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Blood Reviews Mar 2022FLT3 mutations are the most common genetic aberrations found in acute myeloid leukemia (AML) and associated with poor prognosis. Since the discovery of FLT3 mutations... (Review)
Review
FLT3 mutations are the most common genetic aberrations found in acute myeloid leukemia (AML) and associated with poor prognosis. Since the discovery of FLT3 mutations and their prognostic implications, multiple FLT3-targeted molecules have been evaluated. Midostaurin is approved in the U.S. and Europe for newly diagnosed FLT3 mutated AML in combination with standard induction and consolidation chemotherapy based on data from the RATIFY study. Gilteritinib is approved for relapsed or refractory FLT3 mutated AML as monotherapy based on the ADMIRAL study. Although significant progress has been made in the treatment of AML with FLT3-targeting, many challenges remain. Several drug resistance mechanisms have been identified, including clonal selection, stromal protection, FLT3-associated mutations, and off-target mutations. The benefit of FLT3 inhibitor maintenance therapy, either post-chemotherapy or post-transplant, remains controversial, although several studies are ongoing.
Topics: Antineoplastic Agents; Humans; Leukemia, Myeloid, Acute; Mutation; Prognosis; Protein Kinase Inhibitors; fms-Like Tyrosine Kinase 3
PubMed: 34774343
DOI: 10.1016/j.blre.2021.100905 -
Best Practice & Research. Clinical... Jun 2019The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are... (Review)
Review
The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance.
Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Cytarabine; Daunorubicin; Glycine; Humans; Leukemia, Myeloid, Acute; Phenylurea Compounds; Proto-Oncogene Proteins c-bcl-2; Pyridines; Sulfonamides; Triazines
PubMed: 31203996
DOI: 10.1016/j.beha.2019.05.008 -
The New England Journal of Medicine Aug 2017Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population.
METHODS
We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival.
RESULTS
A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups.
CONCLUSIONS
The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Staurosporine; Young Adult; fms-Like Tyrosine Kinase 3
PubMed: 28644114
DOI: 10.1056/NEJMoa1614359 -
Haematologica Feb 2023Research into the underlying pathogenic mechanisms of acute myeloid leukemia (AML) has led to remarkable advances in our understanding of the disease. Mutations now... (Review)
Review
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.
Topics: Humans; Leukemia, Myeloid, Acute; Gemtuzumab
PubMed: 36722402
DOI: 10.3324/haematol.2022.280801 -
American Journal of Hematology Apr 2021Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in extra-cutaneous organs. (Review)
Review
OVERVIEW
Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in extra-cutaneous organs.
DIAGNOSIS
The major criterion is presence of multifocal clusters of spindled MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC CD25 expression, and presence of KITD816V mutation.
RISK STRATIFICATION
Establishing SM subtype as per the World Health Organization classification system is an important first step. Broadly, patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, the latter includes aggressive SM (ASM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). Identification of poor-risk mutations (ie, ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Recently, clinical and hybrid clinical-molecular risk models have been developed to more accurately assign prognosis in SM patients.
MANAGEMENT
Treatment goals for ISM patients are primarily directed towards anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to ameliorate disease-related organ dysfunction. High response rates have been seen with small-molecule inhibitors that target mutant-KIT, including midostaurin (Food and Drug Administration approved) or avapritinib (investigational). Other options for MC cytoreduction include cladribine or interferon-α, although head-to-head comparisons are lacking. Treatment of SM-AHN primarily targets the AHN component, particularly if an aggressive disease such as acute myeloid leukemia is present. Allogeneic stem cell transplant can be considered in such patients, or in those with relapsed/refractory advanced SM. Imatinib has a limited therapeutic role in SM; effective cytoreduction is limited to those with imatinib-sensitive KIT mutations.
Topics: Adult; Algorithms; Animals; Bone Marrow; Disease Management; Disease Models, Animal; Drugs, Investigational; Gain of Function Mutation; Hematologic Neoplasms; Humans; Hydroxyurea; Interleukin-2 Receptor alpha Subunit; Kaplan-Meier Estimate; Leukemia, Mast-Cell; Mast Cells; Mastocytosis, Systemic; Mice; Mice, Transgenic; Mutation, Missense; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Risk Assessment; Tryptases
PubMed: 33524167
DOI: 10.1002/ajh.26118 -
Pharmacological Research Jan 2023Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one of the most important drug targets in the 21st... (Review)
Review
Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one of the most important drug targets in the 21st century. There are 72 FDA-approved therapeutic agents that target about two dozen different protein kinases and three of these drugs were approved in 2022. Of the approved drugs, twelve target protein-serine/threonine protein kinases, four are directed against dual specificity protein kinases (MEK1/2), sixteen block nonreceptor protein-tyrosine kinases, and 40 target receptor protein-tyrosine kinases. The data indicate that 62 of these drugs are prescribed for the treatment of neoplasms (57 against solid tumors including breast, lung, and colon, ten against nonsolid tumors such as leukemia, and four against both solid and nonsolid tumors: acalabrutinib, ibrutinib, imatinib, and midostaurin). Four drugs (abrocitinib, baricitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases (atopic dermatitis, psoriatic arthritis, rheumatoid arthritis, Crohn disease, and ulcerative colitis). Of the 72 approved drugs, eighteen are used in the treatment of multiple diseases. The following three drugs received FDA approval in 2022 for the treatment of these specified diseases: abrocitinib (atopic dermatitis), futibatinib (cholangiocarcinomas), pacritinib (myelofibrosis). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and trilaciclib. This review summarizes the physicochemical properties of all 72 FDA-approved small molecule protein kinase inhibitors including lipophilic efficiency and ligand efficiency.
Topics: Humans; Dermatitis, Atopic; Neoplasms; Protein Kinase Inhibitors; Protein Kinases
PubMed: 36403719
DOI: 10.1016/j.phrs.2022.106552 -
Blood Cancer Journal May 2021Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse... (Review)
Review
Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITD in AML has been clearly proven, the prognostic significance of FLT3-TKD remains speculative. Current guidelines recommend rapid molecular testing for FLT3 at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3 can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3 AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3 AML have improved outcomes in patients with FLT3 AML. Nevertheless, the short duration of remission with single-agent FLT3i's in R/R FLT3 AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i's remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3 AML.
Topics: Aniline Compounds; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Disease Management; Drug Resistance, Neoplasm; Humans; Leukemia, Myeloid, Acute; Mutation; Protein Kinase Inhibitors; Pyrazines; Staurosporine; fms-Like Tyrosine Kinase 3
PubMed: 34045454
DOI: 10.1038/s41408-021-00495-3 -
Lancet (London, England) Aug 2018For several decades, few substantial therapeutic advances have been made for patients with acute myeloid leukaemia. However, since 2017 unprecedented growth has been... (Review)
Review
For several decades, few substantial therapeutic advances have been made for patients with acute myeloid leukaemia. However, since 2017 unprecedented growth has been seen in the number of drugs available for the treatment of acute myeloid leukaemia, with several new drugs receiving regulatory approval. In addition to advancing our therapeutic armamentarium, an increased understanding of the biology and genomic architecture of acute myeloid leukaemia has led to refined risk assessment of this disease, with consensus risk stratification guidelines now incorporating a growing number of recurrent molecular aberrations that aid in the selection of risk-adapted management strategies. Despite this promising recent progress, the outcomes of patients with acute myeloid leukaemia remain unsatisfactory, with more than half of patients ultimately dying from their disease. Enrolment of patients into clinical trials that evaluate novel drugs and rational combination therapies is imperative to continuing this progress and further improving the outcomes of patients with acute myeloid leukaemia.
Topics: Aminoglycosides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Consolidation Chemotherapy; Cytarabine; Gemtuzumab; Genomics; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Patient Selection; Recurrence; Remission Induction; Risk Assessment; Risk Factors; Staurosporine
PubMed: 30078459
DOI: 10.1016/S0140-6736(18)31041-9 -
Leukemia May 2022The 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated... (Review)
Review
Infectious complications of targeted drugs and biotherapies in acute leukemia. Clinical practice guidelines by the European Conference on Infections in Leukemia (ECIL), a joint venture of the European Group for Blood and Marrow Transplantation (EBMT), the European Organization for Research and...
The 9th web-based European Conference on Infections in Leukemia (ECIL-9), held September 16-17, 2021, reviewed the risk of infections and febrile neutropenia associated with more recently approved immunotherapeutic agents and molecular targeted drugs for the treatment of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Novel antibody based treatment approaches (inotuzumab ozogamicin, gemtuzumab ozogamicin, flotetuzumab), isocitrate dehydrogenases inhibitors (ivosidenib, enasidenib, olutasidenib), FLT3 kinase inhibitors (gilteritinib, midostaurin, quizartinib), a hedgehog inhibitor (glasdegib) as well as a BCL2 inhibitor (venetoclax) were reviewed with respect to their mode of action, their immunosuppressive potential, their current approval and the infectious complications and febrile neutropenia reported from clinical studies. Evidence-based recommendations for prevention and management of infectious complications and specific alerts regarding the potential for drug-drug interactions were developed and discussed in a plenary session with the panel of experts until consensus was reached. The set of recommendations was posted on the ECIL website for a month for comments from members of EBMT, EORTC, ICHS and ELN before final approval by the panelists. While a majority of these agents are not associated with a significantly increased risk when used as monotherapy, caution is required with combination therapy such as venetoclax plus hypomethylating agents, gemtuzumab ozogamicin plus cytotoxic drugs or midostaurin added to conventional AML chemotherapy.
Topics: Antibodies, Monoclonal; Biological Therapy; Febrile Neutropenia; Humans; Immunocompromised Host; Infections; Leukemia, Myeloid, Acute; Practice Guidelines as Topic; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 35368047
DOI: 10.1038/s41375-022-01556-7