title: KIR2DS1 genotype predicts for complete cytogenetic response and survival in newly diagnosed chronic myeloid leukemia patients treated with imatinib.
abstract: 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 (RR=1.51, P=0.03) and Sokal risk score (low-risk RR=1, intermediate-risk RR=1.53, P=0.04, high-risk RR=1.69, P=0.034) were the only independent predictors for failure to achieve complete cytogenetic response (CCyR). Furthermore, KIR2DS1 was the only factor predicting shorter progression-free (PFS) (RR=3.1, P=0.03) and overall survival (OS) (RR=2.6, P=0.04). 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%, P=0.003), PFS (85.3 vs 98.1%, P=0.007) and OS (94.4 vs 100%, P=0.015) than KIR2DS1(-) patients. The impact of KIR2DS1 on CCyR was greatest when the ligand for the corresponding inhibitory receptor, KIR2DL1, was absent (P=0.00006). Our data suggest a novel role for KIR-HLA immunogenetics in CML patients on TKI.
authors.affiliation: Department of Hematology, Imperial College London, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Marin
authors.forename: I H
authors.initials: IH
authors.lastname: Gabriel
authors.forename: S
authors.initials: S
authors.lastname: Ahmad
authors.forename: L
authors.initials: L
authors.lastname: Foroni
authors.forename: H
authors.initials: H
authors.lastname: de Lavallade
authors.forename: R
authors.initials: R
authors.lastname: Clark
authors.forename: S
authors.initials: S
authors.lastname: O'Brien
authors.forename: R
authors.initials: R
authors.lastname: Sergeant
authors.forename: C
authors.initials: C
authors.lastname: Hedgley
authors.forename: D
authors.initials: D
authors.lastname: Milojkovic
authors.forename: J S
authors.initials: JS
authors.lastname: Khorashad
authors.forename: M
authors.initials: M
authors.lastname: Bua
authors.forename: A
authors.initials: A
authors.lastname: Alsuliman
authors.forename: A
authors.initials: A
authors.lastname: Khoder
authors.forename: K
authors.initials: K
authors.lastname: Stringaris
authors.forename: N
authors.initials: N
authors.lastname: Cooper
authors.forename: J
authors.initials: J
authors.lastname: Davis
authors.forename: J M
authors.initials: JM
authors.lastname: Goldman
authors.forename: J F
authors.initials: JF
authors.lastname: Apperley
authors.forename: K
authors.initials: K
authors.lastname: Rezvani
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D005260:Female; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D054340:Receptors, KIR / Q000235:genetics*; D012074:Remission Induction; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C496212:KIR2DS1 protein, human; D010879:Piperazines; D011743:Pyrimidines; D054340:Receptors, KIR; D000068877:Imatinib Mesylate