低剂量粒细胞集落刺激因子动员健康供者造血干细胞的研究

 目的　探讨低剂量（5 μg·kg-1·d-1）粒细胞集落刺激因子（G-CSF）对健康供者CD+34细胞动员的效果及造血干细胞最佳采集时间。方法　对2006年2月至2009年4月108例健康供者给予G-CSF 5 μg·kg-1·d-1,在动员后的第4天至第6天收集标本,检测相应时间点的外周血白细胞（WBC）计数、采集物单个核细胞（MNC）计数、采集物中CD+34细胞的比例、粒-巨噬细胞集落形成单位（CFU-GM）培养。结果　动员后采集物中第4天至第6天CD+34细胞比例分别为（0.71±0.08）%、（1.09±0.09）%、（0.57±0.08）%,第4天至第6天CFU-GM产率分别为：（93.33±44.51）／105 MNC、（124.61±57.85）／105 MNC和（80.25±49.24）／105 MNC。CD+34细胞比例和CFU-GM产率均在第5天达到峰值（P＜0.05）,第4天次之（P＜0.05）,第6天再次之（P＜0.05）。动员后采集物中第4天至第6天CD+34细胞量分别为（3.33±1.36）×106／kg、（4.14±1.67）×106／kg、（2.79±1.47）×106／kg,第5天达到峰值（P＜0.05）,第4天次之（P＜0.05）,第6天再次之（P＜0.05）。108例供者采集2次（第4天、第5天）均可满足移植标准。所有供者均无严重不良反应发生。结论　单一低剂量G-CSF能够有效动员健康供者造血干细胞。动员后于第4、第5天行干细胞采集优于第5、第6天。     

Paclitaxel-containing high-dose chemotherapy for relapsed or refractory testicular germ cell tumours

High-dose regimes containing etoposide, carboplatin and an oxazaphospharine can salvage 30-40% of patients with relapsed or refractory male germ cell tumours (GCTs). The additional benefit of paclitaxel in such high-dose therapy has not been tested. Between March 1995 and November 2002, 36 male GCT patients were treated with Carbop-EC-T (paclitaxel 75 mg x m(-2), etoposide 450 mg x m(-2), carboplatin AUC 10 on days -7, -5 and -3 and cyclophosphamide 60 mg x kg(-1) on days -5 and -3) followed by peripheral blood stem cell infusion (day 0). The 1-year overall survival rate for all patients is 67% (median follow-up 29 months). For the 24 patients with cisplatin-sensitive disease, the 1-year overall and event-free survivals are 88 and 64%, respectively. For those with cisplatin refractory or absolutely refractory disease, the 1-year overall survival is 25%. In all, 12 patients relapsed at a median duration of 5 months, 11 of whom have died. There were also six treatment-related deaths, five associated with pneumonitis. Pulmonary toxicity has been reported with paclitaxel in other high-dose regimes. Since altering our protocol so that paclitaxel is infused over 24 h with steroid prophylaxis, only one of 18 patients (13 testicular GCTs and five other tumour types) has had a treatment-related death. Our results suggest that Carbop-EC-T may enable a greater proportion of patients with relapsed and refractory GCTs to enter long-term remission.     

rHuG-CSF动员健康供者外周血造血干细胞的效果观察

目的:观察重组人粒细胞集落刺激因子(recombinant human granulocyte-colony stimulating factor,rHuG-CSF)动员健康供者外周血造血干细胞的效果及影响因素。方法:将本研究中心异基因造血干细胞移植健康供者163例,分别采用3种不同厂家生产的rHuG-CSF进行外周血造血干细胞动员,对其动员效果、受者移植后造血重建等情况进行比较。结果:不同种rHuG-CSF动员后采集的单个核细胞(MNC)及CD34 细胞均能满足临床造血干细胞移植的需要,130例人类白细胞抗原(human leucocyte antigens,HLA)配型相合的同胞受者移植后均获得顺利植入。动员的单个核细胞数及CD34 细胞数与性别无关,而CD34 细胞数在41~60岁年龄组中明显减少(P<0.05);对采集时机的分析显示:第5天采集的单个核细胞数及CD34 细胞数最高(P<0.05),此后逐渐下降。结论:糖基化的及两个非糖基化的rHuG-CSF制剂均能有效地在异基因移植中作为外周血造血干细胞动员剂。     

异基因造血干细胞移植在复发难治淋巴瘤中的应用

复发难治淋巴瘤的治疗仍然是临床上的一大难题,目前主要以大剂量化疗联合自体造血干细胞移植及新药、细胞免疫治疗为主。近年减低强度预处理方案异基因造血干细胞移植（allo-HSCT）及替代供者的应用,使allo-HSCT成为复发难治淋巴瘤有价值的治疗选择。疾病特征、患者临床特点、替代供者的选择、预处理强度及移植相关并发症的管理等因素均影响着患者移植后的生存。allo-HSCT治疗复发难治淋巴瘤的数据主要来源于各移植中心的回顾性报道,前瞻性试验仍缺乏,移植患者的选择及移植时机的把握、移植物来源、预处理强度的选择等仍无统一的标准。文章将围绕这些方面对allo-HSCT在复发难治淋巴瘤中的应用进展进行介绍。     

卵巢恶性生殖细胞肿瘤的治疗(附233例临床分析)

目的探讨改进卵巢恶性生殖细胞肿瘤的治疗方法。方法回顾分析我院收治的２３３例卵巢恶性生殖细胞肿瘤。Ｉ期９４例，Ｉ～ＩＶ期４３例，复发转移９６例。单附件或全宫双附件加大网膜阑尾切除分别为７８例和１５１例，活检４例。单纯手术１７例，手术加放疗和化疗６５例，手术加化疗１５１例。结果全组存活１２７例，Ｉ期存活７８例，Ｉ～ＩＶ期１７例，复发转移３２例。总５年生存率为５５．６％。无性细胞肿瘤预后最好，５年生存率为８４．２％，非无性生殖细胞肿瘤为４４．６％，其中ＰＶＢ、ＢＥＰ方案化疗的生存率较高，为６６．０％和７３．３％。结论卵巢恶性生殖细胞肿瘤对化疗敏感，ＰＶＢ、ＢＥＰ是最有效的化疗方案。早期患者可治愈并保留生育功能；晚期先化疗，肿瘤局限后手术，术后巩固化疗可提高存活率     

聚乙二醇化重组人粒细胞集落刺激因子用于多发性骨髓瘤自体造血干细胞动员的研究

目的探讨聚乙二醇化重组人粒细胞集落刺激因子(PEG-rhG-CSF)用于多发性骨髓瘤(MM)患者外周血造血干细胞动员(PBSCM)的效果及药物经济学价值。方法回顾性分析2015年1月至2017年10月在吉林大学第一医院和中国医学科学院血液病医院住院治疗的91例初治MM患者资料。根据患者意愿,采用大剂量化疗结合皮下注射PEG-rhG-CSF或重组人粒细胞集落刺激因子(rhG-CSF)进行干细胞动员,分别为42、49例。分析两组动员后采集单个核细胞(MNC)数、采集物CD34+细胞数、动员中最高中性粒细胞(mANC)数、动员的费用以及移植后白细胞和血小板植入时间。结果PEG-rhG-CSF组和rhG-CSF组的中位采集MNC数分别为5.86×10⁸/kg[(1.08~24.54)×10⁸/kg]和6.61×10⁸/kg[(0.83~33.80)×10⁸/kg],差异无统计学意义(U=883.00,P=0.245);PEG-rhG-CSF组的中位采集物CD34+细胞数高于rhG-CSF组,分别为5.56×10⁶/kg[(0.94~19.90)×10⁶/kg]和4.82×10⁶/kg[(1.12~14.61)×10⁶/kg],差异有统计学意义(U=732.00,P=0.038)。PEG-rhG-CSF组动员期间中位mANC数较rhG-CSF组低,分别为20.50×109/L[(7.26~61.30)×109/L]和32.08×109/L[(6.92~69.99)×109/L],差异有统计学意义(U=490.00,P=0.001)。自体干细胞移植(ASCT)后,PEG-rhG-CSF组白细胞计数(WBC)恢复至1.0×109/L的时间较rhG-CSF组短[(11.59±1.98)d比(12.93±2.83)d],差异有统计学意义(t=-2.395,P=0.019);PEG-rhG-CSF组血小板计数(Plt)恢复至20.0×109/L的时间也较rhG-CSF组有缩短趋势[(12.86±2.62)d比(14.80±5.47)d],但差异无统计学意义(t=-1.749,P=0.085)。PEG-rhG-CSF组的动员总费用与rhG-CSF组差异无统计学意义[(21405.47±7365.98)元比(22976.83±10264.34)元,t=-0.721,P=0.474]。结论PEG-rhG-CSF联合大剂量化疗是MM患者PBSCM的有效方案,其动员费用与rhG-CSF相当。PEG-rhG-CSF可能是MM患者PBSCM的更好选择。     

大剂量化疗联合自体造血干细胞移植治疗复发、难治性边缘区非霍奇金淋巴瘤疗效观察

 【摘要】　目的　评价大剂量化疗联合自体造血干细胞移植治疗复发、难治性边缘区淋巴瘤的价值。方法　回顾性分析12例接受大剂量化疗或放化疗联合自体造血干细胞移植治疗的复发、难治性边缘区淋巴瘤患者的临床资料。结果　12例患者中,1例发生治疗相关性死亡,1例在移植后出现复发, 4例死于非肿瘤相关性疾病;中位无进展生存期104个月,中位总生存期117个月;6例患者尚无病生存。结论　大剂量化疗联合自体造血干细胞移植治疗复发、难治性边缘区淋巴瘤有效,尤其适用于对利妥昔单抗联合化疗不敏感的患者。     

聚乙二醇重组人粒细胞集落刺激因子在复发难治恶性淋巴瘤自体外周血造血干细胞动员中的应用研究

  目的  比较聚乙二醇重组人粒细胞集落刺激因子（pegylated recombinant human granulocyte colony stimulating factor,PEGrhG-CSF）与粒细胞集落刺激因子（granulocyte colony stimulating factor,G-CSF）在复发难治恶性淋巴瘤自体外周血造血干细胞动员（peripheral blood stem cell mobilization,PBSCM）及自体外周血造血干细胞移植（autologous peripheral stem cell transplantation,APBSCT）后造血重建中疗效及药物经济学差异。  方法  选择2014年7月至2016年10月上海交通大学附属第一人民医院收治的复发难治恶性淋巴瘤患者15例,应用PEG-rhG-CSF动员（试验组）;选择2013年1月至2015年8月上海交通大学附属第一人民医院收治的复发难治恶性淋巴瘤患者15例,应用G-CSF动员（对照组）,进行回顾性分析。  结果  两组患者外周血造血干细胞均动员采集成功,其中试验组和对照组采集物的中位CD34+细胞计数分别为16.2×106/kg和8.9×106/kg（P=0.414）;中位总单核细胞（mononuclear cell,MNC）数量分别为12.4×108/kg和9.9×108/kg（P=0.519）。试验组和对照组的平均动员时间分别为（10.66±1.45）d和（9.33±1.83）d（P=0.234）。动员期间,试验组和对照组的平均粒缺时间分别为（4.20±2.17）d和（3.80±2.04）d（P=0.608）。干细胞回输后,试验组和对照组粒系重建的平均时间分别为（10.14±1.29）d和（10.93±2.69）d（P=0.327）。血小板重建平均时间分别为（10.36±2.27）d和（12.27±3.38）d（P=0.121）。两组在干细胞动员和造血系统重建方面无显著差异。在药物经济学方面,PEG-rhGCSF平均费用明显低于G-CSF,分别为3 960元和（11 479.3±2 401.3）元（P < 0.001）。  结论  PEG-rhG-CSF在复发难治恶性淋巴瘤的自体PBSCM中疗效与传统的G-CSF相当,且可明显降低患者费用,应用前景广泛。      

Sequential high-dose chemotherapy protocol for relapsed poor prognosis germ cell tumors combining two mobilization and cytoreductive treatments followed by three high-dose chemotherapy regimens supported by autologous stem cell transplantation. Results of the phase II multicentric TAXIF trial.

BACKGROUND: High-dose chemotherapy (HD-CT) is able to circumvent platinum resistance of resistant/refractory germ-cell tumors (GCTs), but expectancy of cure remains low. New strategies are needed with new drugs and a sequential approach. MATERIALS AND METHODS: Patients with relapsed poor-prognosis GCTs were scheduled to receive two cycles combining epirubicin and paclitaxel (Taxol) followed by three consecutive HD-CT supported by stem cell transplantation [one course combining cyclophosphamide, 3 g/m(2) + thiotepa, 400 mg/m(2), followed by two ICE regimens (ifosfamide, 10 g/m(2), carboplatin, AUC 20, etoposide, 1500 mg/m(2))]. RESULTS: From March 1998 to September 2001 (median follow-up, 31.8 months), 45 patients (median age, 28 years) were enrolled in this phase II study. Twenty-two patients received the complete course. Twenty-five patients died from progression and five from toxicity. The overall response rate was 37.7%, including an 8.9% complete response rate. The median overall survival was 11.8 months. The 3-year survival and progression-free survival rate was 23.5%. The 'Beyer' prognostic score predicted the outcome after HD-CT. CONCLUSION: Although our results warrant further studies on HD-CT in relapsed poor prognosis GCTs, patients with a Beyer score >2 did not benefit from this approach and should not be enrolled in HD-CT trials. Better selection criteria have to be fulfilled in forthcoming studies.     

单一剂量G-CSF用于异基因外周血造血干细胞动员和移植后造血恢复的临床研究

背景与目的:应用粒系集落刺激因子(granulocytecolony-stimulatingfactor,G-CSF)等动员剂从健康供者中动员和获取造血干细胞用于异基因外周血造血干细胞移植(allogeneicperipheralbloodstemcelltransplantation,allo-PBSCT)已在临床广泛开展,但在其作用机理、给药剂量和给药方案等方面还存在许多问题有待进一步研究。本研究旨在探讨单一剂量的G-CSF(250μg/d)用于allo-PBSCT的外周血干细胞(peripheralbloodstemcell,PBSC)动员以及移植后造血恢复的安全性和有效     

异基因造血干细胞移植后序贯输注供者CIK细胞治疗9例复发/难治性血液肿瘤疗效的初步探讨

目的:评价复发/难治性血液肿瘤患者在未缓解状态下直接采用异基因干细胞移植(allogeneic-peripheralhemopoietic stem cell transplantation,Allo-PBSCT)后,序贯输注体外培养获得的供者细胞因子诱导的杀伤(cytokineinduced killer,CIK)细胞以防治肿瘤复发的疗效及并发症.方法:共收集9例复发/难治性的血液肿瘤患者,均在未缓解状态下直接进行Allo-PBSCT;在患者造血重建后,利用血细胞分离机采集供者外周血中的单个核细胞,体外培养成CIK细胞,分数次输注给患者,观察治疗情况,不良反应及预后.结果:9例患者均顺利造血重建,移植后均获得完全缓解；CIK细胞输注后,4例患者发生移植物抗宿主病,加强免疫抑制治疗后均获好转,1例患者于移植后59 d死于感染,其余患者现已中位随访9.2 (2～20)个月,生活状况良好.结论:Allo-PBSCT序贯输注供者CIK细胞治疗具有较好的疗效,可以挽救治疗复发/难治性血液肿瘤患者,值得进一步扩大病例研究.     

SEAM预处理方案用于复发难治非霍奇金淋巴瘤自体造血干细胞移植的效果分析

目的:探讨SEAM（司莫司汀、依托泊苷、阿糖胞苷及美法仑）方案预处理自体造血干细胞移植（auto-HSCT）治疗复发难治非霍奇金淋巴瘤患者的效果及不良反应。方法:回顾性分析2015年1月至2020年9月于解放军联勤保障部队第九二○医院以SEAM方案预处理auto-HSCT治疗的20例非霍奇金淋巴瘤患者临床资料,观察预处理相关不良反应、移植后造血功能的恢复情况及疾病转归。结果:20例患者中,SEAM方案预处理过程中发生肺部感染1例,恶心、呕吐8例,腹泻3例,发热1例,肺损伤1例,黏膜炎1例。16例患者auto-HSCT后造血功能重建,达粒细胞植入（中性粒细胞≥0.5×10 9/L）的中位时间13 d（8~30 d）,达血小板植入（血小板计数≥20×10 9/L）的中位时间13 d（9~37 d）。中位随访时间27个月（3~65个月）。16例（80%）无病生存,4例死亡,无患者复发和进展,非复发死亡率20%。 结论:行auto-HSCT的非霍奇金淋巴瘤患者对SEAM预处理方案有较好的耐受性,不良反应较小,造血重建恢复快,疗效较好。     

Progression-free and overall survival in patients with relapsed/refractory germ cell tumors treated with single-agent chemotherapy: endpoints for clinical trial design

BACKGROUND:

Refractory germ cell tumor (GCT) patients have a poor prognosis and limited treatment options. The identification of novel active agents may be impaired by use of response as the primary endpoint in phase 2 trials. Improved endpoints could enhance the development of new effective agents.

METHODS:

The characteristics and outcome of refractory GCT patients enrolled in 7 single‐agent phase 2 trials conducted at Memorial Sloan‐Kettering Cancer Center from 1990 to 2008 were reviewed. The study agents were suramin, all‐transretinoic acid, topotecan, pyrazoloacridine, temozolomide, ixabepilone, and sunitinib. The major endpoints evaluated were response, progression‐free survival (PFS), and overall survival (OS).

RESULTS:

Ninety patients (87 male, 3 female) were treated. The primary tumor site was testis in 65 patients, mediastinum in 17 patients, retroperitoneum in 4 patients, and other in 4 patients. Eighty‐six patients had nonseminoma, and 4 patients had pure seminoma. Best responses were 1 (1%) partial response (ixabepilone), 15 (17%) stable disease, and 74 (82%) progressive disease. Median PFS and OS were 1.0 month (95% confidence interval [CI], 0.8‐1.3) and 4.7 months (95% CI, 3.5‐6.4), respectively. Eighty‐six of the 90 patients have died. The 12‐ and 16‐week PFS rates were 9% (95% CI, 3‐15%) and 6% (95% CI, 1%‐11%), respectively.

CONCLUSIONS:

Patients with refractory GCT progressed rapidly to these single agents. PFS and OS may be useful endpoints for designing phase 2 trials testing novel agents in this population. Twelve‐week PFS (with comparison to the 9% benchmark rate reported herein) is the recommended endpoint for phase 2 trial design and median OS (using 4.7 months as the predicted median for the control arm) is suggested for phase 3 trials. Cancer 2012;. © 2011 American Cancer Society.     

粒细胞集落刺激因子对供体造血干细胞移植物中树突状细胞的影响

 目的　探讨粒细胞集落刺激因子（G-CSF）对正常异基因造血干细胞移植供者外周血与骨髓移植物中I型树突状细胞（DC1）、Ⅱ型树突状细胞（DC2）的数量及DC2／DC1比例的影响。方法　以G-CSF 每天10 μg／kg动员5 d后,以流式细胞术（FCM）检测11例G-CSF动员的异基因外周血造血干细胞移植物及20例G-CSF动员的异基因骨髓移植物中的DC1、DC2数量及DC2／DC1比例,并与8例正常供者动员前外周血及10例健康者动员前骨髓进行比较。结果　动员前后骨髓DC2由14.37×106／L增至29.68×106／L（t＝2.433,P＝0.022）,而骨髓DC1分别为13.77×106／L和18.88×106／L（t＝0.625,P＝0.541）;DC2／DC1比例在动员后为1.83±0.81,较动员前的1.12±0.32明显升高（t＝2.685,P＝0.013）。正常供者以G-CSF动员前、后移植物中外周血 DC2数量分别为14.92×106／L和26.76×106／L（t＝2.390,P＝0.029）,DC2／DC1比例分别为1.00±0.37和2.02±1.43（t＝2.158,P＝0.044）,但外周血DC1分别为14.21×106／L和18.02×106／L（t＝0.625,P＝0.541）。结论　移植前以 G-CSF动员正常异基因干细胞移植供者,可选择性提高外周血及骨髓移植物中DC2的数量,而DC1数量无明显增加。     

High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults.

Since the early 1980s high dose chemotherapy with autologous hematopoietic stem cell support was adopted by many oncologists as a potentially curative option for solid tumors, supported by a strong rationale from laboratory studies and apparently convincing results of early phase II studies. As a result, the number and size of randomized trials comparing this approach with conventional chemotherapy initiated (and often abandoned before completion) to prove or disprove its value was largely insufficient. In fact, with the possible exception of breast carcinoma, the benefit of a greater escalation of dose of chemotherapy with stem cell support in solid tumors is still unsettled and many oncologists believe that this approach should cease. In this article, we critically review and comment on the data from studies of high dose chemotherapy so far reported in adult patients with small cell lung cancer, ovarian cancer, germ cell tumors and sarcomas.     

Chemotherapy for germ cell tumors relapsing after high-dose chemotherapy and stem cell support: A retrospective multicenter study of the Austrian Study Group on Urologic Oncology

Background: In most patients with advanced refractory germ cell tumorsundergoing high-dose chemotherapy with stem cell support (HDCT) the diseaseprogresses after HDCT. This study was designed to shed light on theunestablished role of post-HDCT chemotherapy.Patients and methods: In a retrospective multicenter study data of 47evaluable patients from nine centers subjected to post-HDCT chemotherapy forprogression of their germ cell tumors were collected in a questionnairesurvey and analyzed for treatment response and survival.Results: Of 191 patients pretreated by HDCT, 48 (25%) weresubjected to post-HDCT chemotherapy for disease progression. Remission wasachieved in 17 (36%) and marker-negative remission in eight(17%). The median survival time was 26 weeks, 65 weeks for respondersand 13 weeks for non-responders. Only one of 47 evaluable patients achievedsustained complete remission. Remissions significantly correlated with thepost-HDCT interval, the use of ifosfamide and the combination regimens ofcisplatin + etoposide i.v. or ifosfamide and of paclitaxel + ifosfamide orcisplatin. On univariate analysis a longer post-HDCT interval, the use ofcisplatin, paclitaxel and ifosfamide and the combined use of paclitaxel +ifosfamide and/or cisplatin significantly improved the chances of survival.On multivariate analysis only treatment with paclitaxel and ifosfamideretained independent prognostic significance for survival.Conclusions: One third of the patients considered to be candidates forfurther chemotherapy once progressive after HDCT went into remission with again in survival time. Sustained remissions may occur, but are rarely seen.Paclitaxel and ifosfamide appear to be the most effective drugs in theseheavily pretreated patients.     

Dexa-BEAM: an effective regimen for cytoreduction prior to high-dose chemotherapy with autologous stem cell support for patients with relapsed/refractory mantle-cell lymphoma

Mantle-cell lymphoma (MCL) is not a curable disease using conventional chemotherapy. Patients with MCL have the shortest median time to progression and the shortest median survival of all lymphoma subtypes after first-line treatment. In the present study we determined the efficacy of maximal cytoreductive therapy with up to four cycles of Dexa-BEAM (dexamethasone, carmustine [BCNU], etoposide, cytarabine, and melphalan) followed by high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell support (ASCT) for patients with advanced relapsed or refractory MCL. Nine consecutive patients with relapsed or refractory MCL were included. Three patients had partial remission (PR), three patients progressive disease (PD) upon first line tretment, and three patients first or subsequent relapse. After 2 to four cycles of Dexa-BEAM eight patients achieved complete remission (CR), resulting in a response rate of 88%. Six of 8 patients responding to Dexa-BEAM received high-dose chemotherapy HDCT (BEAM) and autologous hematopoietic stem cell transplantation (ASCT). With a median follow up of 24 months six patients are alive. Five of those six patients are still in contiuous CR (range 13-54 months).     

Treatment of refractory metastatic choriocarcinoma with tandem high-dose chemotherapy supported by peripheral blood stem cell transplantation: A case report

Currently, 70% to 80% of patients with advanced germ cell tumors can be cured with cisplatin-based chemotherapy, followed by surgical resection of the residual tumor. The prognosis, however, is uniformly poor for patients who fail to respond to induction chemotherapy. In this report, we describe a patient with retroperitoneal choriocarcinoma and multiple lung metastases, who was refractory to cisplatin-based chemotherapy, but who achieved a durable marker-negative partial response after 2 cycles of high-dose chemotherapy, supported by autologous, peripheral blood stem cell transplantation. The patient is now alive and well, without recurrence, more than 24 months after this therapy.