多发性骨髓瘤移植治疗的现状

多发性骨髓瘤（MM）是浆细胞的恶性疾病占血液系统肿瘤的10％，生存期从几个月到大于10年。MM可通过传统的化疗有效控制但很少能达到完全缓解（CR），治愈几乎没有。大剂量化疗后予自体或异基因造血干细胞移植可提高MM缓解率及生存率。低危病人可行自体干细胞移植（ASCT），特别是序贯ASCT，高危病人应及时行异基因移植或应用新的治疗方法。异基因移植因移植物抗骨髓瘤作用（GVM）有可能治愈MM，但移植相关死亡率（TRM）较高制约了其广泛开展。为提高异基因移植成功率可使用低强度预处理方案。现将MM移植治疗的现状进行综述。     

改良BU/CY预处理异基因造血干细胞移植治疗恶性血液病

异基因造血干细胞移植是治疗恶性血液病的有效方法,造血干细胞移植中预处理方案的选择和顺利进行是保证移植成功的重要部分。我们自2003年以来用改良BU/CY方案对39例恶性血液病患者进行了异基因造血干细胞移植,现报道如下。1资料与方法1.1临床资料39例均为2003年3月-2007年12月在我院住院患者,男22例,女17例;中位年龄30（6-55）岁。     

白血病患者并发真菌肺炎行异基因移植7例临床分析

目的观察并发曲霉菌肺炎的白血病患者行异基因外周血造血干细胞移植的疗效及安全性。方法回顾性分析7例伴曲霉菌肺炎的白血病患者成功完成异基因外周血造血干细胞移植的过程。结果入组7例患者中,男4例,女3例,中位年龄22.8（13-37）岁,随访时间均大于6个月,移植后1个月复查患者嵌合体均为100%完全供者嵌合。移植后平均抗真菌治疗时间为3个月,7例患者肺部真菌感染全部达到显效,造血干细胞100%植入,无1例发生相关死亡。结论伴发曲霉菌肺炎的白血病患者采用有效的抗真菌治疗方案仍然可以接受异基因外周血造血干细胞移植,并不会影响供者造血干细胞植入,且患者耐受性良好,值得进一步研究。     

亲缘异基因造血干细胞移植与STI571治疗慢性粒细胞白血病的临床对比研究

目的：评价对比亲缘异基因造血干细胞移植与酪氨酸激酶抑制剂STI571治疗慢性粒细胞白血病的有效性及安全性。方法：90例慢性粒细胞白血病慢性期患者，分为2组，其中亲缘异基因造血干细胞移植组23例，均采用经典或改良BuCy2方案预处理，短程甲氨蝶呤联合环孢素A（MTX＋CsA）方案预防移植物抗宿主病（GVHD）。STI571组67例，每天应用STI571 400mg，每周复查血常规，每3个月进行骨髓象及细胞遗传学检查，根据血象和骨髓象调整剂量。结果：观察截止时，移植组和STI571组获得细胞遗传学完全缓解率分别为100％和60％（P〈0．01），但移植组和STI571组的2年生存率分别为77．03％和83．33％，2组患者生存率比较差异无统计学意义（P〉0．05）。结论：与异基因造血干细胞移植相比，STI571治疗慢性粒细胞白血病患者治疗相关并发症较少较轻，但获得细胞遗传学完全缓解率较低。     

造血干细胞移植在多发性骨髓瘤治疗中的作用

多发性骨髓瘤（MM）患者发病时年龄50—70岁，40岁以下患者少见，中位发病年龄约55岁。异基因造血干细胞移植（ALLO—HSCT）的年龄上限为55岁（不包括减低预处理剂量移植）。因此，MM能够进行ALLO—HSCT的患者较少。自体造血干细胞移植（AHSCT）具有年龄限制较宽，移植相关病死率低等优点，对MM的治疗具有一定的优势。目前，MM的治疗AHSCT为主。     

异基因外周血造血干细胞移植治疗骨髓增生异常综合征26例临床分析

 骨髓增生异常综合征(MDS)为一组异质性造血干细胞克隆性疾病,异基因造血干细胞移植(allo-HSCT)是目前唯一能够治愈MDS的方法,然而在移植对象、移植时机和预处理方案的选择上仍存在分歧,值得深入研究以提高其疗效。现对异基因外周血造血干细胞移植(allo-PBSCT)治疗26例MDS患者的临床资料进行回顾性分析,为改进临床治疗提供参考。     

侵袭性非霍奇金淋巴瘤的造血干细胞移植治疗

非霍奇金淋巴瘤（NHL）是一组高度异质性的疾病。虽然传统的放疗／化疗结合最新的免疫化疗（Immunochemotherapy）和免疫放射治疗（Radio immunotherapy，RIT）方法可使许多淋巴瘤患者获得长期无病生存，大部分淋巴瘤仍是不可治愈的疾病，对这些难治和复发的淋巴瘤，自体造血干细胞移植（AHSCT）仍是标准的挽救治疗方法；而异基因造血干细胞移植（Allo-HSCT）由于其治疗相关的病死率（TRM）高，只有在年轻患者，特别是高度侵袭性NHL患者或AHS叮后复发的患者采用；而减低剂量的AllO-HSCT（RIST）由于其可以接受的TRM，且可保留移植物抗淋巴瘤反应（Graft versus lymphoma），在NHI，（包括滤泡性淋巴瘤）的挽救治疗中的作用越来越受到重视。以下就几种常见类型的侵袭性NHL的造血干细胞移植临床研究作简要介绍。     

单克隆抗体在恶性血液病自体造血干细胞移植中净化作用研究进展

异基因造血干细胞移植是治疗恶性血液病最有效方法之一,特别是具有高危因素患者,异基因造血干细胞移植尤其为首选治疗。近年来随着免疫学的进展,单克隆抗体(以下简称单抗)在自体造血干细胞移植(AHSCT)体内外净化研究中得到广泛应用。单抗因具有高度特异性大大改善了净化的效果,     

血液肿瘤患者锁骨下静脉置管后并发深静脉血栓3例

目的：探讨非清髓性造血干细胞移植（NST）治疗再生障碍性贫血（再障）的方法及疗效。方法：采用非清髓预处理方案进行造血干细胞移植治疗再生障碍性贫血2例。1例为同胞间HLA配型6个位点完全相合的异基因外周血造血干细胞移植，另1例为同胞间HLA配型6个位点完全相合的脐血移植。预处理方案主要由抗胸腺细胞球蛋白（ATG）和环磷酰胺组成。用环孢素A和霉酚酸酯（MMF）预防移植物抗宿主病（GVHD）。结果：2例患者均获造血重建（分别为＋5及＋9d），2例均未发生GVHD。1例患者在治疗期间未出现感染表现，另1例患者出现CMV感染，给予更昔洛韦病情得以完全控制。2例分别无病生存8及17个月。结论：非清髓造血干细胞移植简便安全，并发症少，疗效好，为治疗再障的有效方法。     

骨髓增生异常综合征患者最佳移植时机选择

骨髓增生异常综合征是一组异质性很强的髓系克隆性疾病，分型众多而治疗原则各异，异基因造血干细胞移植的时机把握属于临床难题。首先基于危险分层来确定低危或较高危患者对于区分移植时机十分关键。应尽量选择KPS≥80%和HCT-CI<3作为适合移植人群的候选标准。对于较高危患者应尽快直接进行移植，不必拘泥于原始细胞比例问题。较低危患者应在常规治疗疗效不佳，或疾病进展，或严重血细胞减少或输血依赖时进行。较低危患者若存在不良遗传学异常或高危基因突变，也应尽快接受异基因造血干细胞移植，IPSS-M积分对这一类患者有重要的提示作用。     

Treatment options for newly diagnosed patients with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is an indolent B-cell malignancy for which early intervention has not been shown to extend survival. However, there are many agents available that are active in this disease. Alkylating agents, the purine analogs, and monoclonal antibodies have all been shown to result in high response rates in patients with previously treated and untreated CLL. These classes of agents have been combined based on in vitro data demonstrating synergism. The purine analogs alone or in combination with alkylating agents and monoclonal antibodies result in greater response rates compared with alkylating agent-based therapy alone. However, improvement in overall survival and cure of patients with CLL has yet to be realized with these available regimens. The best initial therapy of patients with CLL remains a matter of debate.     

Chemoimmunotherapy of chronic lymphocytic leukemia

The past two decades have seen a major paradigm shift in the therapy of chronic lymphocytic leukemia (CLL), with the treatment goal shifting from symptom palliation to the attainment of maximal disease control using the most effective frontline regimens available, thus prolonging survival and possibly leading to cure. The most potent therapeutic regimens developed to date include the chemoimmunotherapy combinations incorporating purine analogs and monoclonal antibodies. We review the evolution of modern chemoimmunotherapy for CLL, and discuss current research directions for further refining the potency of these regimens.     

免疫抑制剂增加炎症性肠病患者淋巴瘤风险的Meta分析

目的 探讨炎症性肠病（IBD）患者使用嘌呤类免疫抑制剂后发生淋巴瘤的风险.方法 检索1990年1月～2013年10月研究IBD患者使用硫唑嘌呤（AZA）或6-巯嘌呤（6-MP）后淋巴瘤发生风险的随机对照试验,按照纳入排除标准筛选文献,使用系统评价的方式对纳入的文献进行Meta分析.结果 本文共纳入9篇文献,共111 713例IBD患者.Meta分析结果显示,IBD患者使用嘌呤类免疫抑制剂后患淋巴瘤的风险比未使用患者的相对危险度（RR）增高了1.46倍（95％ CI1.04 ～2.05,P＜0.05）,经Begg秩检验和Egger＇s回归分析检验显示文献稳定性较好,不存在发表性偏倚.结论 IBD患者使用嘌呤类免疫抑制剂治疗后,患淋巴瘤的风险增加.     

Simvastatin and purine analogs have a synergic effect on apoptosis of chronic lymphocytic leukemia cells

Despite many therapeutic regimens introduced recently, chronic lymphocytic leukemia (CLL) is still an incurable disorder. Thus, there is an urgent need to discover novel, less toxic and more effective drugs for CLL patients. In this study, we attempted to assess simvastatin, widely used as a cholesterol-lowering drug, both as a single agent and in combination with purine analogs—fludarabine and cladribine—in terms of its effect on apoptosis and DNA damage of CLL cells. The experiments were done in ex vivo short-term cell cultures of blood and bone marrow cells from newly diagnosed untreated patients. We analyzed expression of active caspase-3 and the BCL-2/BAX ratio as markers of apoptosis and the expression of phosphorylated histone H2AX (named γH2AX) and activated ATM kinase (ataxia telangiectasia mutated kinase), reporters of DNA damage. Results of our study revealed that simvastatin induced apoptosis of CLL cells concurrently with lowering of BCL-2/BAX ratio, and its pro-apoptotic effect is tumor-specific, not affecting normal lymphocytes. We observed that combinations of simvastatin+fludarabine and simvastatin+cladribine had a synergic effect in inducing apoptosis. Interestingly, the rate of apoptosis caused by simvastatin alone and in combination was independent of markers of disease progression like ZAP-70 and CD38 expression or clinical stage according to Rai classification. We have also seen an increase in γH2AX expression in parallel with activation of ATM in most of the analyzed samples. The results suggest that simvastatin can be used in the treatment of CLL patients as a single agent as well as in combination with purine analogs, being equally effective both in high-risk and good-prognosis patients. One of the mechanisms of simvastatin action is inducing DNA damage that ultimately leads to apoptosis.     

Modern concepts in the treatment of chronic lymphocytic leukemia

Abstract

There has been considerable progress in the treatment of chronic lymphocytic leukemia (CLL) during last 10 years. Purine analogs and monoclonal antibodies have enabled the shift from purely palliative treatment to intensive regimens aiming at complete remissions and possible prolongation of survival. Many patients have now been shown to achieve molecular responses in addition to their hematological remission. Despite this success, virtually all patients with CLL will eventually relapse and will become refractory to treatment. Allogeneic stem cell transplantation offers a chance of definite cure but is feasible in a minority of patients only. Therefore, considerable effort has been devoted to the further development of more conventional CLL management that is applicable to patient population generally affected by the disease. Emerging treatment concepts include novel combination of well-know agents such as rituximab and chlorambucil, fludarabine, cyclophosphamide and alemtuzumab, FCR with mitoxantrone amongst many. Consolidation regimens using mainly alemtuzumab are also increasingly used but are associated with a major increase in severe infections. High-dose steroids in combination with rituximab or alemtuzumab represent a promising option for refractory patients. Modern chemoimmunotherapy with the FCR regimen has also been tested in early stage patients with unfavourable prognostic factors. Finally, a there are a wide variety of novel drugs including bendamustine, a unique cytostatic with combined properties of an alkylating agent and purine analog, the monoclonal antibodies anti-CD20 ofatumumab and the anti-CD23 lumiliximab, thalidomide and its analog lenalidomide, the semi-synthetic flavonoid flavopiridol and other agents which are currently undergoing clinical trials with promising results. This article reviews the recent advances and future possibilities in the treatment of CLL.     

How I treat refractory CLL

Therapy for patients with chronic lymphocytic leukemia (CLL) has greatly changed over the past few years. After years of stagnation, with treatment revolving around the use of rather ineffective drugs such as alkylators, many patients are now being treated with more effective agents such as purine analogs either alone or combined with other drugs and/or monoclonal antibodies. Treatment of patients refractory to these treatments is particularly challenging and should be decided only upon a careful evaluation of the disease, patient characteristics, and prognostic factors. Refractory disease should be clearly separated from relapsing disease. The only curative therapy for patients with CLL, including those with refractory disease, is allogeneic stem cell transplantation. However, the use of allogeneic transplantation is limited because of the advanced age of most patients and the high transplant-related mortality (TRM). Transplants with nonmyeloablative regimens may reduce TRM and allow more patients to receive transplants more safely. For patients in whom an allogeneic transplantation is not feasible or in whom it is deemed inappropriate, participation in phase 2 trials should be encouraged. Finally, to investigate mechanisms to overcome resistance to therapy in CLL and to identify patients that might gain benefit from early, intensive therapies (eg, based on biologic markers) constitute a challenge that needs active investigation.     

Advances in chemotherapy for chronic lymphocytic leukemia

While chemotherapy based on alkylating agents has been the standard treatment of chronic lymphocytic leukemia (CLL) for decades, purine analogues and their combinations have emerged as effective new therapies for previously untreated and pretreated patients. As single agents, fludarabine and cladribine are the most promising, showing higher remission rates compared to chlorambucil. For younger and physically fit patients, the combination of fludarabine and cyclophosphamide has shown benefit. Fludarabine plus epirubicin appears equally potent. The addition of monoclonal antibodies, such as rituximab and alemtuzumab, to purine analogues alone or in combination seems to be even more effective for chemotherapy-naive and pretreated CLL patients. Another promising agent in the armamentarium of therapies for CLL is bendamustine, which has properties of both an alkylating agent and a purine analogue. Clinical trials are ongoing with novel drugs that interfere with cell cycle regulation and signaling molecules in CLL, including flavopiridol, UCN-01, bryostatin 1, depsipeptide, and oblimersen. It remains to be seen whether these chemotherapeutic approaches offer real benefit for patients by prolonging survival with an improved quality of life.     

个体化治疗耐多药肺结核的疗效分析

目的评估个体化治疗方案治疗耐多药肺结核的疗效。方法耐多药肺结核病例34例随机分为个体化治疗组（18例）和标准对照组（16例）,个体化治疗组采用18Pa＋L2＋X（X根据个体的药物敏感试验,选择含两种或三种敏感抗结核药物）方案,标准对照组采用标准化方案,经过治疗后比较两组患者的各项指标及疗效。结果经过治疗个体化治疗组的痰菌阴转、病灶吸收情况、空洞闭合情况及症状改善情况与标准对照组差异无统计学意义（P〉0.05）。结论根据药敏结果建立个体化治疗方案可以合理有效的治疗耐多药肺结核。     

Chemoimmunotherapy for relapsed/refractory and progressive 17p13‐deleted chronic lymphocytic leukemia (CLL) combining pentostatin,alemtuzumab, and low‐dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab‐containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short‐duration regimen combining pentostatin, alemtuzumab, and low‐dose high‐frequency rituximab designed to decrease the risk of treatment‐associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13?) (n = 3). Thirteen (33%) patients had both 17p13? and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty‐six (67%) patients completed therapy, with only five (13%) patients having treatment‐limiting toxicity and no treatment‐related deaths. Twenty‐two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression‐free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B‐cell lymphoma (n = 6). Correlative studies showed that low‐dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low‐dose high‐frequency rituximab is a tolerable and effective therapy for CLL and that low‐dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. Am. J. Hematol. 89:757–765, 2014. © 2014 Wiley Periodicals, Inc.     

New modalities of therapy in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most cormmon form of leukemia in adults in Western countries. After several decades of relative inactivity, important progress has been made in our understanding of the biology and immunology of this disorder. In addition, exciting therapeutic results have been achieved with several new, unique, and effective therapies. The most interesting chemotherapeutic agent is fludarabine, a purine analogue which achieves complete remission in 13% of relapsed or refractory patients and in greater than 30% of previously untreated patients; the overall response rates of 60% and 75%, respectively, are superior to reports with other single agents or combination regimens. Related drugs with promising activity are 2'-deoxycoformycin, and 2-chlorodeoxyadenosine. Preliminary studies are evaluating allogeneic and autologous bone marrow transplantation as potentially curative therapy. Biological approaches exploiting new insights into the immunology of CLL include the use of lymphoid growth factors. Interpretation of results of CLL studies has suffered from variability in eligibility and response criteria, especially definitions of complete remission. Recently published standardized guidelines for CLL clinical trials will facilitate comparisons among therapies and help identify those which are most promising. Continued progress will require integration of laboratory science and clinical investigation.