超高CD34+采集的动员方案序贯二次自体造血干细胞移植治疗难治性 霍奇金淋巴瘤

目的:探讨超高CD34+采集的动员方案后序贯二次自体造血干细胞移植治疗难治性霍奇金淋巴瘤的疗效和安全性。方法:对1例经过多疗程一线、二线、新药、免疫等均难治的霍奇金淋巴瘤患者,予以IA+C方案化疗+G-CSF动员干细胞后采集出超高水平CD34+细胞,之后行自体造血干细胞移植,移植后获得完全缓解,再予序贯第二次自体造血干细胞移植进行巩固治疗。结果:总计输注单个核细胞数13.67×108/kg,CD34+细胞48.68×106/kg,第一次自体造血干细胞移植术后第7天造血功能恢复,复查全身PET-CT提示获得完全缓解,第二次自体造血干细胞移植术后第8天造血功能恢复,两次自体造血干细胞移植相关并发症均在可控范围内。结论:超高CD34+细胞采集的IA+C方案化疗+G-CSF动员可以让患者有机会进行多次自体造血干细胞移植,是临床动员的创新方案。对于难治性霍奇金淋巴瘤,序贯二次自体造血干细胞移植可达到更深层次缓解,且安全性较高,延长患者无疾病生存期及总生存期,为难治性霍奇金淋巴瘤治疗提供更多临床依据。     

异基因造血干细胞移植治疗首例自体移植复发霍奇金淋巴瘤的临床分析

目的探讨霍奇金淋巴瘤自体移植复发后行异基因造血干细胞2次移植的可能性和安全性。方法对1例10年前行自体造血干细胞移植复发的霍奇金淋巴瘤患者,行异基因造血干细胞移植,供者为患者母亲,采用外周血干细胞移植,预处理方案采用氟达拉滨+马法兰+兔抗人淋巴细胞免疫球蛋白,预防移植物抗宿主病采用环孢素A、霉酚酸酯、甲氨蝶呤,输注单个核细胞数14.03×108/kg,CD34+细胞6.57×106/kg。结果 2次移植后移植物成功植入,形成完全供者来源造血,移植后第20天骨髓初步植活,造血功能恢复后患者出现皮肤植物抗宿主病,FISH嵌合状态供者细胞植入率为100%,随访至今一直长期无病生存。结论异基因造血干细胞移植,可有效治疗自体移植复发的霍奇金淋巴瘤,是安全有效的挽救治疗措施。     

外周血造血干细胞移植治疗恶性血液病53例

背景与目的:造血干细胞移植使恶性血液病的预后得到很大的改观,外周血造血干细胞移植(transplantation of peripheral blood stem cells,PBSCT)逐渐取代了骨髓移植(bone marrow transplantation,BMT)而成为造血干细胞移植的主要方式.本研究观察了自体或异基因外周血造血干细胞移植对53例恶性血液病患者的治疗效果.方法:53例恶性血液病患者于2003年7月～2006年5月在郑州大学第一附属医院血液科接受PBSCT治疗,中位年龄37岁.采用G-CSF或化疗联合G-CSF动员外周血干细胞.自体移植患者接受CD34 细胞的中位数为3.0×106/kg,异基因移植患者接受CD34 细胞的中位数为6.2×106/kg;自体移植采用MAC预处理方案,异基因移植采用改良的Bu/Cy预处理方案;移植物抗宿主病(graft versus host disease,GVHD)的预防采用MTX、环孢菌素A联合骁悉,1例1个点不合患者加用抗淋巴细胞球蛋白.结果:移植后中性粒细胞≥0.5×109/L、血小板≥20×109/L的天数在自体移植中分别为13天和19天,在异基因移植中分别为12天和15天;异基因移植中Ⅰ～Ⅲ度急性GVHD(aGVHD)的发生率为31.4%,慢性GVHD(cGVHD)的发生率为71.4%,复发率在自体移植和异基因移植患者中分别为38.9%和5.7%,700天无病生存率在自体移植和异基因移植患者中分别为57.9%和69.5%.结论:自体和异基因外周血造血干细胞移植均能很快地重建造血,是治疗恶性血液病的重要手段之一.     

造血干细胞移植治疗恶性血液病临床研究

 目的 探讨造血干细胞移植（HSCT）治疗恶性血液病的临床疗效及并发症的防治。方法51例急慢性白血病、恶性淋巴瘤、多发性骨髓瘤患者中,36例选择自体造血干细胞移植（auto-HSCT）,15例接受异基因造血干细胞移植（allo-HSCT）,包括HLA不全相合3例及非血缘关系移植4例,混合移植2例;预处理自体移植主要选用CBV,BEAC方案,异基因移植采用BU／CY2及改良的BU／CY方案;移植物抗宿主病（GVHD）的预防采用CsA+MTX或CsA+MTX＋MMF方案。结果 51例患者中49例获得造血重建,在auto-HSCT和allo-HSCT后WBC≥1.0×109／L的中位时间分别为13 d和17 d,血小板≥20×109／L的中位时间分别为21和25 d;40 ％出现aGVHD,26.7 ％出现cGVHD;3.9 %出现HVOD;出血性膀胱炎发生率5.9 ％;CMV感染发生率33.3 ％;62.7 ％出现黏膜炎;54.9 ％出现不同部位的感染;移植相关死亡率3.5 %,随访3～95个月,移植后复发11例,其中auto-HSCT 9例,allo-HSCT 2例。结论 HSCT是目前治疗恶性血液病的最佳方法,但移植期间需要进一步探索如何减少其相关并发症,以提高血液肿瘤的治愈率及延长患者的无病生存时间。     

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。     

自体外周血造血干细胞移植治疗非霍奇金淋巴瘤疗效分析

目的观察高剂量化疗联合自体造血干细胞移植治疗复发和难治性非霍奇金淋巴瘤的疗效。方法1995年至2005年采用大剂量化疗联合自体外周血造血干细胞移植治疗非霍奇金淋巴瘤30例。外周血干细胞动员方法为将常规剂量CHOP方案中CTX增至2500mg/m2,化疗后予G-CSF3.5~5μg/kg的动员方案,当骨髓功能恢复WBC计数达(2~5)×109/L,外周血单核细胞(MNC)计数达20%~30%时分离外周血造血干细胞。预处理方案为异环磷酰胺(IFO)12g/m2,阿糖胞苷(Ara-c)4.5g/m2,足叶乙甙(Vp-16)0.75g/m2。结果30例患者移植后缓解时间为1~108个月,中位缓解期42个月。其中1年无病生存25例(83%),2年22例(73%),3年20例(66.7%)。最长存活9年。全组无移植相关死亡。结论高剂量化疗联合自体造血干细胞移植治疗复发和难治性恶性淋巴瘤的疗效优于常规化疗。     

造血干细胞移植在复发难治霍奇金淋巴瘤中的若干问题

对于复发难治性霍奇金淋巴瘤,目前标准的治疗方案为解救化疗有效后给予大剂量化疗+自体干细胞移植(HDCT/ASCT)。常用的解救方案之间没有优劣,如BEAM,CBV,IGEV等。解救化疗后行PET检查对自体造血干细胞移植有重要的预后价值。降低预处理强度的异基因造血干细胞移植(RIC-allo SCT)可作为ASCT后复发患者一种有效的治疗方法。本文就造血干细胞移植在复发难治性霍奇金淋巴瘤中的若干问题进行综述。     

恶性淋巴瘤分子靶向治疗进展

近年，淋巴瘤的治疗有了突破性的进展，在常规化疗方面，出现了一些新的药物和新方案；在造血干细胞移植方面，自体移植的临床地位得到进一步巩固和提高，对复发耐药复发淋巴瘤，异基因移植特别是非清髓性造血干细胞移植临床研究亦取得了可喜的进展。目前淋巴瘤治疗中最引人注目的是淋巴瘤     

自体造血干细胞移植治疗恶性淋巴瘤的初步临床观察

目的:探讨自体追血干细胞移植(AHSCT)治疗恶性淋巴瘤的疗效.方法:造血干细胞动员采集方案采用移植前化疗敏感方案,如CHOP、DICE和ESHAP,大剂量阿糖胞苷(HD-Ara-C)等联合粒细胞集落刺激因子(G-CSF).预处理则采用BEAC(BCNU、VP-16、Ara-C和CTX)方案.结果:所有患者均采集到足够造血干细胞数,CD34+平均为2.7×108kg-1.移植后所有患者均恢复造血并出现Ⅳ度骨髓抑制,移植相关死亡率为0.移植后8例CR,3例PR.先后有2例进展(复发),其中1例死亡.中位随访时问为24.6个月,2年总生存率为84.6%.结论:AHSCT是一种有效治疗恶性淋巴瘤的方法,安全性好,但对于高危患者仍需探讨新的方法.     

自体造血干细胞移植治疗复发难治非霍奇金淋巴瘤

目的探讨高剂量放化疗联合自体造血干细胞移植治疗复发、耐药侵袭性和高度侵袭性非霍奇金淋巴瘤(NHL)的疗效和安全性。方法23例复发和11例耐药的NHL患者接受了解救化疗和自体造血干细胞采集,采集后进行了自体造血干细胞支持下的高剂量放化疗。结果采集到的全部患者干细胞数均达到了移植要求,CD34+细胞中位数为6.06×106/kg。接受移植的患者经高剂量放化疗治疗后全部出现Ⅳ度骨髓抑制,出现1例移植相关死亡。移植后23例完全缓解,6例部分缓解,5例进展。缓解的患者中,10例复发,中位疾病进展时间(TTP)为7.9个月,复发患者中7例死亡。1例发生第二肿瘤。5年总生存率为60.5%,5年无复发总生存率为58.2%。结论高剂量放化疗联合自体造血干细胞移植治疗复发耐药的侵袭和高度侵袭性NHL疗效高、安全性好,但对于预后差的患者尚需探讨新的方法。     

Humanized anti‐CD19 chimeric antigen receptor‐T cell therapy is safe and effective in lymphoma and leukemia patients with chronic and resolved hepatitis B virus infection

Chimeric antigen receptor‐T (CAR‐T) cell therapy is a promising treatment for CD19⁺ B‐cell malignancies. However, elimination of B cells by anti‐CD19 CAR‐T cells may lead to the reactivation of hepatitis B virus (HBV) and related hepatitis in patients with HBV infection. This study aims to evaluate the safety and efficacy of humanized anti‐CD19 CAR‐T (hCAR‐T) therapy in B‐cell malignancies with HBV infection. Twenty relapsed/refractory (r/r) diffuse large B‐cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL) patients with HBV infection were treated with hCAR‐T therapy. Among them, five hepatitis B antigen‐positive patients who received antiviral prophylaxis did not develop HBV reactivation, including two patients who received both hCAR‐T and allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Among 15 patients with resolved HBV infection, two received antiviral prophylaxis, and the other 13 did not experience HBV reactivation without antiviral prophylaxis. One patient with resolved HBV infection experienced HBV reactivation 6 months after hCAR‐T therapy and sequential allo‐HSCT. Moreover, HBV infection did not affect in vivo expansion of hCAR‐T cells or increase the risk of severe cytokine release syndrome. In conclusion, hCAR‐T therapy is safe and effective in DLBCL and ALL patients with chronic and resolved HBV infection under proper antiviral prophylaxis.     

Prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HbsAg carriers with hemato-oncological neoplasias treated with chemotherapy

Reactivation of hepatitis B virus (HBV) infection is well documented complication of cytotoxic or immunosuppressive therapy in asymptomatic HBV carriers. Its clinical manifestation include fulminant hepatitis which may result in fatal liver failure. With the more widespread use of chemotherapy and hematopoietic stem cell transplantation, the problem of delivering potentially harmful treatment to HBV carriers is becoming increasingly frequent. Until recently the management of HBV reactivation has been mainly supportive. With the introduction of lamivudine, a highly effective nucleoside analogue against HBV with an excellent toxicity profile has become available. However, in light of the possibility that its prolonged use may foster the emergence of mutant lamivudine-resistant HBV strain, caution is required before recommending its widespread use. The present review briefly addresses the epidemiological, pathogenetic and clinical aspects of HBV reactivation as well the predisposing factors to its development. The results obtained with lamivudine both as treatment and as prophylaxis of hepatic flares are analysed in detail in order to provide a rational basis for clinical decisions before treating HBV carriers with chemotherapy.     

Hepatotoxicity of chemotherapy

Patients who will receive chemotherapy require careful assessment of liver function prior to treatment to determine which drugs are not appropriate, and which drugs need dose modification. However, if the hepatic parenchymal abnormalities are caused by an underlying neoplasm and the neoplasm is sensitive to the drugs, it may not be necessary to reduce the dose. Clearly, this is an area where clinical judgment must be used to assess the risk/benefit ratio. Treatment of chronic hepatitis B virus (HBV) involves either the nucleoside analogue lamivudine or interferon alpha. The advantage of lamivudine includes limited adverse effects and the fact that histological improvement has been documented in the majority of patients. Primary prophylaxis with lamivudine may be a well tolerated and effective method to reduce the frequency of chemotherapy-induced HBV reactivation in chronic HbsAg carriers. HbsAg screening is necessary before beginning chemotherapy for non Hodgkin's lymphoma patients. However, the main problem with long-term lamivudine therapy is the emergence of genotypic resistance because of base pair substitution at specific sites within the YMDD locus of the DNA polymerase gene. Significant hepatic dysfunction is uncommon among hepatitis C virus (HCV) infected patients treated with chemotherapy for hematological malignancies. However, infection with elevated AST levels is a significant risk factor for veno-occlusive disease after hematopoietic stem cell transplantation. Clinical judgment and a high index of suspicion remain critical tools in preventing and treating hepatic manifestations of cancer chemotherapy.     

异基因造血干细胞移植中供受体乙肝病毒感染的意义

 目的 分析白血病患者移植前供、受者感染乙型肝炎病毒（HBV）对异基因造血干细胞移植（allo-HSCT）临床结果的影响。方法 对该院1996年5月至2005年2月间进行的31例合并HBV感染的HSCT患者临床资料进行回顾性分析。结果 31例受者均达到造血干细胞植活,乙型肝炎指标供者阳性、受者阴性8例,其中1例26个月死于肝硬化,2例在免疫抑制剂停用后,发展为慢性活动性肝炎;乙型肝炎指标供者阴性、受者阳性20例,其中2例乙型肝炎指标转阴,5例获得HBsAb（+）,4例移植后HBcAb转阴及HBeAb转阴,仅HBsAb（+）,1例转为"HBsAg（+）、HBeAg（+）、HBcAb（+）";乙型肝炎指标供者、受者均阳性3例,1例患者并发肝静脉闭塞病（VOD）,1例获得一过性HbsAg（+）,1例获得HbsAb（+）。结论 HBV感染对干细胞植活时间无明显影响;供、受者感染乙肝病毒不是HSCT的绝对禁忌证;HBsAg（+）及HBV滴度是影响移植后乙型肝炎复发的重要因素;HBsAg（+）的患者可作为HbsAb（+）受者的供者,但对HbsAb（-）受者则应慎重;拉米夫定及乙肝免疫球蛋白联合应用较乙肝疫苗单独使用更能有效地控制HBsAg（+）的供受者在移植后的乙型肝炎疾病的进展;HSCT有可能通过过继免疫治疗乙型肝炎。     

Hepatitis B‐related serological events in hematopoietic stem cell transplant patients and efficacy of lamivudine prophylaxis against reactivation

Reactivation of remote hepatitis B infection (RHBI) is an important cause of morbidity in hematopoietic cell transplant (HCT) patients. We analyzed the prevalence of RHBI in 205 patients who underwent HCT in our centre, serological events related to hepatitis B virus (HBV) reactivation and role of lamivudine prophylaxis in HCT patients with RHBI. The prevalence of RHBI was 14% (28/205 patients). Of these 28 patients, 15 received lamivudine prophylaxis (14 anti‐HBcIgG positive and 1 only anti‐HBs positive) while 13 did not receive lamivudine prophylaxis (12 anti‐HBs positive and 1 anti‐HBcIgG positive). None in prophylaxis group developed HBV reactivation while 12 of 13 in no‐prophylaxis group reactivated (P < 0.001). The rate of HBV reactivation was 10% (21/205 patients), which included 9 patients with no evidence of RHBI pre‐transplant. We conclude that lamivudine prophylaxis protects against HBV reactivation in HCT patients with evidence of RHBI. Lamivudine prophylaxis should be used not only in patients with anti‐HBcIgG positivity but also in those with isolated anti‐HBs positivity pre‐transplant given the high rate of HBV reactivation in these patients. HBV serology cannot identify all cases with RHBI and therefore does not preclude HBV reactivation post‐transplant. Copyright © 2015 John Wiley & Sons, Ltd.     

Risk of hepatitis B reactivation and the role of novel agents and stem-cell transplantation in multiple myeloma patients with hepatitis B virus (HBV) infection

BackgroundThe purpose of the study is to analyse the prevalence of hepatitis B virus (HBV) infection and its incidence of reactivation among multiple myeloma (MM) patients treated in the era of novel therapy in an endemic Asian setting.Patients and methodsFrom 2000 to 2008, 273 patients with newly diagnosed MM were screened for the presence of hepatitis B virus surface antigen and HBV core antibody. HBV-infected patients were prospectively followed for reactivation with serial monitoring of serum alanine transferase and HBV DNA load. The patterns of HBV reactivation in relation to treatment received, exposure to high-dose therapy with autologous stem-cell transplantation (HDT/ASCT) and novel agents were studied.ResultsThe prevalence of HBV infection was 5.5%. Three cases of HBV reactivation despite lamivudine prophylaxis were reported. Two patients reactivated 3–5 months after HDT/ASCT while receiving thalidomide maintenance and one reactivated 3 years after HDT/ASCT and shortly after bortezomib salvage therapy. Emergence of a mutant HBV strain was documented in one patient.ConclusionsUse of prophylaxis may reduce but will not preclude HBV reactivation. Highest risk occurs during immune reconstitution phase of HDT/ASCT. The role of immunomodulatory agents in HBV reactivation needs to be further elucidated. Separate HBV prophylaxis and surveillance guidelines ought to be developed for patients with MM.     

Hepatitis B reactivation in patients positive for hepatitis B surface antigen undergoing autologous hematopoietic cell transplantation

Hepatitis due to reactivation of hepatitis B virus is an important cause of liver-related morbidity and mortality in hepatitis B surface antigen (HBsAg) positive patients undergoing autologous hematopoeitic cell transplantation. With the recent introduction of sensitive serum HBV DNA quantitation assay, the diagnosis of hepatitis B reactivation can now be made more reliably. As these hepatitis are driven by the host immune response to a surge of hepatitis B viral load, the availability of effective nucleoside analogues which can inhibit hepatitis B viral replication has opened up new approaches to this previously untreatable condition. Up till now, two such nucleoside analogues, lamivudine and adefovir dipivoxil, have been approved for the treatment of chronic hepatitis B infection. However, further studies are needed to determine which nucleoside analogues should be chosen in this transplant setting. Due to the high dose chemotherapy generally needed in autologous hematopoeitic cell transplantation, there is a high risk of post-transplant hepatitis B reactivation. Hence, all HBsAg positive patients undergoing autologous hematopoeitic cell transplantation should preferably be treated pre-emptively with nucleoside analogous. An alternative approach is to defer treatment with nucleoside analogous until there is evidence of hepatitis B virological reactivation. However, the latter approach would need the patient's hepatitis B viral load be monitored at a very close interval and might not be cost-effective.     

感染乙肝病毒的恶性淋巴瘤应用拉米夫定预防性治疗的临床观察

目的探讨感染乙肝病毒的非霍奇金淋巴瘤患者化疗前预防应用拉米夫定在降低HBV再激活、减少肝功能损害方面的作用。方法 21例感染HBV的NHL接受CHO方案化疗4～6周期及预防应用拉米夫定抗病毒治疗（A组）,69例NHL接受CHOP方案化疗4～6周期（B组）。结果 A组CR率为38.1%（8/21）,B组CR率为42.0%（29/69）（P=0.2579）;A组有19.0%（4/21）化疗后肝功能损害,B组有14.5%（10/69）化疗后肝功能损害（P=0.0725）;A、B组均未发生HBV再激活。结论感染HBV的NHL应用CHO联合方案治疗及在化疗前预防抗病毒治疗能明显降低HBV再激活、减少肝功能损害。     

Reverse seroconversion of hepatitis B virus after hematopoietic stem cell transplantation

Hepatitis B virus (HBV) reactivation in patients previously positive for hepatitis B surface antibody (HBsAb), so-called reverse seroconversion, has been considered to be a rare complication after hematopoietic stem cell transplantation (HSCT). We experienced two patients who developed reverse seroconversion among nine who were HBsAb positive and Hepatitis B core antibody (HBcAb) positive before HSCT; one after autologous bone marrow transplantation (BMT) and another after allogeneic peripheral blood stem cell transplantation (PBSCT). We reviewed the literature and considered that reverse seroconversion of HBV after HSCT is not uncommon among HBsAb positive recipients. The use of corticosteroids, the lack of HBsAb in donor, and a decrease in serum HBsAb and HBcAb levels may predict reverse seroconversion after HSCT.