Department of Internal Medicine 1 (Oncology, Hematology, Clinical Immunology, and Rheumatology), Saarland University Medical School, Homburg/Saar, Germany.
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
Lancet Haematol. 2022 Feb;9(2):e133-e142. doi: 10.1016/S2352-3026(21)00369-0.
The addition of rituximab to chemotherapy has substantially improved outcomes for patients with B-cell malignancies. The mechanisms of action of rituximab include activation of natural killer cells. Killer-cell immunoglobulin-like receptors (KIRs) mediate natural killer cell function through interaction with HLA. We evaluated the clinical impact of KIR-HLA genotypes on rituximab-containing therapy.
For this post-hoc analysis, we used data from the RICOVER-60 trial (NCT00052936) as the discovery cohort and the CLL8 trial (NCT00281918) as the validation cohort. RICOVER-60 included patients aged 61-80 years with aggressive B-cell lymphoma treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab. CLL8 included patients aged 30-81 years with chronic lymphocytic leukaemia treated with chemotherapy (fludarabine and cyclophosphamide; FC) with or without rituximab. We evaluated the KIR and HLA-C status of 519 patients with available blood samples in the RICOVER-60 trial and the KIR2DS1 and HLA-C status of 549 patients with available blood samples in the CLL8 trial, and evaluated their associations with event-free survival (RICOVER-60), progression-free survival, and overall survival (RICOVER-60 and CLL8).
In the RICOVER-60 trial, 201 (39%) patients were positive for KIR2DS1, 79 (15%) were homozygous for HLA-C2, and 36 (7%) were positive for KIR2DS1 and homozygous for HLA-C2. In the CLL8 trial, 206 (38%) patients were positive for KIR2DS1, 75 (14%) were homozygous for HLA-C2, and 26 (5%) were positive for KIR2DS1 and homozygous for HLA-C2. In the RICOVER-60 trial, both KIR2DS1 and HLA-C status were identified as independent risk factors for survival. KIR2DS1 positivity, homozygosity for HLA-C2, and subsequent KIR2DS1-HLA-C status were associated with adverse clinical outcome in patients receiving rituximab-containing therapy (event-free survival for patients with KIR2DS1-HLA-C2/C2 vs all other patients, HR 2·6 [95% CI 1·4-4·7], p=0·0015; progression-free survival, 2·7 [1·5-5·1], p=0·0013; overall survival, 2·8 [1·5-5·4], p=0·0016) but not in patients receiving CHOP chemotherapy only (event-free survival, 0·9 [0·5-1·7], p=0·85; progression-free survival, 1·1 [0·6-2·0], p=0·81; overall survival, 1·2 [0·6-2·4], p=0·53). A significant interaction between KIR2DS1-HLA-C status and rituximab was observed (p=0·018 for event-free survival and p=0·034 for progression-free survival). In contrast to all other patients, those positive for KIR2DS1 and homozygous for HLA-C2 did not benefit from adding rituximab to CHOP chemotherapy (event-free survival, 1·9 [0·8-4·6], p=0·16; progression-free survival, 1·4 [0·6-3·4], p=0·48; overall survival, 1·6 [0·6-4·3], p=0·33). In the CLL8 trial, KIR2DS1-HLA-C status was confirmed as a predictive marker for benefit from rituximab therapy (p=0·024 for the interaction of KIR2DS1-HLA-C status and rituximab regarding progression-free survival). In contrast to all other patients, those positive for KIR2DS1 and homozygous for HLA-C2 did not benefit from adding rituximab to FC chemotherapy (progression-free survival, 2·1 [0·9-4·9], p=0·094; overall survival, 2·6 [0·5-12·7], p=0·21).
Assessment of KIR2DS1 and HLA-C genotype might identify patients who would not benefit from rituximab, thereby allowing alternative therapies to be given. Further validation of these findings in prospective clinical trials is needed.
F Hoffman La Roche.
利妥昔单抗联合化疗显著改善了 B 细胞恶性肿瘤患者的预后。利妥昔单抗的作用机制包括激活自然杀伤细胞。杀伤细胞免疫球蛋白样受体（KIR）通过与 HLA 的相互作用介导自然杀伤细胞的功能。我们评估了 KIR-HLA 基因型对含利妥昔单抗治疗的临床影响。
本研究采用 RICOVER-60 试验（NCT00052936）的数据作为发现队列，CLL8 试验（NCT00281918）作为验证队列进行了这项事后分析。RICOVER-60 纳入了年龄在 61-80 岁的侵袭性 B 细胞淋巴瘤患者，这些患者接受 CHOP（环磷酰胺、多柔比星、长春新碱和泼尼松）化疗联合或不联合利妥昔单抗治疗。CLL8 纳入了年龄在 30-81 岁的慢性淋巴细胞白血病患者，这些患者接受化疗（氟达拉滨和环磷酰胺；FC）联合或不联合利妥昔单抗治疗。我们评估了 RICOVER-60 试验中 519 例有可用血样的患者的 KIR 和 HLA-C 状态，以及 CLL8 试验中 549 例有可用血样的患者的 KIR2DS1 和 HLA-C 状态，并评估了它们与无事件生存（RICOVER-60）、无进展生存和总生存（RICOVER-60 和 CLL8）的关系。
在 RICOVER-60 试验中，201 例（39%）患者 KIR2DS1 阳性，79 例（15%）HLA-C2 纯合子，36 例（7%）KIR2DS1 阳性且 HLA-C2 纯合子。在 CLL8 试验中，206 例（38%）患者 KIR2DS1 阳性，75 例（14%）HLA-C2 纯合子，26 例（5%）KIR2DS1 阳性且 HLA-C2 纯合子。在 RICOVER-60 试验中，KIR2DS1 和 HLA-C 状态均被确定为生存的独立危险因素。接受含利妥昔单抗治疗的患者中，KIR2DS1 阳性、HLA-C2 纯合子以及随后的 KIR2DS1-HLA-C 状态与不良临床结局相关（KIR2DS1-HLA-C2/C2 与其他所有患者相比，事件无进展生存的 HR 为 2.6 [95%CI 1.4-4.7]，p=0.0015；无进展生存，2.7 [1.5-5.1]，p=0.0013；总生存，2.8 [1.5-5.4]，p=0.0016），但在接受 CHOP 化疗的患者中则不然（事件无进展生存，0.9 [0.5-1.7]，p=0.85；无进展生存，1.1 [0.6-2.0]，p=0.81；总生存，1.2 [0.6-2.4]，p=0.53）。KIR2DS1-HLA-C 状态与利妥昔单抗之间存在显著的相互作用（事件无进展生存的 p=0.018，无进展生存的 p=0.034）。与其他所有患者相比，KIR2DS1 阳性且 HLA-C2 纯合子的患者未从 CHOP 化疗联合利妥昔单抗治疗中获益（事件无进展生存，1.9 [0.8-4.6]，p=0.16；无进展生存，1.4 [0.6-3.4]，p=0.48；总生存，1.6 [0.6-4.3]，p=0.33）。在 CLL8 试验中，KIR2DS1-HLA-C 状态被确认为从利妥昔单抗治疗中获益的预测标志物（p=0.024 用于 KIR2DS1-HLA-C 状态与利妥昔单抗关于无进展生存的相互作用）。与其他所有患者相比，KIR2DS1 阳性且 HLA-C2 纯合子的患者未从 FC 化疗联合利妥昔单抗治疗中获益（无进展生存，2.1 [0.9-4.9]，p=0.094；总生存，2.6 [0.5-12.7]，p=0.21）。
评估 KIR2DS1 和 HLA-C 基因型可能有助于识别不会从利妥昔单抗治疗中获益的患者，从而可以给予替代治疗。需要在前瞻性临床试验中进一步验证这些发现。
罗氏公司。
