P654: allelic polymorphisms of kirs and hlas predict favorable achievement of treatment-free remission in cml: results from the pokstic trial, multicenter retrospective observational study

Background: The survival outcomes in patients with chronic phase chronic myeloid leukemia (CML-CP) dramatically improved following introduction of ABL1 tyrosine kinase inhibitors (TKIs). To achieve treatment-free remission (TFR) becomes one of the therapeutic goals for patients with CML-CP; however, the prognostic factors that predict successful achievement of TFR are unclear. Cancer immunosurveillance against CML is important to maintain for TFR in patients with CML-CP. We previously reported allelic polymorphisms of killer immunoglobulin-like receptors (KIRs) and human leucocyte antigens (HLAs) using next generation sequencing (NGS) were associated with favorable achievement of deep molecular response (DMR) and favorable HLA genotypes were associated with successful achievement of TFR in patients with CML-CP. There is no comprehensive analysis of the polymorphisms in KIRs and HLAs and immune cell fractions in CML-CP patients after discontinuation TKIs has been undertaken, thus we conducted the study to investigate POlymorphisms of Killer immunoglobulin-like receptor which affect Stop Tyrosine kinase inhibitor in patients with Chronic myeloid leukemia (POKSTIC trial); multicenter collaborative observational study. Aims: The aim of the study was to clarify the favorable prognostic factors for achievement of TFR via comprehensive analysis of KIRs and HLAs polymorphisms and immune cell fractions in CML-CP patients who discontinued TKIs. Methods: The study is a sub-study of the DOMEST (imatinib stop study), the DADI and first-line DADI trials (two dasatinib stop studies) approved by the institutional review board of each participating hospital (UMIN000041798). All procedures involving human participants were done in accordance with the principles of the Declaration of Helsinki and all participants provided written informed consent. Allelic genotyping of HLA and KIR genes was performed by GenoDive Pharma Inc. Two-color flow cytometry (FACSCalibur cytometer and BD CellQuest software, version 3.3; BD Biosciences, Franklin Lakes, NJ, USA) was done to assess T cell and natural killer cell profiles before TKIs discontinuation. Results: Seventy six patients enrolled from DOMEST (n=28), DADI (n=15) and first-line DADI trial (n=33) who agreed to participate to the POKSTIC trial. The median age was 63 years (Interquartile range, IQR; 49–70 years); 41 patients were male and 35 were female; and 50, 18, and six patients had low, intermediate, and high Sokal scores, respectively (two patients were missing data). A total of 42 of 76 [55.3%; 95% confidence interval (CI), 43.4–65.6% at 12 months] CML-CP patients discontinued TKIs without molecular relapse. Univariate analysis showed long-term TKI treatment duration (55 months≦) was associated with lower risk of molecular relapse (HR, 0.476 (95% CI, 0.239-0.947, p=0.034), while KIR3DL1 with ligand for HLA-Bw4 (except when Bw4 80I was HLA-A*24:02 only) was associated with higher molecular relapse (HR, 1.986 (95% CI, 1.02-3.868, p=0.044). Multivariate analysis identified KIR3DL1 with HLA-Bw4 (except when Bw4 80I was HLA-A*24:02 only) was independent risk factor for molecular relapse (HR, 2.206 (95% CI, 1.112-4.376, p=0.024). Notably, these patients had significantly lower NK cell fraction at TKI discontinuation (CD16/56 cells, median 499.63/μL vs 629.17/μL, p=0.049). Moreover, combination with presence or absence of activating KIR gene, KIR2DS5 can predict more favorable or worse prognostic patients (HR, 5.854 (95% CI, 1.323-25.89, p=0.020). Summary/Conclusion: Allelic polymorphisms of KIRs and HLAs can reflect NK cell immune response and can predict favorable achievement of TFR in CML.Keywords: Chronic myeloid leukemia, Immunity, treatment-free remission, Tyrosine kinase inhibitor