KIR3DL1-HLA-Bw status in CML is associated with achievement of TFR: the POKSTIC trial, a multicenter observational study

Blood Neoplasia Pub Date : 2024-03-01 DOI:10.1016/j.bneo.2024.100001

Hiroshi Ureshino , Yasunori Ueda , Shin Fujisawa , Kensuke Usuki , Hideo Tanaka , Masaya Okada , Shugo Kowata , Kazunori Murai , Asao Hirose , Motohiro Shindo , Takashi Kumagai , Tomoharu Takeoka , Kazuharu Kamachi , Keisuke Kidoguchi , Takero Shindo , Satoshi Iyama , Junki Inamura , Takafumi Nakao , Tsutomu Kobayashi , Eri Kawata , Shinya Kimura

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Abstract

Achievement of treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation in patients who show a durable deep molecular response (DMR) during TKI treatment of chronic myeloid leukemia in chronic phase (CML-CP) is a therapeutic goal; however, the prognostic factors that predict successful achievement of TFR are unclear. Previously, we reported that killer immunoglobulin-like receptor (KIR) and HLA polymorphisms are associated with achievement of a DMR. Here, we investigated the association between KIR and HLA polymorphisms and TFR. We conducted the POKSTIC (POlymorphisms of Killer immunoglobulin-like receptor, which affect Stop Tyrosine kinase Inhibitor in patients with Chronic myeloid leukemia) trial, a multicenter collaborative observational study that enrolled 76 patients with CML-CP. The median age was 63 years (interquartile range [IQR], 49-70). Of 76 patients, 42 (56.6%; 95% confidence interval [CI], 47.7-66.8 at 6 months) discontinued TKIs without molecular relapse; the median follow-up time for TFR was 24 months (IQR, 16-64). KIR genotyping and allele typing did not identify risk factors for molecular relapse; however, univariate and multivariate analysis identified the combination of KIR3DL1-HLA-Bw4 (an HLA-B allele) as an independent factor for a higher risk of molecular relapse (hazard ratio, 2.206; 95% CI, 1.112-4.376; P = .024). Notably, patients at higher risk of relapse had a significantly lower number of natural killer (NK) cells at TKI discontinuation than the other patients (CD16⁺/CD56⁺ NK cells: median 499.63 cells per μL vs 629.17 cells per μL, respectively; P = .049). Thus, KIR3DL1-HLA-Bw status reflects NK cell responses and is associated with TFR. The study is registered with the UMIN Clinical Trials Registry as #UMIN000041798.

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CML 中的 KIR3DL1-HLA-Bw 状态与 TFR 的实现有关：多中心观察研究 POKSTIC 试验

摘要在酪氨酸激酶抑制剂（TKI）治疗慢性期髓性白血病（CML-CP）期间出现持久深度分子反应（DMR）的患者停用TKI后实现无治疗缓解（TFR）是一项治疗目标；然而，预测成功实现TFR的预后因素尚不清楚。以前，我们曾报道过杀伤性免疫球蛋白样受体（KIR）和 HLA 多态性与 DMR 的实现有关。在此，我们研究了 KIR 和 HLA 多态性与 TFR 之间的关联。我们开展了 POKSTIC（影响慢性髓性白血病患者酪氨酸激酶抑制剂停药的杀手免疫球蛋白样受体多态性）试验，这是一项多中心合作观察性研究，共招募了 76 名 CML-CP 患者。中位年龄为 63 岁（四分位数间距 [IQR]，49-70）。76 名患者中，42 人（56.6%；95% 置信区间 [CI]，47.7-66.8，6 个月）停用 TKIs 后未出现分子复发；TFR 的中位随访时间为 24 个月（IQR，16-64）。KIR 基因分型和等位基因分型并未发现分子复发的风险因素；但单变量和多变量分析发现，KIR3DL1-HLA-Bw4（HLA-B 等位基因）组合是分子复发风险较高的独立因素（危险比为 2.206；95% CI 为 1.112-4.376；P = .024）。值得注意的是，复发风险较高的患者在停用 TKI 时的自然杀伤（NK）细胞数量明显低于其他患者（CD16+/CD56+ NK 细胞：中位数分别为 499.63 cells per μL vs 629.17 cells per μL；P = .049）。因此，KIR3DL1-HLA-Bw 状态反映了 NK 细胞反应并与 TFR 相关。该研究已在 UMIN 临床试验注册中心注册，注册号为 #UMIN000041798。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Neoplasia

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