Non-pharmacologic strategies in hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) may be performed to treat a variety of malignant and non-malignant disorders by eradicating tumor, replacing a non-functioning with a normal immune system, or replenishing a deficient enzyme. While HSCT may provide cure for many patients, barriers such as acute and chronic graft-versus-host disease (a/cGVHD) and graft failure continue to challenge clinicians with considerable potential for morbidity and mortality. A thorough understanding of each disease process is essential to the development of both pharmacologic and non-pharmacologic therapies in this setting; unfortunately, acute and chronic GVHD, are distinct, complex entities, and medications used to prevent and treat them cause significant toxicities and leave patients at high risk for overwhelming infections. Standard pharmacologic therapies that are currently in use are limited in that they have the potential to cause significant toxicity without completely curing the disease. Novel, non-pharmacologic therapies for the prevention and treatment of acute and chronic GVHD must continue to be developed and studied in randomized trials. Given that the potential mechanisms of action of the non-pharmacologic therapies discussed herein attempt to modulate the cellular milieu that supports the development of GVHD, a brief discussion of GVHD and its pathophysiology is warranted; detailed discussions are provided by Cutler et al. and Bolanos-Meade elsewhere in the current issue. We will therefore focus on two non-pharmacological innovative forms of therapy, and potentially, prevention of GVHD.     

Antifungal agents in hematopoietic stem cell transplantation

Invasive fungal infections are major complications of stem cell transplantation associated with significant morbidity and mortality. Allogeneic stem cell transplant recipients are at a significantly greater risk for fungal infection than recipients of autologous transplantation. Although with the wide use of fluconazole prophylaxis the incidence and associated mortality of invasive candidiasis has been minimized, mold diseases remain a significant complication during periods of prolonged immunosuppression for graft versus host disease. Posaconazole prophylaxis during periods of high risk was recently demonstrated to be effective in preventing fungal infections and associated mortality. Preemptive strategy employing laboratory markers and serial CT scans to identify mold infection at an early stage is promising. However its efficacy has to be validated in clinical trials. Several new antifungal agents have been introduced lately, characterized by improved safety profile and broader antifungal spectrum. Voriconazole has become the standard of care for the treatment of invasive aspergillosis. Finally there has been increasing interest on combination therapy for invasive aspergillosis due to the high rate of failure of the currently available antifungals, especially in the profoundly immunocompromised host.     

Indoleamine 2,3-dioxygenase in hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is complicated by unwelcome side-effects that arise on the basis of an altered immune system. Infectious complications and alloreactive T-cell responses trigger a process of ongoing immune activation and inflammation. Negative-feedback mechanisms to counteract inflammation involve the induction of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO), which mediates anti-inflammatory activities and T-cell inhibition via tryptophan catabolism. However, persistent immune activation and generalized release of pro-inflammatory cytokines deviate immune regulation towards chronic suppression incapable to abrogate the inflammatory response. This review focuses on the unique role of tryptophan catabolism in modulating inflammatory processes and T-cell responses after HSCT.     

Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Introduction: Allogeneic hematopoietic stem cell transplantation (alloHSCT) offers potential curative treatment for a wide range of malignant and nonmalignant hematological disorders. However, its success may be limited by post-transplant acute graft-versus-host disease (aGVHD), a systemic syndrome in which donor’s immune cells attack healthy tissues in the immunocompromised host. aGVHD is one of the main causes of morbidity and mortality after alloHSCT. Despite standard GVHD prophylaxis regimens, aGVHD still develops in approximately 40–60% of alloHSCT recipients.

Areas covered: In this review, after a brief summary of current knowledge on the pathogenesis of aGVHD, the authors review the current combination of a calcineurin inhibitor with an antimetabolite with or without added anti-thymocyte globulin (ATG) and emerging strategies for GVHD prevention.

Expert opinion: A new understanding of the involvement of cytokines, intracellular signaling pathways, epigenetics and immunoregulatory cells in GVHD pathogenesis will lead to new standards for aGVHD prophylaxis allowing better prevention of severe aGVHD without affecting graft-versus-tumor effects.     

The use of growth factors in hematopoietic stem cell transplantation

Mobilized, peripheral blood stem cells (PBSC) are increasingly used for both autologous and allogeneic transplants. Granulocyte-colony-stimulating factor is the most widely used cytokine for mobilization. Several different mechanisms of stem cell mobilization have been proposed including protease-dependent and non-protease- dependent mechanisms. In autologous transplants, the addition of chemotherapy to mobilization can enhance the yield of PBSC collected but with substantial adverse effects, and not necessarily faster engraftment. In allogeneic transplants, the use of mobilized PBSC is associated with faster engraftment and donor chimerism compared to bone marrow. In the majority of studies, the rate of acute graft-versus-host disease (GVHD) has not been shown to be significantly higher with PBSC, but the rate of chronic GVHD appears to be increased. Several different strategies have been proposed for patients and donors who fail initial mobilization, including the use of novel agents. AMD3100 (Plerixafor) works by directly inhibiting the interaction between stromal cell-derived factor-1 and its receptor CXCR4, and mobilizes hematopoietic stem cells within hours. It is being studied alone or in conjunction with growth factors for PBSC mobilization in both autologous and allogeneic settings. Although the use of growth factors after PBSC transplantation results in faster neutrophil engraftment its impact on treatment-related mortality and survival does not appear significant. Here, we review the biology and methods of PBSC mobilization, the effect of growth factors on normal donors and the controversies of growth factor use in the post-transplant setting. We also review the data on novel agents for mobilization of stem cells.     

异基因造血干细胞移植后红系恢复影响因素分析

目的探讨异基因造血干细胞移植后影响红系恢复时间的因素。方法回顾分析53例异基因造血干细胞移植患者的移植方式、人血细胞抗原（HLA）相合与否、ABO血型相合与否及亲缘关系的有无对红系恢复时间的影响。结果影响红系恢复时间的因素主要为ABO血型主要不合及受、供者的亲缘关系。结论ABO血型主要不合和非亲缘骨髓移植的患者红系恢复较慢。     

Viral diagnostics and antiviral therapy in hematopoietic stem cell transplantation

Viral infections are important causes of morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. Some viruses, such as the respiratory and gastrointestinal viruses, are acquired from the healthcare or community in the midst of or after HSCT. Other viruses, such as the herpes-virus family, establish latency after resolution of primary infection but then may reactivate during the immunosuppression that occurs with HSCT. Due to the improved sensitivity and turn-around time with PCR-based molecular diagnostic methods, traditional viral diagnostic methods such as viral culture and rapid shell vial are rapidly being replaced or supplemented. Prophylactic and preemptive strategies are increasingly used to limit reactivation of viruses that have established latency. Improvements in diagnostics result in earlier viral detection and antiviral initiation which may improve outcomes. Newly identified viruses such as human metapneumovirus are being increasingly recognized as pathogens in HSCT recipients. Treatment strategies for viral pathogens continue to change as our understanding of these viral diseases improves.     

标准与强化预处理方案对急性淋巴细胞白血病异基因造血干细胞移植后疗效的比较

目的对比分析标准与强化预处理方案对急性淋巴细胞白血病（ALL）异基因造血干细胞移植后疗效的影响。方法标准预处理方案包括TBI＋CY、改良BuCY和GIAC方案,强化预处理方案包括TBI＋CY＋VP-16／VM-26和FA＋TBI＋CY＋VP-16方案。中位随访时间为811d。结果标准组（n=125）与强化组（n=78）移植前疾病状态差异有统计学意义（P〈0．01）,造血重建时间、GVHD发生率和移植相关毒性差异无统计学意义,标准组复发率及死亡率（33．6％,55．2％）均较强化组（26．9％,48．7％）高,但差异均无统计学意义（P=0．433及P=0．450）,其中,CR状态下患者行超强预处理方案移植,其死亡率比标准组明显降低（P：0．017）。两组患者5年总生存率（OS）和无复发生存率（DFS）（44．1±5．6）％、（46．8±7．8）％和（36．5±6．9）％、（44．9±7．5）％,强化组均较标准组高,差异无统计学意义（P=0．831、0．652）。结论强化预处理方案耐受性好,相比标准预处理方案,其Os与DFS均较高。     

网织血小板与造血干细胞移植后造血重建的相关性研究

目的 研究网织血小板(RP)在造血干细胞移植(SCT)中预测骨髓造血重建的价值。方法 应用荧光染料TO和流式细胞仪动态检测18例SCT患移植后外周血RP％，同时监测其白细胞数、血小板数的变化。结果 移植后RP％随血小板下降而下降，并最早开始回升，较血小板回升提前4天；再随血小板数的升高，由峰值迅速回落至正常水平。在异基因骨髓移植(allo-BMT)组，RP％的回升较白细胞、血小板回升提前更显，与自体外周血造血干细胞移植(APBSCT)组有显差异。结论 RP％可能更早反映骨髓移植后造血重建，并不受血小板输注影响。     

造血干细胞移植在自身免疫性疾病中的应用进展

本文分析了近几年造血干细胞移植（HSCT）治疗自身免疫性疾病的临床研究现状,从治疗机理、干细胞动员采集、预处理和临床效果等方面进行了综合分析。目前在类风湿性关节炎、系统性红斑狼疮、1型糖尿病和多发性硬化症等临床应用上研究证明HSCT是治疗自身免疫性疾病的一种有效手段,尤其对病情较重的晚期患者,在其他疗法不能奏效的情况下,不失为一种挽救患者生命的有价值方法。但目前各方报道疗效还不稳定,如何进一步提高疗效、减少复发率是今后的发展方向。     

自体造血干细胞移植治疗晚期恶性实体瘤

目的观察自体造血干细胞 (aulologoushematopoiticstemcelltransplantation ,AHSCT)对晚期恶性实体瘤的疗效及副作用。方法 6例患者中 ,1例行自体骨髓移植 (antologousbonemarrowtranspla tion ,ABMT) ,5例行自体外周血干细胞移植 (autologousperipheralbloodstemcelltransplantationAPBSCT)。预处理方案 :乳腺癌为CEP(CTX ,VP-1 6,DDP) ,恶性淋巴瘤为CEA(CTX ,VP-1 6,Ara-c)方案 ,采集的干细胞 1例 4℃保存 ,72小时内回输 ,其余 5例 - 80℃保存。结果APBSCT动员采集单个核细胞数 7 0 2× 1 0 8 kg ,ABMT和APBSCT后 ,患者中性粒细胞计数恢复到 0 5× 1 0 9/L ,血小板达 50× 1 0 9/L以上的时间平均为 1 0 8天和 1 6 2天。毒副作用主要是骨髓抑制和消化道反应 ,随访至今死亡 2例 ,复发 2例 ,2例无瘤生存。结论AHSCT治疗晚期乳腺癌近期疗效肯定 ,可提高生活质量 ,对恶性淋巴瘤的治疗有效 ,但对反复复发患者需移植后作进一步治疗。     

异基因造血干细胞移植治疗儿童血液病

目的探讨异基因造血干细胞移植治疗儿童血液病的价值。方法采用异基因造血干细胞移植治疗11例儿童血液病，其中再生障碍性贫血2例、白血病7例、骨髓异常增生症1例、非霍奇金淋巴瘤1例；预处理采用氟达拉滨／环磷酰胺（FLU／CTX）或全身放疗／环磷酰胺（TBI／CTX），观察患儿的临床治疗效果。结果10例患儿均移植成功，9例患儿生存，其中7例无病存活，存活最长时间为5．5年；CMV感染3例，继发出血性膀胱炎1例，继发弥漫性GVHD1例。结论异基因造血干细胞移植是治疗儿童血液病的有效方法，值得临床进一步推广。     

Drug–drug interactions in patients receiving hematopoietic stem cell transplantation

Introduction: Recipients of hematopoietic stem cell transplantation (HSCT) are exposed to numerous drugs in both pre- and post-transplantation period, which creates an opportunity for drug–drug interactions (DDIs); if clinically relevant DDIs happen, the risk of adverse treatment outcomes is increased.

Areas covered: This review is focused on DDIs in recipients of HSCT that were observed and published as clinical trials, case series or case reports. Relevant publications were found by the systematic search of the following online databases: MEDLINE, SCOPUS, EBSCO, and SCINDEX.

Expert opinion: The most important DDIs involve cytostatic or immunosuppressant drug on one side, and antimicrobial drugs on the other. The majority of clinically relevant interactions have pharmacokinetic character, involving drug metabolizing enzymes in the liver. Antifungal azoles inhibit metabolism of many cytostatic and immunosuppressant drugs at cytochromes and increase their plasma concentrations. Macrolide antibiotics and fluoroqunolones should be avoided in HSCT recipients, as they have much larger potential for DDIs than other antibiotic groups. HSCT recipients increasingly receive new immunomodulating drugs, and further observational studies are needed to reveal unsuspected DDIs with clinical relevance.     

Induction of tolerance in organ recipients by hematopoietic stem cell transplantation

The use of hematopoietic stem cell transplantation (HSCT) for the establishment of mixed chimerism represents a viable and attractive approach for generating tolerance in transplantation biology, as it generally leads to durable immune tolerance, enabling the subsequent engraftment of organ transplants without the need for a deleterious continuous immunosuppressive therapy. However, in order to apply HSCT to patients in a manner that enables long term survival, transplant-related mortality must be minimized by eliminating the risk for graft-versus-host-disease (GVHD) and by reducing the toxicity of the conditioning protocol. T-cell depleted bone marrow transplants (TDBMT) have been shown to adequately eliminate GVHD. However, even in leukemia patients undergoing supralethal conditioning, mismatched TDBMT are vigorously rejected. This barrier can be overcome through the modulatory activity of CD34 cells, which are endowed with veto activity, by the use of megadose stem cell transplants. In mice, megadoses of Sca+lin-hematopoietic stem cells can induce mixed chimerism following sub-lethal conditioning. Nevertheless, the number of human CD34 cells that can be harvested is not likely to be sufficient to overcome rejection under reduced intensity conditioning (RIC), which might be acceptable in recipients of organ transplantation. To address this challenge, we investigated a novel source of veto cells, namely anti 3rd-party cytotoxic T cells (CTLs) which are depleted of GVH reactivity, combined with megadoses of purified stem cells and a RIC protocol. This approach might provide a safer modality for the induction of durable chimerism.     

恶性血液病自体造血干细胞移植治疗的疗效分析

目的评价自体造血干细胞移植治疗恶性血液病患者的疗效。方法将60例恶性血液病患者分成观察组和对照组。对照组采用单纯化疗治疗,观察组采用自体造血干细胞移植治疗。结果观察组存活率73.33%高于对照组46.67%,差异有统计学意义(P<0.05)。结论自体造血干细胞移植治疗恶性血液病患者相关死亡率低,生存率较高,可作为恶性血液病治疗的重要方法。     

改良预处理方案在单倍体移植治疗恶性血液病中的应

目的 探讨采用改良白消安-环磷酰胺预处理方案行单倍体移植治疗恶性血液病的疗效.方法 采用阿糖胞苷、白消安、环磷酰胺、甲环己亚硝脲及抗胸腺细胞球蛋白联合作为改良白消安-环磷酰胺预处理方案行单倍体移植治疗恶性血液病.结果 6例患者完全植入,＋12 d～＋20 d（回输干细胞前为一,回输干细胞后为＋WBC＞1.0×10^9/L,＋20 d～＋51 d PLT＞20×10^9/L,4例出现急性移植物抗宿主病,其中Ⅰ度1例,Ⅱ度2例,Ⅳ度1例,4例出现慢性移植物抗宿主病,无致命性感染发生,2例出现迟发性出血性膀胱炎,目前无恶性血液病存活13～63个月.结论 采用改良白消安-环磷酰胺顶处理方案行单倍体移植治疗恶性血液病是安全有效的方法.     

单倍体移植治疗恶性血液病的临床研究

目的 探讨单倍体移植治疗恶性血液病的疗效.方法 在单倍体移植时采用阿糖胞苷、马利兰、环磷酰胺、甲基环已亚硝脲联合作为预处理方案,用环磷酰胺、重组人粒细胞集落刺激因子、环孢素、麦考酚酸酯、抗胸腺细胞球蛋白、白细胞介素11及甲氨蝶呤联合预防急性移植物抗宿主病（aGVHD）,治疗8例恶性血液病患者.结果 8例患者完全植入,白细胞＞1.0×10^9/L中位时间为16.3 d（＋12～＋20 d）,Ⅲ～Ⅳ度aGVHD的发生率为12.5%,中位随访时间28.8（4-65）个月,无复发,随访至2010年2月仍存活.结论 在单倍体移植治疗恶性血液病时采用阿糖胞苷、马利兰、环磷酰胺、甲基环己亚硝脲联合作为预处理方案,用环磷酰胺、重组人粒细胞集落刺激因子、环孢素、麦考酚酸酯、抗胸腺细胞球蛋白、白细胞介素11及甲氨蝶呤联合预防aGVHD是一种安全、有效的方法.     

STR基因位点检查在异基因造血干细胞移植中的应用

目的 探讨短串联重复序列(STR)基因位点检查在异基因造血干细胞移植中的应用。方法 采用PCR方法对4例异基因造血干细胞移植、1例非清髓造血干细胞移植的供者和受者移植前、后STR基因进行检测,了解造血干细胞植入情况。结果 4例异基因造血干细胞移植的受者移植后STR基因型与受者移植前STR基因型不同,与供者STR基因型完全相同,提示供者造血干细胞的植入;1例非清髓造血干细胞移植的受者移植后STR基因型表现为患者移植前STR基因型和供者STR基因型的嵌合状态。结论 STR基因位点检查可以用来判断异基因造血干细胞移植的植入情况。