伊马替尼一线治疗慢性粒细胞白血病慢性期患者- 单中心十年回顾性分析*

目的：总结以伊马替尼为一线治疗的慢性粒细胞白血病（chroni cmyeloid leukemia,CML ）初治患者的疗效和生存。方法：回顾性分析南昌大学第一附属医院2003年1 月至2013年12月间收治的295 例CML 初治患者的临床资料,其中185 例为入组格列卫全球患者援助项目（GIPAP）行伊马替尼治疗、30例为干扰素（IFN-α）治疗、50例为羟基脲单药治疗和30例为异基因外周血造血干细胞移植（allogeneic hematopoietic stem cell transplantation ,Allo-HSCT）治疗的患者,分析各组患者的治疗疗效和生存情况。结果：伊马替尼治疗组和Allo-HSCT 治疗组患者完全血液学缓解率（complete hematologic remission ,CHR ）均为96.7% ,完全细胞遗传学缓解率（complete cytogenetic remission,CCyR）为89.7% 和93.3% ,完全分子学缓解率（complete molecular remission ,CMoR）为49.7% 和83.3%（P = 0.001）;而干扰素和羟基脲治疗组CHR 、CCyR和CMoR 均明显低于伊马替尼治疗组和Allo-HSCT 治疗组。伊马替尼组患者的总生存时间（overall survival,OS）明显优于其他组（P < 0.001）,甚至优于Allo-HSCT 治疗组（10年OS为89.0% vs .67.0% ,P < 0.001）。 Cox 多因素分析显示接受伊马替尼治疗（HR= 5.267,95%CI 为1.054～1.940,P = 0.022）和获得CCyR（HR= 9.541,95%CI 为1.692～10.513,P = 0.002）是影响本组患者预后良好的独立因素。结论：CML 初治患者接受伊马替尼治疗可以获得更高的CHR 和CCyR,且OS更优,伊马替尼适合作为中国初治CML 患者的一线治疗。     

Development of PH Positive Chronic Myeloid Leukemia in a Patient with Chronic Lymphocytic Leukemia Treated with Total Body Irradiation: A Rare Association

Philadelphia (ph) chromosome positive chronic myeloid leukemia developed in a patient treated for chronic lymphocytic leukemia after treatment with total body irradiation. The role of radiation in the development of CML is discussed.     

Granulocytic sarcoma: 32 cases and review of the literature

Thirty-two cases of granulocytic sarcoma (GS) are reported in this paper. Age range was from 16 - 70 years. GS was accompanied by AML in 13 cases, ALL (My+) in one case, CML in 11 cases and MDS in two cases. GS was diagnosed simultaneously with leukemia in five cases and preceded the leukemia in eight. Lymph node and soft tissue were the most commonly detected localizations. Seven cases had first been diagnosed as NHL. Histopathologically blastic, immature and mature variants were found in 11, nine and 11 cases respectively and overall survival was shortest in the blastic type. Myeloperoxidase and lysozyme were found to be positive in 30 and 24 cases respectively. Therapy was radiation in five cases and surgery in three. Systemic chemotherapy was given to the cases. The clinical outcome of the patients after the diagnosis of GS was poor. GS is a unique entity; prognosis is poor but it is important to detect the signaling pathways associated with migration of myeloid cells to the extra-medullary tissues. The critical factors for detecting this interesting tumor are to be aware of this disease, cooperation between clinician and pathologist and the application of special stains to detect the myeloid origin.     

应用COX计分法探讨72例ph( )慢性粒细胞性白血病的预后分析

我院对1959—1991年72例Ph’( )慢性粒细胞性白血病(CML)的初诊资料进行预后分析,用 COX 危险因子计分法对稳定期组58例、加速期组5例、急变期组9例进行统计学处理,三组间预后因素与Ph’( )、肝肿大、脾肿大、外周血原始细胞>8%、外周血有核红细胞≥1%,骨髓纤维化>5%有关。并对照近年来国内外有关 CML 的预后分析予以探讨。     

Dendritic cell vaccines for leukemia patients

Dendritic cells are the most professional antigen-presenting cells to elicit T-cellular responses toward microbial agents and cancer cells. The graft-versus-leukemia effect observed after allogeneic stem cell transplantation strongly suggests that T lymphocytes play a major role in the rejection of leukemic cells. This graft-versus-leukemia effect might be enhanced through dendritic cell vaccination. The characterization of leukemia-specific antigens eliciting immune responses in the autologous host has prompted researchers and clinicians to broaden the spectrum of dendritic cell vaccines to hematological malignancies. Recently, the focus is on acute myeloid leukemia and chronic lymphocytic leukemia. This review summarizes data on the administration of autologous and allogeneic dendritic cells to leukemia patients as an interesting approach in cellular therapy of leukemias.     

伊马替尼治疗慢性粒细胞白血病患者在生育时中断药物治疗对胎儿和患者自身的影响

目的:分析伊马替尼治疗慢性粒细胞白血病（chronic myeloid leukemia,CML）患者在生育时中断药物治疗对胎儿和患者自身的影响。方法:回顾性分析本科室21例CML合并妊娠患者在接受伊马替尼治疗后的影响。结果:21名接受伊马替尼治疗的CML患者中有6名为意外怀孕,15名为计划怀孕。有生育意愿的女性患者需达到血液学或细胞学缓解至少两年,在受孕前1个月和孕期前3个月停服伊马替尼,男性患者则在生育前一个月停止接受伊马替尼的治疗。所有意外受孕的患者在孕期均未停止服用伊马替尼。21名患者共生产9名男婴和7名女婴（其中1名尿道下裂,1名轻度脑水肿）,其余有2名自然流产,3名选择性流产。结论:鼓励接受伊马替尼治疗的CML患者有计划的生育,对于治疗期间意外怀孕的患者,伊马替尼则会导致自然流产或先天性异常。     

Dasatinib in chronic myeloid leukemia: A limited Indian experience

Aim: To report our experience of the use of dasatinib in various phases of chronic myeloid leukemia (CML). Methods: Ten patients in various phases of CML, not responding to imatinib and started on dasatinib, were included and analyzed. The baseline characteristics of the patients and their salient features including the duration and response to initial therapy as well as to dasatinib, were noted. Results: Before starting dasatinib three patients were in chronic phase of CML while seven others were in the progressive phase (accelerated and blast phase) of CML. Half the patients developed transient grade 3 and 4 toxicities to dasatinib. Overall, the tolerability of the drug in all 10 patients was acceptable and none discontinued treatment. Three patients died due to progressive disease while the remaining seven are continuing the drug with the disease still under cytogenetic or hematological remission. Of the 10 patients, seven achieved complete hematological response and two of the accelerated phase/blast crisis patients achieved complete cytogenetic response. Overall, dasatinib was able to control disease for a median of 20.6 months. Conclusion: Despite small sample size and insufficient information on mutational analysis, dasatinib is effective in CML in INdia. Cost limits the use of second‐generation tyrosine kinase inhibitors in India. Our observation is not suitable for survival analysis but the difference made by dasatinib in progressive disease and its tolerability needs to be acknowledged.     

Characterization of several leukemia-associated antigens inducing humoral immune responses in acute and chronic myeloid leukemia

To design a specific immunotherapy for leukemia patients, the identification of leukemia-associated antigens (LAAs) is a pivotal step. Antileukemic effects after hematopoetic stem cell transplantation for myeloid leukemias are observed and might be related to the recognition of LAAs. Using the serological screening of an expression library (SEREX) of K562 cells, we identified 16 different clones encoding LAAs eliciting a humoral immune response, among them the heat shock proteins HSJ2 and HSP70, the M-phase phosphoprotein 11 (MPP11), the BRCA1-associated protein (BRAP), the Jkappa recombination binding protein (RBPJkappa) and the receptor for hyaluronic acid mediated motility (RHAMM). Serological responses to MPP11 were observed in 7/19 (37%) of patients with acute myeloid leukemia (AML) and 6/16 (38%) of patients with chronic myeloid leukemia (CML), but not in healthy volunteers (0/20). IgG antibodies directed against MPP11 were also detected in 25-50% of the sera of patients with solid tumors such as melanoma, renal cell, ovarian and breast carcinoma. mRNA expression of MPP11 was detected in 20/20 AML patients and 7/10 patients with CML. In normal tissues, strong mRNA expression of MPP11 was only detected in testis. By real-time PCR, we detected upregulation of MPP11 in leukemic blasts. Simultaneous humoral immune responses to 2 or more of the 16 LAAs identified here was observed, suggesting the feasibility of a polyvalent vaccination as an option for immunotherapies in leukemia patients.     

Expression of c-kit Receptor (CD 117) and CD34 in Leukemic Cells

The expression of c-kit receptor (c-kit R; CD117) and CD34 was examined in acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML) in blastic transformation (BT), and myelofibrosis (MF) in myeloid BT. In myeloid leukemia including AML, CML-myeloid BT and MF-myeloid BT, both c-kit R and CD34 were expressed synchronously, while in lymphoid leukemia including ALL and CML-lymphoid BT, only CD34 was highly expressed. A close correlation between c-kit R and CD33 expression and an inverse correlation between c-kit R and CD 19 expression were observed when all of the myeloid plus lymphoid leukemia cells were analysed. There was a close correlation between c-kit R and CD34 expression in the myeloid leukemia cells, c-kit R expression may be associated with myeloid phenotypes of leukemic cells and may be useful for the diagnosis of myeloid leukemia. The literature of c-kit R expression in leukemic cells is reviewed here and the comparison of c-kit R and CD34 expression in normal hematopoietic progenitor cells with those on the leukemic counterparts was discussed.     

慢性淋巴细胞白血病合并急性髓系白血病多学科协作诊疗1例

天津医科大学肿瘤医院血液科2014年6月收治慢性淋巴细胞白血病（chronic lymphocytic leukemia,CLL）患者1例,该患者第1个周期化疗1个月后,在原有CLL细胞亚群的基础上发现另一群急性髓系白血病（acute myeloid leukemia,AML）细胞亚群。此后,虽然未经针对性治疗,但肿瘤在较长时间内（约11个月余）均呈现稳定状态。通过回顾患者前期的相关检查,明确此病例为极其罕见的CLL/AML。汇集综合血液科、分子诊断科、病理科等多学科的诊疗意见和延伸讨论,本研究通过此病例对CLL/AML、肿瘤二次打击学说与肿瘤树状演化模型有了比较全面和直观的认识。      

Dynamics and management of cytopenias associated with dasatinib therapy in patients with chronic myeloid leukemia in chronic phase after imatinib failure

BACKGROUND:

The incidence, dynamics, and management of cytopenias were investigated in patients with chronic myeloid leukemia in chronic phase (CP CML) who received dasatinib therapy after imatinib failure.

METHODS:

Data were analyzed from 130 patients with CP CML who were treated with dasatinib from November 2003 to March 2006 in phase 1 (n = 22) or phase 2 or 3 (n = 108) studies for the development of grade 2 to 4 cytopenia (according to the National Cancer Institute Common Terminology Criteria [version 3.0]).

RESULTS:

Grade 2 to 4 neutropenia and/or thrombocytopenia occurred in 94 (72%) patients during dasatinib therapy and grade 3 to 4 occurred in 67 (52%) patients. Of the 94 patients who developed grade 2 to 4 neutropenia and/or thrombocytopenia, 64 (68%) also developed at least grade 2 anemia, and 16 (17%) developed grade 3 to 4 anemia. Management of cytopenias included transient dasatinib interruption in 35 (37%) patients, filgrastim in 12 (14%) patients, recombinant erythropoietin in 29 (45%) patients, and interleukin‐11 in 3 (5%) patients. Factors associated with an increased risk for developing grade 2 to 4 cytopenias were longer time from diagnosis to treatment, prior interferon or imatinib therapy, and a lower white blood cell count at the initiation of dasatinib therapy.

CONCLUSIONS:

Hematologic toxicity was frequent during dasatinib therapy in patients with CP CML, particularly at doses >100 mg daily. Treatment interruption and/or dose reduction as well as growth factor support were found to be safe and efficacious strategies to facilitate the continuous administration of dasatinib. Cancer 2009. © 2009 American Cancer Society.     

Very long-term follow-up results of imatinib mesylate therapy in chronic phase chronic myeloid leukemia after failure of interferon alpha therapy

BACKGROUND:

The long‐term outcome of patients with chronic phase chronic myeloid leukemia treated with imatinib after failure of interferon alpha therapy has not been detailed.

METHODS:

In total, 368 patients were analyzed. Univariate and multivariate survival analyses were conducted using standard statistical methods.

RESULTS:

Overall, 247 patients (67%) achieved a complete cytogenetic response (CCyR). Of the 327 patients who were studied, 207 patients (63%) achieved a major molecular response (MMR), and 99 patients (30%) had undetectable breakpoint cluster region/c‐abl oncogene (BCR‐ABL) levels at some time during therapy. The estimated 10‐year survival rate was 68%, the progression‐free survival rate was 67%, and the event‐free survival rate was 51%. In multivariate analysis, age ≥60 years, hemoglobin <10 g/dL, bone marrow basophils ≥5%, any peripheral blasts, and clonal evolution were independent adverse factors for survival. The estimated 7‐year survival rate according to the presence of no factors (n = 154), 1 or 2 factors (n = 190), or ≥3 factors (n = 24) were 93%, 70%, and 25%, respectively (P < .01). Achieving an MMR, a CCyR, or a partial cytogenetic response at 12 months was associated with significantly better 10‐year survival rate in a landmark analysis (10‐year survival rate, 80%‐90%) compared with achieving a minor cytogenetic response or a complete hematologic response (10‐year survival rate, 55%‐65%) or another response (10‐year survival rate, 10%). In a landmark analysis that included imatinib response at 12 months, achieving a major cytogenetic response or better (hazard ratio, 0.12; P < .001) and achieving a complete hematologic response or a minor cytogenetic response (hazard ratio, 0.36; P = .003) were significant favorable prognostic factors.

CONCLUSIONS:

The current results indicated that the estimated 10‐year survival rate of 68% for patients with chronic myeloid leukemia who receive imatinib after failure on interferon has improved. Cancer 2012;118: 3116–22. © 2011 American Cancer Society.     

An approach to the management of chronic myeloid leukemia in British Columbia

Chronic myeloid leukemia (cml) is a myeloproliferative disorder whose therapy has changed dramatically since the late 1990s. With the introduction of the tyrosine kinase inhibitor (tki) imatinib mesylate, the treatment outcomes for patients with cml have improved markedly, and hematopoietic stem-cell transplantation is no longer routinely offered as first-line therapy for most patients in chronic phase.However, resistance to tki therapy is increasingly being recognized, and alternative therapy is needed for this group of patients. In addition, the development of models predicting response to tki therapy is desired, so that appropriate treatment strategies can be used for individual patients. The present report serves to outline the approach to the treatment of cml in British Columbia and to highlight areas of ongoing research.     

Chronic Lymphocytic Leukemia Associated with Myelodysplastic Syndrome and/or Chronic Myeloid Leukemia: Evidence for Independent Clonal Chromosomal Evolution

We describe the cytogenetic findings of three cases with simultaneous or sequential development of a B-chronic lymphocytic leukemia (B-CLL) and either a myelodysplastic syndrome (MDS) in 2 cases or a chronic myeloid leukemia (CML) in one case. The coexistence of these two hematologic malignancies leads to questions about their cell of origin. Through analysis of the cytogenetic abnormalities, we studied the derivation of both malignancies. The cytogenetic analyses of these three patients were simultaneously studied from both peripheral blood and bone marrow. Furthermore unstimulated short-time (USSTC) and long-time (72-96 hours) stimulated cultures (LTSC) were systematically performed. In all cases, we have demonstrated the independent bi-clonal evolution. This is the first report ever described for patients with CLPD and MDS and/or MPD shown to arise from distinct chromosomal abnormalities.     

CD33抗体为主方案治疗难治性白血病

目的:评估CD33抗体为主方案治疗难治性白血病的疗效和不良反应。方法:采用CD33抗体为主方案对11例难治性白血病进行治疗。结果:CD33抗体为主方案治疗总有效率54%,其中完全缓解(CR)为36%,除血小板未完全缓解外均达到完全缓解标准(CRP)为18%,治疗后中位生存时间4.8月,缓解后中位生存时间8.2月。2例慢性粒细胞白血病急粒变均完全缓解,且BCR/ABL(-)。1例难治性急性淋巴白血病在缓解后即行异基因干细胞移植,至今无病生存已9月。不良反应有骨髓抑制(100%)、输注相关寒战发热(90%),肝静脉闭塞综合症(VOD)发生率55%,发生在干细胞移植后的患者和年龄大于60岁的患者。结论:本组资料显示CD33抗体为主方案对表达CD33的急慢性白血病有一定疗效。对于移植后复发和年龄大于60岁的患者,在使用CD33抗体时需注意患者肝脏情况,一旦出现VOD,及时处理。对于用药后缓解的患者,应尽早行异基因干细胞移植。     

慢性粒细胞白血病急性变36例临床分析

自１９７８年元月至１９９３年４月经血液学确诊的慢性粒细胞白血病急性变（简称慢位急变）患者３６例，其中急粒变者３３例占９１．６６％，急淋变２例，嗜碱性粒细胞变１例。从慢粒转为急变的病程为３个月～１４年，平均４６个月。从急变到死亡者平均６个月，最长者２年。对慢粒的预后因素、急变的前兆监测及治疗进行了讨论。     

慢性粒细胞白血病急性变32例临床分析

３２例慢粒急变中，急粒变２４例，急淋变５例，急单变，急粒－单变及红白血病变各１例。急变后骨疼，肝脾肿大的发生率及外周血，ＷＢＣ数和骨髓中原始细胞数均明显增加。初诊时年龄≤２０岁；脾大超过肋缘；外周血ＷＢＣ＞１００×１０９／Ｌ及ｐｈ（－）者的病程明显短于初诊时年龄＞２０岁；脾肋下未及；外周血ＷＢＣ＜１００×１０９／Ｌ及ｐｈ（＋）者（Ｐ＜０．０５）。急淋变，脾大＜１０ｃｍ；骨髓中原始细胞＜６０％和ｐｈ（＋）者存活期分别长于急粒变，脾大＞１０ｃｍ；原始细胞＞６０％及ｐｈ（－）者（Ｐ＜０．０５）平均存活期３．２３±２．７９月。