伊马替尼治疗慢性粒细胞白血病的最新进展

慢性粒细胞白血病(CML)是一种以携带费城染色体(Ph)异常造血细胞克隆扩增为特征的骨髓增殖性血液疾病。t(9;22)q(34;11)染色体易位导致BCR-ABL融合基因的形成,该融合基因编码产生具有高酪氨酸激酶活性的BCR-ABL融合蛋白,成为CML发病的主要原因。除异基因造血干细胞移植外,CML的     

复发难治性急性淋巴细胞白血病治疗方案对照研究

复发难治性急性淋巴细胞白血病(ALL)总体预后较差,生存期短,异基因造血干细胞移植是惟一可能治愈的方案。但是即使采用更积极的造血干细胞移植治疗,其3年存活率也仅达到16%。高剂量化疗方案在获得较佳缓解率的同时常常伴有严重感染等并发症,从而影响后续移植的进行。我们设计应用吡喃阿霉素(THP)或者阿克拉霉素(Acla)与小剂量阿糖胞苷(Ara-C)、粒细胞集落刺激因子(G-CSF)组成的CAG或TAG预激方案对复发难治性ALL患者进行再诱导治疗。现报道如下。     

Ph染色体阳性白血病患者经伊马替尼治疗后行异基因造血干细胞移植的疗效观察

目的探讨Ph染色体阳性白血病患者经伊马替尼治疗后行异基因造血干细胞移植的疗效。方法回顾性分析2001年6月至2005年6月北京大学人民医院血液病研究所住院的难治性Ph染色体阳性的39例白血病患者经伊马替尼治疗后再行异基因造血干细胞移植的效果,观察伊马替尼对造血重建、移植物抗宿主病(GVHD)、总存活率(OS)、无病存活率(DFS)、复发率和移植相关并发症的影响。结果伊马替尼治疗后,18例患者血液学完全缓解,9例骨髓缓解,4例部分缓解,4例无效或疾病进展,总有效率79.49%,无重度非血液学毒性反应;移植后中性粒细胞和血小板植活中位时间分别为14d和13.5d;Ⅱ~Ⅳ度和Ⅲ~Ⅳ度急性GVHD累积发生率分别为61.53%和15.38%;根据对伊马替尼治疗的效应分为完全缓解组和未完全缓解组,其3年预期OS和DFS分别为(73.51±9.61)%对(36.36±14.50)%和(61.28±12.37)%对(31.25±13.98)%,3年累积复发率为20.41%对75.00%;4例患者死于重度移植相关并发症。结论应用伊马替尼后行异基因造血干细胞移植是一种安全、有效的治疗难治性Ph染色体阳性白血病的方法,尤其达完全缓解后行移植,可望提高此类患者的临床治愈率。     

预激方案治疗急性髓细胞白血病的临床研究

目的:探讨预激方案治疗急性髓细胞白血病的临床疗效。方法:对30例急性髓细胞白血病患者采用CAG方案化疗,如1疗程未获缓解,可接受第2疗程治疗。监测临床症状、体征血常规及骨髓细胞学检查。结果:总完全缓解率73.3%,感染发生率为50.0%,4例严重感染。化疗后外周血白细胞最低值平均为1.02(0.33～2.46)×109/L,低于1.0×109/L的中位时间为7(0～12)d。结论:预激方案治疗急性髓细胞白血病疗效肯定,不良反应小。     

伊马替尼对BCR/ABL融合基因阳性的急性巨核细胞白血病原代细胞凋亡作用的研究

目的:研究酪氨酸激酶抑制剂伊马替尼(imatinib)对BCR/ABL融合基因阳性的急性巨核细胞白血病原代细胞凋亡的作用,探讨急性巨核细胞白血病的治疗。方法:报告1例急性巨核细胞白血病的临床及实验室特征;应用骨髓细胞直接法和24h短期培养法制备染色体和R显带技术进行细胞遗传学分析;多重RTPCR方法同时检测29种白血病融合基因。取患者骨髓白血病细胞,台盼蓝拒染实验观察伊马替尼对细胞生长曲线的影响;流式细胞仪分析细胞周期。结果:①该例患者的染色体核型为46,XX,t(1;16)(q22;q22),未见Ph染色体;表达BCR/ABLb2a2mRNA,临床治疗效果差,生存期短。②伊马替尼可以抑制该原代白血病细胞的生长,促其凋亡,使大部分细胞受阻于G0/G1期。结论:伊马替尼可以诱导BCR/ABL阳性急性巨核细胞白血病原代细胞的凋亡。     

AAG方案治疗难治性急性淋巴细胞白血病疗效观察

急性白血病是血液系统常见的恶性肿瘤，总体来看，联合化疗的缓解率较高，完全缓解率达70％以上，但约30％左右的成人急性淋巴细胞白血病（ALL）的缓解率低，且缓解后复发率高，长期生存率低．故复发难治的ALL的治疗是困扰血液科医务工作者的难题，再次诱导缓解能否成功直接决定其有无机会进行如骨髓移植等治疗的关键。近3年我们试用AAG方案治疗难治性ALL，取得了较好的疗效，现报告如下。     

格列卫治疗Ph+急性白血病2例报告

费城染色体 (Ph染色体 )虽为慢性粒细胞白血病 (CML)的标志性染色体 ,但也见于 5 %的儿童急性淋巴细胞白血病 (ALL)、1 5 %～ 30 %的成人ALL以及 2 %的急性粒细胞白血病 (AML) 〔1〕。格列卫为针对Ph染色体的分子靶向药物。我院最近采用格列卫治疗Ph+急性白血病 (AL)住院患者 2例 ,现报告如下。1 　 病例报告例 1　男 ,2 9岁。诊断为急性混合细胞白血病。检查骨髓象示原始细胞占 97%。外周血血常规示原始细胞占 74%。采用三色免疫荧光流式细胞术进行骨髓细胞免疫分型 ;以CD45设门 ,病态细胞占 99% ,其中CD1 0 96% ,CD1 999% ,CD33…     

尼洛替尼治疗伊马替尼耐药的慢性髓系白血病的临床观察

目的:探讨尼洛替尼在伊马替尼耐药的慢性髓系白血病( CML)患者中的疗效及不良反应.方法:9例伊马替尼耐药的CML患者,其中慢性期6例,进展期3例,持续口服尼洛替尼400 mg 2次/d,观察其疗效及不良反应.结果:6例CML慢性期患者,5例获得完全血液学反应,2例获得主要细胞遗传学反应;3例CML进展期患者均获得血液...     

CAG方案治疗复发性急性髓细胞白血病疗效观察

目的:探讨CAG方案对复发性急性髓细胞白血病(AML)的临床疗效和不良反应.方法:选择在我院治疗的复发AML 46例,复发后20例选用CAG方案:阿克拉霉素(ACR)10～14 mg·m-2·d-1 (第1～4天,10～14天),静脉滴注;阿糖胞苷(Ara-C)10 mg·m-2·d-1 q12h(第1～14天),皮下注射;粒细胞集落刺激因子(G-CSF)200 μg·m-2·d-1(第1～14天),皮下注射.26例选用对照方案:①DAH:柔红霉素40 mg·m-2·d-1(第1～3天);Ara-c 200 mg·m-2·d-1(第1～7天),高三尖杉酯碱(HHT)3～4 mg·m-2·d-1(第1～7天);②MAE:米托蒽醌(Mito)10 mg·m-2·d-1(第1～3天),Ara-c 200 mg·m-2·d-1(第1～7天),依托泊甙(VP-16)60 mg·m-2·d-1(第1～5天).结果:强化疗组26例,经上述化疗1个疗程后6例获得完全缓解(CR),部分缓解(PR)10例,未缓解(NR)10例.PR和NR 20例患者中6例一般情况差,未能继续强化疗,换用CAG方案;14例予第2个疗强化疗,CR 4例,NR 10例;2疗程CR共10例(38.4%).26例CAG组第1个疗程CR 12例,PR 10例,NR 4例.PR和NR 14例予以CAG第2个疗程治疗,CR 8例,PR 2例,NR 4例,2疗程CR共18例(69.2%).2组CR率差异有统计学意义(P<0.05).CAG组骨髓抑制不明显,不良反应也低.结论:复发AML治疗中,CAG方案是较对照组方案更为有效的且不良应低的治疗方法.     

尼洛替尼治疗伊马替尼耐药的慢性髓系白血病临床分析

目的:探讨尼洛替尼治疗伊马替尼耐药的慢性髓系白血病(CML)的疗效及安全性。方法:收集伊马替尼治疗失败而接受尼洛替尼治疗的10例患者,其中慢性期7例,加速期2例,急变期1例。接受伊马替尼治疗的平均时间为36.7个月,停用原因为丧失疗效或未达主要分子学反应(MMR)7例、进展至加速期或急变期2例、原发性耐药1例。4例患者检测出5个点突变,其中1例慢性期患者检出2个突变点。10例患者接受尼洛替尼的剂量均为400mg q12h,每个月复查血常规,每3个月监测细胞遗传学及分子生物学缓解情况(FISH及RQ-PCR法),定期监测肝肾功能、胰酶、电解质及心电图等,并记录有无皮疹、头痛等不良反应。结果:10例患者接受尼洛替尼治疗的平均时间为12.5(3～30)个月。8例获得主要遗传学反应以上疗效,其中5例获得完全细胞遗传学反应,3例获得MMR。2例加速期患者中,1例恢复至慢性期并持续获得MMR,1例死亡。1例急单变患者(Ph+伴附加染色体异常)获部分细胞遗传学反应后丧失疗效,最终死亡。不良反应依次为轻度皮疹6例、胆红素升高3例、转氨酶升高2例、头痛1例、血糖升高1例及3/4级血液学不良反应1例。结论:尼洛替尼结合ABL激酶的效价更高,选择性更强,能抑制除T315I、Y253H、F359V/C及E255K/V以外的致伊马替尼耐药的点突变,且不良反应少,可用于伊马替尼耐药及不耐受的慢性期或加速期CML。     

Mammalian target of rapamycin inhibitor rapamycin enhances anti‐leukemia effect of imatinib on Ph+ acute lymphoblastic leukemia cells

BCR‐ABL fusion gene typically causes a type of acute lymphoblastic leukemia (ALL), known as Ph+ ALL. Although imatinib (IM) treatment induced high rates of complete response (CR), serious acute and late complications are frequent, whereas more vexatiously resistance to chemotherapy and clinical relapse develops. Therefore, the efficacy of treatment in Ph+ ALL is still to be determined. In this study, we focused our attention on the potential benefit of rapamycin (RAPA), an mammalian target of rapamycin (mTOR) inhibitor, in combination with IM on a Ph+ ALL cell line SUP‐B15 and a primary Ph+ ALL sample in vitro. Analysis of cell proliferation showed that RAPA (50 nm ) plus IM exerted good synergistic effect on Ph+ ALL cells. Notably, we found that IM treatment induced the abnormal activation of the components of mTOR signaling pathway and p‐BCR‐ABL, whereas RAPA potently eliminated this deleterious side effect induced by IM and might overcome the resistance to IM. The synergistic effect was also associated with the increase in autophagy, which seemed to have an opposite role with apoptosis in Ph+ ALL cells, and cell cycle arrest in G₁ phase. Altogether, our results suggested that IM in combination with RAPA was more effective for Ph+ ALL cells than IM alone.     

Analysis of 20-year follow-up study of LVP regimen for adult acute lymphoblastic leukemia

In an attempt to develop a new intensive chemotherapy for adults with untreated acute lymphoblastic leukemia (ALL), 3 sequential programs were designed for 62 patients (age range, 15 to 74 years; median age, 32 years) consisting of the LVP-79 (1979-1984, 27 patients), LVP-85 (1984-1986, 14 patients), and LVP-87 (1987-1989, 21 patients) regimens. The influence of clinical and biologic characteristics on the patient outcome was also examined. L-asparaginase (L-asp), vincristine, and prednisolone, defined collectively as LVP, were administered for induction chemotherapy in all protocols. After achieving complete remission (CR), patients underwent 2 years of multi-agent consolidation, intensification, and maintenance therapy consisting of various combinations. No significant differences were noted between the 3 groups regarding CR rate or survival. In total, 47 of 62 patients (75.8%) achieved CR. The median overall survival (OS) and median CR durations were 550 days and 341 days, respectively. Overall, the estimated survival rate at 20 years was 18.1%. The disease-free survival rate at 20 years was 26.2%. According to univariate analysis, the most favorable pretreatment characteristic for achieving CR was age. A younger age (<40 years of age), platelet count >30 x 10(9)/L, having L1 morphology (French-American-British [FAB]classification subtype), female sex, and the absence of chromosomal abnormalities also helped improve survival rate. According to multivariate analysis, presence of Ph chromosome was found to be a major influencing factor for OS. Although higher doses of L-asp were administered than those used in previous studies, the adverse effect of L-asp was rarely identified. Therefore, it should be considered one of the key drugs for treatment of adult ALL. Further strategies still need to be developed to obtain better survival in adult ALL.     

Impact of reinduction regimens for relapsed and refractory acute lymphoblastic leukemia in adults

The clinical outlook for adults with acute lymphoblastic leukemia (ALL) has Improved with the use of intensive chemotherapy. Complete remissions (CR) are achieved in 80% of adults but the majority relapse on maintenance chemotherapy and a few exhibit primary resistance to induction therapy. This report compares the various salvage treatments and provides guidance in selecting a regimen with the optimum clinical outcome. Regimens using high-dose ara-C (HDAC) in combination with mltoxantrone, amsacrine, or idarublcin are superior to HDAC alone or with L-asparaginase. The sequential administration of methotrexate and L-asparaginase Is equally effective. The duration of second CR is short for all chemotherapeutic regimens. © 1994 Wiley-Liss, Inc.     

A Phase I/II study of nilotinib in Japanese patients with imatinib-resistant or -intolerant Ph+ CML or relapsed/refractory Ph+ ALL

Nilotinib is a second-generation BCR-ABL kinase inhibitor with improved potency and selectivity compared to imatinib. A Phase I/II dose-escalation study was designed to evaluate the efficacy, safety, and pharmacokinetics of nilotinib in Japanese patients with imatinib-resistant or -intolerant Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL). A total of 34 patients were evaluated in this analysis and had a median duration of drug exposure of 293 (range 13–615) days. All 6 CML-CP patients without complete hematologic response (CHR) at baseline rapidly achieved CHR. A major cytogenetic response was achieved in 94% of patients with CML-CP, including a complete cytogenetic response in 69%. A major molecular response was achieved by 56%. These responses were also observed in patients with CML in advanced stages and Ph+ ALL. Non-hematologic adverse events were mostly mild to moderate. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 50 and 28% of patients, respectively. Overall, the results of this study suggest that nilotinib induced significant responses in imatinib-resistant or -intolerant patients with CML-CP and CML in advanced stages and Ph+ ALL. The results of this study confirmed the efficacy and safety of nilotinib in Japanese patients.     

FLAG-IDA in the treatment of refractory/relapsed adult acute lymphoblastic leukemia

Relapsed or refractory adult acute lymphoblastic leukemias (ALL) have poor prognosis. The strategy for treating these patients is through reinduction chemotherapy followed by allogeneic stem cell transplantation, provided that the toxicity of the salvage regimen is acceptable. Twenty three patients with relapsed/refractory adult ALL were treated with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA). Five patients had primary refractory disease, and 18 were in first relapse. Nine (39.1%) patients achieved complete remission (CR) following salvage therapy, whereas 13 (56.5%) patients were refractory, and one patient died in aplasia due to infection. In patients achieving remission, the median time to reach absolute neutrophil count (ANC) more than 0.5×10⁹/l and 1×10⁹/l was 20 (range 16–25) and 24 (range 20–28) days from the start of chemotherapy, respectively. Platelet levels of more than 20×10⁹/l and 100×10⁹/l were achieved in a median time of 23 (range 19–25) and 33 (range 28–39) days, respectively. Fever more than 38.5°C was observed in 18 of 23 patients (78.2%), 13 had fever of unknown origin, and 5 had documented infections. Nonhematological side effects, consisting mainly of mucositis (18/23 or 78.2%) and transient liver toxicity increase (10/23 or 43.4%), were generally tolerated. All nine patients who achieved CR received a second course with FLAG-IDA, and seven patients underwent allogeneic stem cell transplantation (four from a matched donor, one from a mismatched donor, and two from an unrelated donor), while two did not reach that stage due to early relapse from CR. The median overall survival (OS) for all 23 patients was 4.5 (range 1–38) months; for the nine responders, the disease-free survival (DFS) and the OS were 6 (range 3–38) and 9 (7–38) months, respectively; the seven patients who received allogeneic stem cell transplantation had a DFS of 10 (range 7–38) months. In our experience, FLAG-IDA is a well-tolerated regimen in relapsed/refractory ALL patients; the toxicity is acceptable, enabling patients who have achieved CR to receive allogeneic transplantation.     

Ph1-chromosome positive acute lymphoblastic leukemia: Is t(9;22) the initial abnormality?

We report a case of pre-B-cell acute lymphoblastic leukemia (ALL) with the Ph¹-chromosome, t(9;22) translocation and P190 associated BCR/ABL rearrangement. One cell with the Ph¹-chromosome and t(9;22) also had del(5q). Interestingly, another diploid cell with iso(17q) lacked the Ph¹-chromosome and t(9;22). This finding, similar to one reported in chronic myelogenous leukemia, is consistent with the possibility that abnormality manifest as chromosome instability antedates the Ph¹-chromosome and t(9;22) in some cases of Ph¹-chromosome positive acute leukemia.     

A therapeutic trial of decitabine and vorinostat in combination with chemotherapy for relapsed/refractory acute lymphoblastic leukemia

DNA hypermethylation and histone deacetylation are pathways of leukemia resistance. We investigated the tolerability and efficacy of decitabine and vorinostat plus chemotherapy in relapse/refractory acute lymphoblastic leukemia (ALL). Decitabine (15 mg/m² iv) and vorinostat (230 mg/m² PO div BID) were given days 1–4 followed by vincristine, prednisone, PEG‐asparaginase, and doxorubicin. Genome wide methylation profiles were performed in 8 matched patient bone marrow (BM) samples taken at day 0 and day 5 (postdecitabine). The median age was 16 (range, 3–54) years. All patients had a prior BM relapse, with five relapsing after allogeneic transplant. The most common nonhematological toxicities possibly related to decitabine or vorinostat were infection with neutropenia (grade 3; n = 4) and fever/neutropenia (grade 3, n = 4; grade 4, n = 1). Of the 13 eligible patients, four achieved complete remission without platelet recovery (CRp), two partial response (PR), one stable disease (SD), one progressive disease (PD), two deaths on study and three patients who did not have end of therapy disease evaluations for an overall response rate of 46.2% (CRp + PR). Following decitabine, significant genome‐wide hypo‐methylation was observed. Comparison of clinical responders with nonresponders identified methylation profiles of clinical and biological relevance. Decitabine and vorinostat followed by re‐Induction chemotherapy was tolerable and demonstrated clinical benefit in relapsed patients with ALL. Methylation differences were identified between responders and nonresponders indicating interpatient variation, which could impact clinical outcome. This study was registered at www.clinicaltrials.gov as NCT00882206. Am. J. Hematol. 89:889–895, 2014. © 2014 Wiley Periodicals, Inc.     

甲磺酸伊马替尼治疗120例慢性髓性白血病的临床研究

目的观察甲磺酸伊马替尼（IM）治疗Ph染色体阳性和（或）BCR／ABL基因阳性的慢性髓性白血病（CML）的疗效和安全性。方法对90例Ph染色体阳性和（或）BCR／ABL基因阳性CML慢性期（CP）患者,持续口服IM,400mg／d;30例CML疾病进展期（加速期／急变期）患者,持续口服IM,600mg／d。服药期间定期复查血常规、骨髓细胞学、染色体和（或）BCR／ABL基因等指标,并随访观察。结果（1）CML—CP患者总的完全血液学缓解率（CHR）、完全细胞遗传学缓解率（CCyR）和完全分子遗传学疗效（CMR）分别为73．3％（66／90）、66．7％（60／90）、54．4％（49／90）;治疗前是否接受过干扰素治疗对CHR、CCyR和CMR均无明显影响;服药前病程≤6个月的CMR优于〉6个月者。初次达到CHR的时间与首次达CCyR的时间、首次达CCyR的时间与BCR／ABL首次转阴时间之间均存在相关性,而初次达CHR的时间与BCR／ABL首次转阴时间则无明显相关性。（2）进展期CML患者的CHR、CCyR、CMR分别为43．3％（13／30）、25．9％（7／27）、25．0％（7／28）,总病死率为30．0％（9／30）。（3）年龄≤25岁患者的病死率高于〉25岁者,差异有统计学意义（P〈0．05）。（4）白细胞减少达Ⅲ级者有19例（16．0％）,发生于治疗后5～20周。血小板减少达Ⅲ级者有21例（18．0％）,发生于治疗后3～16周。主要的非血液系统毒性为双下肢水肿、骨痛和皮疹等,但均程度轻微。结论IM对初治CML及经干扰素治疗失败的CML有较高的CHR及CCyR且起效迅速,对CML—CP疗效显著优于进展期;不良反应程度轻微,患者易于耐受。