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。     

甲磺酸伊马替尼治疗进展期慢性髓细胞白血病14例疗效分析

慢性髓细胞白血病(CML)是起源于造血干细胞的恶性克隆性疾病,由于9号染色体的ABL基因与22号染色体的BCR基因相互易位形成BCR/ABL融合基因,表达P210蛋白,具有异常的酪氨酸激酶活性,激活细胞信号传导途径,促进细胞增殖,抑制细胞凋亡.     

甲磺酸伊马替尼治疗慢性粒细胞白血病54例近期疗效观察

目的 观察甲磺酸伊马替尼(imatinib)治疗慢性粒细胞白血病(CML)的近期疗效。方法 54例CML患者接受imatinib治疗,其中慢性期(CP)17例,加速期(AP)13例,急变期(BC)24例。imatinib用法：CP患者400mg／d,AP和BC患者600mg／d,均为餐后一次顿服。治疗前全面查体,查血象、骨髓象、Ph染色体和(或)bcr／abl融合基因。治疗期间第1个月每周查血象2次,1个月后每周或2周1次。每2～4周查一次肝、肾功能。待血液学取得完全缓解(CR)后择期复查骨髓、Ph染色体和(或)bcr／abl基因。根据血象和患者对药物耐受情况及时调整药物剂量。结果 经中位时间5个月(1～10个月)随访,17例CML CP期患者16例(94．1％)取得血液学CR,其中6例(35．2％)Ph染色体转阴;13例AP患者8例(61．5％)回到CP;24例BC患者9例(37．5％)回到CP。药物不良反应有造血功能抑制、眶周和下肢轻度水肿、全身肌肉关节酸痛和恶心、呕吐、低热(37．5～38℃)、皮疹、胆红素升高等。结论 imatinib对CML有较好近期疗效,其疗效以CP最好,AP其次,BC较差。远期疗效有待进一步观察。药物不良反应可以耐受。     

甲磺酸伊马替尼治疗慢性粒细胞白血病附加异常Ph阳性克隆的预后意义

目的探讨甲磺酸伊马替尼（伊马替尼）治疗后慢性粒细胞白血病（CML）具有附加异常的Ph阳性克隆的演变及其预后意义。方法收集37例CML加速期和急变期患者的骨髓标本培养24h,G显带进行核型分析。结果伊马替尼治疗前患者的附加染色体种类主要有双Ph、＋8、i（17q）等,其次还有-Y、除i（17q）外17号的异常、inv（3q）等,以及少见的易位和其他异常。伊马替尼治疗后具有附加异常的Ph阳性克隆比例发生扩增、基本不变、比例下降、完全消失等4种形式的演变。24例加速期患者中有2例获得完全细胞遗传学缓解（CCyR）,13例急变期患者中2例获CCyR。附加异常克隆扩增／不变组的中位生存时间和无疾病进展时间显著短于比例下降／完全消失组（P〈0．05）。结论有附加染色体异常的Ph阳性CML患者伊马替尼治疗后附加异常克隆比例可以下降甚至完全消失,获得CCyR,并伴生存期延长。     

国产甲磺酸伊马替尼一线治疗慢性髓性白血病慢性期患者的临床效果及安全性分析

目的:分析国产甲磺酸伊马替尼(商品名:格尼可)治疗慢性髓性白血病慢性期(CML-CP)患者的临床疗效和安全性。方法:回顾性分析62例一线服用格尼可治疗的CML-CP患者的临床资料。根据患者Sokal预后风险评分、耐受情况适当调整伊马替尼剂量,即300～600 mg/d。分析患者用药3、6、12个月获得的最佳反应、分子生物学反应,采用χ²检验比较各Sokal积分组达到的最佳反应率,统计药物引起的不良反应。结果:62例接受格尼可治疗的CML-CP患者,治疗后3个月时完全血液学缓解(CHR)率为90.32%,BCR-ABL^IS≤10%为75.81%,分子学缓解为9.68%;治疗后6个月时CHR率为95.16%,BCR-ABL^IS≤1%为70.97%,分子学缓解为30.65%;治疗后12个月时所有患者达到CHR,50.00%的患者获得分子学缓解。按照Sokal评分将62例患者分为高危组7例、中危组19例和低危组36例,在治疗后3、6、12个月,3组最佳反应发生率比较均差异无统计学意义(χ²=5.49、3.8...     

甲磺酸伊马替尼治疗晚期慢性粒细胞白血病致多浆膜腔积液2例

目的通过2例晚期慢性粒细胞白血病(CML)患者接受甲磺酸伊马替尼治疗后出现多浆膜腔积液的病例分析和文献复习,探讨甲磺酸伊马替尼在治疗晚期慢性粒细胞白血病中的安全性.方法对2例甲磺酸伊马替尼治疗晚期慢性粒细胞白血病的临床资料进行分析并结合文献复习使其在今后治疗中可能出现的不良反应引起重视.结果2例分别确诊为晚期慢性粒细胞白血病的患者接受甲磺酸伊马替尼治疗后,出现多浆膜腔积液.结论甲磺酸伊马替尼治疗晚期慢性粒细胞白血病时可能会出现严重的不良反应.     

甲磺酸伊马替尼治疗晚期慢性粒细胞白血病致多浆膜腔积液2例

目的:通过2例晚期慢性粒细胞白血病(CML)患者接受甲磺酸伊马替尼治疗后出现多浆膜腔积液的病例分析和文献复习,探讨甲磺酸伊马替尼在治疗晚期慢性粒细胞白血病中的安全性。方法:对2例甲磺酸伊马替尼治疗晚期慢性粒细胞白血病的临床资料进行分析并结合文献复习使其在今后治疗中可能出现的不良反应引起重视。结果:2例分别确诊为晚期慢性粒细胞白血病的患者接受甲磺酸伊马替尼治疗后,出现多浆膜腔积液。结论:甲磺酸伊马替尼治疗晚期慢性粒细胞白血病时可能会出现严重的不良反应。     

进一步提高慢性髓细胞白血病的治疗水平

自甲磺酸伊马替尼（伊马替尼,ST1571）2000年6月被美国食品和药品管理局（FDA）批准成为慢性髓细胞白血病（CNL）的治疗药物以来,凡经IFNα治疗失败的患者,伊马替尼可使50％患者获完全性细胞遗传学缓解（CCR）,75％慢性期可进入CCR,加速期中的80％可获血液学反应（HR）,急变期患者30％可获完全性血液学反应（CHR）,从而,伊马替尼已成为目前CNL患者最为标准化的治疗药物。虽有如此好的结果,但不少进展期病例常无效,原本有效的慢性期最终转成耐药。尽管慢性期细胞遗传学反应率很高,但不少患者经PCR检测仍可察觉微小残留病变。在国际随机研究过程中,证明约38％患者可有≥3个对数级的BCR-ABL水平的杀灭率,约4％-10％患者BCR—ABL转阴。而分子水平上缓解率的改善是当前CNL治疗追求的主要目标。目前,一些新的治疗策略,诸如大剂量伊马替尼、伊马替尼为基础的联合治疗以及某些新药的应用等,均有可能进一步改善CNL的疗效。     

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。     

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...     

Imatinib-induced acute generalized exanthematous pustulosis (AGEP) in two patients with chronic myeloid leukemia

Imatinib mesylate blocks bcr/abl kinase activity effectively, and thus is a promising drug in Philadelphia chromosome positive leukemias. While under imatinib treatment high hematological and cytogenetic response rates could be observed, usually only mild non-hematological side-effects like skin rash, edema, and muscular cramps occur. Here we report two severe cases of acute generalized exanthematous pustulosis due to imatinib. In both patients the generalized pustular eruptions could be observed 12 wk after initiation of imatinib treatment. Numerous microbiological investigations excluded an infectious etiology, and histopathology of cutaneous lesions was consistent with acute generalized exanthematous pustulosis. Accordingly, withdrawal of imatinib led to a restitutio at integrum of the integument. Our report confirms another single observation of acute generalized exanthematous pustulosis in chronic myeloid leukemia under imatinib therapy, and confirms that this is a rare but proven adverse effect of imatinib.     

Effects of the mean daily doses of imatinib during the first year on survival of patients with chronic myeloid leukemia in Japan: a study of the Hokkaido Hematology Study Group

In this study, we retrospectively analyzed 213 Japanese patients with chronic myeloid leukemia (CML) treated with imatinib mesylate. In 150 evaluable patients, mean daily doses were 400 mg or more in 42 patients, 300–400 mg in 42 patients, 200–300 mg in 44 patients and <200 mg in 22 patients. Complete hematologic response was observed in all the 84 patients treated with mean daily doses of 300 mg or more and complete cytogenetic response was achieved in 94.8% of those patients. In comparison with the effects of 300 mg or more, mean daily doses of 200–300 mg led to less complete cytogenetic response (78.6% vs. 94.8%, P  < 0.01), shorter complete cytogenetic remission duration (81.3% vs. 95.6% at 24 months, P  = 0.01), and lower overall survival (90.0% vs. 98.8% at 36 months, P  = 0.03). This study suggests that the mean daily doses of 300 mg (roughly equivalent to 100,000 mg/yr) or more may improve overall survival and that mean daily doses of imatinib during the first year may be one of the prognostic factors for CML in Japan.     

Predictive parameters for imatinib failure in patients with chronic myeloid leukemia

Objective: Until recently, imatinib was the standard first-line treatment in chronic myeloid leukemia (CML). The inclusion of nilotinib and dasatinib as first-line options in CML raised a debate on treatment selection. The aim of our study was to analyze predictive parameters for imatinib response as the first-line treatment of CML patients.

Methods: The study included 168 consecutive patients with chronic phase Philadelphia-positive CML who were diagnosed and treated with Imatinib 400?mg once daily at a single university hospital. Numerous parameters were analyzed in terms of imatinib response including comorbidities as well as occurrence of second malignancies.

Results: After the median follow-up of 87 months in 61 patients (36.3%), the imatinib failure was verified. Cox regression analysis identified hepatomegaly (p?=?0.001), leukocytosis?≥?100?×?109/l (p?=?0.001), blood blasts?≥?1% (p?=?0.002), and the presence of additional cytogenetic aberrations (p?=?0.002) as predictors of Imatinib failure. Based on these findings, a new prognostic model was developed according to which imatinib failure had 17% (8/47) of patients in low risk, 34.9% (30/86) of patients in intermediate risk, and 76.7% (23/30) of patients in high-risk group (HR?=?3.973, 95% CI for HR 2.237–7.053, p?Conclusion: The new score allows better selection of patients who are suitable for treatment with imatinib and may guideline the clinical decision for front-line treatment of CML.     

Discontinuation of imatinib in Japanese patients with chronic myeloid leukemia

It was recently recognized that some chronic myeloid leukemia patients with a complete molecular response could sustain that response after discontinuation of imatinib. To characterize the clinical outcomes and profiles of chronic phase chronic myeloid leukemia patients who could discontinue imatinib, we conducted a nationwide survey in Japan. Among 3,242 imatinib-treated chronic myeloid leukemia patients, we identified 50 who had discontinued imatinib for at least six months; of these we analyzed 43. Molecular recurrence was detected in 19 patients, and a complete molecular response rate was estimated to be 47% following imatinib discontinuation. Based on multivariate regression analysis, imatinib dose intensity and prior interferon-α administration were independently predictive of molecular recurrence within 12 months. The depth of the molecular response should be a factor influencing long-term sustained complete molecular response after discontinuation of imatinib. Additionally, an immunological mechanism modified by interferon-α might control chronic myeloid leukemia stem cells.     

Pulmonary hypertension in patients with chronic myeloid leukemia

Dasatinib, a tyrosine kinase inhibitor (TKI), induces pulmonary hypertension (PH) in patients with chronic myeloid leukemia (CML). However, information on other TKIs is limited.We retrospectively analyzed PH prevalence by reviewing transthoracic echocardiography (TTE) findings in a population of Korean CML patients treated with TKI at a single hospital between 2003 and 2020. PH was defined as a high PH probability according to the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines.Of the 189 patients treated with TKI(s) during the study period, 112 (59.3%) underwent TTE. Among the 112 patients treated with a TKI for a median of 40.4 months (range: 1.1–167.2 months), PH was found in 12 (10.7%), most frequently in those treated with dasatinib (ie, in 3 [7.5%] of 40 of those treated with imatinib, 1 [3.1%] of 32 of those treated with nilotinib, and 8 [21.6%] of 37 of those treated with dasatinib). PH resolved in 4 (50.0%) of the 8 dasatinib-treated patients after discontinuation of the agent. One nilotinib-treated and all three imatinib-treated patients recovered from PH. In multivariate analyses, age >60 years, dasatinib treatment, and positive cardiopulmonary symptoms/signs at the time of transthoracic echocardiography were statistically significant risk factors for developing PH.These results show that PH is induced not only by dasatinib, but also by imatinib and nilotinib. Careful screening for PH during any TKI treatment may thus be warranted in patients with CML.     

Early intervention during imatinib therapy in patients with newly diagnosed chronic-phase chronic myeloid leukemia: a study of the Spanish PETHEMA group

Background

Despite the favorable results of imatinib front line in chronic-phase chronic myeloid leukemia there is room for improvement.

Design and Methods

Early intervention during imatinib therapy was undertaken in 210 adults with chronic-phase chronic myeloid leukemia less than three months from diagnosis (Sokal high risk: 16%). Patients received imatinib 400 mg/day. At three months, dose was increased if complete hematologic response was not achieved. At six months, patients in complete cytogenetic response were kept on 400 mg and the remainder randomized to higher imatinib dose or 400 mg plus interferon-alfa. At 18 months, randomized patients were switched to a 2^nd generation tyrosine kinase inhibitor if not in complete cytogenetic response and imatinib dose increased in non-randomized patients not in major molecular response.

Results

Seventy-two percent of patients started imatinib within one month from diagnosis. Median follow-up is 50.5 (range: 1.2–78) months. At three months 4 patients did not have complete hematologic response; at six months 73.8% were in complete cytogenetic response; among the remainder, 9 could not be randomized (toxicity or consent withdrawal), 17 were assigned to high imatinib dose, and 15 to 400 mg + interferon-alpha. The low number of randomized patients precluded comparison between the two arms. Cumulative response at three years was: complete hematologic response 98.6%, complete cytogenetic response 90% and major molecular response 82%. On an intention-to-treat basis, complete cytogenetic response was 78.8% at 18 months. At five years, survival was 97.5%, survival free from accelerated/blastic phase 94.3%, failure free survival 82.5%, and event free survival (including permanent imatinib discontinuation) 71.5%.

Conclusions

These results indicate the benefit of early intervention during imatinib therapy (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00390897","term_id":"NCT00390897"}}NCT00390897).