A Pilot Study of UM171-Expanded Cord Blood Grafts for Tandem Auto/Allogeneic Hematopoietic Cell Transplant in High and Ultra-High-Risk Myeloma Patients.

IF 3.6 3区 医学 Q2 HEMATOLOGY
Jean Roy, Sandra Cohen, Guy Sauvageau, Imran Ahmad, Valentyn Fournier, Rafik Terra, Pierre Caudrelier, Stéphanie Thiant, Gabrielle Thauvette, Nadia Bambace, Jean-Sébastien Delisle, Silvy Lachance, Thomas Kiss, Léa Bernard, Denis Claude Roy, Olivier Veilleux, Richard LeBlanc
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引用次数: 0

Abstract

Multiple myeloma (MM) remains associated with a poor outcome, particularly in patients with advanced disease and high-risk (HR) cytogenetics. To date, the only curative treatment is allogeneic (allo) hematopoietic cell transplantation (HCT), but high incidences of graft versus host disease (GVHD), nonrelapse mortality (NRM) and disease progression remain important obstacles. Cord blood (CB) transplantation has been associated with low rates of relapse and chronic (c) GVHD, but its use has declined because of high incidences of infections, severe acute GVHD and high NRM. In other hematologic malignancies, UM171-expanded CB transplants have led to improved outcomes, allowing for the selection of smaller, better HLA-matched units. We aimed to investigate the safety and feasibility of single UM171-expanded single CB unit transplantation in frontline tandem auto/allo HCT for HR/ultra-HR MM patients. Newly diagnosed MM patients ≤ 65 years with an ISS stage II/III and del(17p), t(4;14), t(14;16), t(14;20), del(1p) or +1q, R-ISS 3, ≥ 2 cytogenetic abnormalities, or plasma cell leukemia without a sibling donor and availability of a 5-7/8 matched CB graft with ≥ 0.5 x 105 CD34+/kg and ≥ 1.5 x 107 TNCs/kg were eligible to this phase I/II prospective study (ClinicalTrials.gov NCT03441958). After induction and autologous HCT, patients received a reduced intensity conditioning regimen and were infused with 7-day UM171-expanded CD34+ cells, along with the lymphocytes contained in the CD34-negative fraction. The primary endpoints were feasibility of UM171 expansion, safety, kinetics of engraftment, incidences and maximum grades of acute and cGVHD at 1 and 2 years, assessment of measurable residual disease (MRD) and quality of life (QoL). Between 05/2018 and 11/2021, 20 patients were enrolled. One patient had an unsuccessful CB expansion with UM171, leaving 19 patients with a median age of 56 years. Median CD34+ cell dose infused after expansion was 4.62 x 106/kg (range: 0.79 to 5.76). Median times to achieve absolute neutrophil counts of 0.1 and 0.5 x 109/L were D+6 and D+10.5; median time to reach ≥ 20 x 109/L platelets was D+36. Full donor chimerism was achieved in all cell lineages by D+120 in recipients of reduced intensity conditioning. Cumulative incidences of grade II-IV, grade III-IV acute GVHD and moderate/severe cGVHD at 12 months were 68.4% (95% CI: 46 to 90), 5.3% (95% CI: 0% to 16%), and 10.5% (95% CI: 0% to 25%), respectively. With a median follow-up of 2.9 years (range: 0.46 to 5.3), cumulative incidences of relapse, PFS, OS and NRM at 3 years were 36.8% (95% CI: 14 to 59), 47.4% (95% CI: 29 to 76), 68.4% (95% CI: 50 to 93) and 15.8% (95%CI: 0 to 33), respectively. Median time to complete immunosuppression discontinuation was D+238. No unexpected adverse events were observed. Only one of 7 patients alive at 2 years with negative MRD at transplant has relapsed. Non-relapsing patients had a QoL after transplant similar to the general population. UM171-expanded CB transplant in HR/ultra-HR myeloma patients is feasible and allows the use of single CB units with a low risk of cGVHD. Patients with negative pretransplant MRD might benefit most from a UM171-expanded CB transplant.

UM171扩增脐带血移植物用于高危和超高危骨髓瘤患者串联自体/异体造血细胞移植的试点研究。
背景:多发性骨髓瘤(MM多发性骨髓瘤(MM)的预后仍然很差,尤其是晚期患者和高危(HR)细胞遗传学患者。迄今为止,唯一可治愈的治疗方法是异基因(allo)造血细胞移植(HCT),但移植物抗宿主疾病(GVHD)、非复发死亡率(NRM)和疾病进展的高发病率仍是重要障碍。脐带血(CB)移植的复发率和慢性(c)移植物抗宿主疾病(GVHD)发生率较低,但由于感染、严重急性GVHD和高NRM发生率较高,脐带血移植的使用已经减少。在其他血液系统恶性肿瘤中,UM171扩增的CB移植改善了预后,可以选择更小、HLA匹配更好的单位:我们的目的是研究在一线串联自体/异体 HCT 治疗 HR/ultra-HR MM 患者时进行单个 UM171 扩增的单个 CB 单位移植的安全性和可行性:研究设计:新诊断的MM患者,年龄≤65岁,ISS II/III期,del17p、t4,14、t14,16、t14,20、del1p或+1q、R-ISS 3、≥2细胞遗传学异常,或浆细胞白血病,无同胞供者,有5-7/8匹配的CB移植物,CD34+/kg≥0.5 x 105 CD34+/kg且≥ 1.5 x 107 TNCs/kg的患者有资格参加这项I/II期前瞻性研究(ClinicalTrials.gov NCT03441958)。诱导和自体造血干细胞移植后,患者接受强度降低的调理方案,并输注7天的UM171扩增CD34+细胞以及CD34阴性部分所含的淋巴细胞。主要终点是UM171扩增的可行性、安全性、移植动力学、1年和2年后急性和cGVHD的发生率和最大分级、可测量残留疾病(MRD)的评估以及生活质量(QoL):结果:在2018年5月至2021年11月期间,共有20名患者入组。一名患者使用 UM171 进行 CB 扩增失败,剩下 19 名患者,中位年龄为 56 岁。扩增后输注的 CD34+ 细胞剂量中位数为 4.62 x 106/kg(范围:0.79-5.76)。中性粒细胞绝对计数达到0.1和0.5 x 109/L的中位时间分别为D+6和D+10.5;血小板达到≥20 x 109/L的中位时间为D+36。在减低强度调理的受者中,所有细胞系的供体嵌合率在D+120前均已达到。12个月时,II-IV级、III-IV级急性GVHD和中度/重度cGVHD的累积发生率分别为68.4%(95% CI:46-90)、5.3%(95% CI:0-16%)和10.5%(95% CI:0-25%)。中位随访时间为 2.9 年(范围:0.46-5.3),3 年时复发、PFS、OS 和 NRM 的累积发生率分别为 36.8%(95% CI:14-59)、47.4%(95% CI:29-76)、68.4%(95% CI:50-93)和 15.8%(95%CI:0-33)。完全停用免疫抑制剂的中位时间为 D+238。未观察到意外不良事件。在移植时MRD为阴性且存活2年的7名患者中,只有1人复发。未复发患者移植后的生活质量与普通人群相似:UM171扩增CB移植在HR/超HR骨髓瘤患者中是可行的,而且可以使用单个CB单位,发生cGVHD的风险较低。移植前MRD阴性的患者可能会从UM171扩增CB移植中获益最多。
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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来源期刊
CiteScore
7.00
自引率
15.60%
发文量
1061
审稿时长
51 days
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