α—干扰素联合羟基脲治疗慢性粒细胞白血病的疗效观察

目的 探讨ＩＮＦ－α联合羟基脲治疗慢性粒细胞白血病的效果。方法 对１２例Ｐｈ１阳性和ｂｃｒ／ａｂｌ基因阳性的ＣＭＬ患者进行治疗并定期观察治疗前后血象，骨髓象，染色体和ｂｃｒ／ａｂｌ基因的变化。结果 全部病例均达血液学缓解，其中１例达细胞遗传学部分缓解，另１例不仅达细胞遗传学完全缓解，而且在治疗１６个月ｂｃｒ／ａｂｌ基因消失。     

慢性髓系白血病的bcr—abl基因疫苗治疗

开展ｂｃｒ－ａｂｌ基因疫苗治疗慢性髓系白血病（ＣＭＬ）的关键在于该融合基因表达产物能否诱导机体产生细胞毒性Ｔ细胞（ＣＴＬ）。本文从ｂｃｒ－ａｂｌ融合基因产生的分子生物学基础,基因转移,基因疫苗作用机制以及免疫接种途径等方面对基因疫苗治疗ＣＭＬ作一综述。     

慢性粒细胞白血病发病机制的研究

为探讨慢性粒细胞白血病（ＣＭＬ）的发生及发展机制。对４３例不同疾病阶段的患者进行了细胞遗传学的研究，发现９２％的初治及７３％的治疗后患者存在Ｐｈ染色体，６５％的加速期及急变期患者还伴有附加染色体改变；同时对３７例患者进行了分子生物学的检测，９５％的患者存在ｂｃｒ／ａｂｌ融合基因，其中包括４例Ｐｈ阴性患者，融合基因持续存在于整个病程中，且转录本ｂ２ａ２及ｂ３ａ２同样可见，未发现有ｅ１ａ２。结果表明ＣＭＬ的发生及进展存在着特异性的细胞遗传学及分子生物学基础，ｂｃｒ／ａｂｌ融合基因检测是ＣＭＬ诊断最灵敏且特异的方法，但预后意义不大     

bcr-abl融合基因抑制K562细胞凋亡的研究

目的研究ｂｃｒａｂｌ融合基因在慢性粒细胞白血病细胞（ＣＭＬ）凋亡调控中的作用。方法用人工合成的与ｂｃｒａｂｌｍＲＮＡ（ｂ３ａ２型）融合点碱基序列互补的反义寡聚脱氧核苷酸（ＡＳＯＤＮ）作用于体外培养的ＣＭＬ细胞株Ｋ５６２细胞,观察Ｋ５６２细胞凋亡的情况。结果ｂｃｒａｂｌ融合基因表达受抑后,Ｋ５６２细胞凋亡显著增加。结论ｂｃｒａｂｌ融合基因可抑制ＣＭＬ细胞凋亡,这可能是ＣＭＬ发病的主要机制。     

慢性粒细胞白血病的治疗

慢性粒细胞白血病（ＣＭＬ）是造血细胞肿瘤性疾病 ,它以具有独特的Ｐｈ 染色体（约９０%～９５%病例）以及融合基因ｂｃｒ／ａｂｌ形成为特点 ,其克隆性增生进展不可避免的由慢性期进入加速期和急变期。尽管治疗ＣＭＬ的药物很多 ,尤其是干扰素应用以来 ,虽使ＣＭＬ患者生存期有所延长 ,但均难以达到根治。治疗ＣＭＬ首要目的是达到血液学完全缓解（ＣＨＲ） ,最终完全细胞遗传学缓解（ＣＣＲ） ,而达治愈。经多年研究及临床实践证实 ,到目前为止 ,只有异基因造血干细胞移植才是最有效的根治方法。ＣＭＬ未治疗的自然病程约为３１个月 ,如…     

干扰素及异体骨髓移植对慢性粒细胞白血病细胞β2整合素及L—选择素表达的

目的 探讨慢性粒细胞白血病（ｃｈｒｏｎｉｃ ｍｙｅｌｏｃｙｔｉｃ ｌｅｕｋｅｍｉａ,ＣＭＬ）细胞黏附分子Ｌ－ｓｅｌｅｃｔｉｎ（ＣＤ６２Ｌ）、Ｍａｃ－１（ＣＤ１１ｂ）、ＬＦＡ－１（ＣＤ１１ａ）的表达与ＣＭＬ的发生、疗效的关系。方法 采用三色流式细胞仪检测３４例ＣＭＬ骨髓ＣＤ３４＾＋ＣＤ３８＾－－＋细胞表达ＬＦＡ－１、Ｍａｃ－１、Ｌ－ｓｅｌｅｃｔｉｎ的表达。结果 初治的ＣＭＬ３４＾＋ＣＤ３８＾－－＋细胞黏附分子Ｌ－ｓｅｌｅｃｔｉｎ、ＬＦＡ－１明显低于正常造血细胞的表达。Ｌ－ｓｅｌｅｃｔｉｎ的表达与Ｐｈ’阳性细胞数呈负相关（ｒ＝－０．６８）。８例ＣＭＬ经干扰素治疗后,其Ｌ－ｓｅｌｅｃｔｉｎ、Ｍａｃ－１、ＬＦＡ－１的表达均正常。结论 ＣＭＬＣＤ３４阳性细胞黏附分子Ｌ－ｓｅｌｅｃｔｉｎ、ＬＦＡ－１的低表达反映了ＣＭＬ细胞     

联合应用bcr-abl融合基因反义寡核苷酸与c-myb基因反义寡核苷酸对K562细胞作用的研究

目的：研究联合应用ｂｃｒ－ａｂｌ融合基因硫代磷酸反义寡核苷酸（Ａｓｐｏ）及ｃ－ｍｙｂ基因Ａｓｐｏ对Ｋ５２细胞作用效果。方法：Ａｓｐｏ与Ｋ５６２细胞共培养后,台盼蓝拒染法计死活细胞数;甲基纤维素半固体培养法培养ＣＦＵ－Ｋ５６２;流式细胞仪测定细胞Ｐ２１０蛋白表达及细胞凋亡率;ＲＴ－ＰＣＲ半定量检测细胞ｂｃｒ－ａｂｌｍＲＮＡ;电镜观察凋亡细胞形态学改变。结果：例置显微镜下观察到联合应用两种Ａｓｐｏ时,浓度各为５ｕｍｏｌ／Ｌ组Ｋ５６２细胞仍呈克隆状态生长,作用２４ｈ细胞Ｐ２１０蛋白表达明显受抑制,表达率〈２％;作用１２０ｈ细胞生长抑制率为６１．７％,Ｐ２１０恢复为２５．７％,凋亡率为２２．５％。两种浓度各为１０ｕｍｏｌ／Ｌ组Ｋ５６２细胞生长疏散,作用１２０ｈ细胞生长抑制率达９２．２％,Ｐ２１０仍未恢复,凋亡率为２２．     

慢性粒细胞白血发病机制的研究

为探讨慢性粒细胞白血病（ＣＭＬ）的发生及发展机制，对４３例不同疾病阶段的患者进行了细胞遗传学的研究，发现９２％的初治及７３％的治疗后患者存在Ｐｈ染色体，６５％的加速期及急变期患者还伴有附加染色本改变；同时对３７例患者进行了分子生物学的检测。９５％的患者存在ｂｃｒ／ａｂｌ融合基因，其中包括４例Ｐｈ阴性患者，融合基因持续存在的整个病程中，且转录本ｂ２ａ２及ｂ３ａ２同样可见，未发现有ｅ１ａ２结果表明ＣＭ     

THE THERMOSENSITIVITY OF HUMAN GINGIVAL SQUAMOUS CARCINOMA Ca9－22 CELLS WITH ONCOGENE erbB－1／EGFR

ＴＨＥＴＨＥＲＭＯＳＥＮＳＩＴＩＶＩＴＹＯＦＨＵＭＡＮＧＩＮＧＩＶＡＬＳＱＵＡＭＯＵＳＣＡＲＣＩＮＯＭＡＣａ９－２２ＣＥＬＬＳＷＩＴＨＯＮＣＯＧＥＮＥｅｒｂＢ－１／ＥＧＦＲＺｈａｎｇＳｈａｎｗｅｎ;Ｅ．Ｋａｎｏ;Ｙ．Ｙａｍａｚａｋｉ;Ｓ．Ｈａｙａｓｈ...     

重组干扰素α—2b治疗晚期恶性肿瘤的作用

目的为验证干扰素α－２ｂ治疗晚期恶性肿瘤的疗效和毒性,用重组干扰素α－２ｂ（ｒ－ＩＦＮα－２ｂ）治疗恶性肿瘤１０２例。方法采用ｒ－ＩＮＦα－２ｂ肌肉注射,每周２次,第１周３×１０６ＩＵ／次;第２周６×１０６ＩＵ／次;第３～８周９×１０６ＩＵ／次。结果９０例可评价疗效的患者中,总有效率为１６．７％（１５／９０）,其中肾癌的有效率为１０．８％（４／３７,２例ＣＲ,２例ＰＲ）,恶性黑色素瘤的有效率为１４．３％（４／２８,４例ＰＲ）,恶性淋巴瘤的有效率为４／８（４例ＰＲ）,乳腺癌的有效率为３／１５（３例ＰＲ）,２例多发性骨髓瘤均无效。ＣＲ患者的中位缓解期为４０个月,而ＰＲ患者的中位缓解期只有４．８个月。主要不良反应为流感样症状,胃肠道反应和较轻微骨髓抑制。结论ｒ－ＩＦＮα－２ｂ具有一定抗肿瘤活性,可以将其作为第二线药物治疗肾癌、黑色素瘤及恶性淋巴瘤。     

Combination therapy of chronic myelogenous leukemia with busulfan and bestatin

We demonstrated the clinical effectiveness of combination therapy with Busulfan and Bestatin in 13 patients with Philadelphia chromosome positive chronic myelogenous leukemia, including 9 in chronic phase and 4 in acute phase. Sequential cytogenetic studies and molecular analysis of the breakpoint cluster regions were performed every 2 months. Complete hematologic remissions were observed in all 13 patients. Five minor cytogenetic responses, 2 partial cytogenetic remissions and 2 complete cytogenetic remissions were observed. All of the 4 patients in early chronic phase achieved cytogenetic remission and in 3 of them there was a complete disappearance of rearranged restrictive fragments of the bcr gene. In contrast, 4 of the 5 patients in late chronic phase failed to achieve cytogenetic remission and only 1 achieved minor cytogenetic response, suggesting excellent effects, particularly in patients with early disease. It is clear from this pilot study that combining Bestatin with Busulfan is an effective way to reduce or eliminate Ph1 positive clone and to maintain this status.     

bcr/abl融合基因检测在慢性粒细胞白血病治疗中的应用

目的:探讨患者bcr/abl融合基因检测在慢性粒细胞白血病(CML)治疗效果判断及微小残留病灶监测方面的价值。方法:应用RT蛳PCR方法定期检测羟基脲(Hu)联合α蛳干扰素(IFN蛳α)与异基因造血干细胞移植(allo蛳HSCT)治疗慢性粒细胞白血病患者前后bcr/abl融合基因表达情况。结果:IFN蛳α治疗组与allo蛳HSCT治疗组完全血液学缓解率分别为85.7 %、100 %,两者差异无显著性(P>0.01);两组分子生物学缓解率分别为9.52 %、87.5 %,差异有显著性(P<0.01)。结论:bcr/abl融合基因监测可以作为CML评价疗效的指标,适用于微小残留病变的监测。     

Results of therapy with interferon alpha and cyclic combination chemotherapy in patients with philadelphia chromosome positive chronic myelogenous leukemia in early chronic phase

The objective of the study was to investigate the toxicity and efficacy of cyclic combination therapy offered to patients with Ph-positive CML having a sub-optimal response to IFN-alpha. Patients in early chronic phase CML were treated with IFN-alpha at 5MU/m(2) daily. Patients who did not achieve cytogenetic response after 6 months of IFN-alpha therapy, or Ph-suppression to less than 35% Ph-positive cells (partial cytogenetic response) after 12 months of therapy were offered cyclic intensive chemotherapy every 6 months, with IFN-alpha maintenance between cycles. The initial 3 cycles included daunorubicin, vincristine, cytosine arabinoside (ara-C) and prednisone (DOAP). Later cycles were given with cyclophosphamide replacing daunorubicin (COAP). Of 74 patients treated, 61 (82%) achieved complete hematologic response (CHR): 51 (69%) had a cytogenetic response, which was major (Ph < 35%) in 31 (42%), and complete in 23 (31%). Fifty-five patients (74%) achieved CHR by 6 months of therapy, 38 (69%; 51% of total) with a cytogenetic response - 13 (24%) had a major cytogenetic response. Seventeen patients received at least 1 course of DOAP therapy. Median survival of the overall cohort of patients was 120 months. With a median follow-up of 145 months (103+ to 155+ months), 40 patients (54%) have died. The median duration of cytogenetic response was 35 months (range 3 to 149+ months) and the estimated 10-year cytogenetic response rate was 37%. A durable complete cytogenetic response was observed in 16 patients (20%) with a median duration of 139+ months (range 12+ to 149+ months), 11 of them (15%) are now off IFN-alpha therapy for a median of 57+ months (range 12+ to 128+ months). The projected 10-year survival was 50% for the study group versus 35% for 208 patients who received other IFN-alpha based regimens at the MD Anderson Cancer Center (p<.01). In conclusion, the addition of intensive chemotherapy may improve survival in patients with CML who have not obtained an adequate cytogenetic response on an IFN-alpha-based regimen.     

Elderly patients with Ph+ chronic myelogenous leukemia (CML): results of imatinib mesylate treatment

Thirty-five patients with Ph+ CML aged more than 60 years were treated with imatinib. Twenty-four patients (group A) were in late chronic phase (CP) and eleven patients (group B) were in accelerated/blastic phase (AP/BP). In group A, complete haematological response (CHR) was achieved by all patients; seventeen patients (70.8%) attained a complete cytogenetic response (CCR), one (4.1%) attained a partial CR, one (4.1%) a minor CR (Ph+ 70%) and five (21%) were resistant (Ph+ 100%), toxicity was mild: seven patients had a transient cytopenia, three a skin reaction, one a moderate oedema and one muscular pain. After a median follow-up of 15 months, 1 patient died in progression and 23 patients are alive (2 in BP and 21 in persisting response). In group B, one patient died after 3 months in aplastic phase from sepsis, three patients were resistant and seven patients (63.7%) achieved CHR; of these, four obtained CCR. After a median follow-up of 17 months, 4 patients have died from progressive disease, 6 are alive; 1 in AP and 5 in CHR (4 of them being in CCR). Present data indicate that imatinib is safe also in elderly with clinical results as good as in younger patients.     

Megakaryocyte features and bcr/abl translocation in chronic myeloid leukemia following imatinib mesylate (STI571) therapy--a fluorescence in-situ hybridization study

Following therapy with imatinib (STI571) hematologic and cytogenetic response in chronic myeloid leukemia (CML) is associated with conspicuous alterations of bone marrow (BM) morphology. Besides reduction of cellularity and fibrosis, small megakaryocytes characteristic for this disorder were replaced by large, normally appearing cells of this lineage. However, it is not known whether and to which extent these changes are accompanied by a loss of the bcr/abl translocation. Therefore an immunohistochemical (CD61) and fluorescence in-situ hybridization (FISH) study was performed on sequential BM biopsies in 5 patients with CML receiving STI571 without any pretreatment. Morphometric analysis revealed that the prevalent population of 47% micromegakaryocytes (size < or = 150 microm2) was significantly reduced (15%) during therapy and that a conspicuous shift to medium-sized and large megakaryocytes occurred. According to FISH analysis in the initial BM biopsy sections 71% of all myeloid cells exhibited the bcr/abl gene and concerning megakaryopoiesis about 65% of the prominent micromegakaryocytes displayed positive signals. After treatment this peculiar cell population decreased significantly while the emerging large megakaryocytes (52%) totally lacked a bcr/abl labeling. Because cytogenetic response and reduction of micromegakaryocytes seem to be linked, this feature may be useful to monitor therapeutic efficacy by evaluating BM morphology.     

Characteristics and outcome of patients with Philadelphia chromosome negative,bcr/abl negative chronic myelogenous leukemia

BACKGROUND: Up to 5% of patients with chronic myelogenous leukemia (CML) do not have the Philadelphia (Ph) translocation t(9;22)(q34;q11) or a bcr/abl molecular rearrangement. Although the diagnostic criteria of this entity are still under debate, there is general agreement that patients with Ph negative, bcr/abl negative CML have a severe clinical course that is not affected significantly by current treatment options. METHODS: A population of 76 patients with bcr/abl negative CML who had received minimal or no previous therapy was characterized carefully with the intent of investigating clinical and hematologic variables and their association with survival by univariate, correlation, and multivariate analyses. A group of 73 patients with Ph negative CML who were not tested for the bcr/abl rearrangement (bcr/abl unknown) was analyzed separately and used for extension of the analysis. RESULTS: In the bcr/abl negative patient population, the median overall survival was 24 months. At the time of the analysis, 38 patients (50%) had died, and blastic transformation preceded death in 31%. Chromosomal abnormalities were found in 30% of the 76 patients, with trisomy 8 the most common abnormality. Complex chromosomal abnormalities were rare, and monosomy 7 was not observed. Survival was not affected significantly by treatment. Multivariate analysis identified older age (> 65 years), anemia (hemoglobin < 10 g/dL), and severe leukocytosis (white blood cells > 50 x 10(9)/L) as variables with independent prognostic significance for poor survival. A prognostic scoring system stratified patients into a low-risk group (53%) and a high-risk group (47%), with median survivals of 38 months and 9 months, respectively. CONCLUSIONS: Bcr/abl negative CML is a distinct clinical entity associated with very poor prognosis. Two risk categories are identifiable using a simple scoring system based on age, hemoglobin level, and leukocyte number.     

The Clinical Significance of Achieving Different Levels of Cytogenetic Response in Patients With Chronic Phase Chronic Myeloid Leukemia After Failure to Front-Line Therapy: Is Complete Cytogenetic Response the Only Desirable Endpoint?

Many patients with chronic myeloid leukemia who have failed initial therapy with a tyrosine kinase inhibitor achieve a cytogenetic response that is not complete (ie, partial or minor). This study analyzes the clinical benefit of such responses and identifies value in achieving such responses. Patients with less than complete cytogenetic response to second -line therapy or beyond should be considered to have benefit from therapy and the value of this considered in the context of which alternative options are available.BackgroundComplete cytogenetic response (CCyR) is the gold standard for response to therapy for patients with chronic myeloid leukemia (CML) because it is associated with a survival benefit. However, patients who have failed initial therapy with a tyrosine kinase inhibitor (TKI) frequently achieve only partial or minor cytogenetic responses. The clinical benefit of such responses is unclear.Patients and MethodsWe analyzed the records of all 165 consecutive patients treated in clinical trials with TKI as second-line therapy or beyond after failure to prior imatinib therapy.ResultsA CCyR was achieved with second-line TKI therapy or beyond in 52% of patients, whereas 7% achieved a partial cytogenetic response (PCyR), 14% a minor cytogenetic response (mCyR), 14% complete hematologic response (CHR) only, and 17% no response. The 3-year survival probability was 98% for those with CCyR, compared to 83% with PCyR, 83% for mCyR, 76% for CHR, and 71% for no response. Survival free from transformation rates at 3 years were 93%, 73%, 84%, 88%, and 0%, respectively.ConclusionsCCyR is associated with the greatest survival benefit among patients treated with second-line therapy or beyond and remains the optimal cytogenetic goal of therapy. However, patients with partial and minor cytogenetic response derive a benefit compared to patients who have no response. This benefit should be recognized and evaluated against any alternative option available to a given patient before a change in therapy is recommended.     

高三尖杉酯碱治疗慢性粒细胞白血病

 　目的　研究高三尖杉酯碱（HHT）治疗慢性粒细胞白血病（CML）的疗效及安全性。方法　12例初诊CML患者,HHT 2.5 mg·m-2·d-1,静脉滴注维持6 h以上,持续14 ~ 21 d为 1个疗程。有效者每月HHT维持治疗,并以外周血中性粒细胞绝对值≥1.0×109／L、血小板≥40×109／L调整用药时间,一般用药5～14 d。每3个月或3个疗程后复查染色体。6个月后以羟基脲（Hu）维持治疗。结果　12例患者中,7例（58.3 %）获血液学完全缓解（CHR）,3个疗程后,总的细胞遗传学反应率50 %（3例CCR,3例MCR）;另5例（41.7 %）在治疗3个月内进入加速期或急变期（4例发生在HHT 1个疗程后）。12例患者中有6例出现严重骨髓抑制,均发生于CHR者。结论　HHT治疗CML-CP,可获得较高的血液学和细胞遗传学缓解率,但也可能早期进入加速期或急变期。