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话题:骨髓生长因子用于干细胞移植NCCN指南2016V2

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张品良大夫

山东省肿瘤医院

呼吸内科

发表于:2017-01-20

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Myeloid Growth Factors骨髓生长因子

NCCN Guidelines Version 2.2016
NCCN指南2016第2版山东省肿瘤医院肿瘤内科张品良

Discussion 讨论

Mobilization and Post Hematopoietic Cell Transplant
造血细胞动员与移植后

MGFs are commonly administered in the transplant setting, either for mobilization of hematopoietic progenitor cells or as supportive care after transplantation.
在移植情况下通常给予骨髓生长因子动员造血祖细胞或作为移植后的支持治疗。

Mobilization with Growth Factors in the Autologous Setting
生长因子用于自体动员

Mobilization of PBPCs by G-CSF has largely replaced bone marrow collection for autologous transplantation due to ease of collection, avoidance of general anesthesia, and more rapid recovery of blood counts. Most data are focused on filgrastim, although studies suggest that single-dose pegfilgrastim has similar efficacy.
对于自体移植,用G-CSF动员PBPCS由于容易采集、不需要全身麻醉且血细胞计数恢复更迅速,因此已基本上代替了骨髓采集。大多数资料主要集中于非格司亭,不过研究提示单剂培非司亭具有相似的疗效。

While apheresis usually commences on the fourth or fifth day of G-CSF initiation when it is used as a single agent, recent studies have shown that the addition of the CXCR4 inhibitor plerixafor to chemo-mobilization accelerated the increase in PBPC count. This may be used as a rescue strategy when PBPC yield is poor, or when the CD34+ cell count does not reach the target level. Plerixafor is indicated for patients who were heavily pre-treated or had prior treatment with greater than 10 cycles of cytotoxic chemotherapy, or those who have had failed prior collection attempts that failed or who exhibit risk factors for being poor mobilizes due to more than 6 cycles of lenalidomide or fludarabine, or radiation to the pelvis. One retrospective analysis demonstrated that pegfilgrastim resulted in a better PBPC yield than filgrastim, requiring less use of rescue plerixafor, but there have not been any randomized trials that address the effect of plerixafor when used in combination with pegfilgrastim.
当其作为一个单药时,机采通常在G-CSF的第4或第5天开始,最近的研究表明,化学动员添加趋化因子受体4抑制剂普乐沙福可提高PBPC数。这可作为PBPC产率差或CD34+细胞计数达不到目标水平时的一个挽救策略。普乐沙福适用于强烈预处理或既往细胞毒化疗大于10周期或既往收集尝试已失败或由于来那度胺或氟达拉滨超过6周期或骨盆照射具有动员不良危险因素证据的患者。一项回顾性分析表明,培非司亭的PBPC产率优于非格司亭,较少需要使用普乐沙福挽救,但并无任何随机试验证明当与培非司亭联合使用时普乐沙福的效果。

While filgrastim-sndz has been accepted as an equivalent treatment option to filgrastim for patients with FN, there is discussion among medical professions regarding equivalency in hematopoietic cell mobilization or in patients with chronic neutropenia. There are data to support the use of filgrastim-sndz in the autologous hematopoietic cell transplant setting. However, the panel acknowledges the limitations of these studies regarding long-term outcomes and the potential impact of the different manufacturing processes. Therefore, while it is reasonable to substitute with filgrastim-sndz, clinicians should be alert to any complications presented in the literature or in their patients. Accurate and timely disclosure of any variation in expected outcome with the biosimilar compared to the originator filgrastim will be of paramount importance.
而非格司亭-山德士已被接受作为中性粒细胞减少性发热患者一个与非格司亭等效的治疗选择,在医学界关于在造血干细胞动员或慢性中性粒细胞减少症患者中的等效性有争议。有数据支持非格司亭-山德士用于自体造血细胞移植。不过,专家组承认这些研究远期结果的局限性和不同制造工艺的潜在影响。因此,尽管用非格司亭-山德士替代是合理的,但是,临床医生应该警惕文献或其患者存在的任何并发症。准确、及时披露使用非格司亭生物仿制药与原研药相比预期结果的任何差异将是至关重要的。

The NCCN Panel recommends administration of filgrastim, filgrastim-sndz, or tbo-filgrastim as a single agent or as part of a chemo-mobilization regimen, starting on the day after completion of chemotherapy (category 2A). Several regimens are effective in chemo-mobilization of hematopoietic progenitors, including cyclophosphamide, ICE, DHAP, VTD-PACE, and others. Studies using GM-CSF as a single mobilization agent or in sequential combination with G-CSF reported good yields of PBPC in normal donors. Although both MGFs have been used for mobilization, G-CSF has been favored for this purpose. The use of concurrent filgrastim or filgrastim-sndz and sargramostim is a category 2B recommendation. For select patients with NHL or multiple myeloma, filgrastim, filgrastim-sndz, or tbo-filgrastim can be given followed by plerixafor.
NCCN小组建议给予非格司亭、非格司亭-山德士或梯瓦-非格司亭作为单药或化学动员方案的一部分,在化疗结束后的当天开始(2A类)。在造血祖细胞的化学动员方面,一些方案是有效的,包括环磷酰胺、ICE、DHAP、VTD-PACE等。在正常献血者中使用单一GM-CSF或序贯联合G-CSF作为动员剂的研究报告PBPC产率好。尽管两种骨髓生长因子均已用于动员,但是作为动员,G-CSF一直受青睐。同时使用非格司亭或非格司亭-山德士和沙格司亭是2B类推荐。对于选择性的NHL或多发性骨髓瘤患者,可以给予非格司亭、非格司亭-山德士或梯瓦-非格司亭序贯普乐沙福。

Mobilization with Growth Factors in the Allogeneic Setting
生长因子用于异基因动员

Initially, there were concerns about mobilization in the allogeneic setting due to normal donor toxicity and the risk for graft-versus-host disease (GVHD) in the recipient, but studies have demonstrated G-CSF to be well-tolerated by donors without an effect on long-term survival. The use of plerixafor in normal donors is currently under study. Tbo-filgrastim has also been shown to mobilize PBPC for allogeneic transplantation in both healthy donors and in patients with multiple myeloma and lymphoma, but the data are limited, and mobilization is not listed as an approved indication. Studies of filgrastim-sndz have been predominately in the settings of autologous PBPC mobilization and in support of count recovery after transplant, whereas data are sparse in the allogeneic setting. The smaller studies in allogeneic progenitor cell donors have suggested that there are no short-term safety issues; however, the long-term data are not yet available. A single retrospective study of filgrastim-sndz in comparison to filgrastim for mobilization in normal donors reported that 3 out of 18 donors mobilization in the filgrastim-sndz group failed without any mobilization failures in the filgrastim group. Neutrophil and platelet count recovery after allogeneic transplant were similar in both arms. The World Marrow Donor Association recommends against the use of filgrastim biosimilars in unrelated donors based on extrapolation from autologous transplant data.
在异基因情况下动员,最初担心正常供者毒性和受者移植物抗宿主病(GVHD)风险,但研究已证明供者对G-CSF耐受性良好,对长期生存没有影响。在正常供体中使用普乐沙福,目前正在研究。已证明梯瓦-非格司亭可用于健康供体与多发性骨髓瘤和淋巴瘤患者的异基因移植动员PBPC,但资料有限,因此动员未列为一个获得批准的适应症。非格司亭-山德士在自体PBPC动员和移植后计数恢复的支持方面的研究占绝大多数,但是异基因情况下的数据很分散。少量异基因祖细胞供体的研究提示没有近期安全性的问题;不过,还没有可用的远期数据。一项独立回顾性非格司亭-山德士与非格司亭在正常供者中动员比较的研究报告,非格司亭-山德士组中18例供者有3例动员失败,而非格司亭组无一例动员失败。在异基因移植后,中性粒细胞与血小板计数恢复两组相似。世界骨髓捐赠者协会基于自体移植数据推断,劝告反对在无关供者中使用非格司亭生物仿制药。

The NCCN Panel recommends single-agent filgrastim (category 2A, preferred), filgrastim-sndz (category 2B), or tbo-filgrastim (category 2B) for allogeneic hematopoietic cell mobilization and for granulocyte transfusion. The addition of plerixafor in selection patients is a category 2B recommendation.
对于异基因的造血干细胞动员和粒细胞输注,NCCN小组推荐单剂非格司亭(2A类,首选)、非格司亭-山德士(2B类)或梯瓦-非格司亭(2B类)。在选择的患者中增加普乐沙福是一个2B类推荐。

Growth Factors as Part of Supportive Care After Transplant
生长因子作为移植后支持治疗的一部分

Consensus is lacking on the use of growth factors in the post-transplant setting. G-CSF administration after high-dose chemotherapy and autologous PBPC transplantation has been shown to expedite neutrophil recovery in prospective randomized trials. However, results were mixed on the impact of G-CSF on duration of hospital stay, infections, and survival. A systematic review comparing filgrastim and pegfilgrastim in the autologous setting, including a randomized trial of 80 patients, concluded that the two are at least equally effective.
缺乏在移植后情况下使用生长因子的共识。前瞻性随机试验已证明,在大剂量化疗与自体PBPC移植后给予G-CSF可以加快中性粒细胞恢复。然而,G-CSF对住院时间、感染以及生存的影响喜忧参半。一项比较非格司亭和培非司亭用于自体移植的系统回顾,包括一项随机试验的80例患者,得出结论,至少两者同样有效。

Similarly, data are conflicting on G-CSF as a supportive care measure for allogeneic transplant recipients, with some studies associating G-CSF with worse clinical outcome. However, it has been used routinely to alleviate the delayed recovery of blood counts after umbilical cord blood transplant, because there is a significant delay in the rate and kinetics of neutrophil and platelet engraftment after cord blood transplant as compared to marrow or mobilized PBPC grafts. GM-CSF has been demonstrated to promote hematopoietic recovery after autologous hematopoietic cell transplantation or delayed autologous engraftment. GM-CSF therapy has been shown to improve treatment outcome in patients with hematologic malignancies who previously had graft failure following bone marrow transplant. GM-CSF has also been administered to patients with hematologic malignancies leading to decreased neutropenia, decreased morbidity, and decreased hospitalization during autologous hematopoietic cell transplant.
同样,G-CSF作为异基因移植受者支持治疗措施的数据冲突,一些研究将G-CSF与更糟的临床预后相联系。无论如何,它已常规用于缓解脐血移植后血细胞计数的延迟恢复,因为脐带血移植后,在中性粒细胞和血小板植入率和速度方面,与骨髓或动员的PBPC移植相比,有显著的延迟。已证实在自体造血细胞移植或自体植入延迟后,GM-CSF能促进造血恢复。已证明GM-CSF治疗可改善恶性血液病患者以前骨髓移植植入失败后的治疗转归。GM-CSF还用于恶性血液病患者,可减少自体造血细胞移植期间的中性粒细胞减少症、降低发病率并缩短住院时间。

The NCCN Panel recommends consideration of MGFs in the supportive care setting post-autologous hematopoietic cell transplant. Filgrastim, filgrastim-sndz, tbo-filgrastim, pegfilgrastim, and sargramostim (all category 2A) can be considered in the supportive care setting.
NCCN小组推荐在自体造血干细胞移植后的支持治疗情况下,考虑骨髓生长因子。在支持治疗情况下,可考虑非格司亭、非格司亭-山德士、梯瓦-非格司亭、培非司亭和沙格司亭(均为2A类)。

Dosing and Administration
剂量与给药

For dosing information, see Myeloid Growth Factors in Mobilization and Post Hematopoietic Cell Transplant in the algorithm.
关于剂量信息,见动员和造血干细胞移植后工作步骤中的骨髓生长因子。


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