国产甲磺酸伊马替尼治疗初诊慢性粒细胞白血病慢性期临床观察

目的 甲磺酸伊马替尼作为治疗慢性粒细胞白血病(chronic myelogenous leukemia,CML)-慢性期(chronic phase,CP)患者的一线治疗药物,国产药物应用的安全性和有效性尚缺乏系统评价参考.本研究探讨国产甲磺酸伊马替尼治疗初诊CML-CP患者的早期血液学、细胞遗传学、分子学反应与安全性.方法 收集2014-03-01-2015-10-31就诊于新疆自治区人民医院血液科的43例初诊CML-CP患者,给予国产甲磺酸伊马替尼(昕维?R)400 mg/d口服,治疗3、6、12个月时进行骨髓细胞学、染色体、FISH与骨髓BCR-ABL融合基因转录本水平评估,观察评估患者血液学反应、细胞遗传学反应和分子学反应及安全性.结果 43例患者治疗满3个月时,42例(97.7%)达完全血液学反应(complete hematologic response,CHR);35例(81.4%)达主要细胞遗传学反应(major cytogenetic response,MCyR),其中11例(25.6%)达完全细胞遗传学反应(complete cytogenetic response,CCyR);30例(69.8%)达国际标准化BCR-ABL转录本水平(BCR-ABLIS)≤10%,4例(9.3%)达BCR-ABLIS≤0.1%.17例患者治疗满6个月时,均达CHR(100.0%);11例(64.7%)达CCyR;12例(70.6%)达BCR-ABLIS≤1%,其中4例(23.5%)达BCR-ABLIS≤0.1%.5例患者治疗满12个月,4例达CCyR;2例BCR-ABLIS≤1%,2例BCR-ABLIS≤0.1%,1例BCR-ABLIS>10%.血液学不良反应:3/4级白细胞减少、血小板减少和贫血发生率分别为20.9%、23.3%和16.3%.非血液学不良反应发生率分别为水肿76.7%,恶心呕吐51.2%,骨关节肌肉酸痛39.5%),皮疹20.9%,发热11.6%,腹泻11.6%,肝功能损害2.3%.无4/4级血液学与非血液学不良反应.结论 国产甲磺酸伊马替尼治疗初诊CML-CP患者的近期疗效肯定,不良反应可耐受,但仍需长期观察研究.     

格列卫治疗干扰素治疗失败的慢性粒细胞性白血病47例疗效观察

用格列卫治疗对干扰素耐药的慢粒患者47例,慢性期(CP)400mg/d,加速期(AP)600mg/d,急变期(BC)800mg/d,持续用药时间为4.5个月(2～9个月)。结果CP组23例,22例(95.7%)达血液学完全缓解(CHR),达CHR的中位时间为18d(5～27d),47.8%(11/23)获显著遗传学缓解(MCR)。AP组13例,血液学反应为84.6%(11/13),其中8例(61.5%)达CHR,达CHR的中位时间为21d(14～31d);30.8%(4/13)获MCR。BC组11例,血液学反应为63.6%(7/11),3例(27.3%)达CHR,达CHR的中位时间25d(17～36d);27.3%(3/11)获MCR。从投药开始48周的总生存率为89.4%,其中CP为100%,AP为92.3%,BC为63.6%。初步研究结果提示,格列卫对干扰素治疗失败的慢粒各期患者有较高的血液学及遗传学缓解率。     

格列卫治疗干扰素治疗失败的慢性粒细胞性白血病47例疗效观察

用格列卫治疗对干扰素耐药的慢粒患者47例，慢性期(CP)400mg／d，加速期(AP)600mg／d，急变期(BC)800mg／d，持续用药时间为4．5个月(2～9个月)。结果：CP组23例，22例(95．7％)达血液学完全缓解(CHR)，达cHR的中位时间为18d(5～27d)，47．8％(11／23)获显著遗传学缓解(MCR)。AP组13例，血液学反应为84．6％(11／13)，其中8例(61．5％)达CHR，达CHR的中位时间为21d(14～31d)；30．8％(4／13)获MCR。BC组11例，血液学反应为63．6％(7／11)，3例(27．3％)达CHR，达CHR的中位时间25d(17～36d)；27．3％(3／11)获MCR。从投药开始48周的总生存率为89．4％，其中CP为100％，AP为92．3％，BC为63．6％。初步研究结果提示，格列卫对干扰素治疗失败的慢粒各期患者有较高的血液学及遗传学缓解率。     

格列卫治疗20例慢性粒细胞白血病临床观察

目的：评价格列卫治疗慢性粒细胞白血病(CML)的效果和不良副作用。方法：CML慢性期(CP)患者口服格列卫400mg/d。CML加速期、急变期(BC)患者口服格列卫400mg-600mg/d。结果：11例CML-CP患者均取得血液学完全缓解(HCR)。9例CML-AP和CML-BC患者4例取得HCR(37％)。7例CML-CP患者在3个月～6个月内4例取得遗传学完全缓解(56％)。CML—CP患者Ⅲ级白细胞(WBC)减少1例,血小板(BPC)减少2例。CML-AP和CML-BC患者,4例发生Ⅲ级-Ⅳ级WBC减少和BPC减少。而非血液学不良副作用,无Ⅲ级或Ⅳ级以上的毒副作用。结论：格列卫治疗CML-CP具有较高的HCR和细胞遗传学反应,CML-BC患者亦可取得较好的血液学反应。格列卫不良副作用发生率低．尤其CML-CP患者为安全。而CML-AP和CML-BC患者治疗期间,需加强支持治疗。     

慢性髓性白血病的现代治疗

 伊马替尼（IM）以及二代酪氨酸激酶抑制剂（TKI）的问世不仅彻底改革了慢性髓性白血病（CML）的治疗模式, 也成为其他肿瘤发病机制和治疗研究的范例。 IM可使90 %以上慢性期患者获得血液学缓解,80 %以上的患者获得遗传学完全缓解（CCyR）及主要分子学缓解（MMoR）。明显延长无病生存期,使CML自然病程大为改观。然而,也存在目前难以克服的缺点：TKI并非疾病基因清除剂,对CML干细胞不敏感,获得CCyR／MMoR者仍需长期持续服用,小部分患者发生抗药或不耐受。现阶段的TKI 仍是根治CML的起始。     

干扰素α-2b联合低剂量阿糖胞苷治疗慢性髓细胞白血病的临床研究

目的:探讨慢性髓细胞白血病(CML)患者使用干扰素α蛳2b(IFNα蛳2b)联合低剂量阿糖胞苷(LD Ara蛳C)治疗,其血液学和细胞遗传学的缓解率,寻找治疗CML的新途径。方法:采用IFNα蛳2b(300万U/d)+Ara蛳C(20mg·m2·d-1,每月用10 d)治疗CML慢性期(CP)患者30例,检测治疗后血液学缓解率和细胞遗传学缓解率,并与IFNα蛳2b+羟基脲(Hu)治疗组和单纯Hu治疗组作对照。结果:Hu+IFNα蛳2b+LD Ara蛳C治疗组治疗6个月的CHR率、总CHR率和Ph染色体阳性细胞下降病例百分数均显著高于IFNα蛳2b+Hu治疗组(P=0.004、P<0.005和P=0.009)和单纯Hu治疗组(P=0.006、P<0.005和P<0.005),CML急变发生率低于单纯Hu治疗组(P<0.005),而且发生急变的时间晚,5 a生存率明显高于IFNα蛳2b+Hu治疗组(P=0.014)和单纯Hu治疗组(P<0.005)。结论:CML(CP)患者采用IFNα蛳2b+LD Ara蛳C治疗可显著提高CML患者的CHR率,提高CML患者的细胞遗传学缓解率,延长CML患者的生存期。     

HHT+LD-Ara-C方案治疗对干扰素无效慢性粒细胞白血病的疗效观察

目的：观察高三尖杉酯碱(HHT)和小剂量阿糖胞苷(LD-Ara-C)对干扰素-α(IFN-α)治疗无效的慢性期慢性粒细胞白血病(CML)的治疗效果。方法：随机选择25例IFN--治疗无效的CML患者经HHT+LD-Ara-C方案治疗后观察其血液学和细胞遗传学反应。结果：80％患者达到血液学缓解，32％患者产生细胞遗传学反应。结论：HHT+LD-Ara-C方案对于IFN-α治疗无效的CML具有较理想的治疗效果。     

慢性粒细胞白血病435例甲磺酸伊马替尼治疗后血液学不良反应

目的 探讨甲磺酸伊马替尼(IM)治疗慢性粒细胞白血病(CML)慢性期患者的血液学不良反应发生情况.方法 回顾性分析郑州大学附属肿瘤医院2013年1月至2015年1月接受IM治疗的435例CML慢性期患者血液学不良反应的发生情况,比较不同临床病理因素分层患者血液学不良反应的发生率.结果 截至随访终点,435例慢性期患者中361例(83.0％)血象正常,74例(17.0％)发生血液学不良反应.61例(14.0％)出现中性粒细胞减少,其中Ⅲ、Ⅳ级9例(14.8％);60例(13.8％)出现血小板减少,其中Ⅲ、Ⅳ级11例(18.3％);50例(11.5％)出现贫血,其中Ⅲ、Ⅳ级5例(10.0％);33例(7.6％)出现全血细胞减少.血液学不良反应多发生于治疗后2～3周.对治疗前病程、脾脏大小、Sokal评分、是否使用干扰素、融合基因、染色体、是否获得完全细胞遗传学缓解、是否获得主要分子学反应、Karnofsky评分9个因素组内患者血液学不良反应发生率进行比较,差异均有统计学意义(均P＜0.05).年龄、性别、体质量指数(BMI)、是否吸烟喝酒4个因素组内患者血液学不良反应发生率比较,差异均无统计学意义(均P＞ 0.05).结论 如果IM治疗CML的初期发生Ⅰ、Ⅱ级血液学不良反应,可继续用药,若发生Ⅲ～Ⅳ级血液学不良反应时需减量或停药,患者血象在治疗4～6周后趋于稳定.在IM治疗CML后期出现严重血液学不良反应时,需进行骨髓形态学、分子生物学等相关检查,明确疾病分期,必要时可更换为二代酪氨酸激酶抑制剂.     

格列卫治疗缓解的慢性粒细胞白血病脑膜复发1例

1 病例介绍 患者,女,33岁,4年前经血液学及细胞遗传学检查确诊为Ph+慢性粒细胞白血病(CML)慢性期.经用羟基脲加脾区照射,症状改善,脾脏缩小,血液学获完全缓解.后间断羟基脲及干扰素治疗.     

STI571治疗慢性髓系白血病的临床疗效与毒副作用观察

背景与目的:bcr-abl融合基因翻译的蛋白产物P210bcr-abl的酪氨酸激酶(proteintyrosinekinase,PTK)活性异常增高被认为是导致慢性髓系白血病(chronicmyeloidleukmeia,CML)发病的根本原因。STI571能高效特异性抑制P210bcr-abl的PTK活性,在临床应用中获得了显著的疗效,但对急变期患者的治疗效果维持时间短。本研究观察和比较了STI571治疗慢性期与加速/急变期CML患者的临床疗效和所发生的不良反应,并从细胞遗传学的角度对急变期患者STI571耐药机制进行初步的分析。方法:选择接受STI571治疗的CML患者22例,其中慢性期6例,加速/急变期16例。按照血液学缓解和细胞遗传学缓解的标准,结合骨髓细胞形态学分析、骨髓细胞G显带技术分析和间期荧光原位杂交检测结果,对患者STI571治疗前和治疗3个月后的血液学和细胞遗传学缓解情况进行分析,并对3个月内出现耐药复发的患者进行核型演化分析。同时密切观察各系统发生的不良反应及严重程度。结果:6例(100%)慢性期CML患者获血液学完全缓解和细胞遗传学缓解,4例(25%)加速/急变期CML患者获血液学完全缓解,8例(50%)获不同程度的细胞遗传学反应。获血液学完全缓解和细胞遗传学反应的百分率两组比较均有统计学差异(P<0.05)。3例急变期CML患者出现耐药复发,其中2例可见2Ph和其它新     

Anagrelide and imatinib mesylate combination therapy in patients with chronic myeloproliferative disorders

PURPOSE: The tyrosine kinase inhibitor imatinib mesylate inhibits the function of the Bcr-Abl oncoprotein associated with Philadelphia-positive chronic myelogenous leukemia (CML). Anagrelide suppresses megakaryocyte proliferation and differentiation. The objectives of this study were to investigate the feasibility and safety of imatinib mesylate and anagrelide combination therapy in patients with Ph-positive CML or chronic myeloproliferative disorders (MPD) with persistent thrombocythemia. METHODS: This study was a retrospective review of all available records of patients with chronic MPD presenting to the M.D. Anderson Cancer Center between October 1998 and May 2002, treated with imatinib mesylate combined with anagrelide. RESULTS: Of 22 patients identified, 18 had Ph-positive CML (chronic phase, 16 patients; accelerated phase, 2 patients), 1 had agnogenic myeloid metaplasia (AMM), 2 had essential thrombocythemia (ET) and 1 had MPD transformed into refractory anemia with excess blasts (RAEB). The median age was 57 years (range 26-82 years). The median dose of imatinib mesylate administered was 400 mg (range 300-800 mg) and the median dose of anagrelide was 1.5 mg (range 0.5-4.0 mg). Imatinib mesylate and anagrelide combination therapy was feasible and tolerable. Of the 18 patients with Ph-positive CML, 15 in chronic phase and 1 in accelerated phase achieved a complete hematologic response (CHR), and 9 of the 18 achieved cytogenetic response (complete in 8 patients). No responses were noted in patients with AMM, ET or MPD transformed into RAEB. CONCLUSIONS: The combination of imatinib mesylate and anagrelide was safe and was associated with an 89% CHR rate in patients with CML in chronic phase and persistent thrombocythemia.     

Analysis of the impact of imatinib mesylate therapy on the prognosis of patients with Philadelphia chromosome-positive chronic myelogenous leukemia treated with interferon-alpha regimens for early chronic phase

BACKGROUND: The effect on prognosis of adding imatinib mesylate to the treatment of patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) has not been explored fully. The objective of the current study was to evaluate the benefit of adding imatinib to the treatment sequence of patients with early chronic phase Ph-positive CML who received interferon alpha (IFN)-based regimens as frontline therapy. METHODS: A total of 201 patients with early chronic phase Ph-positive CML who were treated on our 3 recent frontline IFN-based programs and were impacted early by the availability of sequential therapy with imatinib were analyzed. Their outcome was compared with that of a historical control group of 293 patients treated from 1982 until 1990 who were treated with IFN programs for early chronic phase CML and who did not have the opportunity of early access to imatinib (because it was not available during that period). Multivariate analysis was used to evaluate the independent effect of imatinib therapy on survival. RESULTS: Of 201 patients who were treated, 159 patients (79%) had their regimen changed sequentially to imatinib after a median duration of 14 months of IFN therapy. Of 139 patients who continued evaluation at our institution, 101 patients (73%; 64% of the total group) achieved a complete cytogenetic response, and 20 of 80 patients analyzed (25%; 10% of the total group) had no disease according to molecular studies (quantitative polymerase chain reaction studies). The estimated 5-year survival rate for the total study group of 201 patients was 86%. Survival of this group was significantly superior to the historic control group of IFN-treated patients who did not have the benefit of imatinib (P = 0.03). The trend also was observed within defined CML risk groups. Imatinib therapy was confirmed as an independent, significant, favorable prognostic factor for survival by multivariate analysis, after accounting for the independent prognostic effect of pretreatment prognostic factors (P = 0.005). CONCLUSIONS: The current analysis is the first to indicate the independent, favorable effect of imatinib on the survival of patients with Ph-positive CML.     

Prediction of initial cytogenetic response for subsequent major and complete cytogenetic response to imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia

BACKGROUND: Obtaining a major (Philadelphia chromosome [Ph] of < 35%) or a complete cytogenetic response (Ph of 0%) has been associated with excellent long-term survival. Cytogenetic response may continue to improve with therapy. Because early allogeneic stem cell transplantation (SCT) may be associated with a better outcome, early parameters predicting for subsequent cytogenetic responses would optimize the treatment decision-making. METHODS: The current study was performed to analyze whether early cytogenetic responses may be predictive of later major or complete cytogenetic responses to imatinib mesylate therapy in patients with Ph-positive chronic myelogenous leukemia (CML). RESULTS: Two hundred sixty-one patients with Ph-positive, chronic-phase CML after failure with interferon therapy who were treated with imatinib mesylate therapy were analyzed. A persistence of 100% Ph-positive cells after > or = 6 months of imatinib mesylate therapy was associated with a major cytogenetic response rate of 9-13% and a complete cytogenetic response rate of 0-4%. However, a minor cytogenetic response after 3-12 months of therapy still was associated with high rates of major (68-83%) or complete (35-54%) cytogenetic response rates. CONCLUSIONS: Patients with Ph-positive, chronic-phase CML who have persistent 100% Ph-positive disease after > or = 6 months of imatinib mesylate therapy may be offered allogeneic SCT or considered for alternative investigational therapies.     

U.S. Food and Drug Administration Drug Approval Summary: conversion of imatinib mesylate (STI571; Gleevec) tablets from accelerated approval to full approval.

Imatinib mesylate (Gleevec, Novartis Pharmaceuticals East Manruer, NJ) received accelerated approval on May 10, 2001 for the treatment of patients with chronic myeloid leukemia (CML) in (a) chronic phase after failure of IFN-alpha therapy, (b) accelerated phase, and (c) blast crisis. The accelerated approval was accompanied by a postmarketing commitment by Novartis Pharmaceuticals to continue patient follow-up to determine duration of treatment response and survival. The present review, based on a safety and efficacy report submitted on December 20, 2002, summarizes data applicable to the conversion of these three CML indications to full approval status. RESULTS: Chronic phase CML: Five hundred thirty-two chronic phase CML patients who had not benefited from prior IFN therapy were treated at a starting imatinib mesylate dose of 400 mg p.o. qd; dose escalation to 800 mg p.o. qd was allowed. Patients had received a median of 14 months of IFN therapy at doses > or =25 million IU/wk and were all in late chronic phase, with a median time from diagnosis of 32 months. Median duration of imatinib mesylate treatment was 29 months, with 81% of patients treated for > or =24 months (maximum 31.5 months). Initial favorable treatment responses were sustained. An estimated 87.8% of patients who had a major cytogenetic response maintained their response 2 years after their initial response. After 2 years of treatment, an estimated 85.4% of patients were free of progression to accelerated phase or blast crisis, and the estimated overall survival was 90.8% (95% confidence interval, 88.3-93.2). Accelerated phase CML: Patients enrolled totaled 293: 235 with CML accelerated phase, 48 with relapsed/refractory acute lymphocytic leukemia, 2 with relapsed/refractory acute myelocytic leukemia, and 8 with relapsed/refractory CML in lymphoid blast crisis. Patients received imatinib mesylate 400 or 600 mg p.o. qd. Dose escalation was permitted, to a maximum of 800 mg/d, taken as 400 mg bid. Efficacy results were improved in patients receiving imatinib mesylate 600 mg qd versus patients receiving 400 mg qd. The median duration of hematologic response was 29 versus 17 months and the estimated 24-month maintained hematologic response rate was 61% versus 42%. The median survival of patients treated with imatinib mesylate 600 mg qd was not reached versus 20.9 months for patients receiving 400 mg qd. Estimated 24-month survival rate was 66% versus 46%. The median survival in the advanced leukemia population (acute lymphocytic leukemia, acute myelocytic leukemia, and lymphoid blast crisis) was only 5 months, and only two patients are still on treatment. Blast crisis CML: A total of 260 patients were recruited. The imatinib mesylate dose was initially 400 mg qd (37 patients) but was subsequently increased to 600 mg qd (223 patients). Patients receiving imatinib mesylate 600 mg qd had a higher hematologic response rate than did patients receiving 400 mg (33% versus 16%). Major cytogenetic responses occurred in 15% of the 260 study patients. The overall median survival was 6.9 months: 7.1 months for patients treated with imatinib mesylate 600 mg and 4.7 months for patients receiving imatinib mesylate 400 mg. Estimated 12-month survival rate for all study patients was 32.1% and estimated 24-month survival rate was 18.3%. Safety: Imatinib mesylate was generally well tolerated, but relatively frequent reports of common toxicity criteria grade 3/4 neutropenia and thrombocytopenia were encountered. The most frequently reported adverse events included gastrointestinal disturbances, edema, rash, and musculoskeletal complaints. These rarely led to discontinuation of therapy. CONCLUSIONS: The results confirm those of the interim analysis and suggest that imatinib mesylate represents an effective therapeutic agent for the treatment of patients with CML in chronic phase after failure of IFN-alpha therapy, in blast crisis, and in accelerated phase.     

甲磺酸马替尼治疗慢性髓细胞白血病急性髓性变的疗效

背景与目的:慢性髓细胞白血病急性髓性变后,治疗非常困难,预后极差。本文旨在探讨特异性BCR/ABL酪氨酸激酶抑制剂(甲磺酸马替尼,格列卫)治疗慢性髓细胞白血病急性髓性变的疗效。方法:甲磺酸马替尼治疗组19例与历史对照组22例均先用含阿糖胞苷的标准化疗方案诱导治疗2疗程后,治疗组用甲磺酸马替尼400mg/d继续巩固或诱导治疗,治疗4周如无效,则将剂量增加至600mg/d,继续治疗8周;如有效,则用该剂量继续维持,仍无效则停用。历史对照组则采用其他方案继续巩固或诱导治疗。结果:治疗组标准诱导治疗无效的16例患者用甲磺酸马替尼治疗,6例(38%)取得完全的血液学缓解,获大部分遗传学效应;2例(13%)获部分血液学缓解,1例(6%)回到慢性期,获小部分遗传学效应;总的血液学有效率为56%。存活1年者6例(38%)。对照组诱导治疗无效的18例患者采用其他方案诱导化疗,仅2例(11%)取得完全的血液学缓解;1例(6%)获部分血液学缓解,总有效率为17%;1年内存活者仅1例(6%)。两组比较,差异有显著性(P<0.05)。结论:甲磺酸马替尼治疗慢性髓细胞白血病急性髓性变疗效高、生存时间延长,且耐受性好。但仍存在复发和耐药问题。     

Intensive combination chemotherapy and autologous bone marrow transplantation leads to the reappearance of Philadelphia chromosome-negative cells in chronic myelogenous leukemia.

Fifteen patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who were ineligible for allogeneic bone marrow transplantation (BMT) or alpha-interferon therapy were included in this study. Eight patients were in the first late chronic phase, five were in the second chronic phase, one was in the accelerated phase, and one was in the blastic phase. Autologous bone marrow cells (median, 2.5 x 10(8) nucleated cells/kg) were stored at a median of 30 months after diagnosis. Patients were treated with cyclophosphamide (1.5 g/m2 daily for 4 days), carmustine (BCNU) (300 mg/m2), and etoposide (VP-16) (250 mg/m2 daily for 3 days) (CBV), followed by reinfusion of autologous bone marrow. Hematopoietic recovery was rapid, and toxicity was mild to moderate in 14 patients. One patient died of cytomegalovirus pneumonitis. Eight of 15 patients showed Ph suppression to less than 90% Ph-positive metaphases after autologous BMT. Major cytogenetic responses (Ph suppression to less than 35% Ph-positive metaphases) developed in four patients. Cytogenetic responses were observed in 4 of 11 patients infused with 100% Ph-positive marrows, and in all 4 patients infused with Ph-mosaic marrows (mixture of diploid and Ph-positive cells). Better results were observed when autologous BMT was performed in the chronic phase compared with the advanced phases. The major cytogenetic responses have lasted for 3, 4, 12, and 15+ months, whereas minor cytogenetic responses lasted for only a short time (less than 2 months). Three of seven patients (43%) in the chronic phase with previous resistance to alpha-interferon therapy became sensitive to alpha-interferon therapy after autologous BMT. The authors concluded that intensive chemotherapy followed by autologous BMT produced cytogenetic remissions in patients with Ph-positive CML and reinduced disease sensitivity to alpha-interferon therapy in patients previously resistant to it. This is particularly useful when treatment is given during the chronic phase and stem cells are collected at a time of previous cytogenetic remission.     

附加染色体异常的费城染色体阳性慢性粒细胞白血病患者临床特征及预后分析

目的:探讨附加染色体异常的费城染色体（Ph）阳性慢性粒细胞白血病（CML）患者的临床特征及预后。方法:回顾性分析2009年1月至2019年1月于青岛大学附属医院诊断的351例Ph + CML患者资料,患者均经R显带技术进行骨髓染色体核型分析。总结初诊时附加染色体异常Ph + CML患者临床特征及核型,采用Kaplan-Meier法分析不同核型患者总生存（OS）差异。 结果:351例Ph + CML患者中,32例（9.1%）为变异易位。初诊时附加染色体异常47例,包括慢性期29例、加速期3例和急变期15例,分别占全组慢性期的9.15%（29/317）、加速期的25.00%（3/12）和急变期的68.18%（15/22）,各期附加染色体异常发生率差异有统计学意义（ χ2=50.799, P<0.05）;47例附加染色体异常的Ph + CML患者中,13例为附加3种以上染色体异常的复杂核型,慢性期、加速期、急变期复杂核型比例分别为13.79%（4/29）、33.33%（1/3）、53.33%（8/15）,差异有统计学意义（ χ2=9.26, P<0.05）。慢性期患者中最常见的附加染色体异常为双Ph（48.28%,14/29）、-Y（10.34%,3/29）,急变期患者中最常见的为+8（26.67%,4/15）、双Ph（26.67%,4/15）。Kaplan-Meier生存分析显示,Ph + CML患者中,初诊时附加染色体异常者OS较非异常者差（ χ2=61.138, P<0.05）;初诊时附加染色体异常的Ph + CML患者中,复杂核型者OS较非复杂核型者差（ χ2=4.945, P<0.05）。 结论:附加染色体异常与CML疾病进展密切相关;附加染色体异常的Ph + CML患者的预后较只有Ph易位的患者差。附加染色体越复杂,CML急变的可能性越大,预后也越差;在CML治疗过程中出现附加染色体异常也可能导致急变的进展。     

Effects of age on prognosis with imatinib mesylate therapy for patients with Philadelphia chromosome-positive chronic myelogenous leukemia

BACKGROUND: Older age is a consistent poor prognostic factor in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). Whether this is related to an intrinsic worse disease biology or to inadequate drug delivery or excessive treatment-associated toxicity is unknown. The availability of imatinib mesylate, a selective, Bcr-Abl-targeted therapy that is administered orally with minimal side effects, may clarify whether older age would remain an adverse factor (thus, implying a different age-related CML biology). METHODS: Seven hundred forty-seven patients in different phases of Ph-positive CML who were treated with imatinib from 1999 until the time of last follow-up were evaluated. Among them, 187 patients had newly diagnosed, early chronic phase CML; 351 patients had chronic phase CML after interferon alpha (IFN) failure; 133 patients had accelerated phase CML; and 76 patients had blastic phase CML. The imatinib daily dose varied from 400 mg to 800 mg orally, according to the protocol design. Patients were categorized into a group of older patients (age 60 years or older) or younger patients (age younger than 60 years). Their characteristics, responses to therapy, and survival were compared by univariate and multivariate analyses. RESULTS: One hundred eighty-seven patients had newly diagnosed CML, and 49 patients (26%) were in the older age group. Older patients had similar cytogenetic response rates and survival compared with younger patients. Among 351 patients with late chronic phase CML after IFN failure, 120 patients (34%) were in the older age group. Although the older patients had a lower incidence of achievement of complete cytogenetic response (Ph, 0%) by univariate analysis (56% vs. 44%; P = 0.05), age was not found to be an independent poor prognostic factor in the multivariate analysis. Similarly, older age was not an adverse poor prognostic factor for survival. Forty-two of 133 patients (32%) with accelerated phase CML were older. The incidence of any cytogenetic response was lower in older patients (53% vs. 33%; P = 0.04), but age was not significant in the multivariate analysis. Older patients also had a trend toward worse survival (P = 0.09) that was not significant in the multivariate analysis. Twenty-eight of 76 patients (37%) evaluated in blastic phase were older. Older age was not a significant prognostic factor either for achieving response or for survival. CONCLUSIONS: With imatinib therapy, older age appears to have lost much of its prognostic relevance. This suggests that the previous poor prognosis observed with older age was related to treatment-associated factors (e.g., toxicity with allogeneic transplantation or with IFN therapy) rather than to an intrinsic, different disease biology of CML in older patients.     

Results of triple therapy with interferon-alpha,cytarabine, and homoharringtonine,and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase

BACKGROUND: Before the discovery of imatinib mesylate, a Bcr-Abl selective tyrosine kinase inhibitor, three agents, interferon-alpha (IFN-alpha), cytarabine (ara-C), and homoharringtonine (HHT), had demonstrated activity against Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) as single agents and in couplet combinations. The goals of the current study were to evaluate the efficacy of the triple combination regimen with IFN-alpha, ara-C, and HHT in newly diagnosed Ph-positive CML and to assess the impact of the added sequential therapy with imatinib on overall prognosis. METHODS: Ninety patients with Ph-positive CML in early chronic phase received the triple regimen. Therapy consisted of 5 million units (MU)/m(2) IFN-alpha subcutaneously (s.c. daily, ara-C 10 mg s.c. daily, and HHT 2.5 mg/m(2) by continuous infusion over 24 hours daily x 5 every month. After a median duration of 16.5 months of therapy, 78 patients had their therapy changed to 400 mg orally administered imatinib daily. RESULTS: With the triple regimen, 85 patients (94%) achieved complete hematologic response and 67 patients (74%) had a cytogenetic response (Ph suppression to < or = 90%) which was complete (Ph 0%) in 20 patients (22%) and major in 42 patients (46%). Myelosuppression was significant, resulting in considerable reductions in the dose schedules. After 12 months of therapy, the median IFN-alpha dose was 1.6 MU/m(2) daily, the median ara-C dose was 1.85 mg daily, and the median number of HHT days was 2 every month. Only three patients developed blastic phase while receiving the triple regimen. With the change to imatinib therapy, currently 57 patients (63%) are in complete cytogenetic response and 69 patients (76%) in major cytogenetic response. With a median follow-up time of 46 months for the total study group, the estimated 5-year survival rate was 88%, and only 8 patients (9%) to date have developed blastic phase. CONCLUSIONS: The sequence of IFN-alpha, ara-C, and HHT followed by imatinib (imposed by the discovery of the latter drug) resulted in an estimated 5-year survival rate of 88%. This finding suggests that imatinib combination regimens may improve the prognosis in CML.     

Imatinib mesylate therapy improves survival in patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia in the chronic phase: comparison with historic data

BACKGROUND: The International Randomized study of Interferon-alpha plus cytarabine (IFN-alpha plus ara-C) versus STI571 (imatinib mesylate) [IRIS trial] in patients with newly diagnosed Philadelphia chromosome (Ph)-positive, chronic-phase chronic myelogenous leukemia (CML) has not shown (to date) a survival advantage for imatinib. This was most likely because approximately 90% of patients receiving IFN-alpha plus ara-C changed to imatinib therapy after a median of 8 months into therapy. METHODS: The authors analyzed the results with imatinib therapy in patients with newly diagnosed Ph-positive CML in chronic phase and compared their outcome with patients who received IFN-alpha regimens. A total of 187 patients with Ph-positive CML in early chronic phase treated with imatinib were compared with a historic group of 650 similar patients treated with IFN-alpha regimens from 1982 until 1997. RESULTS: Patients who received imatinib were significantly older and had significantly more bone marrow basophilia and less leukocytosis. The complete cytogenetic response (Ph 0%) rates were better with imatinib (81% vs. 32%; P < 0.001), as were the survival rates (30-month estimated survival rates 98% vs. 88%; P = 0.01). A multivariate analysis of the total study group of 837 patients identified imatinib therapy to be a significant independent favorable prognostic factor for survival (P = 0.01). CONCLUSIONS: The current study is the first to indicate the survival advantage of imatinib compared with IFN-alpha, the previous standard of care, in patients with early chronic-phase CML.