TY - JOUR
T1 - KIR2DS1 genotype predicts for complete cytogenetic response and survival in newly diagnosed chronic myeloid leukemia patients treated with imatinib
AU - Marin, D.
AU - Gabriel, I. H.
AU - Ahmad, S.
AU - Foroni, L.
AU - De Lavallade, H.
AU - Clark, R.
AU - O'Brien, S.
AU - Sergeant, R.
AU - Hedgley, C.
AU - Milojkovic, D.
AU - Khorashad, J. S.
AU - Bua, M.
AU - Alsuliman, A.
AU - Khoder, A.
AU - Stringaris, K.
AU - Cooper, N.
AU - Davis, J.
AU - Goldman, J. M.
AU - Apperley, J. F.
AU - Rezvani, K.
N1 - Funding Information:
We would like to acknowledge the participating centers in the SPIRIT 1 trial, the SPIRIT study Team especially Caroline Hodgson, Claire Oyston, Lynn Seeley, Wendy Banks, Meg Buckley and the support of the NCRN CML working group, United Kingdom. We acknowledge the support of the National Institute for Health Research (NIHR) Biomedical Research Center (BRC), United Kingdom. This work was supported by the NIHR BRC London, (grant no. P31514) and Leuka registered charity, 286231.
PY - 2012/2
Y1 - 2012/2
N2 - Natural killer (NK) cells are expanded in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitors (TKI) and exert cytotoxicity. The inherited repertoire of killer immunoglobulin-like receptors (KIR) may influence response to TKI. We investigated the impact of KIR-genotype on outcome in 166 chronic phase CML patients on first-line imatinib treatment. We validated our findings in an independent patient group. On multivariate analysis, KIR2DS1 genotype (RR1.51, P0.03) and Sokal risk score (low-risk RR1, intermediate-risk RR1.53, P0.04, high-risk RR1.69, P0.034) were the only independent predictors for failure to achieve complete cytogenetic response (CCyR). Furthermore, KIR2DS1 was the only factor predicting shorter progression-free (PFS) (RR3.1, P0.03) and overall survival (OS) (RR2.6, P0.04). The association between KIR2DS1 and CCyR, PFS and OS was validated by KIR genotyping in 174 CML patients on first-line imatinib in the UK multi-center SPIRIT-1 trial; in this cohort, KIR2DS1() patients had significantly lower 2-year probabilities of achieving CCyR (76.9 vs 87.9%, P0.003), PFS (85.3 vs 98.1%, P0.007) and OS (94.4 vs 100%, P0.015) than KIR2DS1() patients. The impact of KIR2DS1 on CCyR was greatest when the ligand for the corresponding inhibitory receptor, KIR2DL1, was absent (P0.00006). Our data suggest a novel role for KIR-HLA immunogenetics in CML patients on TKI.
AB - Natural killer (NK) cells are expanded in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitors (TKI) and exert cytotoxicity. The inherited repertoire of killer immunoglobulin-like receptors (KIR) may influence response to TKI. We investigated the impact of KIR-genotype on outcome in 166 chronic phase CML patients on first-line imatinib treatment. We validated our findings in an independent patient group. On multivariate analysis, KIR2DS1 genotype (RR1.51, P0.03) and Sokal risk score (low-risk RR1, intermediate-risk RR1.53, P0.04, high-risk RR1.69, P0.034) were the only independent predictors for failure to achieve complete cytogenetic response (CCyR). Furthermore, KIR2DS1 was the only factor predicting shorter progression-free (PFS) (RR3.1, P0.03) and overall survival (OS) (RR2.6, P0.04). The association between KIR2DS1 and CCyR, PFS and OS was validated by KIR genotyping in 174 CML patients on first-line imatinib in the UK multi-center SPIRIT-1 trial; in this cohort, KIR2DS1() patients had significantly lower 2-year probabilities of achieving CCyR (76.9 vs 87.9%, P0.003), PFS (85.3 vs 98.1%, P0.007) and OS (94.4 vs 100%, P0.015) than KIR2DS1() patients. The impact of KIR2DS1 on CCyR was greatest when the ligand for the corresponding inhibitory receptor, KIR2DL1, was absent (P0.00006). Our data suggest a novel role for KIR-HLA immunogenetics in CML patients on TKI.
KW - chronic myeloid leukemia
KW - imatinib response
KW - killer immunoglobulin-like receptors
KW - natural killer cells
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U2 - 10.1038/leu.2011.180
DO - 10.1038/leu.2011.180
M3 - Review article
C2 - 21844874
AN - SCOPUS:84856704243
SN - 0887-6924
VL - 26
SP - 296
EP - 302
JO - Leukemia
JF - Leukemia
IS - 2
ER -