Liu Xiaoqing, Chai Xingxing, Yu Qingling, Wang Wei, Long Qiqiang, Gong Yuemin, Zhang Yawen, Qiao Chun, Hao Jianping, He Guangsheng
Department of Hematology, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, 210000, China.
Department of Hematology, The Second Lianyungang People's Hospital Affiliated to Kangda College of Nanjing Medical University, Lianyungang, 222000, China.
Ann Hematol. 2025 Apr;104(4):2351-2360. doi: 10.1007/s00277-025-06371-5. Epub 2025 Apr 23.
Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder where somatic STAT3 mutation is common. Although LGLL has been described as an underlying condition associated with pure red cell aplasia (PRCA), the clinical characteristics and therapeutic response of LGLL - associated PRCA are largely unclear. We evaluated a set of 81 patients with LGLL - associated PRCA. Comparative analysis was performed on the clinical characteristics, responses to immunosuppressive therapy, and survival outcomes in patients with STAT3 mutation. Among the 81 LGLL - associated PRCA patients, 21 cases (26%) were STAT3 mutant, and 60 were wild - type. Of 21 patients with STAT3 mutation, 15 cases (71%) were positive for exon 21 mutation, 4 cases (19%) for exon 20 mutation, one for dual mutation in exon 20 and 21, and one for exon 13 mutation. The Y640F was the most commonly detected mutation (42.9%). Patients with STAT3 mutations had a higher percentage of reticulocytes (0.88% vs. 0.28%, P = 0.039) and red cell distribution width - coefficient of variation (18.8% vs. 15.8%, P = 0.008) compared to wild - type. Those with the STAT3 Y640F mutation had a younger median age at onset (44 years vs. 65 years, P = 0.007) and a higher peripheral blood lymphocyte ratio (63.7% vs. 34.4%, P = 0.033). The complete response rate (CRR) and overall response rate (ORR) of STAT3 mutated patients treated with cyclosporine (CsA) were 31.3% (5/16) and 56.3% (9/16), respectively, with no difference compared to the STAT3 wild - type (32.8%, 50%) (P = 0.909; P = 0.658). Although no statistical significance was found, the CRR and ORR of the CP regimen (consisted of cyclophosphamide and prednisone) were higher than CsA among STAT3 mutated individuals (53.8% vs. 31.3%, P = 0.274; 84.6% vs. 56.3%, P = 0.130). Reduction or discontinuation of immunosuppressive agents was the main cause of relapse. The relapse rate of the CP regimen was lower than CsA in this whole cohort (24.0% vs. 68.4%, P = 0.001), as well as in the STAT3 mutant group (18.2% vs. 77.8%, P = 0.022). STAT3 Y640F was the most common hotspot mutation in LGLL - associated PRCA. Patients with STAT3 mutation treated with CsA showed comparable responses to wild - type. CP regimen had a lower relapse rate and could be considered as a salvage therapy after CsA failure.
大颗粒淋巴细胞白血病（LGLL）是一种罕见的淋巴细胞增殖性疾病，其中体细胞STAT3突变很常见。虽然LGLL已被描述为与纯红细胞再生障碍性贫血（PRCA）相关的基础疾病，但LGLL相关PRCA的临床特征和治疗反应在很大程度上尚不清楚。我们评估了一组81例LGLL相关PRCA患者。对STAT3突变患者的临床特征、免疫抑制治疗反应和生存结果进行了比较分析。在81例LGLL相关PRCA患者中，21例（26%）为STAT3突变型，60例为野生型。在21例STAT3突变患者中，15例（71%）外显子21突变阳性，4例（19%）外显子20突变阳性，1例外显子20和21双重突变阳性，1例外显子13突变阳性。Y640F是最常检测到的突变（42.9%）。与野生型相比，STAT3突变患者的网织红细胞百分比更高（0.88%对0.28%，P = 0.039），红细胞分布宽度变异系数更高（18.8%对15.8%，P = 0.008）。携带STAT3 Y640F突变的患者发病年龄中位数更年轻（44岁对65岁，P = 0.007），外周血淋巴细胞比例更高（63.7%对34.4%，P = 0.033）。接受环孢素（CsA）治疗的STAT3突变患者的完全缓解率（CRR）和总缓解率（ORR）分别为31.3%（5/16）和56.3%（9/16），与STAT3野生型（32.8%，50%）相比无差异（P = 0.909；P = 0.658）。虽然未发现统计学意义，但在STAT3突变个体中，CP方案（由环磷酰胺和泼尼松组成）的CRR和ORR高于CsA（53.8%对31.3%，P = 0.274；84.6%对56.3%，P = 0.130）。免疫抑制剂的减量或停用是复发的主要原因。在整个队列中，CP方案的复发率低于CsA（24.0%对68.4%，P = 0.001），在STAT3突变组中也是如此（18.2%对77.8%，P = 0.022）。STAT3 Y640F是LGLL相关PRCA中最常见的热点突变。接受CsA治疗的STAT3突变患者的反应与野生型相当。CP方案复发率较低，可考虑作为CsA治疗失败后的挽救治疗。
