甲磺酸伊马替尼治疗慢性粒细胞白血病的临床观察

目的:总结甲磺酸伊马替尼(IM)治疗Ph阳性慢性粒细胞白血病(CML)患者的临床观察体会。方法:收集110例Ph阳性CML慢性期(CP)患者、6例加速期(AP)患者和4例急变期(BC)患者分别口服IM 400、600或800 mg/d。通过血液学、细胞遗传学和分子遗传学指标来判断疗效。结果:CP患者完全血液学反应(CHR)率、主要细胞遗传学反应(MCyR)率和完全细胞遗传学反应(CCyR)率分别为98.2%、90.9%和80.9%;AP分别为66.7%、33.3%和16.7%,P值分别为0.002、0.000和0.000。其中CP患者中肝肾功能不全的患者需减少IM剂量。27例经干扰素治疗失败的CP患者IM治疗仍有效。第1年高随访(1次/月)CP患者CCyR达81.9%,非高随访则为63.6%,P=0.005 2。服药前肾功能不全和肝功能不全较脏器功能正常的CP患者服药6个月内发生3~4级血液学毒副反应概率增高,服药6个月后有所减少。结论:IM对CP患者包括干扰素治疗失败的有较高疗效,对AP和BC患者有一定近期疗效。肝肾功能不全的患者易出现血液学毒副反应,需要药物剂量调整。     

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。     

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.     

Update on practical aspects of the treatment of chronic myeloid leukemia with imatinib mesylate

Imatinib (imatinib mesylate, Gleevec? [formerly known as STI571], Novartis Pharmaceuticals, Basel, Switzerland) is a protein tyrosine kinase inhibitor that is approved by the US Food and Drug Administration for patients with all phases of chronic myeloid leukemia (CML). Imatinib is remarkably effective as treatment for CML in the chronic phase (at a dosage of 400 mg/d) and the accelerated phase (at 600 mg/d). At this time, it remains to be seen whether the chronic phase of CML can be extended sufficiently in some patients so that they are functionally "cured," and also whether the increased rate of major molecular response induced by doses of imatinib higher than 400 mg/d will further improve overall survival of patients with CML in the chronic phase. The value of molecular monitoring of response in patients with CML in the chronic phase is examined. Although imatinib 800 mg/d can induce dramatic responses in patients with myeloid blast crisis, lymphoid blast crisis, and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the responses are usually incomplete and of short duration. We discuss the role of imatinib in relation to allogeneic stem cell transplantation (particularly in younger patients), recognizing that the data upon which any decisions can be made are relatively immature. Finally, recent data on new tyrosine kinase inhibitors capable of overcoming primary or acquired resistance to imatinib are reviewed.     

Update on practical aspects of the treatment of chronic myeloid leukemia with imatinib mesylate

Imatinib (imatinib mesylate, Gleevec® [formerly known as STI571], Novartis Pharmaceuticals, Basel, Switzerland) is a protein tyrosine kinase inhibitor that is approved by the US Food and Drug Administration for patients with all phases of chronic myeloid leukemia (CML). Imatinib is remarkably effective as treatment for CML in the chronic phase (at a dosage of 400 mg/d) and the accelerated phase (at 600 mg/d). At this time, it remains to be seen whether the chronic phase of CML can be extended sufficiently in some patients so that they are functionally "cured," and also whether the increased rate of major molecular response induced by doses of imatinib higher than 400 mg/d will further improve overall survival of patients with CML in the chronic phase. The value of molecular monitoring of response in patients with CML in the chronic phase is examined. Although imatinib 800 mg/d can induce dramatic responses in patients with myeloid blast crisis, lymphoid blast crisis, and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the responses are usually incomplete and of short duration. We discuss the role of imatinib in relation to allogeneic stem cell transplantation (particularly in younger patients), recognizing that the data upon which any decisions can be made are relatively immature. Finally, recent data on new tyrosine kinase inhibitors capable of overcoming primary or acquired resistance to imatinib are reviewed.     

Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients

BackgroundThis study explored the impact of genetic polymorphisms in cytochrome P450 (CYP) enzymes and transporters on the plasma trough concentration of imatinib mesylate (IM) and clinical response in chronic myeloid leukemia (CML).Patients and methodsIn total, 82 patients with CML who had been administered 400 mg IM daily for over 6 months were genotyped for 11 single-nucleotide polymorphisms in nine genes (CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC22A1, SLC22A2 and ABCG2) using blood samples. The trough imatinib concentration and clinical responses were assessed 6 months after the initiation of IM therapy.ResultsThe CC, CA and AA genotypes in ABCG2 421C>A gave significantly different frequencies for the major molecular response (MMR) (P = 0.02). However, no significant differences were found between the genotypes of the CYP enzymes and transporters identified in this study and the imatinib plasma trough concentrations and clinical response frequencies, except for the correlation of ABCG2 with MMR.ConclusionsThe results of the present study may indicate that the ABCG 421C>A genetic polymorphism influences the MMR of imatinib in patients with CML.     

氟马替尼与伊马替尼治疗初诊慢性粒细胞白血病的有效性和安全性比较

目的：比较氟马替尼与伊马替尼治疗初诊慢性粒细胞白血病（CML）的有效性和安全性。方法采用多中心、随机、阳性药物平行对照的研究方法,对24例符合条件的初诊费城染色体阳性 CML慢性期（Ph+ CML-CP）患者给予6个周期（24周）的氟马替尼400 mg／d、600 mg／d 和伊马替尼治疗,分别在给药前及给药后2、4、6、8、10、12、16、20、24周进行血液学评价,给药前及给药后12、24周进行形态学、细胞遗传学和分子生物学评价。结果在有效性方面,治疗6个周期,氟马替尼600 mg／d 组的主要分子学缓解（MMR）率高于伊马替尼组,差异有统计学意义[44.44%（4／9）比14.29%（1／7）,P＝0.017]。治疗3个周期,氟马替尼600 mg／d 组 bcr-ablIS≤10%的患者比例高于伊马替尼组,差异有统计学意义（P＝0.002）;药代动力学／药效动力学分析也提示氟马替尼600 mg／d 较400 mg／d 更有可能使患者在早期获得分子学反应。在安全性方面,氟马替尼400 mg／d 组、氟马替尼600 mg／d 组和伊马替尼组Ⅲ～Ⅳ级不良事件的发生率差异无统计学意义（P＞0.05）。氟马替尼组较常见皮肤毒性和胃肠道反应,常见的不良事件为腹泻,未发生心脏和心血管系统不良反应,水肿的发生率低于伊马替尼组。结论氟马替尼可以安全有效地治疗初诊 Ph+ CML-CP 患者,600 mg／d 是一个较为合适的临床起始剂量。氟马替尼和伊马替尼在临床上具有相似的安全性。     

Dasatinib or high‐dose imatinib for chronic‐phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily

BACKGROUND:

In patients with chronic‐phase chronic myeloid leukemia (CP‐CML), imatinib resistance is of increasing importance. Imatinib dose escalation was the main treatment option before dasatinib, which has 325‐fold more potent inhibition than imatinib against unmutated Bcr‐Abl in vitro. Data with a minimum of 2 years of follow‐up were available for the current study of dasatinib and high‐dose imatinib in CP‐CML resistant to imatinib at daily doses from 400 mg to 600 mg.

METHODS:

A phase 2, open‐label study was initiated of 150 patients with imatinib‐resistant CP‐CML who were randomized (2:1) to receive either dasatinib 70 mg twice daily (n = 101) or high‐dose imatinib 800 mg (400 mg twice daily; n = 49).

RESULTS:

At a minimum follow‐up of 2 years, dasatinib demonstrated higher rates of complete hematologic response (93% vs 82%; P = .034), major cytogenetic response (MCyR) (53% vs 33%; P = .017), and complete cytogenetic response (44% vs 18%; P = .0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the high‐dose imatinib arm. Major molecular response rates also were more frequent with dasatinib than with high‐dose imatinib (29% vs 12%; P = .028). The estimated progression‐free survival also favored dasatinib (unstratified log‐rank test; P = .0012).

CONCLUSIONS:

After 2 years of follow‐up, dasatinib demonstrated durable responses and improved response and progression‐free survival rates relative to high‐dose imatinib. Cancer 2009. © 2009 American Cancer Society.     

慢性粒细胞白血病患者血浆伊马替尼浓度检测与临床疗效分析

 目的　探讨慢性粒细胞白血病（CML）患者服用伊马替尼治疗后,伊马替尼血浆浓度在个体间的差异以及与临床疗效的关系。方法　2005年7月至2008年2月开始服用伊马替尼治疗的CML患者共51例纳入研究,其中男 34例,女 17例,服用剂量300 mg／d 9例、400 mg／d 37例,600 mg／d 5例;采用高效液相色谱法（HPLC）测定患者空腹伊马替尼血浆谷浓度;SPSS13.0软件进行统计分析。结果　伊马替尼血浆谷浓度与服用剂量有关,且个体之间差异较大,为（342～4688）ng／ml;300 mg／d剂量组的伊马替尼血浆谷浓度为（1037±514）ng／ml,低于400 mg／d剂量组的（2123±1016）ng／ml（t＝2.34,P＝0.032）;300 mg／d剂量组的治疗有效率为66.67 %（6／9）,低于400 mg／d剂量组的89.19 %（33／37）（χ2＝7.14,P＝0.008）;在300、400 mg／d剂量组中,39例治疗有效,伊马替尼血浆谷浓度高于治疗效果不理想患者,差异有统计学意义（t＝2.25,P＝0.037）;受试者工作特征曲线（ROC曲线）结果提示伊马替尼血浆谷浓度低于1050 ng／ml者,其临床疗效可能较差,敏感度为84.6 %,特异度为71.1 %。结论　CML患者服用伊马替尼治疗后药物血浆浓度与服用剂量有关,不同个体间差异较大,血浆谷浓度低于1050 ng／ml提示其临床疗效可能较差。     

Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications.

PURPOSE: The organic cation transporter OCT-1 mediates active transport of imatinib. We recently showed that low OCT-1 activity is a major contributor to suboptimal response in chronic myeloid leukemia (CML) patients treated with imatinib. The relevance of OCT-1 activity and efflux pumps in determining intracellular uptake and retention (IUR) of dasatinib was assessed. EXPERIMENTAL DESIGN: The effect of OCT inhibitors on [14C]dasatinib and [14C]imatinib IUR was compared using peripheral blood mononuclear cells from newly diagnosed CML patients. The role of efflux transporters was studied using ABCB1- and ABCG2-overexpressing cell lines and relevant inhibitors. RESULTS: Unlike imatinib, there was no significant difference in the dasatinib IUR at 37 degrees C and 4 degrees C (P = 0.8), and OCT-1 inhibitors including prazosin did not reduce dasatinib IUR significantly. In CML mononuclear cells, prazosin inhibitable IUR was significantly higher for imatinib than dasatinib (6.38 versus 1.48 ng/200,000 cells; P = 0.002; n = 11). Patients with high OCT-1 activity based on their imatinib uptake had IC50(dasatinib) values equivalent to patients with low OCT-1 activity. Dasatinib IUR was significantly lower in ABCB1-overexpressing cell lines compared with parental cell lines (P < 0.05). PSC833 (ABCB1 inhibitor) significantly increased the dasatinib IUR (P < 0.05) and reduced IC50(dasatinib) (from 100 to 8 nmol/L) in K562-DOX cell line. The ABCG2 inhibitor Ko143 significantly increased dasatinib IUR in ABCG2-overexpressing cell lines and reduced IC(50)(dasatinib). CONCLUSION: Unlike imatinib, dasatinib cellular uptake is not significantly affected by OCT-1 activity, so that expression and function of OCT-1 is unlikely to affect response to dasatinib. Dasatinib is a substrate of both efflux proteins, ABCB1 and ABCG2.     

Clinical Algorithms for the Treatment of Patients With Chronic Myeloid Leukemia: The 2010 Perspective

Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative disorder. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph) that results in the synthesis of the BCR-ABL fusion protein, a constitutively active tyrosine kinase (TK). The introduction of imatinib, a TK inhibitor (TKI) specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience a loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). In patients for whom standard-dose imatinib therapy (400 mg/day) fails, imatinib dose escalation (600-800 mg/day) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients experiencing drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the newer TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historical response, adverse event tolerance level, and risk factors.     

Phase 1 study of lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib

BACKGROUND: Lonafarnib is an orally bioavailable nonpetidomimetic farnesyl transferase inhibitor with significant activity against BCR-ABL-positive cell lines and primary human chronic myeloid leukemia (CML) cells. Lonafarnib can inhibit the proliferation of imatinib-resistant cells and increases imatinib-induced apoptosis in vitro in cells from imatinib-resistant patients. METHODS: The authors conducted a phase 1 study of lonafarnib in combination with imatinib in patients with CML who failed imatinib therapy. The starting dose level for patients with chronic phase (CP) disease was imatinib, 400 mg/day, plus lonafarnib at a dose of 100 mg twice daily. The starting dose levels for accelerated phase (AP) and blast phase (BP) disease were 600 mg/day and 100 mg twice daily, respectively. RESULTS: A total of 23 patients were treated (9 with CP, 11 with AP, and 3 with BP) for a median of 25 weeks (range, 4-102 weeks). Of those with CP disease, 2 patients had grade 3 (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) dose-limiting toxicities (DLTs) at the 400 + 125-mg dose, including diarrhea (2 patients), vomiting (1 patient), and fatigue (1 patient). In patients with AP/BP disease, DLTs were observed at the 600 + 125-mg dose and was comprised of diarrhea (1 patient) and hypokalemia (1 patient). Eight patients (35%) responded; 3 with CP disease achieved a complete hematologic response (CHR) (2 patients) and a complete cytogenetic response (1 patient). Three patients with AP disease responded (2 CHR, 1 partial cytogenetic response), and 2 patients with BP disease demonstrated hematologic improvement. Pharmacokinetics data suggest no apparent increase in exposure or changes in the pharmacokinetics of either lonafarnib or imatinib when they are coadministered. CONCLUSIONS: The results of the current study indicate that the combination of lonafarnib and imatinib is well tolerated and the maximum tolerated dose of lonafarnib is 100 mg twice daily when combined with imatinib at a dose of either 400 mg or 600 mg daily.     

Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase

BACKGROUND:

Imatinib mesylate given orally at a daily dose of 400 mg is the standard of care as initial therapy for patients with chronic myeloid leukemia (CML) in chronic phase (CML‐CP). Treatment guidelines propose dose escalation based on clinical assessments of disease response.

METHODS:

Response and survival were analyzed in a cohort of patients (n = 106) with newly diagnosed CML‐CP who were enrolled on the International Randomized Study of Interferon and STI571 (IRIS) trial, who began treatment with imatinib at a dose of 400 mg daily, and who subsequently underwent dose escalation to either 600 mg or 800 mg daily. Reasons for dose escalation were evaluated retrospectively based on 2 sets of criteria: the IRIS protocol‐defined criteria (n = 39 patients) and the European LeukemiaNet (ELN) recommendations (n = 48 patients).

RESULTS:

Among all 106 patients who underwent dose escalation, the rates of freedom from progression to accelerated phase or blast phase and overall survival were 89% and 84% at 3 years after dose increase, respectively. A cytogenetic response was obtained in 42% of patients who had their dose escalated based on protocol criteria and in 38% of patients who had their dose escalated according to the ELN recommendations.

CONCLUSIONS:

The results from this retrospective analysis supported imatinib dose escalation as an appropriate initial option for patients with CML‐CP who were experiencing suboptimal cytogenetic response or resistance. Cancer 2009. © 2008 American Cancer Society.     

Correlation between genetic polymorphisms of the hOCT1 and MDR1 genes and the response to imatinib in patients newly diagnosed with chronic-phase chronic myeloid leukemia

The association between seven polymorphisms in the genes hOCT1 and MDR1, encoding for imatinib transporter proteins, and the response to imatinib 400 mg/daily was investigated in 65 patients newly diagnosed with chronic-phase chronic myeloid leukemia. The AA genotype at the rs6935207 hOCT1 polymorphic locus was not detected in patients with inadequate response to imatinib. The CC genotype at the rs1045642 (C3435T) MDR1 locus was associated with primary failure, whereas a T allele at the rs2032582 (G2677T/A) MDR1 locus seemed to protect from primary failure. Beside, the MDR1 haplotype 1236T-2677G-3435C was more frequently found in patients primarily resistant to imatinib.     

Achievement of complete molecular responses in late chronic phase chronic myeloid leukaemia patients treated with pulsed imatinib while in minimal residual disease

Chronic myeloid leukaemia (CML) patients in chronic phase (CP) are currently treated with a standard dose of imatinib of 400 mg/daily. However, once in complete cytogenetic remission (CCR) it is possible that some patients maintain this status with reduced dose of the drug. Here, we describe five cases of CML in late CP, which were switched to imatinib while in CCR after interferon alpha (IFNα) and reached complete and stable molecular remission with intermittent drug administration at 400 mg/every 20 days/month.     

The effect of dose increase of imatinib mesylate in patients with chronic or accelerated phase chronic myelogenous leukemia with inadequate hematologic or cytogenetic response to initial treatment.

PURPOSE: Imatinib mesylate is a tyrosine kinase inhibitor with high affinity for the BCR-ABL fusion protein expressed by the hematopoietic cells in chronic myelogenous leukemia (CML). Some patients with chronic-phase or accelerated-phase CML either relapse after an initial response or are refractory to imatinib, prompting us to evaluate the efficacy of dose increase in such patients. EXPERIMENTAL DESIGN: Twelve chronic-phase patients initially receiving 400 mg/day and 4 patients with accelerated phase initially receiving either 400 mg/day (two patients) or 600 mg/day (two patients) had their dose increased (14 to 800 mg/day and 2 to 600 mg/day) because of progressive disease (usually clonal evolution) or inadequate cytogenetic response after at least 1 year of therapy. RESULTS: Six patients had major cytogenetic responses after dose increase (3 complete and 3 partial). Two others had minor cytogenetic responses. Two patients with clonal evolution transiently lost the additional clonal aberrations. Almost all of the responses occurred within 6 months, and were typically 3-6 months in duration. However, 3 patients have continuing major cytogenetic responses of >18 months duration. Dose increase was well tolerated, with thrombocytopenia, mild leukopenia, and exacerbation of prior edema being the most common adverse events. CONCLUSIONS: Although increasing the dose of imatinib can benefit a subgroup of patients with CML with either an inadequate cytogenetic response or disease progression, our results suggest the majority will not have a sustained meaningful response, and that other options, such as allogeneic stem cell transplant or investigational therapies, also need to be considered at the time of dose increase.     

Long-term outcomes in the second-line treatment of chronic myeloid leukemia: a review of tyrosine kinase inhibitors

Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative neoplasm. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph), which results in the synthesis of the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) fusion oncoprotein, a constitutively active tyrosine kinase. The introduction of imatinib, a tyrosine kinase inhibitor (TKI) that is specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). For patients with CML, failure on standard-dose imatinib therapy (400 mg daily), imatinib dose escalation (600-800 mg daily) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients who experience drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutation status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historic response, adverse-event tolerance, and risk factors.     

Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia.

PURPOSE: Chronic myelogenous leukemia (CML) results from the breakpoint cluster region-Abl fusion gene product, a tyrosine kinase involved in cell division and apoptosis. Imatinib, an orally administered inhibitor of the breakpoint cluster region-Abl tyrosine kinase, is capable of blocking proliferation and inducing apoptosis in CML cell lines. In this report, we describe the preclinical profile of imatinib and the data submitted in the New Drug Application that led to its marketing approval. EXPERIMENTAL DESIGN: Chemistry manufacturing and controls, animal toxicology, and biopharmaceutical data are described. Results of Phase I and Phase II clinical studies in patients with CML in blast crisis (CML-BC), in accelerated phase (CML-AP), and in chronic phase disease-resistant or intolerant to IFN-alpha (CML-CP) are summarized. The basis for marketing approval and postmarketing commitments by the pharmaceutical company are discussed. RESULTS: Toxicology studies in the rat, dog, and monkey show the hematological, renal, and hepatobiliary toxicity of imatinib. Pharmacokinetic studies in patients with CML demonstrate 98% imatinib bioavailability. The elimination half-lives of the parent drug and the major active metabolite, CGP74588, from plasma are approximately 18 and 40 h, respectively. Approximately 81% of the drug is eliminated in 7 days, 68% in the feces and 13% in the urine. Cytochrome P-450 3A4 is the main enzyme responsible for imatinib metabolism. Phase I and II clinical studies were conducted. The Phase I study, in 83 CML patients, evaluated oral imatinib doses from 25 to 1000 mg/day. Dose-limiting toxicity was not observed. The three Phase II studies, in CML-CP, CML-AP, and CML-BC, enrolled 1027 patients. CML-CP patients received 400 mg/day imatinib, whereas CML-AP and CML-BC patients generally received 600 mg/day imatinib. Primary study endpoints were cytogenetic response rate (CML-CP) and hematological response rate (CML-AP and CML-BC). The cytogenetic response rate for CML-CP patients was 49%. The hematological response rate of CML-AP and CML-BC patients was 63 and 26%, respectively. The most common imatinib adverse events were nausea, vomiting, myalgia, edema, and diarrhea. Elevated liver enzymes and/or bilirubin were reported in 27 patients (2.6%). CONCLUSIONS: On May 10, 2001, imatinib mesylate (Gleevec, formerly known as STI-571 and Glivec), manufactured and distributed by Novartis Pharmaceuticals, East Hanover, NJ, was approved by the United States Food and Drug Administration for the treatment of CML in three clinical settings: CML-BC, CML-AP, and CML-CP. This report summarizes the Food and Drug Administration's review of the New Drug Application.     

Clinical Trials in Chronic Myeloid Leukemia

The introduction of the tyrosine kinase inhibitor (TKI) imatinib in the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) has substantially improved the outcome of CML patients. Despite the positive results, problems and questions remained. This was the rationale to setup trials for treatment optimization, where imatinib was administered in higher dose and/or in combination with other therapy but where also new and potentially more efficacious second-generation TKI, nilotinib and dasatinib, were investigated. This review summarizes data of recently published first-line studies with the standard treatment imatinib 400 mg as one study arm. Results of randomized comparisons to higher-dose imatinib treatment, nilotinib or dasatinib are discussed. With regard to outcome interpretation, general aspects on statistical issues and endpoint definitions are put into focus. Considering decidedly increased longevity thanks to TKI treatment, future research should include the evaluation of the quality of life (QoL). Relating also to QoL, safe ways of drug discontinuation need to be investigated.