KIR2DL5B genotype predicts outcomes in CML patients treated with response-directed sequential imatinib/nilotinib strategy.

Killer immunoglobulin-like receptors (KIRs) on natural killer (NK) cells have been shown to predict for response in chronic phase-chronic myeloid leukemia (CP-CML) patients treated with tyrosine kinase inhibitors. We performed KIR genotyping in 148 newly diagnosed CP-CML patients treated with a novel sequential imatinib/nilotinib strategy aimed at achievement of optimal molecular responses at defined time points. We found the presence of KIR2DL5B to be associated with inferior transformation-free survival and event-free survival and an independent predictor of inferior major molecular response (BCR-ABL1 ≤0.1%) and molecular response 4.5 (BCR-ABL1 ≤0.0032%). This suggests a critical early role for NK cells in facilitating response to imatinib that cannot be overcome by subsequent intensification of therapy. KIR genotyping may add valuable prognostic information to future baseline predictive scoring systems in CP-CML patients and facilitate optimal frontline treatment selection.

[1]  D. Marin,et al.  KIR2DS1 genotype predicts for complete cytogenetic response and survival in newly diagnosed chronic myeloid leukemia patients treated with imatinib , 2012, Leukemia.

[2]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[3]  N. Kröger,et al.  Early administration of donor lymphocyte infusions upon molecular relapse after allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia: a study by the Chronic Malignancies Working Party of the EBMT , 2014, Haematologica.

[4]  D. Greco,et al.  Killer-cell immunoglobulin-like receptor gene profile predicts good molecular response to dasatinib therapy in chronic myeloid leukemia. , 2012, Experimental hematology.

[5]  J. Grandis,et al.  Bortezomib up-regulates activated signal transducer and activator of transcription-3 and synergizes with inhibitors of signal transducer and activator of transcription-3 to promote head and neck squamous cell carcinoma cell death , 2009, Molecular Cancer Therapeutics.

[6]  Robert Gray,et al.  A Proportional Hazards Model for the Subdistribution of a Competing Risk , 1999 .

[7]  C. Carcassi,et al.  Homozygosity for killer immunoglobin-like receptor haplotype A predicts complete molecular response to treatment with tyrosine kinase inhibitors in chronic myeloid leukemia patients. , 2013, Experimental hematology.

[8]  S. Mustjoki,et al.  Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy. , 2010, Blood.

[9]  D. White,et al.  Which TKI? An embarrassment of riches for chronic myeloid leukemia patients. , 2013, Hematology. American Society of Hematology. Education Program.

[10]  K. Campbell,et al.  [Natural killer cells and cancer. Regulation by the killer cell Ig-like receptors (KIR)]. , 2010, Zhongguo fei ai za zhi = Chinese journal of lung cancer.

[11]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[12]  D. Middleton,et al.  Investigation of killer cell immunoglobulin-like receptor (KIR) gene diversity: KIR2DL2, KIR2DL5 and KIR2DS5. , 2008, Tissue antigens.

[13]  P Parham,et al.  Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors. , 1997, Immunity.

[14]  Francisco Cervantes,et al.  European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. , 2013, Blood.

[15]  Peter Parham,et al.  Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia. , 2009, Blood.

[16]  P. Parham,et al.  Pregnancy immunogenetics: NK cell education in the womb? , 2010, The Journal of clinical investigation.

[17]  P. Grambsch,et al.  A Package for Survival Analysis in S , 1994 .

[18]  A. Cambon-Thomsen,et al.  Linkage disequilibrium organization of the human KIR superlocus: implications for KIR data analyses , 2010, Immunogenetics.

[19]  K. Rezvani,et al.  Dasatinib may overcome the negative prognostic impact of KIR2DS1 in newly diagnosed patients with chronic myeloid leukemia. , 2012, Blood.

[20]  C. Tam,et al.  TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. , 2015, Blood.

[21]  S. Mustjoki,et al.  Chronic Myeloid Leukemia Patients in Prolonged Remission following Interferon-α Monotherapy Have Distinct Cytokine and Oligoclonal Lymphocyte Profile , 2011, PloS one.

[22]  M. López-Botet,et al.  KIR2DL5: An Orphan Inhibitory Receptor Displaying Complex Patterns of Polymorphism and Expression , 2012, Front. Immun..

[23]  Andrew R. Jones,et al.  Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations , 2010, Nucleic Acids Res..

[24]  L. Zitvogel,et al.  Immunological aspects of cancer chemotherapy , 2008, Nature Reviews Immunology.