Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative and useful strategy in high-risk relapsing CLL. Minimal Residual Disease (MRD) assessment at 12 months post-HSCT is predictive of relapse. This phase 2 study aimed to achieve M12 MRD negativity (MRDneg) using MRD-driven immune-intervention (Md-PII) algorithm based on serial flow-cytometry blood MRD, involving cyclosporine tapering followed if failure by donor lymphocytes infusions. Patients had high-risk CLL according to 2006 EBMT consensus, in complete or partial response with lymphadenopathy < 5 cm and comorbidity score ≤ 2. Donors were HLA-matched sibling or matched unrelated (10/10). Forty-two enrolled patients with either 17p deletion (front-line, n=11; relapse n=16) or other high-risk relapse (n=15) received reduced intensity-conditioning regimen before HSCT and were submitted to Md-PII. M12-MRDneg status was achieved in 64% versus 14.2% before HSCT. With a median follow-up of 36 months (range, 19-53), 3-year overall survival, non-relapse mortality and cumulative incidence of relapse are 86.9% (95%CI, 70.8-94.4), 9.5% (95%CI, 3.7-23.4) and 29.6% (95%CI, 17.3-47.7). Incidence of 2-year limited and extensive chronic graft versus host disease (cGVHD) is 38% (95%CI, 23-53) and 23% (95%CI, 10-36) including 2 cases post Md-PII. Fifteen patients converted to MRDneg either after CsA withdrawal (n=12) or after cGVHD (n=3). As a time-dependent variable, MRDneg achievement at any time-point correlates with reduced relapse (HR=0.14 [0.04-0.53], p=0.004) and improvement of both progression free (HR=0.18 [0.06-0.6], p<0.005) and overall (HR: 0.18 [0.03-0.98], p=0.047) survival. These data highlight the value of MRD-driven immune-intervention to induce prompt MRD clearance in the therapy of CLL.

译文

:同种异体造血干细胞移植(HSCT)仍然是高危复发性CLL的潜在治愈和有用策略。 HSCT后12个月的最小残留疾病(MRD)评估可预测复发。这项2期研究旨在通过基于连续流式细胞术血液MRD的MRD驱动的免疫干预(Md-PII)算法来实现M12 MRD阴性(MRDneg),涉及环孢素渐缩,如果供体淋巴细胞输注失败。根据2006年EBMT共识,患者发生高危CLL,完全或部分缓解,淋巴结病<5 cm,合并症评分≤2。供体为HLA匹配兄弟姐妹或匹配的无关亲戚(10/10)。入组四十二例17p缺失(一线,n = 11;复发n = 16)或其他高危复发(n = 15)的患者在HSCT之前接受了降低强度的治疗方案,并接受了Md-PII治疗。 M12-MRDneg状态的获得率为64%,而HSCT前为14.2%。中位随访期为36个月(范围19-53),3年总生存率,非复发死亡率和累积复发率分别为86.9%(95%CI,70.8-94.4),9.5%(95%) CI为3.7-23.4)和29.6%(95%CI为17.3-47.7)。两年有限且广泛的慢性移植物抗宿主病(cGVHD)的发生率为38%(95%CI,23-53)和23%(95%CI,10-36),包括2例Md-PII后病例。 CsA停药后(n = 12)或cGVHD(n = 3)后有15例患者转变为MRDneg。作为随时间变化的变量,在任何时间点的MRDneg成就均与复发率降低(HR = 0.14 [0.04-0.53],p = 0.004)和无进展进展的改善(HR = 0.18 [0.06-0.6],p < 0.005)和总体生存率(HR:0.18 [0.03-0.98],p = 0.047)。这些数据强调了MRD驱动的免疫干预在CLL治疗中诱导迅速清除MRD的价值。

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