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.     

An evaluation of glasdegib for the treatment of acute myelogenous leukemia

ABSTRACT

Introduction

Despite recent advances in the treatment of adult acute myelogenous leukemia (AML), the overall outcome remains dismal especially in high-risk AML patients, including the elderly and the relapsed/refractory populations. In this setting, various clinical trials have recently explored novel therapeutic agents either used alone or in combination with intensive chemotherapy or low-intensity treatments.     

Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia

Introduction: Gemtuzumab ozogamicin (GO) is an antibody-drug conjugate consisting of a monoclonal antibody targeting CD33 linked to a cytotoxic derivative of calicheamicin. Despite the known clinical efficacy in relapsed/refractory acute myeloid leukemia (AML), GO was withdrawn from the market in 2010 due to increased early deaths witnessed in newly diagnosed AML patients receiving GO + intensive chemotherapy. In 2017, new data on the clinical efficacy and safety of GO administered on a fractionated-dosing schedule led to re-approval for newly diagnosed and relapsed/refractory AML.

Areas covered: Addition of fractionated GO to chemotherapy significantly improved event-free survival of newly diagnosed AML patients with favorable and intermediate cytogenetic-risk disease. GO monotherapy also prolonged survival in newly diagnosed unfit patients and relapse-free survival in relapsed/refractory AML. This new dosing schedule was associated with decreased incidence of hepatotoxicity, veno-occlusive disease, and early mortality.

Expert commentary: GO represents the first drug-antibody conjugate approved (twice) in the United States for AML. Its re-emergence adds a valuable agent back into the armamentarium for AML. The approval of GO as well as three other agents for AML in 2017 highlights the need for rapid cytogenetic and molecular characterization of AML and incorporation into new treatment algorithms.     

Vosaroxin is a novel topoisomerase-II inhibitor with efficacy in relapsed and refractory acute myeloid leukaemia

Introduction: Vosaroxin is a first-in-class anti-cancer quinolone that inhibits topoisomerase-II leading to cell cycle arrest and apoptosis. It has shown efficacy in a range of solid organ and haematopoietic tumours in vitro, and several clinical trials are underway or completed in the field of Acute Myeloid Leukaemia (AML). The treatment of relapsed and refractory AML is a clinical challenge, where long-term survival is rare without allogeneic haematopoietic stem cell transplantation.

Areas covered: We review the data from the published clinical trials of vosaroxin, including the recently presented Phase III VALOR study. In combination with intermediate dose cytarabine, vosaroxin almost doubled complete response (CR) rates in relapsed and refractory AML compared with cytarabine alone, and prolonged median survival by 1.4 months.

Expert opinion: Vosaroxin is a promising new agent in the treatment of AML, with the potential to improve CR rates in a high-risk group of patients with relapsed and refractory AML. However, higher CR rates have been associated with higher rates of treatment-related morbidity and mortality, especially in elderly/unfit patients. Maximising the potential of vosaroxin will therefore require the identification of patients most likely to benefit from vosaroxin-containing combination regimens.     

Lenalidomide in multiple myeloma: current role and future directions

Importance of the field: Lenalidomide and other new agents are improving survival of multiple myeloma patients. This review describes current data on lenalidomide in myeloma and how the unique properties of lenalidomide may lend its use in new settings, such as maintenance and preventive therapy.

Areas covered in this review: This review covers the activity of lenalidomide in multiple myeloma, efficacy in both newly diagnosed and relapsed/refractory patients, how to manage effectively common adverse events observed with lenalidomide, and its potential use in new settings based on clinical trials published up to 2009.

What the reader will gain: This review describes the mechanism of action of lenalidomide in myeloma which provides the basis for its clinical use in newly diagnosed, relapsed/refractory, and high-risk smoldering myeloma in combination with other agents. Strategies to reduce or effectively manage myelosuppression and thromboembolic events, the main adverse events associated with lenalidomide plus dexamethasone therapy, are also described.

Take home message: Lenalidomide is an oral immunomodulatory drug that is highly effective in treating multiple myeloma, has a favorable safety profile and is now being evaluated as maintenance therapy, preventive therapy and in combination with other new agents.     

Clinical management of mantle cell lymphoma in the elderly

ABSTRACT

Introduction: Mantle cell lymphoma (MCL) is a disease with an indolent histology, but mostly aggressive clinical course. While treatment can yield more promising results in younger patients, the disease is most diagnosed at a median age of approximately 70 years, and treatment in this group still presents a major challenge for oncohematologists. Unfortunately, due to comorbidities and poorer general status, the implementation of intensive treatment approaches with the cytarabine-based regimens and autologous stem cell transplantation is generally not possible, and the disease remains incurable, especially in elderly patients.

Areas covered: In this paper, the authors discuss the therapeutic options available for older patients with MCL in the first line and relapsed/refractory settings, indicating new therapeutic options, which may achieve longer remissions and overall survival.

Expert opinion: Although great progress has been made in the treatment of MCL in recent years, there remains a need for new treatment lines which can allow improved patient outcomes. Novel agents targeting altered the signal transduction pathways in MCL cells may offer more promise than traditional chemotherapy or immunochemotherapy and are currently being tested in clinical trials.     

The clinical development of FLT3 inhibitors in acute myeloid leukemia

Introduction: Activating mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur at high frequency in acute myeloid leukemia (AML), being detected in > 30% of patients at diagnosis and carrying a profound negative prognostic impact. The development of effective small molecule inhibitors of FLT3 has been the focus of an intensive international research effort in recent years.

Areas covered: The published results of the first decade of clinical trials of FLT3-targeted tyrosine kinase inhibitors are critically reviewed. Over this period, a first generation of compounds has followed an orderly progression from monotherapy studies through combination with chemotherapy and into advanced stage international trials in both relapsed and newly-diagnosed AML. Correlative laboratory studies performed alongside several of these studies have been highly illuminating, demonstrating close correlations between clinical activity and effective inhibition of FLT3, and highlighting potential drug resistance mechanisms.

Expert opinion: Clinical responses to several of the early multi-targeted agents were hindered by unfavorable pharmacokinetics and lack of potency. Newer, more potent FLT3 inhibitors such as sorafenib and AC220 possess the ability to achieve more sustained in vivo inhibition of FLT3 and have shown highly promising activity in early clinical studies. As these agents enter advanced stage trials, they carry the potential to make a major clinical impact in this disease. In future, FLT3 inhibitors may be effectively used in combination with other molecularly targeted agents.     

The preclinical discovery of vosaroxin for the treatment of acute myeloid leukemia

Introduction: Acute myeloid leukemia (AML) represents a disease with a very poor outcome and remains an area of significant unmet need necessitating novel therapeutic strategies. Among novel therapeutic agents, vosaroxin is a first-in-class anticancer quinolone derivative that targets topoisomerase II and induces site-selective double-strand breaks in DNA, leading to tumor cell apoptosis.

Areas covered: Herein, the authors provide a comprehensive review of the preclinical development of vosaroxin. This includes coverage of vosaroxin’s mechanism of action in addition to its pharmacology and of the main studies reported over the past few years with vosaroxin when used to treat adult AML.

Expert opinion: Given that vosaroxin is associated with fewer potential side effects, it may be of benefit to elderly patients with relapsed/refractory AML and to those with additional comorbidities who have previously received an anthracycline and cytarabine combination. Furthermore, vosaroxin also was seen to be active in multidrug-resistant preclinical models. However, further studies have to be performed to better evaluate its place in the armamentarium against AML.     

Chemotherapy options for previously untreated acute myeloid leukemia

Introduction: Intensive chemotherapy with cytarabine and an anthracycline for untreated acute myeloid leukemia (AML) has remained largely unchanged over the past 40 years, despite many large trials examining the choice and dosing of these agents.

Areas covered: We will review the major published clinical trials for untreated AML that have established the dosing choice and schedule for intensive therapy, as well as trials for patients not eligible for more intensive therapy. We will also discuss treatment considerations for subgroups of patients.

Expert opinion: While one or two cycles of anthracycline and cytarabine-based combination regimens remain the standard of care for younger and older patients with AML deemed fit to receive induction chemotherapy, controversy remains regarding the optimal selection and dosing schedule for anthracyclines. Low-intensity regimens, such as low-dose cytarabine and hypomethylating agents, can achieve a complete response even with adverse risk features, and can be used in a fit subset of older patients not eligible for clinical trial or transplant. Incorporation of new targeted agents, such as tyrosine kinase and small-molecule inhibitors, combined with better selection of drugs for unique patient cohorts, will likely be necessary to substantially improve outcomes in AML.     

Investigational FMS-like tyrosine kinase 3 inhibitors in treatment of acute myeloid leukemia

Introduction: Outcomes for the majority of patients with acute myeloid leukemia (AML) remain poor. Over the past decade, significant progress has been made in the understanding of the cytogenetic and molecular determinants of AML pathogenesis. One such advance is the identification of recurring mutations in the FMS-like tyrosine kinase 3 gene (FLT3). Currently, this marker, which appears in approximately one-third of all AML patients, not only signifies a poorer prognosis but also identifies an important target for therapy. FLT3 inhibitors have now undergone clinical evaluation in Phase I, II and III clinical trials, as both single agents and in combination with chemotherapeutics. Unfortunately, to date, none of the FLT3 inhibitors have gained FDA approval for the treatment of patients with AML. Yet, several promising FLT3 inhibitors are being evaluated in all phases of drug development.

Areas covered: This review aims to highlight the agents furthest along in their development. It also focuses on those FLT3 inhibitors that are being evaluated in combination with other anti-leukemia agents.

Expert opinion: The authors believe that the field of research for FLT3 inhibitors remains promising, despite the historically poor prognosis of this subgroup of patients with AML. The most promising areas of research will likely be the elucidation of the mechanisms of resistance to FLT3 inhibitors, and development of potent FLT3 inhibitors alone or in combination with hypomethylating agents, cytotoxic chemotherapy or with other targeted agents.     

Investigational therapies targeting CD37 for the treatment of B-cell lymphoid malignancies

Introduction: While chemotherapy still remains a cornerstone of oncologic therapy, immunotherapy with monoclonal antibodies has steadily improved the treatment strategy for several hematologic malignancies. New treatment options need to be developed for relapsed and refractory non-Hodgkin lymphoma (NHL) patients. Currently, novel agents targeting specific molecules on the surface of lymphoma cells, such as anti-CD37 antibodies, are under considerable investigation. Here we report on anti-CD37 targeting for the treatment of patients with B-cell NHL.

Areas covered: CD37 seems to be the perfect therapeutic target in patients with NHL. The CD37 antigen is abundantly expressed in B-cells, but is absent on normal stem cells and plasma cells. It is hoped that anti-CD37 monoclonal antibodies will increase the efficacy and reduce toxicity in patients with both newly diagnosed and relapsed and refractory disease. Recent clinical trials have shown promising outcomes for these agents, administered both as monotherapy and in combination with standard chemotherapeutics.

Expert opinion: The development of new therapeutic options might help to avoid cytotoxic chemotherapy entirely in some clinical settings. This article presents the latest state of the art on the new treatment strategies in NHL patients. It also discusses recently approved agents and available clinical trial data.     

Novel drugs for the treatment of chronic pruritus

ABSTRACT

Introduction: Chronic pruritus (CP) is a multidimensional condition severely affecting the quality of life of those affected. Although a multitude of topical and systemic agents are recommended for CP of different origins, the condition often remains refractory to treatment. However, a deeper understanding of the pathophysiology of CP is leading to the development of novel antipruritic drugs.

Areas covered: This paper reviews antipruritic therapies in development by gathering data from recently published articles and clinical trials databases. Interleukin-31 antibodies and other biologics, neurokinin-1 receptor antagonists, opioid-receptor agonists/antagonists, TrkA-antagonists, and ileal bile acid transporter inhibitors are discussed.

Expert opinion: Clinical trials have rendered promising data on the antipruritic efficacy and safety of novel drugs, but further studies are necessary to enhance our understanding of the different conditions associated with CP. High-quality clinical trial data is necessary for these agents to be approved for the treatment. Basic research should be intensified to identify pathways relevant for CP and to further the development of new specific antipruritic drugs.     

Endothelin as a target for drug development: Recent progress

Introduction: The prognosis of acute myeloid leukemia (AML) is improved in the last two decades, even though induction and consolidation chemotherapy has not involved new drugs. The more effective use of well-known agents as well as refinement of supportive care during the inevitable phase of severe pancytopenia following intensive chemotherapy accounts for the reduction of treatment-related death rate. In addition, mortality due to allogeneic and autologous stem cell transplantation has also been reduced, due to adoption of more effective therapies for graft versus host disease and other transplant-related complications.

Areas covered: The multitude of chromosomal and molecular abnormalities makes the treatment of AML a challenging prospect. In addition, genetic aberrations are not mutually exclusive and coexist in the leukemic cells. As a consequence, the clinical development of new biologic agents proceeds slowly. Data for this review were identified from PubMed and references from relevant articles published in English from 2000 to 2011.

Expert opinion: In Phase II studies, different new agents have been found to be active in AML and are currently under investigation in Phase III trials also in combination with conventional chemotherapy. In the near future, we would have more information about the possibility of introducing new drugs into daily practice.     

Enasidenib for the treatment of acute myeloid leukemia

Introduction: In August 2017, the United States Federal Drug Administration (FDA) approved enasidenib (Idhifa, Celgene/Agios) for adults with relapsed and refractory acute myelogenous leukemia (AML) with an IDH2 mutation. Enasidenib targets cells with mutant copies of isocitrate dehydrogenase-2 (IDH2), inhibiting the oncometabolite 2-hydroxyglutarte (2-HG) formed by the mutant IDH2.

Areas covered: We review the studies leading to enasidenib’s approval, as well as common side effects and safety issues experienced during the clinical trials. There is a focus on the diagnosis and treatment of these side effects including differentiation syndrome.

Expert commentary: We are experiencing a revolution in the understanding of the mechanism of AML. A majority of the effort has been concentrated on targeting gene mutations or pathway activations with precision therapeutics. Enasidenib is beneficial in a patient population that previously had limited treatment options. However, given the fact that enasidenib is a highly specific inhibitor of an early stable mutation, it is questionable whether a strategy of targeting a single mutation or pathway in relapsed AML will allow for better than the 20% complete remission (CR) rate observed with this therapy. The proper role for single mutation targeting in AML needs to be carefully considered.     

New developments in the management and treatment of newly diagnosed and relapsed/refractory multiple myeloma patients

Introduction: The introduction of autologous stem cell transplantation as well as novel agents such as proteasome inhibitors (bortezomib) and immunomodulatory drugs (IMiDs; thalidomide and lenalidomide) have significantly improved long-term outcome of multiple myeloma patients. However, patients with high-risk disease at diagnosis had less benefit from these new strategies. In addition, myeloma patients with lenalidomide and bortezomib double-refractory disease have a very poor survival.

Areas covered: Several next generation novel agents are active in patients with double-refractory disease including carfilzomib and pomalidomide. Various monoclonal antibodies are also promising in the setting of relapsed/refractory disease, including daratumumab, elotuzumab and lorvotuzumab mertansine. This editorial will focus on the most promising next generation novel agents for the treatment of multiple myeloma.

Expert opinion: Incorporation of these new novel agents in frontline therapies will lead to more effective and less toxic combination therapies. Furthermore, new diagnostic techniques such as gene-expression profiling and next-generation sequencing will hopefully result in more personalized treatments for molecularly-defined subgroups.     

An evaluation of enasidenib for the treatment of acute myeloid leukemia

ABSTRACT

Introduction: Despite recent progress, the prognosis of acute myeloid leukemia remains poor, mainly in older and in relapsed/refractory patients. Recently, a large number of novel agents have been developed thanks to a better understanding of its pathogenesis. Among these, the potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib (formerly AG-221), has demonstrated promising antileukemic activity by targeting IDH2 mutations.

Area covered: This review describes the mechanisms of action, the pharmacodynamic and pharmacokinetic properties, the safety, and efficacy of enasidenib. Phase I/II/III clinical trials are also reported and discussed.

Expert opinion: Enasidenib is a novel agent able to differentiate leukemic blasts in functional, maturating cells. This drug is characterized by oral bioavailability and good tolerability. As a monotherapy, it demonstrates clinical and laboratorial improvement, in 19.6% and 38.8% of cases respectively. Differentiation syndrome is the most relevant, potentially life-threatening side effect, which physicians must be aware of. The authors believe that the way forwards now is to explore the role of enasidenib as a chemoresistance revertant when associated with chemotherapy, as a ‘bridge to transplant’ or when associated other novel agents if we wish to maximize its use.     

Current investigational drugs in psoriasis

Introduction : The advent of biologic therapies has revolutionized the treatment of psoriasis. Increased understanding of immunogenetic pathways has allowed for the development of more selective targeted biologic therapies. Multiple new treatments are currently in development for the treatment of psoriasis. Preliminary data for many of these agents, particularly with regard to agents targeting the IL-23/Th17 pathway, are promising. Proven long-term safety, however, is an absolute necessity with newly developed drugs, and should, therefore, still be considered second-line agents to current established treatments with long-term safety data.

Areas covered : This review details the mechanisms of action of drugs currently in development or in clinical trials for the treatment of psoriasis, using clinical trial registries and associated publications. Readers will gain a comprehensive overview about the mechanism of action of emerging treatments targeting various immune pathways deeply involved in psoriasis. Pathogenesis, clinical efficacy and safety data for these treatments are discussed where available.

Expert opinion : Psoriasis remains a heavily undertreated systemic immune-mediated disease despite increased understanding of immunopathogenesis of the disease and advent of a multitude of novel therapeutic agents with potentially improved bioavailability and safety profiles. Limitations, however, remain in the realm of topical agents for treatment of mild to moderate psoriasis, which has seen little progress over the years. A concerted effort will need to be made among researchers, clinicians and patient advocacy groups to ensure new therapeutic agents are developed and gain proper exposure.