含G-CSF预激的化疗在难治/复发性急性白血病治疗中的研究进展

难治与复发急性白血病(acute leukemia,AL)是白血病治疗中的最棘手的问题,患者病情进展迅速,并且难以治愈,且容易复发,甚至危及生命.近年来,多种化疗药物的联合给药方案,在AL的治疗中,取得了较好的临床疗效.含细胞因子的预激化疗方案能够动员处于静止期的白血病细胞进入细胞周期,增强化疗药物特别是周期特异性药物的杀伤作用,提高化疗缓解率,清除白血病微小残留病灶.笔者就含G-CSF预激的化疗在难治/复发性AL治疗中的应用作一综述.     

急性白血病长期生存相关因素研究

 目的　分析影响急性白血病（AL）长期生存的因素。方法　对143例中27例长期生存5年以上AL患者的临床资料进行回顾分析,AL患者诱导缓解期采用强烈联合化疗,并实行个体化用药原则,坚持缓解后正规的巩固强化治疗,长期随访观察,根据情况调整用药方案。结果　AL 143例中达到完全缓解112例（78.3 %）,27例（18.9 %）达5年以上长期生存。结论　影响AL长期生存的主要因素为AL类型、白血病细胞负荷、髓外白血病、个体化治疗、达到完全缓解的时间、强化治疗的时间、规范的缓解后治疗等。     

TE T2基因阳性急性髓细胞白血病38例分析

目的：分析TET2基因阳性急性髓细胞白血病（AML）患者的临床及实验室特点,探讨可能影响治疗效果的因素。方法：收集38例TET2基因突变阳性AML患者的临床及实验室资料,并回顾性分析其中可能影响治疗效果的因素,TET2基因检测采用实时定量PCR方法。结果：38例患者中21例接受化疗,获得完全缓解（CR）12例（57．14％）,未缓解（NR）5例（23．81％）,疾病进展（PD）4例（19．05％）。应用不同化疗方案治疗后缓解率不同,应用去甲基化治疗的4例第一个疗程治疗后均达到完全缓解,未应用去甲基化治疗的17例中CR 8例（47．06％）、NR 5例（29．41％）、PD 4例（23．53％）。白血病细胞免疫表型CD34阴性、CD13阴性、CD33阳性者化疗后CR率更高,差异具有统计学意义（P＜0．05）。TET2基因阳性AML患者的CR率与年龄、性别、发病时白细胞计数、血红蛋白、血小板计数、白血病细胞免疫表型（CD56、CD9、HLA－DR）、是否伴有其他预后基因及复杂染色体核型无明显相关性。结论：TET2基因阳性AML患者的CR率与化疗方案及白血病细胞免疫表型CD34、CD13及CD33相关。去甲基化治疗可提高TET2基因阳性AML患者的CR率。影响TET2基因阳性AML患者疗效及长期生存的因素尚需进一步探讨。     

急性白血病骨髓白血病细胞数下降的预后意义

 【摘要】　目的　评价初发急性白血病化疗前后骨髓白血病细胞数下降的预后意义。方法　回顾性分析29例初发急性白血病患者化疗前后骨髓白血病细胞数资料,比较持续缓解组（9例）、复发组（6例）、未缓解组（8例）和早期死亡组（6例）化疗前白血病细胞数、诱导化疗后的白血病细胞数和总生存时间的相关性。结果　持续缓解组、复发组、未缓解组和早期死亡组化疗前的骨髓白血病细胞数分别为81.50 %、84.75 %、70.75 %、93.00 %,差异无统计学意义（P＝0.196）,化疗前骨髓白血病细胞数与总生存时间不相关（r＝0.140,P＝0.470）;化疗后骨髓白血病细胞数分别为15.50 %、7.75 %、59.00 %、56.00 %,差异有统计学意义（P＝0.045）,化疗后骨髓白血病细胞数与总生存时间有相关性（r＝-0.342,P＝0.021）。结论　急性白血病化疗前的骨髓白血病细胞数与预后无关,化疗后的骨髓白血病细胞数与患者的完全缓解率及长期生存有关。     

急性白血病治疗进展

新的化疗药物的问世，化疗策略的优化，造血干细胞移植的应用，以及支持治疗的改进，急性白血病（AL）的完全缓解率（CR）和长期无病存活（LFS）率逐年提高。目前，化疗仍是主要的治疗手段。采用有效、足量及个体化的化疗，使患者在最短时间内达到CR。CR后的巩固化疗尽量杀灭残留白血病细胞，是取得LFS的关键。本文重点介绍AL化疗的进展，对造血干细胞移植效果及支持治疗方面的进展略有涉及。一、急性髓细胞白血病（AML）的治疗（－）诱导缓解1、DA3＋7方案：柔红霉素（DNR）30～50mg／m’／日计第1～3日，阿糖胞昔（Ara－C）100…     

氟达拉滨联合阿糖胞苷及粒细胞集落刺激因子治疗儿童难治及复发性急性白血病

 【摘要】　目的　观察氟达拉滨（Flud）联合阿糖胞苷（Ara-C）及粒细胞集落刺激因子（G-CSF）（FLAG）方案治疗儿童难治及复发性急性白血病（AL）的疗效及患者不良反应。方法　9例复发及难治性AL患儿接受了FLAG方案治疗,Flud 每天30 mg／m2,第1天至第5天,静脉滴注30 min;Ara-C每天2 g／m2,Flud应用后4 h静脉滴注,第1天至第5天。G-CSF 5 μg?kg-1?d-1,中性粒细胞＜0.5×109／L时开始应用,用至中性粒细胞 ≥1×109／L。9例患儿中急性髓系白血病（AML）8例,急性淋巴细胞白血病（ALL）1例;难治性AL 5例,复发性AL 4例。结果　9例患儿中经1个疗程化疗达完全缓解（CR）6例,部分缓解（PR）2例,总有效（CR+PR）率 88.9 %（8／9）。6例CR患者中2例行造血干细胞移植,现均无瘤生存;患者主要不良反应是感染、骨髓抑制和胃肠道反应。结论　FLAG方案治疗儿童难治及复发性AL缓解率高,不良反应可以耐受,是治疗儿童难治及复发性AL的一个选择,为后续的造血干细胞移植提供了机会。     

PI3K、Akt mRNA在白血病中的表达及其临床意义

 目的　分析成年人各型急性白血病（AL）和慢性粒细胞白血病（CML）中PI3K及其下游信号分子Akt mRNA的表达情况及其与白血病诊断、治疗及预后的关系。方法　研究对象分为AL初治组63例、缓解组10例、复发组7例,CML组14例,对照组11例。用半定量反转录聚合酶链反应技术检测各组PI3K、Akt的mRNA表达水平。结果　PI3K在AL初治组、复发组、CML组表达水平高于对照组,而且CML组高于AL缓解组;Akt在CML组表达高于AL缓解组、对照组,复发组高于对照组。AL初治组PI3K、Akt mRNA表达阳性者缓解率低,阴性者缓解率高。结论　PI3K／Akt信号转导通路在转录水平参与了白血病的发生、发展;该通路成分阳性表达的AL患者缓解率低。     

急性白血病患者预后相关的临床病理学因素

急性白血病（acute leukemia，AL）是血液系统常见的恶性肿瘤，其自然病程仅2～4个月。现在AL达到化疗完全缓解（complete remission，CR）已不困难，提高患者长期生存（overall survival，OS）率已成为急需解决的课题。近20年来，国内成人急性淋巴细胞白血病（acute lymphatic leukemia，ALL）和急性髓性细胞白血病（Acute Non-lymphatic Leukemia，ANLL）患者中20％～30％可长期无病生存，但能够CR超过5年以上且0S的病例不多，CR后OS达10年以上者更少。我们对近10年来文献报道的425例急性白血病长期存活患者的临床资料加以分析，以探讨影响AL患者长期存活的多个因素及其相互关系，以期客观有效地指导，临床治疗，提高患者的长期生存率。     

急性髓系白血病（非M3）化疗后骨髓油滴和巨核细胞数变化规律及其预后意义

 目的　探讨急性髓系白血病（AML）（非M3）患者化疗后骨髓油滴和巨核细胞数变化规律及其预后意义。方法　对99例初诊AML（非M3）患者资料进行回顾性分析,评价规范治疗各阶段骨髓油滴及巨核细胞数变化及其对总体生存（OS）率、无病生存（DFS）率的影响。结果　99例患者中位DFS为 21（2～88）个月,3年DFS率为47.3 %,中位OS 70（4～89）个月,3年OS率55.8 %。诱导化疗达完全缓解（CR）后骨髓油滴随着诱导缓解后化疗次数增加呈增加趋势,而巨核细胞数呈减少趋势。将单因素分析提示有意义的诱导缓解后第2次化疗后巨核细胞数变化率、诱导缓解后第1～3次化疗后骨髓油滴变化、骨髓纤维化分级、初诊乳酸脱氢酶值、白血病细胞免疫分型、起病时骨髓白血病细胞比例及诱导化疗结束后第7～10天残留白血病细胞比例等观察指标纳入多因素分析,结果提示起病时骨髓白血病细胞比例小于50 %、诱导缓解后第3次化疗后骨髓油滴较诱导化疗CR期增多对于延长患者DFS时间有独立预后意义（P＝0.010、0.018）;而诱导化疗结束后第7～10天残留白血病细胞比例≥10 %及诱导缓解后第2次化疗后骨髓巨核细胞数变化率≤-50 %为OS的独立不良预后因素（P＝0.009、0.038）。结论　AML（非M3）患者达CR后,随着诱导缓解后化疗次数增加骨髓油滴呈增加趋势,而巨核细胞数呈减少趋势。动态观察骨髓油滴及巨核细胞计数有助于患者预后判断。     

急性白血病Survivin和B7-1基因的表达及临床意义

 目的　研究Survivin和B7-1基因在急性白血病（AL）患者中的表达及临床意义。方法　应用RT-PCR检测64例AL患者Survivin和B7-1 mRNA的表达水平，14例健康人为对照，K562、HL-60细胞株为阳性对照。结果　Survivin的阳性表达率高于健康对照，且在初治AL中的表达水平较健康对照组明显升高，治疗缓解后Survivin表达下降，复发时表达水平升高；同时患者B7-1基因的表达率于对照组没有差异，但半定量后的表达水平明显较正常低，且初发和缓解患者表达量差异无统计学意义；在初治AL患者中Survivin阳性患者缓解率低于表达阴性的患者。结论　Survivin和B7-1基因表达的紊乱可能在AL的发病中起着重要作用，并与AL复发和预后相关。     

Clinically isolated mandibular relapse in childhood acute leukemia

With improved methods for preventing extramedullary relapse in the leptomeninges and gonads, the problem of clinically isolated relapse at other sites has become more significant. The authors report here two children with acute leukemia who developed mandibular relapse while in complete hematologic remission. One had been off chemotherapy for acute lymphoid leukemia for 2.5 years. The other child is apparently the first patient with promyeloid morphologic features to experience relapse at this site. Both children are in second complete remission and off treatment after local radiation therapy and second courses of chemotherapy. Review of these two and five previously reported isolated mandibular relapses in childhood leukemia indicate that they are usually delayed until after cessation of therapy. Treatment with radiation and combination chemotherapy can result in long remission and possibly cure.     

Improved survival of children with isolated CNS relapse of acute lymphoblastic leukemia: a pediatric oncology group study .

PURPOSE: Isolated meningeal relapse in children with acute lymphoblastic leukemia (ALL) usually has been followed by bone marrow relapse and limited survival. The purpose of this study was to prevent marrow relapse by administering intensive therapy before delayed craniospinal radiation. PATIENTS AND METHODS: Eighty-three patients with ALL in first bone marrow remission with an isolated CNS relapse were treated with systemic chemotherapy known to enter into the CSF and intrathecal chemotherapy for 6 months. Craniospinal irradiation (24 Gy cranial/15 Gy spinal) was then administered, followed by 1.5 years of maintenance chemotherapy. RESULTS: All 83 patients achieved a second remission. The 4-year event-free survival (EFS) rate was 71.1% +/- 5.3%. There was a fourfold increased risk of relapse for children whose initial remission was less than 18 months. The 4-year EFS rate for patients with a first complete remission >/= 18 months was 83.3% +/- 5.3%, and for those with a first complete remission less than 18 months, it was 46.2% +/- 10.2% (P =.0002.) There was a low incidence of neurologic toxicity and an unexpectedly high rate of allergic reactions to L-asparaginase. Five patients developed secondary malignancies: two with acute nonlymphoblastic leukemia during therapy, one with myelodysplasia after therapy, and two with brain tumors 1.5 to 2 years after cessation of therapy. CONCLUSION: For children with ALL and an isolated CNS relapse, treatment that delays definitive craniospinal irradiation by 6 months to allow for more intensive systemic and intrathecal chemotherapy results in better EFS than has been previously reported. Using this approach, the long-term prognosis for children with first complete remission >/= 18 months is comparable to that at the time of original diagnosis of ALL.     

骨髓TPO及受体c-MPL表达变化在急性髓系白血病化疗中的意义

目的探讨急性髓系白血病化疗前后骨髓血小板生成素（Thrombopoietin,TPO）及受体c-MPL的变化及其意义。方法  采用ELISA法和流式细胞仪检测急性髓系白血病初治患者化疗前、化疗缓解后及复发患者骨髓TPO以及c-MPL的表达水平。结果  AML初治患者化疗前骨髓TPO及c-MPL的表达分别为（162.21±39.92）ng/ml、（6.04±4.072）%,明显低于复发组的（213.19±48.34）ng/ml、（11.23±5.225）%,化疗前及复发组均明显高于对照组的（122.14±25.75）ng/ml、（2.84±0.724）%;AML患者化疗缓解后TPO及c-MPL的表达分别为（115.82±22.32）ng/ml、（2.81±1.306）%,与对照组比较差异无统计学意义（P>0.05）。各组骨髓TPO与c-MPL的表达呈正相关性。结论 （1）TPO及c-MPL的高表达对AML的诊断具有提示意义,化疗后TPO及c-MPL降至正常,可作为评判AML化疗效果及是否缓解的重要指标;（2）TPO及c-MPL在复发患者骨髓细胞中的表达较初发AML白血病患者明显增高,提示TPO/c-MPL信号通路的高表达可能与急性髓系白血病治疗后复发及难治相关。     

单倍型供者淋巴细胞输注治疗复发性急性白血病

 目的　探讨难治性复发性急性白血病单倍型淋巴细胞输注的疗效。方法　2006年4月至2007年10月应用单倍型淋巴细胞输注治疗复发性急性髓性白血病（AML）3例（M2 2 例,M4 1例）,复发性急性淋巴细胞白血病（ALL）1例,4例复发患者在二线方案化疗无效后,采集供者淋巴细胞,子女供父母3例,母供子1例,供者淋巴细胞在输注前,患者再次接受了不同方案的化疗,白细胞较低时输注供者的淋巴细胞,平均输注细胞2.3（1.4～3.1）×108／kg,输注前淋巴细胞接受了6～8 Gy 60Coγ射线照射。结果　3例AML患者1例获得了完全缓解（CR）,2例有效,1例ALL无效。4例患者输注单倍型供者淋巴细胞后无移植物抗宿主病的发生,未出现严重的骨髓抑制,1例患者发生了带状疱疹病毒感染。结论　单倍型供者淋巴细胞输注配合化疗对难治复发的AML有疗效,输注细胞的数量及照射的剂量需进一步探讨。     

Identification of early relapsing patients with adult acute nonlymphocytic leukemia by bone marrow biopsy after initial induction chemotherapy

Bone marrow biopsies obtained from 69 adult patients with acute nonlymphocytic leukemia (ANLL) six to 10 days after initial induction chemotherapy were reviewed blindly to detect the presence of residual leukemia. Discrimination between the presence or absence of leukemic cells was provided by assessment of the numbers, clustering, and nuclear morphology of blasts and promyelocytes. Twenty-six patients had frank leukemia, 25 had no apparent leukemic cells, and 18 had focal residual leukemia. Of 25 patients whose bone marrow contained no detectable residual leukemic cells, 21 gained complete remission without further chemotherapy. These patients had a median duration of remission of 278 days, with five patients still remaining in remission for 578-882 days. Similarly, all of the 18 patients who had focal residual leukemia achieved complete remission without additional chemotherapy; however, all have relapsed with a median duration of remission of 163 days. This study indicates that patients with foci of residual leukemia in their one-week posttreatment bone marrow samples readily achieve remission, but carry a substantial leukemic burden that increases the likelihood of early relapse.     

Combined chemotherapy with m-amsacrine in high-risk patients with acute non-lymphocytic leukemia

Thirteen patients (7 male, 9 female) aged 22-71 years (means = 55 years) with acute non-lymphocytic leukemia and contraindications for anthracyclin therapy were treated with combined chemotherapy using m-amsacrine primarily or in relapse. The main reasons for avoiding cardiotoxic substances were overt cardiac insufficiency and former administration of daunorubicin with more than 540 mg/m2 body surface area. Amsacrine was combined with 6-thioguanine, VP 16-213 and cytosine arabinoside in conventional or high dosage. Eight out of 13 patients (62%) achieved complete remission after one or two courses of chemotherapy. One patient showed partial remission and could be brought into complete remission with another chemotherapy using high-dose ara-C and mitoxantrone. Three patients died in aplasia after chemotherapy and 1 other patient had to be regarded as a complete non-responder. Remission duration and survival time for the 8 successfully-treated patients so far is 1-12 months; however, medians have not yet been reached, since only one of the eight patients relapsed after 6 months of complete remission. These data indicate a high efficacy of m-amsacrine in combined chemotherapy for acute non-lymphocytic leukemia in high-risk patients with contraindications for anthracyclins.     

Extra-medullary relapse of leukemia following allogeneic bone marrow transplantation.

The curative effect of allogeneic bone marrow transplantation (BMT) for acute and chronic leukemia is attributed to the intensive conditioning chemotherapy with or without radiotherapy, as well as an immune-mediated graft versus leukemia (GVL) effect. A different pattern of relapse has been observed after allogeneic BMT for patients with leukemia. Compared with treatment using conventional chemotherapy alone, isolated extra-medullary relapse of disease appears to be seen more commonly after allogeneic BMT. While a full donor's hematopoiesis may be retained, prolonged morphological remission has been observed in the recipient's bone marrow. There appears to be a population of leukemic cells with an affinity to extra-medullary tissues. The failure of the leukemic clone to repopulate the recipient's marrow suggests the presence of a more profound GVL effect in the marrow environment. The optimal treatment for extra-medullary relapse of leukemia following allogeneic BMT remains uncertain. In the case of isolated extra-medullary relapses following BMT, the leukemia may still be responsive to further treatment with chemotherapy and/or radiotherapy. The prognosis is poor in general, but prolonged survival has been observed in some of these patients. With the preservation of donor's hematopoiesis in the recipient's marrow, the use of intensive chemotherapy followed by donor lymphocyte or stem cell re-infusion is a promising option.     

Relapse of leukemia and lymphoma after marrow transplant: a review of cases with extramedullary relapse

We review our cases of leukemia and lymphoma relapse after allogeneic marrow transplant and describe here a series of 10 patients with extramedullary (EM) relapse. In the 13 relapses in acute myeloid leukemia, 5 cases had EM involvement. There were 3 EM involvement out of 13 acute lymphoblastic leukemia relapses, one EM disease in 11 chronic myeloid leukemia relapses and one case of lymphoma with EM relapse. A common observation is that in some of these cases, EM relapse occurred in the presence of continuous marrow remission, In those cases with both marrow and EM involvement marrow remission could often be achieved and maintained temporarily while EM disease progressed despite chemotherapy or immunotherapeutic measures such as immunosuppressant withdrawal and donor lymphocyte infusion. Survival in partial remission after relapse could be prolonged in some cases but eventual death from progressive disease was often the case.     

Allogeneic marrow transplantation for acute nonlymphoblastic leukemia

Bone marrow transplantation (BMT) from an HLA-matched sibling donor can cure 15% of end-stage patients with refractory acute leukemia. Failures are largely due to acute or chronic graft-versus-host disease, idiopathic or cytomegalovirus-associated interstitial pneumonitis, veno-occlusive disease of the liver, opportunistic infections, and leukemia relapse. The post-BMT leukemia relapse rate has been reduced from 65% to 20-40% by performing BMT in first complete remission (CR). Overall, about 50% of such patients become long-term tumor-free survivors. Younger patients do far better than older ones. A prospective comparative trial for acute nonlymphoblastic leukemia (ANL) in first CR revealed that BMT was more likely than chemotherapy to be fatal within the first 6 months after induction but that the probability of long-term tumor-free survival thereafter was significantly greater after BMT than after chemotherapy. It is recommended that patients less than 30 years old with ANL should undergo BMT while in first CR, whereas those patients over 30 years old should postpone BMT to the earliest sign of relapse.     

Re-induction of complete remissions in adults with acute non-lymphocytic leukemia

Thirty-five adults with acute non-lymphocytic leukemia in relapse following an initial remission were treated with intensive combination chemotherapy. Each patient received one of three re-induction programs which had already proven effective in the treatment of newly-diagnosed patients. Twenty (57%) of the patients undergoing re-induction therapy achieved complete remission. Clinical features which predicted a favorable response to therapy were female gender, rapid achievement of first remission, absence of infection, low plasma fibrinogen and serum LDH levels, and normal hepatic enzymes. Patients were more likely to respond if they also received at least one chemotherapeutic agent during re-induction to which they had not been previously exposed. The median duration of complete remission was 4.4 months (range 1–94+ months). Second remissions lasted over one year in four patients and two patients currently remain in complete remission at 49 and 94 months. Median survival for all patients who achieved remission was 10 months compared to only 2.5 months for those failing therapy. Since the re-induction of complete remission prolongs survival and can be accomplished in the majority of patients with leukemia in relapse, consideration should be given to using established intensive treatment programs prior to experimental chemotherapy in adults with advanced leukemia.