745-54. ©2018 AACR.

Spousal hematopoietic stem cell transplantation.

We report a pilot series of five patients who received stem cell transplantation (SCT) from a spouse for post-transplant relapse or rejection. The inclusion criterion regarding HLA disparities was three or fewer antigen mismatches in the graft-versus-host direction at the HLA-A, B, and DR loci. Four patients received spousal SCT as a third transplant attempt after post-transplant relapse and one as rescue for graft rejection. The reduced intensity conditioning (RIC) regimen consisted of fludarabine, melphalan, and anti-thymocyte globulin (ATG) with 3 Gy of total body irradiation (TBI) for relapse cases and ATG plus 4 Gy of TBI for the rejection case. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, methylprednisolone, and mycophenolate mofetil. Peripheral blood stem cells were transplanted. Granulocyte engraftment was achieved in all cases between days 9 and 11 (median, 10) with complete spousal chimerism. In three of the five patients, no acute GVHD was observed, while one case developed grade III GVHD and one case grade IV. All four patients evaluable for the anti-leukemic effect achieved complete remission; however, all relapsed between 106 and 334 day post-transplant, and died between days 152 and 548. We suggest that spousal SCT can be performed as a repetitive SCT using a RIC regimen with low-dose ATG and steroid-containing GVHD prophylaxis.