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 role of FLT3 kinase as an AML therapy target

FMS-like tyrosine kinase-3 (FLT3) is a tyrosine kinase receptor involved in the survival and expansion of hematopoietic stem progenitors. A constitutively activated, mutated form of FLT3, is expressed in approximately 30% of de novo acute myeloid leukemia (AML) and about 6% of acute lymphoblastic leukemia (ALL) cases. Since mutant FLT3 has emerged as an attractive therapeutic target, there are several FLT3 inhibitors currently undergoing evaluation in different phases of clinical trials. However, although many aspects of the intracellular signaling mediated by oncogenic FLT3 have been revealed, what is the best strategy to inhibit FLT3 and how FLT3 inhibitors should be developed for AML treatment is poorly defined. Despite promising in vitro studies, where most FLT3 inhibitors show potent efficacy at nanomolar concentrations, clinical responses in AML patients are moderate and temporary. Furthermore, under prolonged therapy, FLT3 mutation-positive leukemic cells rapidly develop resistance to FLT3 inhibitors when used as monotherapy. Considering that there is no uniform mechanism of resistance triggered by FLT3 inhibitors, it will be necessary to develop new agents that target FLT3, and that can be used consecutively or in combination with conventional cytotoxic therapeutics. On the other hand, given that overexpression of FLT3 ligand (FL), occurring after myelosuppressive therapy, reduces the efficacy of FLT3 inhibitors, targeting both FL and FLT3 kinase, might be more effective approach in AML treatment. Here, we summarize up-to-date studies on FLT3 structure, its mutation status and role in malignant signal trafficking. We also review why FLT3 targeted therapies have not revolutionized AML treatment.     

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.     

Fms样酪氨酸激酶抑制剂治疗急性髓性白血病的新进展

Fms样酪氨酸激酶(FLT3)属于Ⅲ型受体酪氨酸蛋白激酶家族,其异常表达见于大部分急性髓性白血病(AML)病人,包括野生型受体与配体的协同表达,内部串连复制及活化环突变,表达持续性磷酸化活化的FLT3,对预后的判断具有重要意义。FLT3抑制剂主要有5类及热休克蛋白90抑制剂,实验室研究与初步的临床试验显示出其对AML的治疗价值。     

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.     

FLT3 and acute myelogenous leukemia: biology, clinical significance and therapeutic applications

Acute myelogenous leukemia (AML) is a difficult disease to treat, and better treatments are needed. Molecular targeted therapy represents a novel therapeutic approach. The FLT3 tyrosine kinase receptor is mutated in approximately one-fourth to one-third of patients with AML. Normally, binding of FLT3 ligand to the FLT3 receptor leads to phosphorylation of tyrosine residues and activation of the receptor. This in turn leads to induction of intracellular signaling pathways essential to regulation of cell proliferation and apoptosis. Two classes of FLT3 activating mutations have been identified in AML patients: internal tandem duplications (ITDS) and point mutations in the activating loop of the kinase domain. Both mutations result in constitutive FLT3 tyrosine kinase activity and lead to transformation of hematopoietic cell lines in vivo and in vitro. FLT3 ITDs are also an independent poor prognostic factor for overall survival and disease free survival in patients with AML. Therefore, targeting FLT3 mutations represents a potential therapeutic target for AML. This review will discuss the biology and clinical significance of FLT3 and FLT3 mutations in cell growth and signaling. In addition, I will discuss some of the novel FLT3 inhibitors which are entering clinical trials for AML.     

Novel FLT3 tyrosine kinase inhibitors

Acute myeloid leukaemia (AML) is an aggressive haematological malignancy that is curable in approximately 40% of cases. Activating mutations of the receptor tyrosine kinase FLT3 (FMS-like tyrosine kinase-3) are the single most common molecular abnormalities in AML and are associated with a distinctly worse prognosis. In an effort to target this mutation and improve outcomes in this subgroup of AML patients, several novel small-molecule FLT3 tyrosine kinase inhibitors are currently in development. Some of these FLT3 inhibitors are useful only as laboratory tools, while others clearly have clinical potential. These compounds are derived from a wide variety of chemical classes and differ significantly both in their potency and selectivity. This review summarises these developments and examines these novel agents with regard to both the assays used to characterise them and their clinical potential.     

Novel FLT3 tyrosine kinase inhibitors

Acute myeloid leukaemia (AML) is an aggressive haematological malignancy that is curable in ~ 40% of cases. Activating mutations of the receptor tyrosine kinase FLT3 (FMS-like tyrosine kinase-3) are the single most common molecular abnormalities in AML and are associated with a distinctly worse prognosis. In an effort to target this mutation and improve outcomes in this subgroup of AML patients, several novel small-molecule FLT3 tyrosine kinase inhibitors are currently in development. Some of these FLT3 inhibitors are useful only as laboratory tools, while others clearly have clinical potential. These compounds are derived from a wide variety of chemical classes and differ significantly both in their potency and selectivity. This review summarises these developments and examines these novel agents with regard to both the assays used to characterise them and their clinical potential.     

FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML

An appealing therapeutic target in AML is constitutively activated, mutant FLT3, which is expressed in a subpopulation of AML patients and is generally a poor prognostic indicator in patients under the age of 65. There are currently several FLT3 inhibitors that are undergoing clinical investigation. However, the discovery of drug-resistant leukemic blast cells in FLT3 inhibitor-treated AML patients has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to circumvent drug resistance. Here, we provide an overview of FLT3 inhibitors under preclinical and clinical investigation, and we discuss mechanisms whereby AML cells develop resistance to FLT3 inhibitors, and the ways in which combination therapy could potentially be utilized to override drug resistance. We discuss how the cross-talk between major downstream signaling pathways, such as PI3K/PTEN/Akt/mTOR, RAS/Raf/MEK/ERK, and Jak/STAT, can be exploited for therapeutic purposes by targeting key signaling molecules with selective inhibitors, such as mTOR inhibitors, HSP90 inhibitors, or farnesyltransferase inhibitors, and identifying those agents with the ability to positively combine with inhibitors of FLT3, such as PKC412 and sunitinib. With the widespread onset of drug resistance associated with tyrosine kinase inhibitors, due to mechanisms involving development of point mutations or gene amplification of target proteins, the use of a multi-targeted therapeutic approach is of potential clinical benefit.     

Tandutinib, an oral, small-molecule inhibitor of FLT3 for the treatment of AML and other cancer indications

An improved understanding of acute myelogenous leukemia (AML) over the past two decades has led to a characterization of associated recurring cytogenetic abnormalities. AML is often driven by the overexpression or constitutive activation of receptor tyrosine kinases such as Fms-like tyrosine kinase 3 (FLT3), which serves as a good therapeutic target. Millennium Pharmaceuticals Inc's tandutinib (MLN-518) is an orally active inhibitor of FLT3 kinase and family members PDGFR beta and c-Kit. Tandutinib inhibited FLT3 phosphorylation, downstream signaling and malignant growth in vitro and in animal models. The drug exhibited limited activity as a single agent in phase I and II clinical trials in patients with AML and myelodysplastic syndrome, but displayed promising antileukemic activity (90% complete remissions) in a phase I/II trial in patients with newly diagnosed AML when administered in combination with cytarabine and daunorubicin. Phase II clinical trials for tandutinib are ongoing in patients with AML or renal cell carcinoma.     

VX-322: a novel dual receptor tyrosine kinase inhibitor for the treatment of acute myelogenous leukemia

In acute myelogenous leukemia (AML), the FLT3 receptor tyrosine kinase (RTK) is highly expressed with 30% of patients expressing a mutated, constitutively active form of this protein. To inhibit this receptor, VX-322 was developed and found to be very potent against both the FLT3 and c-KIT RTKs with enzyme K(i) values of <1 nM and a cellular IC(50) between 1 and 5 nM. It was efficacious in a FLT3-ITD dependent myeloproliferative mouse model, doubling survival compared to other FLT3 inhibitors, with 25% of the mice cured. Upon treatment of primary AML patient blast cells, the dual inhibition of FLT3 and c-KIT was superior to inhibitors targeting a single RTK. Thus, this compound may represent an improved pharmacologic and selectivity profile that could be effective in the treatment of AML.     

Midostaurin treatment in FLT3-mutated acute myeloid leukemia and systemic mastocytosis

Introduction: A number of tyrosine kinase inhibitors (TKIs) have been developed that inhibit the constitutively activated kinase activity caused by activating tyrosine kinase mutations, such as FLT3 or KIT, thus interrupting signaling pathways. Currently, midostaurin is the only approved TKI as monotherapy for aggressive systemic mastocytosis (SM), SM with associated hematological neoplasm, or mast cell leukemia displaying a KIT mutation as well as in combination with standard intensive chemotherapy for adult patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML).

Areas covered: We provide a concise review of the pharmacology, tolerability and clinical efficacy of midostaurin and emerging new treatment options for ASM and FLT3-mutated AML.

Expert commentary: Currently, midostaurin is the only approved TKI in aggressive SM, SM with associated hematological neoplasm, or mast cell leukemia inducing responses including complete remissions. With regard to AML, midostaurin is the first drug to receive regulatory approval in this indication in the molecularly defined subgroup of AML with FLT3 mutations. By introduction of this new standard in AML with FLT3 mutations, the bare has been raised for future approvals of next generation FLT3 inhibitors which will be based increasingly on head to head comparisons with midostaurin.     

Targeting FLT3 kinase in acute myelogenous leukemia: progress, perils, and prospects

Activating mutations of the FLT3 receptor tyrosine kinase are the most common recurring genetic abnormality in acute myelogenous leukemia (AM). Inhibition of FLT3 kinase activity by small molecule inhibitors has been proposed as a novel therapeutic approach AML. The pre-clinical and clinical development of candidate FLT3 inhibitors will be reviewed.     

The role of quizartinib in the treatment of acute myeloid leukemia

Introduction: Approximately one-third of the patients with acute myeloid leukemia (AML) harbor internal tandem duplication (ITD) in the gene encoding FMS-like tyrosine kinase 3 (FLT3-ITD), which is associated with poor prognosis. Over the course of the last decade, several FLT3 inhibitors have been developed. Nevertheless, the pharmacokinetic limitations of some of these compounds as well as their potency have limited their therapeutic efficacy. Quizartinib (AC220) is a second-generation FLT3 inhibitor that has shown promising activity in AML in Phase II clinical trials.

Areas covered: The pharmacokinetic, mechanism of action and resistance as well as clinical studies of quizartinib in AML are reported here in detail

Expert opinion: Quizartinib is potent and selective FLT3 tyrosine kinase inhibitor with significant activity in both FLT3-mutant and wild-type AML. The quality and duration of achievable response thus far seen with this agent is suboptimal. Quizartinib in combination with chemotherapy might result in improved outcome and results of these trials are eagerly awaited. In addition, quizartinib in combination with other agents tackling the bone marrow microenvironment and FLT3 cooperative pathways may enhance response to quizartinib.     

Small molecule FLT3 tyrosine kinase inhibitors

Activating mutations of FLT3 (FMS-Like Tyrosine kinase-3) are the most common molecular abnormality in acute myeloid leukemia (AML). Their presence is associated with a worse prognosis, and the recognition of this has led to the development of several new small molecule FLT3 tyrosine kinase inhibitors. In this review, we summarize these developments and compare and contrast these novel agents both with regards to the assays used to characterize them as well as to their clinical potential.     

Molecularly targeted therapies for pediatric acute myeloid leukemia: progress to date

While acute myeloid leukemia (AML) is significantly less common than acute lymphoblastic leukemia (ALL) in childhood, it is significantly more deadly with only half as many children likely to be cured with standard therapy. In addition, the typical treatment for AML is among the most toxic of treatments for pediatric cancer; it includes intensive multiagent chemotherapy and, often, hematopoietic stem cell transplantation. Given the poor prognosis of pediatric AML and the significant toxicity of standard AML therapy, novel therapies are needed. Improved understanding of the molecular and cellular biology of leukemia has facilitated the development of molecularly targeted therapies.In this article, we review progress to date with agents that are showing promise in the treatment of pediatric AML including targeted immunoconjugates, inhibitors of signaling molecules (e.g. FMS-like tyrosine kinase 3 [FLT3], farnesyltransferase, and mammalian target of rapamycin [mTOR]), agents that target epigenetic regulation of gene expression (DNA methyltransferase inhibitors and histone deacetylase inhibitors), and proteasome inhibitors. For the specific agents in each of these classes, we summarize the published preclinical data and the clinical trials that have been completed, are in progress, or are being planned for children with AML. Finally, we discuss potential challenges to the success of molecularly targeted therapy including demonstrating adequate targeting of leukemia stem cells, developing synergistic and tolerable combinations of agents, and designing adequately powered clinical trials to test efficacy in molecularly defined subsets of patients.     

Lestaurtinib,a multitargeted tyrosinse kinase inhibitor: from bench to bedside

Importance of the field: Internal tandem duplication of the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) is a common recurring mutation in acute myeloid leukemia (AML) with normal karyotype, and the presence of FLT3-ITD confers a poor prognosis on this large subgroup of AML patients. Since the discovery of lestaurtinib as a potent FLT3 inhibitor, in 1985, there has been considerable interest in the development of this agent (CEP-701, Cephalon, Frazer, PA, USA) for treatment of this population.

Areas covered in this review: An extensive literature search was conducted that included published articles and abstracts on the preclinical and clinical development of this agent spanning the last decade.

What the reader will gain: The review describes the historical development of this agent and reviews the available preclinical and clinical data on lestaurtinib and expands on potential future directions in development of this agent.

Take home message: Lestaurtinib is a multi targeted tyrosine kinase inhibitor which has been shown to potently inhibit FLT3 at nanomolar concentrations in preclinical studies, leading to its rapid development as a potential targeted agent for treatment of AML. Phase I studies have shown lestaturtinib to be an active agent particularly when used in combination with cytotoxic drugs. Currently, Phase II and Phase III studies are underway aiming to establish the future of this agent as a treatment option for patients with FLT3-ITD AML.     

FLT3在急性白血病靶向治疗中的研究进展

FMS-like Tyrosine Kinase 3(FLT3)是一种受体酪氨酸激酶,在造血干细胞、前体B细胞等的增殖、分化以及存活中具有重要作用。急性白血病的发病往往伴随着FLT3的异常活化,FLT3突变是造成其异常活化的主要原因,且FLT3突变的患者往往具有较差的预后。FLT3抑制剂的研究为白血病靶向治疗提供了广阔的前景。     

New therapeutic approaches to acute myeloid leukemia

Background: The heterogeneity of acute myeloid leukemia (AML) has been established by many new insights into the pathogenesis and treatment of patients with AML. Understanding the basic cellular and molecular pathogenesis of leukemic cells is vital to the development of new treatment approaches. Objective/methods: To review progress until now with agents that are showing promise in the treatment of AML, we summarize the published preclinical and clinical trials that have been completed. Results: Based on recent progress of investigations, more specifically targeted agents have been developed for the treatment of AML such as tyrosine kinase inhibitors, monoclonal antibodies, epigenetic agents, antiangiogenic agents, and farnesyl transferase inhibitors. Conclusion: In the future, in addition to performing therapeutic trials of these agents, it will be important to identify other highly specific therapeutic agents based on our evolving understanding of the biology of AML.