Second-generation tyrosine kinase inhibitors as first-line treatment strategy in newly diagnosed chronic phase chronic myeloid leukemia patients

Recent results of phase II trials which used dasatinib or nilotinib as single agent, or phase III trials comparing second-generation tyrosine kinase inhibitors to imatinib, showed greater potency of these two inhibitors in newly diagnosed chronic myeloid leukemia (CML) patients in chronic phase (CP). In the present review we detail and summarize clinical results of both agents as first-line therapeutic strategy, and also discuss on critical points emerged from the last follow-up of trials comparing new generation tyrosine kinase inhibitors with imatinib. In terms of safety, dasatinib and nilotinib have shown favorable toxicity profile, with peculiar and distinct pattern of adverse events. Based on these results, USA FDA approved both drugs as first-line treatment in newly diagnosed CML: now several therapeutic strategies are available to treat patients at onset of disease. Longer follow-up is however needed to prove the advantages of faster and deeper responses in terms of disease progression compared to imatinib.     

Comparative efficacy of nilotinib and dasatinib in newly diagnosed chronic myeloid leukemia: a matching-adjusted indirect comparison of randomized trials

Abstract

Objective:

Nilotinib and dasatinib have not been directly compared in a randomized trial for the treatment of newly diagnosed chronic myeloid leukemia in the chronic phase (CML-CP). The purpose of this study was to indirectly compare rates of major molecular response (MMR), progression-free survival (PFS) and overall survival by month 12 with nilotinib and dasatinib treatment of newly diagnosed CML-CP.     

The expanding role of nilotinib in chronic myeloid leukemia

Importance of the field: Several therapeutic options, including tyrosine kinase inhibitors, exist for the treatment of patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Despite impressive results, there is room for improvement for those patients who are either resistant or intolerant to imatinib.

Areas covered in this review: An overview is given on the clinical results with nilotinib, a rationally designed second-generation tyrosine kinase inhibitor, as first- and second-line therapy in patients with Ph-positive CML. Important factors in predicting resistance to nilotinib and guiding therapeutic decisions are addressed.

What the reader will gain: Knowledge on the clinical efficacy and safety of nilotinib after imatinib failure and as first-line treatment. Point mutations in the kinase domain (KD) of BCR-ABL1 are important determinants of clinical sensitivity to currently available tyrosine kinase inhibitors, including nilotinib. Information on specific BCR-ABL1 KD mutations and safety profiles assist in therapeutic decision making.

Take home message: Nilotinib is a highly effective and well-tolerated therapeutic option in patients with Ph-positive CML after imatinib failure. Early evidence demonstrating increased efficacy has allowed expanding nilotinib to previously untreated patients in chronic phase. Insights into mechanisms of resistance to tyrosine kinase inhibitors and predictive factors for response will allow for a more individualized use of these agents.     

早期应用尼洛替尼治疗慢性髓性白血病的疗效观察

目的观察早期应用尼洛替尼治疗慢性髓性白血病(CML)的疗效及不良反应。方法观察我院2013年11月至2015年8月收治的10例CML患者,使用高杉尖三酯碱和/或羟基脲将白细胞降至20×10~9/L以下后口服尼洛替尼治疗。其中慢性期8例,每日口服尼洛替尼600 mg;加速期2例,每日口服尼洛替尼800 mg。监测患者治疗前后的血液学、细胞遗传学、分子生物学、血液生化学等指标,评价其疗效及不良反应。结果所有患者治疗满3个月时均达到CHR。8例慢性期患者中,7例达到CCyR,1例达到PCyR。2例BCR-ABLIS转录水平<1%,6例>1%而<10%。2例加速期的患者中,1例达到CCyR,1例无细胞遗传学缓解。2例BCR-ABLIS转录水平>1%而<10%。在治疗满6个月的9例患者中,7例慢性期患者均达到CCyR。3例达到MMR,3例BCRABLIS转录水平>0.1%而<1%,1例BCR-ABLIS转录水平>1%而<10%。2例加速期患者中,1例维持CCyR,另外1例细胞遗传学依旧未发生缓解。2例分子生物学均达到MMR。1例慢性期患者在治疗第8个月时发生急髓变。在治疗满12个月的6例患者中,4例慢性期患者均为CCyR。3例为MMR,1例BCR-ABLIS转录水平<1%。2例加速期患者中,1例为CCyR,1例细胞遗传学依旧未发生缓解。2例均为MMR。10例患者均未发生严重的不良反应。常见的不良反应为1~2级的血红蛋白减少、皮疹、关节及肌肉酸痛等。结论早期应用尼洛替尼治疗慢性髓性白血病安全有效。     

Adherence to treatment with second-line therapies,dasatinib and nilotinib,in patients with chronic myeloid leukemia

Abstract

Background and objective:

Previous studies have shown that long-term outcomes are more favorable for patients newly diagnosed with chronic myeloid leukemia (CML) if a complete cytogenetic response is achieved within ≤12?months of diagnosis. Because continuous and adequate dosing is important to achieve this outcome, it is important to understand treatment adherence as part of managing long-term CML therapy. While studies regarding imatinib suggest that adherence varies widely, data addressing adherence to newer breakpoint cluster region–Abelson (BCR-ABL) inhibitors (dasatinib and nilotinib) are sparse. This study evaluates real-world adherence in patients diagnosed with CML receiving dasatinib or nilotinib as second-line therapy.     

Population pharmacokinetic and exposure-response analyses of guanfacine in Japanese pediatric ADHD patients

Guanfacine hydrochloride extended-release tablet (GXR) is approved for child and adolescent patients with attention-deficit/hyperactivity disorder (ADHD). The aims of this study were to develop a population pharmacokinetic model of guanfacine after administration of GXR and to evaluate factors influencing the pharmacokinetics of guanfacine in pediatric ADHD patients. A population pharmacokinetic analysis was performed using 3231 plasma concentration data items of guanfacine for pediatric ADHD patients aged 6–17 years obtained from clinical studies in Japan and the US. In addition, the relationship of the ADHD Rating Scale IV (ADHD RS-IV, efficacy endpoint) total score with exposure to guanfacine was assessed for Japanese pediatric ADHD patients. A one-compartment model with first-order absorption and lag time well described the plasma concentration data of guanfacine in pediatric ADHD patients. Body weight was selected as a covariate of apparent total body clearance and apparent volume of distribution. There was no pharmacokinetic difference between Japanese and non-Japanese pediatric ADHD patients. The results suggested a tendency of exposure-dependent reduction in the ADHD RS-IV total score, whereas the reduction was observed even at low plasma exposure levels compared with the placebo group.     

Nilotinib: in the first-line treatment of newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase

Nilotinib is an effective first-line treatment for newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (CML) in chronic phase. It is an aminopyrimidine-based, high-affinity inhibitor of the tyrosine kinase activity of BCR-ABL. It thus decreases ABL-associated cell proliferation and kinase autophosphorylation. At 12 months, a significantly greater proportion of nilotinib 300?mg twice daily recipients experienced a major molecular response (primary endpoint) than those receiving imatinib 400?mg once daily, in the randomized, open-label, multicentre ENESTnd study in adults with newly diagnosed Philadelphia chromosome-positive CML in chronic phase. Moreover, a significantly greater proportion of nilotinib 300?mg twice daily than imatinib recipients had a complete molecular response at 12 months. Complete cytogenetic response rates were also significantly higher in the nilotinib 300?mg twice daily group than in the imatinib group at 12 months. Treatment differences in molecular response rates remained significant in an updated analysis, with data from a minimum follow-up of 24 months. Nilotinib 300?mg twice daily was generally well tolerated in the ENESTnd study. While nilotinib is associated with an increase in corrected QT interval (QTc), the incidence of cardiac-related adverse events in nilotinib recipients in the ENESTnd study was low.     

伊马替尼治疗Ph染色体阳性慢性粒细胞白血病的临床观察

目的:评价酪氨酸激酶抑制剂伊马替尼治疗Ph染色体阳性慢性粒细胞白血病的有效性及安全性。方法:90例慢性粒细胞白血病患者,其中慢性期67例,非慢性期23例(加速期14例,急变期9例),每天应用剂量分别为400,600mg。每周复查血常规,每3个月进行骨髓象及细胞遗传学检查,根据血象和骨髓象调整剂量。结果:观察截止时,84例(93.3%)获得血液学完全缓解;68例可评价遗传学效应,35例(51.5%)发生主要遗传学效应(慢性期30例,加速期3例,急变期2例),其中31例(88.6%)为遗传学完全缓解(慢性期27例,加速期2例,急变期2例)。11例(12.2%)患者发生严重白细胞和/或血小板减少,但可通过调整剂量控制。严重非血液学不良反应发生较少。结论:伊马替尼治疗Ph染色体阳性慢性粒细胞白血病患者疗效较好,可获得较高的完全血液学缓解率和主要细胞遗传学缓解率,起效迅速,且不良反应较少,可耐受或自行消失。     

The current role of high-dose imatinib in chronic myeloid leukemia patients, newly diagnosed or resistant to standard dose

INTRODUCTION: The majority of patients affected by chronic myeloid leukemia (CML) are expected to obtain a favorable outcome with standard-dose imatinib. However, a third of patients do not achieve the desired effect and must be considered resistant. One of the early strategies to overcome initial resistance was the use of high doses (600 - 800 mg) of imatinib: before the advent of second-generation tyrosine kinase inhibitors, some standard-dose-resistant patients gained benefits from the use of dose-escalation imatinib. Intensification with higher doses of the drug was used in newly diagnosed patients with the aim to improve cytogenetic and molecular responses. AREAS COVERED: In this article, the authors review data of several trials testing high-dose imatinib after resistance to standard dose. Literature about high-dose imatinib used front-line as single treatment or with different combinations is also examined. A literature search for relevant studies was undertaken mainly in PubMed or through published conference abstracts. The aim of this review is to summarize the efficacy and safety of this option either as front-line or as a rescue therapy in chronic-phase CML patients and to discuss the future role of this treatment modality. EXPERT OPINION: Literature evidence supports the fact that high-dose imatinib can induce sustained responses in a subset of patients with cytogenetic failure or acquired resistance, but it seems less effective in patients with haematological failure or in molecular suboptimal responders. In newly diagnosed patients, high-dose imatinib produced increased response rates, which in some instances were not significant compared with standard dose.     

大剂量伊马替尼、达沙替尼和尼洛替尼治疗慢性髓性白血病的成本效用分析

目的：分析大剂量伊马替尼、达沙替尼和尼洛替尼治疗对标准剂量伊马替尼耐药的慢性髓性白血病患者的成本效用。方法：计算三种治疗方案下患者的效用和花费的成本,在马尔可夫模型（Markov）中以3个月为周期进行5年的模拟并对结果做成本效用比较。结果：尼洛替尼治疗方案累计成本为1 595 289.10元,健康效用为1.276 4质量调整生命年（QALYs）,相比于尼洛替尼,大剂量伊马替尼组的增量成本效用比（ICUR）为-22 759 433.08（￥/QALYs）,达沙替尼组为-30 960 469.51（￥/QALYs）。结论：尼洛替尼方案累计成本最低且获得最多的QALYs,为绝对优势方案。     

尼洛替尼/达沙替尼对比伊马替尼治疗初诊慢性期慢性髓系白血病的Meta分析

目的系统评价尼洛替尼/达沙替尼对比伊马替尼治疗初诊慢性期慢性髓系白血病(CML)的疗效和血液学安全性。方法计算机检索Cochrane图书馆、Pub Med、中国期刊全文数据库、万方数据库等,纳入尼罗尼替/达沙替尼(试验组)对比伊马替尼(对照组)治疗慢性期CML的随机对照试验(RCT)。提取资料并交叉核对,对纳入的研究进行质量评价,采用Rev Man 5.2统计学软件进行Meta分析。结果共纳入8项RCT,合计1 375例患者。Meta分析结果显示,与对照组相比,试验组3年累计主要分子学反应(MMR)增高[RR=1.31,95%CI(1.20,1.44),P<0.000 01]、3年累计MR4增高[RR=2.27,95%CI(1.78,2.90),P<0.000 01],3年累计MR4.5增高[RR=2.0,95%CI(1.58,2.53),P<0.000 01];2年、1年、9个月、6个月、3个月累计MMR,2年累计MR4.5,2年和1年累计完全细胞遗传学反应(CCy R)均增高。而3年总体生存(OS)率[RR=1.01,95%CI(0.99,1.04),P=0.18]、3年无进展生存(PFS)率[RR=1.35,95%CI(0.89,2.04),P=0.16]组间比较无显著差异。试验组3~4级血小板减少发生率高于对照组[RR=1.59,95%CI(1.20,2.12),P=0.001],但不良反应相关的治疗终止发生率[RR=1.23,95%CI(0.88,1.70),P=0.22]不增加。结论尼洛替尼/达沙替尼作为慢性期CML治疗的首选可能获益更多,但还需要更多高质量RCT、更长期的随访进一步验证。     

尼洛替尼与伊马替尼治疗慢性粒细胞白血病早期临床疗效比较

目的 比较尼洛替尼与伊马替尼治疗慢性粒细胞白血病（CML）的早期（3个月时）疗效以及安全性。方法 选取2007年1月至2017年12月安徽省立医院确诊CML的患者129例,采用随机数字表法按照1∶7分为尼洛替尼组（18例）和伊马替尼组（111例）。两组患者服药3个月后门诊复查骨髓形态学、BCR-ABL融合基因国际标准值（BCR-ABL^IS）,比较两组患者的BCR-ABL^IS结果,评价两组患者的疗效（主要指标为BCR-ABL^IS≤10%的达标率、BCR-ABL^IS≤0.0032%的比例）以及药物的安全性（白细胞减少、血小板减少、贫血等血液学毒性;Q-T间期延长,以及肝功能损害、骨骼肌肉疼痛、水肿、皮疹、消化道症状等不良反应发生情况）。结果 尼洛替尼组患者治疗3个月时达到BCR-ABL^IS≤10%、BCR-ABL^IS≤0.0032%的比例均高于伊马替尼组（94.44%vs 69.37%;55.55%vs 27.92%）,差异均有统计学意义（P<0.05）;两组患者药物安全性比较,差异无统计学意义（P>0.05）。结论 尼洛替尼治疗CML的早期分子学反应达标率以及患者分子学反应的深度均高于伊马替尼组,两种药物不良反应发生情况无显著差异。