Venglar Ondrej, Kapustova Veronika, Anilkumar Sithara Anjana, Zihala David, Muronova Ludmila, Sevcikova Tereza, Vrana Jan, Vdovin Alexander, Radocha Jakub, Krhovska Petra, Hrdinka Matous, Turjap Michal, Popkova Tereza, Chyra Zuzana, Broskevicova Lucie, Simicek Michal, Koristek Zdenek, Hajek Roman, Jelinek Tomas
Faculty of Science, University of Ostrava, Ostrava, Czech Republic.
Department of Hematooncology, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
Br J Haematol. 2024 Apr;204(4):1439-1449. doi: 10.1111/bjh.19141. Epub 2023 Oct 9.
Induction therapy followed by CD34 cell mobilisation and autologous transplantation represents standard of care for multiple myeloma (MM). However, the anti-CD38 monoclonal antibodies daratumumab and isatuximab have been associated with mobilisation impairment, yet the mechanism remains unclear. In this study, we investigated the effect of three different regimens (dara-VCd, isa-KRd and VTd) on CD34 cells using flow cytometry and transcriptomics. Decreased CD34 cell peak concentration and yields, longer collection and delayed engraftment were reproduced after dara-VCd/isa-KRd versus VTd induction in 34 patients in total. Using flow cytometry, we detected major changes in the proportion of apheresis product and bone marrow CD34 subsets in patients treated with regimens containing anti-CD38 therapy; however, without any decrease in CD38high B-lymphoid progenitors in both materials. RNA-seq of mobilised CD34 cells from 21 patients showed that adhesion genes are overexpressed in CD34 cells after dara-VCd/isa-KRd and JCAD, NRP2, MDK, ITGA3 and CLEC3B were identified as potential target genes. Finally, direct in vitro effect of isatuximab in upregulating JCAD and CLEC3B was confirmed by quantitative PCR. These findings suggest that upregulated adhesion-related interactions, rather than killing of CD34 cells by effector mechanisms, could be leading causes of decreased mobilisation efficacy in MM patients treated with anti-CD38 therapy.
诱导治疗后进行CD34细胞动员和自体移植是多发性骨髓瘤（MM）的标准治疗方案。然而，抗CD38单克隆抗体达雷妥尤单抗和isatuximab与动员受损有关，但其机制仍不清楚。在本研究中，我们使用流式细胞术和转录组学研究了三种不同方案（dara-VCd、isa-KRd和VTd）对CD34细胞的影响。在总共34例患者中，与VTd诱导相比，dara-VCd/isa-KRd诱导后再现了CD34细胞峰值浓度和产量降低、采集时间延长和植入延迟的情况。使用流式细胞术，我们在接受含抗CD38治疗方案的患者中检测到单采产品和骨髓CD34亚群比例的主要变化；然而，两种材料中的CD38高表达B淋巴细胞祖细胞均未减少。对21例患者动员的CD34细胞进行RNA测序表明，dara-VCd/isa-KRd和JCAD、NRP2、MDK、ITGA3和CLEC3B后，粘附基因在CD34细胞中过表达，被确定为潜在的靶基因。最后，通过定量PCR证实了isatuximab在体外直接上调JCAD和CLEC3B的作用。这些发现表明，上调的粘附相关相互作用，而非效应机制对CD34细胞的杀伤作用，可能是接受抗CD38治疗的MM患者动员疗效降低的主要原因。
