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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 -
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 -
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 -
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 -
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 -
The Lancet. Haematology Aug 2021Addition of the BCL2 inhibitor venetoclax to lower intensity therapy has been shown to improve overall survival in older (aged 75 years or older) and unfit patients with...
Venetoclax plus intensive chemotherapy with cladribine, idarubicin, and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a cohort from a single-centre, single-arm, phase 2 trial.
BACKGROUND
Addition of the BCL2 inhibitor venetoclax to lower intensity therapy has been shown to improve overall survival in older (aged 75 years or older) and unfit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to investigate the activity of venetoclax combined with intensive chemotherapy in patients aged 65 years or younger with acute myeloid leukaemia.
METHODS
This cohort study was done at the MD Anderson Cancer Center in the USA, as part of the single-centre, single arm, phase 2, CLIA trial. Here we report on the independent cohort investigating the safety and activity of venetoclax added to intensive chemotherapy (the CLIA regimen [cladribine, high-dose cytarabine, idarubicin]). Eligible patients were aged 18-65 years with a new diagnosis of acute myeloid leukaemia, mixed phenotype acute leukaemia, or high-risk myelodysplastic syndrome (≥10% blasts or International Prognostic Scoring System ≥2 [intermediate]), who received no previous potentially curative therapy for leukaemia. Patients received cladribine (5 mg/m) and cytarabine (1·5 g/m for patients aged <60 years, 1 g/m for patients aged ≥60 years) intravenously on days 1-5 and idarubicin (10 mg/m) intravenously on days 1-3. Consolidation was cladribine (5 mg/m) and cytarabine (1 g/m for patients aged <60 years and 0·75 g/m for patients aged ≥60 years) on days 1-3 and idarubicin (8 mg/m) on days 1-2. Venetoclax (400 mg) was given on days 2-8 with each course. Patients with a known FLT3-ITD or FLT3-TKD mutation received midostaurin or gilteritinib. The primary outcome was composite complete response (complete response plus complete response with incomplete blood count recovery). Secondary outcomes were overall response, duration of response, event-free survival, overall survival, and safety. This trial was registered with ClinicalTrials.gov, NCT02115295.
FINDINGS
Between Feb 25, 2019, and March 23, 2021, 77 patients were assessed for eligibility, 50 of whom were enrolled. Median age was 48 years (IQR 37-56). 47 (94% [95% CI 83-98]) patients had composite complete response, with the same proportion also having an overall response; two (4% [1-14]) patients did not respond, and one (2% [0-11]) patient died during induction. 37 (82% [95% CI 68-92]) of 45 patients had undetectable measurable residual disease (MRD). At a median follow-up of 13·5 months (IQR 6·4-19·5), the median duration of response, event-free survival, and overall survival were not reached. At 12 months, the estimated duration of response was 74% (95% CI 60-92), event-free survival was 68% (54-85), and overall survival was 85% (75-97). The most common adverse events of grade 3 or worse were febrile neutropenia (42 [84%] patients), infection (six [12%]), and alanine aminotransferase elevations (six [12%]). There was one death during induction in a patient treated with CLIA-venetoclax plus a FLT3 inhibitor. Two patients died of infectious complications while in complete response in consolidation cycles, both of whom had FLT3-mutated acute myeloid leukaemia and were receiving combined therapy with a FLT3 inhibitor. No deaths were deemed to be treatment related.
INTERPRETATION
Venetoclax added to CLIA was safe and active in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, producing high rates of durable MRD-negative remissions and encouraging event-free survival and overall survival.
FUNDING
MD Anderson Cancer Center.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cladribine; Cohort Studies; Cytarabine; Female; Follow-Up Studies; Humans; Idarubicin; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Remission Induction; Risk Factors; Sulfonamides; Young Adult
PubMed: 34329576
DOI: 10.1016/S2352-3026(21)00192-7 -
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 -
Journal of Clinical Medicine Oct 2023Acute myeloid leukemia (AML) is a highly aggressive illness distinguished by the accumulation of abnormal hematopoietic precursors in both the bone marrow and peripheral... (Review)
Review
Acute myeloid leukemia (AML) is a highly aggressive illness distinguished by the accumulation of abnormal hematopoietic precursors in both the bone marrow and peripheral blood. The prevalence of FLT3 gene mutations is high and escalates the probability of relapse and mortality. The survival rates for AML patients, particularly those over 65, are low. FLT3 mutation screening at diagnosis is mandatory, and FLT3 inhibitors are crucial in treating AML patients with mutations. There are two categories of FLT3 mutations: FLT3-ITD located in the juxtamembrane domain and FLT3-TKD in the tyrosine kinase domain. FLT3-ITD is the most common type, affecting nearly a quarter of patients, whereas FLT3-TKD only affects 6-8% of patients. FLT3 inhibitors are now crucial in treating AML patients with FLT3 mutations. When dealing with FLT3-mutated AML, the recommended course of treatment typically involves chemotherapy and midostaurin, followed by allogeneic hematopoietic cell transplantation (HCT) to maximize the likelihood of success. Maintenance therapy can lower the risk of relapse, and gilteritinib is a better option than salvage chemotherapy for relapsed or refractory cases. Clinical trials for new or combined therapies are the most effective approach. This review discusses treatment options for patients with FLT3-mutated AML, including induction chemotherapy and options for relapsed or refractory disease. Additional treatment options may become available as more studies are conducted based on the patient's condition and susceptibility.
PubMed: 37892567
DOI: 10.3390/jcm12206429 -
Blood Advances Sep 2022We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed...
We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR], 0.55; P < .001); both in younger (HR, 0.59; P < .001) and older patients (HR, 0.42; P < .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P < .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.
Topics: Adolescent; Adult; Aged; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Middle Aged; Protein-Tyrosine Kinases; Staurosporine; Young Adult; fms-Like Tyrosine Kinase 3
PubMed: 35486475
DOI: 10.1182/bloodadvances.2022007223