Summary
In the past few years research in the underlying pathogenic mechanisms of acute myeloid leukaemia (AML) has led to remarkable advances in our understanding of the disease. Cytogenetic and ...molecular aberrations are the most important factors in determining response to chemotherapy as well as long‐term outcome, but beyond prognostication are potential therapeutic targets. Our increased understanding of the pathogenesis of AML facilitated by next‐generation sequencing has spurred the development of new compounds in the treatment of AML, particularly the creation of small molecules that target the disease on a molecular level. Many of the hopeful predictions outlined in our AML review of 2018 are now therapeutic realities: gemtuzumab ozogamicin, venetoclax, FLT3 inhibitors (midostaurin, gilteritinib), IDH inhibitors (ivosidenib, enasidenib), CPX‐351, glasdegib, oral decitabine, and oral azacitidine. Others may soon be (quizartinib, APR246 magrolimab, menin inhibitors). The wealth of positive data allows reconsideration of what might soon be new standards of care in younger and older patients with AML. In this review we give an overview of recently approved therapies in AML and address present and future research directions.
Genomic investigations of acute myeloid leukemia (AML) have demonstrated that several genes are recurrently mutated, leading to new genomic classifications, predictive biomarkers, and new therapeutic ...targets. Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 30% of all AML cases, with the internal tandem duplication (ITD) representing the most common type of FLT3 mutation (FLT3-ITD; approximately 25% of all AML cases). FLT3-ITD is a common driver mutation that presents with a high leukemic burden and confers a poor prognosis in patients with AML. The prognostic value of a FLT3 mutation in the tyrosine kinase domain (FLT3-TKD), which has a lower incidence in AML (approximately 7-10% of all cases), is uncertain. Accumulating evidence demonstrates that FLT3 mutational status evolves throughout the disease continuum. This so-called clonal evolution, together with the identification of FLT3-ITD as a negative prognostic marker, serves to highlight the importance of FLT3-ITD testing at diagnosis and again at relapse. Earlier identification of FLT3 mutations will help provide a better understanding of the patient's disease and enable targeted treatment that may help patients achieve longer and more durable remissions. First-generation FLT3 inhibitors developed for clinical use are broad-spectrum, multikinase inhibitors; however, next-generation FLT3 inhibitors are more specific, more potent, and have fewer toxicities associated with off-target effects. Primary and secondary acquired resistance to FLT3 inhibitors remains a challenge and provides a rationale for combining FLT3 inhibitors with other therapies, both conventional and investigational. This review focuses on the pathological and prognostic role of FLT3 mutations in AML, clinical classification of the disease, recent progress with next-generation FLT3 inhibitors, and mechanisms of resistance to FLT3 inhibitors.
Research into the underlying pathogenic mechanisms of acute myeloid leukemia (AML) has led to remarkable advances in our understanding of the disease. Mutations now allow us to explore the enormous ...diversity among cytogenetically defined subsets of AML, particularly the large subset of cytogenetically normal AML. Despite the progress in unraveling the tumor genome, only a small number of recurrent mutations have been incorporated into risk-stratification schemes and have been proven to be clinically relevant, targetable lesions. The current World Health Organization Classification of myeloid neoplasms and leukemia includes eight AML categories defined by recurrent genetic abnormalities as well as three categories defined by gene mutations. We here discuss the utility of molecular markers in AML in prognostication and treatment decision-making. New therapies based on targetable markers include IDH inhibitors (ivosidenib, enasidenib), venetoclax-based therapy, FLT3 inhibitors (midostaurin, gilteritinib, and quizartinib), gemtuzumab ozogamicin, magrolimab and menin inhibitors.
Summary
In the past few years, research in the underlying pathogenic mechanisms of acute myeloid leukaemia (AML) has led to remarkable advances in our understanding of the disease. Cytogenetic and ...molecular aberrations are the most important factors in determining response to chemotherapy as well as long‐term outcome, but beyond prognostication are potential therapeutic targets. Our increased understanding of the pathogenesis of AML, facilitated by next‐generation sequencing, has spurred the development of new compounds in the treatment of AML, particularly the creation of small molecules that target the disease on a molecular level. Various new agents, such as tyrosine kinase inhibitors, immune checkpoint inhibitors, monoclonal or bispecific T‐cell engager antibodies, metabolic and pro‐apoptotic agents are currently investigated within clinical trials. The highest response rates are often achieved when new molecularly targeted therapies are combined with standard chemotherapy. Presented here is an overview of novel therapies currently being evaluated in AML.
Oral use of the selective FLT3 kinase inhibitor gilteritinib in patients who had relapsed or refractory acute myeloid leukemia with
FLT3
mutations led to a median overall survival of 9.3 months (vs. ...5.6 months with standard chemotherapy) and complete remission with full or partial hematologic recovery in 34.0% of patients (vs. 15.3%).
Since the Food and Drug Administration approval of imatinib for treatment of chronic myeloid leukemia in 2001, tyrosine kinase inhibitors (TKIs) have become a mainstay in the care of many ...malignancies. In acute myeloid leukemia (AML), activating mutations in the FMS-like tyrosine kinase 3 (
FLT3
) gene result in survival and proliferation of leukemic blasts and are associated with adverse prognosis. Therefore, the FLT3 receptor is an appealing target for inhibition. Multiple small molecule TKIs are currently in development for
FLT3
-mutated AML, and agents are beginning to show promising efficacy. In other malignancies, the development of resistance to TKIs during the course of therapy has proven to be a challenge, and thus far, in clinical trials of FLT3 TKIs, resistance to inhibition represents a significant barrier to successful FLT3 inhibition. Understanding the mechanisms of resistance and overcoming these obstacles to target inhibition will be central to the success of these agents.
The recently updated World Health Organization (WHO) Classification of myeloid neoplasms and leukemia reflects the fact that research in the underlying pathogenic mechanisms of acute myeloid leukemia ...(AML) has led to remarkable advances in our understanding of the disease. Gene mutations now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, particularly the large subset of cytogenetically normal AML. Despite the progress in unraveling the tumor genome, only a small number of recurrent mutations have been incorporated into risk‐stratification schemes and have been proven to be clinically relevant, targetable lesions. We here discuss the utility of molecular markers in AML in prognostication and treatment decision making, specifically highlighting the aberrations included in the current WHO classification.
This randomized, open-label, phase 2b study (NCT01565668) evaluated the efficacy and safety of 2 dosing regimens of quizartinib monotherapy in patients with relapsed/refractory (R/R) FLT3-internal ...tandem duplication (ITD)–mutated acute myeloid leukemia (AML) who previously underwent transplant or 1 second-line salvage therapy. Patients (N = 76) were randomly assigned to 30- or 60-mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral quizartinib dihydrochloride. Allelic frequency of at least 10% was defined as FLT3-ITD–mutated disease. Coprimary endpoints were composite complete remission (CRc) rates and incidence of QT interval corrected by Fridericia's formula (QTcF) of more than 480 ms (grade 2 or greater). Secondary endpoints included overall survival (OS), duration of CRc, bridge to transplant, and safety. CRc rates were 47% in both groups, similar to earlier reports with higher quizartinib doses. Incidence of QTcF above 480 ms was 11% and 17%, and QTcF above 500 ms was 5% and 3% in the 30- and 60-mg groups, respectively, which is less than earlier reports with higher doses of quizartinib. Median OS (20.9 and 27.3 weeks), duration of CRc (4.2 and 9.1 weeks), and bridge to transplant rates (32% and 42%) were higher in the 60-mg groups than in the 30-mg group. Dose escalation occurred in 61% and 14% of patients in the 30- and 60-mg groups, respectively. This high clinical activity of quizartinib at the evaluated doses is consistent with previous reports with an improved safety profile. Need to dose-escalate more than half of patients who received quizartinib 30 mg also supports further investigation of treatment with quizartinib 60 mg/day.
•Quizartinib at 60 mg/day (vs 30 mg/day) was associated with higher overall response, survival, and bridge to transplant.•The benefit-risk profile of quizartinib in relapsed or refractory FLT3-ITD–mutated AML warrants further evaluation of 60-mg once-daily dose.
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Genomic studies have revealed significant branching heterogeneity in cancer. Studies of resistance to tyrosine kinase inhibitor therapy have not fully reflected this heterogeneity because resistance ...in individual patients has been ascribed to largely mutually exclusive on-target or off-target mechanisms in which tumors either retain dependency on the target oncogene or subvert it through a parallel pathway. Using targeted sequencing from single cells and colonies from patient samples, we demonstrate tremendous clonal diversity in the majority of acute myeloid leukemia (AML) patients with activating FLT3 internal tandem duplication mutations at the time of acquired resistance to the FLT3 inhibitor quizartinib. These findings establish that clinical resistance to quizartinib is highly complex and reflects the underlying clonal heterogeneity of AML.
•Polyclonal mechanisms of resistance, demonstrated by single-cell analysis, occur in the majority of AML patients who relapse on quizartinib.
Purpose of Review
This review aims to summarize the pathophysiology, clinical presentation, and management of acute myeloid leukemia (AML) with FMS-like tyrosine kinase-3 (FLT3) mutations.
Recent ...Findings
The recent European Leukemia Net (ELN2022) recommendations re-classified AML with FLT3 internal tandem duplications (FLT3-ITD) as intermediate risk regardless of Nucleophosmin 1 (NPM1) co-mutation or the FLT3 allelic ratio. Allogeneic hematopoietic cell transplantation (alloHCT) is now recommended for all eligible patients with FLT3-ITD AML. This review outlines the role of FLT3 inhibitors in induction and consolidation, as well as for post-alloHCT maintenance. It outlines the unique challenges and advantages of assessing FLT3 measurable residual disease (MRD) and discusses the pre-clinical basis for the combination of FLT3 and menin inhibitors. And, for the older or unfit patient ineligible for upfront intensive chemotherapy, it discusses the recent clinical trials incorporating FLT3 inhibitors into azacytidine- and venetoclax-based regimens. Finally, it proposes a rational sequential approach for integrating FLT3 inhibitors into less intensive regimens, with a focus on improved tolerability in the older and unfit patient population.
Summary
The management of AML with FLT3 mutation remains a challenge in clinical practice. This review provides an update on the pathophysiology and therapeutic landscape of FLT3 AML, as well as a clinical management framework for managing the older or unfit patient ineligible for intensive chemotherapy.
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