Bortezomib in Combination with Cyclophosphamide and G-CSF for Hematopoietic Stem Cell Mobilization in Patients with Multiple Myeloma
Bortezomib in Combination with Cyclophosphamide and G-CSF for Hematopoietic Stem Cell Mobilization in Patients with Multiple Myeloma
复制标题
硼替佐米联合环磷酰胺和 G-CSF 动员多发性骨髓瘤患者的造血干细胞
作者：
B. Bagal;Anant Gokarn;A. Bonda;Swapnil Chavan;S. Punatar;L. Nayak;S. Kannan;L. Mathew;N. Patkar;P. Tembhare;M. Poojary;S. Ojha;P. Subramanian;S. Gujral;T. Saikia;N. Khattry
背景：蛋白酶体抑制剂(PI)已成为多发性骨髓瘤一线治疗不可或缺的一部分。小鼠模型实验表明，PI给药后，造血干细胞通过下调VLA-4(VLA-4)从骨髓到外周血中动员，VLA-4通过与血管细胞黏附分子(VCAM-1)相互作用介导造血干细胞与骨髓微环境的黏附。博替佐米联合G-CSF用于动员的人体研究取得了令人鼓舞的结果，没有额外的毒性，也没有观察到恶性浆细胞动员。以环磷酰胺为基础的化疗动员在干细胞产量方面具有优势，并且能够克服先前来那度胺治疗对干细胞采集的不利影响。在本研究中，我们在环磷酰胺-GCSF(B-Cy-GCSF)化疗动员方案中加入了Bortezomib，以研究Bortezomib对干细胞采集的影响，并与我们早期仅使用环磷酰胺-GCSF(Cy-GCSF)动员方案进行了比较。
方法：选择2016年3月至2018年6月间年龄18~70岁的多发性骨髓瘤患者为研究对象。入选诱导治疗后至少部分缓解且周围神经病变不超过1级的患者。患者分别于第1、4、8、11天给予硼替佐米1.3 mg/m2，第8、9天给予环磷酰胺(Cy)1g/m2，从第11天开始分两次给予G-CSF 10µg/kg，直至至少5×106/kg的目标干细胞采集量。从第14天开始监测外周血CD34(PB CD34)计数，当达到20个/µL以上时开始采集，记录达到峰值的外周血CD34计数、采集所需天数、CD34剂量产率和植入动力学，并与早期接受Cy-GCSF化疗动员的患者进行比较。这些患者在d1和d2接受Cy1g/m2治疗，从d4开始接受G-CSF10mcg/kg治疗，从d7开始监测PBCD34。
结果：2016年3月至2018年6月共纳入37例患者。研究队列的中位年龄为46岁(范围27-63岁)，其中27人(73%)为男性。接受治疗的中位数为1人(范围1到2人)，8人(21.6%)在干细胞采集前接受了来那度胺治疗。L(27.5-306)外周血CD_(34)细胞峰值中位数为71.3个/微米。CD34细胞采集中位数为9.21×106/kg(4.95~17.1)。目标CD34细胞采集在一天的中位数(范围1-2)后实现。中性粒细胞和血小板植入的中位时间分别为11.5天和13.5天。这些结果与从2008年5月到2016年2月在我们中心接受Cy-GCSF化疗动员的88名患者进行了比较，如表1所示。在Cy-G-CSF队列中，目标CD34所需收获的中位数为2(范围1-4)，CD34细胞产量的中位数为8.2×106/kg(0.4-24.2)。
B-Cy-GCSF动员后，58.6%的患者一次采血CD34细胞产量达到5×106/kg，而Cy-G-CSF动员组为44.3%，但差异无统计学意义(p=0.1)。Cy-GCSF组化疗失败3例(3.4%)，而硼替佐米组无一例失败。
结论：B-Cy-GCSF动员的患者具有更高的干细胞产量和更少的采集天数。这一策略应该在更大的患者队列中进行探索。
没有要申报的相关利益冲突。
Background: Proteasome inhibitors (PI) have become integral part of front-line treatment of multiple myeloma. Murine model experiments have shown mobilization of hematopoietic stem cells from bone marrow to peripheral blood after PI administration via down regulation of very late antigen 4 (VLA-4) which mediate adherence of hematopoietic stem cells to the bone marrow microenvironment via interaction with vascular cell adhesion molecule (VCAM-1). Human studies with bortezomib in combination with G-CSF for mobilization have yielded encouraging results with no additional toxicity and no malignant plasma cell mobilization was observed. Cyclophosphamide based chemo-mobilization offers advantage in term of higher stem cell yield and is able to overcome adverse impact of prior lenalidomide therapy on stem cell harvest. In the current study we added bortezomib to cyclophosphamide-GCSF (B-Cy-GCSF) chemo-mobilization regimen to study the effect of bortezomib on stem cell harvest and compared this with our earlier protocol of only cyclophosphamide-GCSF (Cy-GCSF) mobilization.
Methods: Patients of multiple myeloma aged between 18 to 70 years were eligible for the study in the period between March 2016- June 2018. Patients after induction therapy achieving at least partial response and having no more than grade 1 peripheral neuropathy were enrolled. Patients received bortezomib at a dose of 1.3 mg/m2 on day 1, 4, 8 and 11 and cyclophosphamide (Cy) was administered at a dose of 1 g/m2 on day 8 and 9 followed by G-CSF 10µg/kg in two divided doses from day 11 onwards till target stem cell collection of at least 5 X 106/Kg. The peripheral blood CD34 (PB CD34) counts were monitored from day 14 and harvest was initiated when it reached above 20 cells/µL. The peak PB CD34 count achieved, the number of days of harvest required, the CD34 dose yield and the engraftment kinetics were recorded and compared with earlier patients who had undergone Cy-GCSF chemo-mobilization. These patients had received Cy 1 g/m2 on d1 and d2, G-CSF 10 mcg/kg from d4 onwards and PBCD34 monitored from d7 onwards.
Result: A total of 37 patients were enrolled between March 2016 and June 2018. Median age of study cohort was 46 years (range 27-63) and 27 (73 %) were males. Median lines of therapy received were 1 (range 1 to 2) and 8 (21.6 %) had received lenalidomide prior to stem cell harvest. The median peak peripheral blood CD34 cell counts 71.3 cells /µL (range 27.5 -306). Median CD34 cells collected were 9.21 X 106 /Kg (range 4.95-17.1). Target CD34 cell collection was achieved after a median of one day harvest (range 1-2). Median time to neutrophil and platelet engraftment was 11.5 and 13.5 days respectively. These results were compared with 88 patients who had undergone Cy-GCSF chemo-mobilization earlier at our center from May 2008 till February 2016 as seen in Table1 . In Cy- G-CSF cohort, median number of harvest required for target CD34 was 2 (range 1-4) and median CD34 cell yield was 8.2 X 106/Kg (0.4-24.2).
Target CD34 cells yield of 5 X 106/Kg was achieved with single apheresis in 58.6% of patients after B-Cy-GCSF mobilization as compared to 44.3% in Cy-G-CSF group, although this was not statistically significant (p=0.1). While 3(3.4 %) had failed chemo-mobilization after Cy-GCSF, none of patients in bortezomib group had mobilization failure.
Conclusion: Patients undergoing B-Cy-GCSF mobilization have higher stem cell yield and required less days of harvest. This strategy should be explored in a larger cohort of patients.
No relevant conflicts of interest to declare.