Nilotinib for the treatment of Philadelphia-chromosome-positive chronic myeloid leukemia

Importance of the field: Although the introduction of imatinib revolutionized the management of chronic myeloid leukemia (CML), some patients exhibit resistance or intolerance to the drug. Nilotinib induces high and rapid rates of cytogenetic and molecular responses. With recent approval for newly diagnosed patients with chronic phase CML, the current algorithm for treatment will probably be transformed.

Areas covered in this review: This review will describe evaluations of nilotinib in all phases of CML from 1995 to the present. Early preclinical data and Phase I, Phase II and Phase III evaluations will demonstrate the role of nilotinib in newly diagnosed CML, as well as in imatinib-resistant or imatinib-intolerant disease.

What the reader will gain: Mutations in the BCR-ABL kinase domain are responsible for the majority of resistance to imatinib. In comparison with imatinib, nilotinib displays increased selectivity and potency at inhibiting proliferation of BCR-ABL expressing cells. Although several mutations, including T315I, remain resistant to nilotinib, activity in all phases of CML has been reported.

Take home message: Nilotinib induces high and rapid rates of cytogenetic and molecular response, with less progression to advanced forms of disease compared with imatinib. Considering that the rapid achievement of these clinical milestones has been associated with positive long-term outcomes, nilotinib as initial therapy in patients with CML in chronic phase represents the future in CML treatment. Longer follow-up is necessary to recognize survival advantages.     

Current concerns of undertreatment and overtreatment in chronic myeloid leukemia based on European LeukemiaNet 2013 recommendations

Introduction: The aim of this paper is to indicate optimal tyrosine kinase inhibitor (TKI) administration practices based on European LeukemiaNet (ELN) 2013 recommendations for chronic myeloid leukemia (CML). Likewise, current concerns of undertreatment and overtreatment with TKIs during the long-term clinical course of CML will be outlined.

Areas covered: Currently available TKIs for the management of CML are reviewed. The survival benefit of TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib) for the CML is excellent. The CML and TKI literature search was made in PubMed with particular focus on the clinical trials, recommendations, guidelines and expert opinions, as well as the ELN CML 2013 recommendations.

Expert opinion: Initial TKI treatment for low-risk chronic phase CML is imatinib 400 mg; high-Sokal risk and/or CML patients with complex karyotypic abnormalities would require more powerful second-generation TKIs (dasatinib 100 mg or nilotinib 600 mg). Absence of early molecular response after 6 months, complete cytogenetic response after 12 months and major molecular response after 18 months may require a more powerful TKI switch. If one of the two second-generation TKIs (nilotinib or dasatinib) was used as first-line therapy and failed, the other (dasatinib or nilotinib) could be administered.     

Tyrosine kinase inhibitors in acute and chronic leukemias

Introduction: Since the initial approval of imatinib much has been learned about its resistance mechanisms, and efforts have continued to improve upon BCR-ABL tyrosine kinase inhibitor therapy. Targeted therapy with TKIs has continued to be an area of active research and development in the care of acute and chronic leukemia patients.

Areas covered: This article reviews current approved and investigational TKI treatments for chronic myelogenous leukemia (CML), Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph + ALL) and acute myelogenous leukemia (AML).

Expert opinion: There are now more potent BCR-ABL TKIs approved, which allow for additional options when determining front-line and second-line CML and Ph + ALL treatments. The T315I mutation is an ever-present challenge. Ponatinib, a pan BCR-ABL TKI, while still under investigation, is very hopeful with its ability to overcome T315I mutations in resistant CML and Ph + ALL patients. Because nilotinib and dasatinib have not been directly compared, at present we recommend selecting one or the other based on the side-effect profile, drug interactions, patient comorbidities, and mutational status. FLT-3 inhibition is of particular interest in AML patients with FLT-3 internal tandem duplication mutations; this type of targeted therapy continues to be studied.     

A retrospective analysis of therapy adherence in imatinib resistant or intolerant patients with chronic myeloid leukemia receiving nilotinib or dasatinib in a real-world setting

Abstract

Objectives:

To compare adherence to second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib in patients with imatinib resistant or intolerant chronic myeloid leukemia (CML) receiving second-line therapies.     

Second line small molecule therapy options for treating chronic myeloid leukemia

Introduction: Approximately 33% of chronic myeloid leukemia (CML) patients discontinue treatment with imatinib in the long-term due to resistance and/or intolerance. Second-generation tyrosine kinase inhibitors (TKIs) (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) have added complexity to the treatment paradigm for this disease.

Areas covered: Second generation TKIs, approved as second-line treatment in all phases of the disease, are highly effective in patients resistant to and/or intolerant to imatinib and are extremely active against all the resistant BCR-ABL1 mutations, with the exception of T3151. Ponatinib, active against all BCR-ABL1 mutants including T315I, became widely used for resistant patients in all phases of disease after previous therapies. Other drugs, such as ABL001, which targets the myristoyl pocket of the ABL1 kinase, are currently in development, to offer therapeutic alternatives for resistant patients to ATP-binders.

Expert opinion: In this review, we summarize the efficacy of second line small molecules available. Specific safety profiles have emerged for each drug from sponsored clinical trials in the long-term. Stratification of patients according to comorbidities and cardiovascular risk is now needed to individualize second line treatment. Combinations of different drugs with different mechanisms of action will be used in the future to decrease the incidence of resistance.     

Treatment options for chronic myeloid leukemia

Introduction : The bcr-abl tyrosine kinase inhibitors (TKIs) are the cornerstone treatment for chronic myeloid leukemia (CML). However, there are many topics related to therapy that remain debated.

Areas covered : The aim of this paper is to give the reader a comprehensive review of how to treat CML at diagnosis, how to monitor the disease and a brief read of special populations and case scenarios. It describes the first-line (imatinib) and second-line (nilotinib and dasatinib) TKIs currently used for the treatment of CML, including landmark studies proving their efficacy, side effect profile, dosage and use in special populations. It also reviews the current guidelines regarding treatment and monitoring of the disease while on TKIs, along with an overview of treatment in advanced stages, the role of allogeneic stem cell transplantation and investigational drugs.

Expert opinion : Although imatinib represented a mayor therapeutic advancement over conventional chemotherapy, second-generation TKIs offer higher rates of optimal response and should be used as the frontline therapy. Patients with the T315I mutation carry a worse prognosis and should be offered allogeneic stem cell transplantation. The treatment in advanced stages of CML remains suboptimal and bench, translational and clinical research is encouraged.     

Bcr-Abl tyrosine kinase inhibitors: a patent review

Introduction: Breakpoint cluster region Abelson (Bcr-Abl) tyrosine kinase (TK) is a constitutively activated cytoplasmic TK and is the underlying cause of chronic myeloid leukemia (CML). To date, imatinib represents the frontline treatment for CML therapy. The development of resistance has prompted the search for novel Bcr-Abl inhibitors.

Areas covered: This review presents a short overview of drugs already approved for CML therapy and of the compounds that are in clinical trials. The body of the article deals with Bcr-Abl inhibitors patented since 2008, focusing on their chemical features.

Expert opinion: The search for Bcr-Abl inhibitors is very active. We believe that a number of patented compounds could enter clinical trials and some could be approved for CML therapy in the next few years. Overall, Bcr-Abl inhibitors constitute a very appealing research field that can be expected to expand further.     

Nilotinib therapy in chronic myelogenous leukemia

Imatinib mesylate (Gleevec; Novartis, Basel, Switzerland) is a highly effective inhibitor of the deregulated kinase activity of BCR-ABL in chronic myelogenous leukemia (CML) and represents the current standard of care for patients with this disease. Mutations within the ABL kinase domain that interfere with drug binding have been identified as the main mechanism of resistance to imatinib. Currently, more than 50 different BCR-ABL mutants conferring varying degrees of resistance to tyrosine kinase inhibitors have been identified. Nilotinib (Tasigna; Novartis) is a second-generation tyrosine kinase inhibitor with 30-fold higher potency against BCR-ABL kinase than imatinib. Notably, nilotinib is active against a wide range of imatinib-resistant or-intolerant patients, except for T315I. Results from the pivotal phase II studies of nilotinib for patients with CML after failure or intolerance to imatinib therapy indicate that nilotinib has a favorable toxicity profile and is highly efficacious in this setting. Studies exploring the efficacy of nilotinib as front-line therapy for patients with newly diagnosed CML are ongoing. Here, we review the preclinical and clinical development of nilotinib for the treatment of CML.     

Tyrosine kinase inhibitors in the treatment of unresectable or metastatic gastrointestinal stromal tumors

Introduction: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. Proliferation of GIST is driven by activating mutations in the KIT or PDGFRA genes that found in most sporadic GISTs. Surgery is the main remedial measure for primary GIST, and imatinib is the principal therapeutic of choice for unresectable or metastatic GIST. Imatinib revolutionized treatment for unresectable or metastatic GISTs; however, resistance to imatinib has inevitably developed for most GIST patients.

Areas covered: PubMed was searched to find biological studies of GIST and clinical trials of molecularly targeted agents on unresectable or metastatic GISTs, and the key papers found have been reviewed. In this paper, the standard therapy which includes imatinib, sunitinib and regorafenib for unresectable or metastatic GIST has been reviewed and molecular mechanisms of resistance for tyrosine kinase inhibitors (TKIs) have been postulated and discussed. Treatment measures for resistant GIST and therapeutic choices after the standard therapy have also been described.

Expert opinion: The standard therapy for unresectable or metastatic GISTs is first-line imatinib, second-line sunitinib and third-line regorafenib. After standard therapy, best supportive care or clinical trials is recommended in the guidelines. However, patients may benefit from continuation of TKIs beyond disease progression and from rechallenge of TKIs used previously.     

Outcomes with frontline nilotinib treatment in Turkish patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase

Objective: Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with chronic myeloid leukemia in chronic phase (CML-CP). This study was the first prospective evaluation of the efficacy and safety of nilotinib in Turkish patients with newly diagnosed CML-CP. The primary endpoint of the study was the rate of major molecular response (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [BCR-ABL1^IS]) by 12 months.

Methods: Patients with newly diagnosed CML-CP were treated with nilotinib 300 mg twice daily. This analysis was based on the first 12 months of follow-up in a 24-month study.

Results and Conclusions: Of 112 patients enrolled, 66.1% (80% CI, 59.7–72.0%) achieved MMR and 22.3% achieved a deep molecular response of MR^4.5 (BCR-ABL1^IS ≤ 0.0032%) by 12 months. During the first year of treatment, 1 patient progressed to blast crisis and 2 patients died. Safety results were consistent with previous studies. Most adverse events (AEs) were grade 1/2. Most frequently reported nonhematologic AEs of any grade were elevations in bilirubin, alanine aminotransferase, and triglycerides. These results support the use of nilotinib 300 mg twice daily as a standard-of-care treatment option for patients with newly diagnosed CML-CP.     

Nilotinib for treatment of gastrointestinal stromal tumors: out of the equation?

Introduction: Imatinib, a selective tyrosine kinase inhibitor (TKI), is currently the standard treatment for unresectable and metastatic gastrointestinal stromal tumors (GISTs). However, the disease control time by imatinib is limited due to intolerance or resistance. Nilotinib, a second-generation TKI, is expected to show enhanced clinical efficacy against advanced GIST.

Areas covered: PubMed and ClincalTrial.gov were searched to identify clinical trials of nilotinib for GIST. The key words used were GIST and nilotinib and/or AMN107. This review summarizes the clinical trials of nilotinib for advanced GIST and outlines current understanding of the clinical usefulness of nilotinib in GIST therapy.

Expert opinion: Clinical trials of nilotinib for advanced GIST were readily advanced from a Phase I study to Phase III studies. Unfortunately, the clinical utility of nilotinib was not demonstrated by the randomized control trials either in patients with imatinib-resistant GIST or in patients who used nilotinib as the first-line treatment. On the basis of the trial results, nilotinib is not recommended for GIST therapy generally. Nevertheless, a comparable number of patients showed significant response with different side-effect profiles from imatinib. Thus, this new TKI may still merit attention as an important alternative to imatinib in advanced GIST patients who are intolerant to imatinib.     

ABL激酶区突变的检测与伊马替尼耐药

目的研究慢性粒细胞白血病(chronic myeloid leukemia,CML)患者ABL酪氨酸激酶区突变及伊马替尼耐药。方法用巢式RT-PCR对35例CML患者骨髓液BCR-ABL mRNA内ABL激酶区序列进行逆转录、扩增,测序和同源性比较分析ABL激酶区突变,并分析其伊马替尼耐药。结果 35例患者检出突变16例,阳性率45.71%。CML慢性期、加速期、急变期患者突变率分别为47.83%(11/23)、50%(1/2)和40%(4/10),其差异无显著性(P=0.858);16例突变患者中,共检出26种点突变,包括Y253H、T315I、F317L、M351T、L387F、A380D、H396R、G398R、D455G、E459K和1例185 bp碱基缺失突变等。其中A269V、D274G、S286G、V299M、C305Y、R307W、G312R、I314V、L324Q、K356E、D381G、K403E、K419E、L471P、A474T和S485P突变暂未见文献报道,可能为新的突变。在这些新发现的突变中,D274G、S286G、C305Y和K356E等突变可能与伊马替尼(imatinib,IM)治疗抗性有关。结论约半数患者存在ABL激酶区突变,突变位点广泛,性质多样,既存在单一位点突变,也可多位点同时存在,突变的发生与年龄、性别无关,部分突变与伊马替尼耐药有关。ABL基因激酶区突变检测有助于酪氨酸激酶抑制剂疗效的评估、治疗方案的调整。     

An evaluation of brigatinib as a promising treatment option for non-small cell lung cancer

ABSTRACT

Introduction: Brigatinib is a second-line inhibitor for the treatment of rearranged anaplastic lymphoma kinase (ALK) in lung cancer patients which has significant activity against brain metastases. This tyrosine kinase inhibitor (TKI) overcomes a wide range of ALK mutations which confer therapeutic resistance and is increasingly applied in first-line therapy due to improved benefit for patients compared to crizotinib, the current standard of care.

Areas covered: The authors review the development and characteristics of brigatinib and discuss the optimal clinical use and sequence of the application of ALK inhibitors in patients progressing under therapy.

Expert opinion: ALK-rearranged NSCLC can be treated with a broad range of approved and novel inhibitors at various stages of therapy, including the second-line therapeutic brigatinib. Besides this TKI, the second-line ALK inhibitors alectinib and ceritinib, as well as the third-line lorlatinib are approved for the treatment of ALK-positive NSCLC patients. The main challenge is to find sequences and combinations of ALK inhibitors which provide the best benefit for the patients.     

New Bcr-Abl inhibitors in chronic myeloid leukemia: keeping resistance in check

Targeted therapy with the Abl kinase inhibitor imatinib has markedly improved the outlook for patients with chronic myeloid leukemia (CML). Breakpoint cluster region (Bcr)-Abl signaling is reactivated at the time of resistance, predominantly due to mutations in the kinase domain of Bcr-Abl that interfere with drug binding. This discovery prompted the development of new Abl kinase inhibitors, among which nilotinib and dasatinib have gained regulatory approval. Despite excellent results in patients with imatinib-resistant or imatinib-intolerant CML treated with nilotinib or dasatinib, early indications suggest that: the cross-resistant Bcr-Abl^T315I mutant is disproportionately represented among patients who relapse on these therapies; each Abl inhibitor exhibits vulnerabilities to certain kinase domain mutations. We review new inhibitors of Bcr-Abl, including preliminary information on inhibitors of Bcr-Abl^T315I and discuss the potential of combined Abl kinase inhibitor therapy to pre-empt resistance. Improved Abl inhibitor therapies will be useful in achieving maximum disease control but a clinical T315I inhibitor remains a high priority.     

Flying under the radar: the new wave of BCR-ABL inhibitors

The introduction of the BCR-ABL kinase inhibitor imatinib mesylate (Gleevec; Novartis) revolutionized the treatment of chronic myeloid leukaemia (CML). However, most patients with CML receiving imatinib still harbour molecular residual disease and some develop resistance associated with ABL kinase domain mutations. The second-generation BCR-ABL inhibitors nilotinib (Tasigna; Novartis) and dasatinib (Sprycel; Bristol-Myers Squibb) have shown significant activity after imatinib failure in clinical trials, but still face similar obstacles to imatinib, including negligible activity against the frequent BCR-ABL T315I mutation and modest effects in advanced phases of CML. Various medicinal chemistry efforts, in part aided by structural studies of the ABL kinase-imatinib complex have resulted in the synthesis of a new generation of BCR-ABL inhibitors, some of which have shown encouraging preliminary activity in clinical trials, including against T315I mutants. Here, we discuss these emerging therapies, which have the potential to improve the outcome of patients with CML.     

Gilteritinib for the treatment of relapsed and/or refractory FLT3-mutated acute myeloid leukemia

ABSTRACT

Introduction: The receptor tyrosine kinase FLT3 is the most commonly mutated gene in acute myeloid leukemia (AML). FLT3-internal tandem duplication mutations are associated with an increased risk of relapse, and a number of small molecule inhibitors of FLT3 have been developed. The highly potent and selective FLT3 kinase inhibitor gilteritinib is the first tyrosine kinase inhibitor approved as monotherapy for the treatment of relapsed and/or refractory FLT3-mutated AML.

Areas covered: We review the biology and prognostic significance of FLT3 mutations in AML and discuss the pharmacology, clinical efficacy, and toxicity profile of gilteritinib. We also summarize important differences among the various FLT3 inhibitors that are currently approved or under development and highlight areas of ongoing research.

Expert opinion: Gilteritinib has been shown to improve survival compared to salvage chemotherapy in relapsed and/or refractory FLT3-mutated AML. Gilteritinib is orally available with a favorable toxicity profile and as such is quickly becoming the standard of care for this patient population. Ongoing clinical trials are evaluating gilteritinib in combination with frontline chemotherapy, in combination with other agents such as venetoclax and azacitidine for patients who are ineligible for standard induction therapy, and as a maintenance agent.     

A safety evaluation of omacetaxine mepesuccinate for the treatment of chronic myeloid leukemia

ABSTRACT

Introduction: Therapy of chronic myeloid leukemia (CML) has been completely transformed by the development of tyrosine kinase inhibitors (TKIs). However, a subset of patients will fail TKI therapy due to resistance or intolerance. Omacetaxine mepesuccinate (OM), a protein translation inhibitor, is currently the only approved therapy that does not directly target the kinase domain. It has activity for CML patients irrespective of the phase or underlying kinase domain mutation status.

Areas covered: We searched the MEDLINE database for articles published in English on homoharringtonine or omacetaxine from 1970 to present. This article reviews the pharmacokinetics of OM and its clinical evolution for the treatment of CML pre- and post TKI development. Toxicity profile, drug administration and future directions are also discussed.

Expert opinion: OM represents a unique addition to the CML therapeutic armamentarium with its distinct mechanism of action and activity. The adverse event profile is manageable and with subcutaneous administration at the approved dose, cardiac toxicity is no longer a concern. The recent approval of home administration will facilitate access to this therapy and increase patient compliance. We conclude with specific scenarios where OM use should be considered in CP and AP-CML patients in the era of TKI therapy.