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Activating FLT3 mutations plays a crucial role in leukemogenesis, but identifying the optimal candidates for FLT3 inhibitor therapy remains controversial. This study aims to explore the impacts of FLT3 mutations in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) and to compare the mutation profiles between the two types to inspire the targeted application of FLT3 inhibitors. We retrospectively analyzed 243 ALL and 62 AML cases, grouping them into FLT3-mutant and wild-type categories, respectively. We then assessed the associations between FLT3 mutations and the clinical manifestations, genetic characteristics, and prognosis in ALL and AML. Additionally, we compared the distinct features of FLT3 mutations between ALL and AML. In ALL patients, those with FLT3 mutations predominantly exhibited hyperdiploidy (48.6% vs. 14.9%, p < 0.001) and higher FLT3 expression (108.02 [85.11, 142.06] FPKM vs. 23.11 [9.16, 59.14] FPKM, p < 0.001), but lower expression of signaling pathway-related genes such as HRAS, PIK3R3, BAD, MAP2K2, MAPK3, and STAT5A compared to FLT3 wild-type patients. There was no significant difference in prognosis between the two groups. In contrast, AML patients with FLT3 mutations were primarily associated with leucocytosis (82.90 [47.05, 189.76] G/L vs. 20.36 [8.90, 55.39] G/L, p = 0.001), NUP98 rearrangements (30% vs. 4.8%, p = 0.018), elevated FLT3 expression (74.77 [54.31, 109.46] FPKM vs. 34.56 [20.98, 48.28] FPKM, p < 0.001), and upregulated signaling pathway genes including PIK3CB, AKT1, MTOR, BRAF, and MAPK1 relative to FLT3 wild-type, correlating with poor prognosis. Notably, internal tandem duplications were the predominant type of FLT3 mutation in AML (66.7%) with higher inserted base counts, whereas they were almost absent in ALL (6.3%, p < 0.001). In summary, our study demonstrated that the forms and impacts of FLT3 mutations in ALL differed significantly from those in AML. The gene expression profiles of FLT3-related pathways may provide a rationale for using FLT3 inhibitors in AML rather than ALL when FLT3 mutations are present. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by various molecular abnormalities that significantly impact its pathogenesis and prognosis. Currently, the prognosis of AML patients is stratified on the basis of co-existing chromosomal and genetic abnormalities. AML patients with NPM1 or CEBPA mutations, which are frequently identified in cytogenetically normal AML, are classified in the favorable-risk group, although approximately 40% of patients relapse. Similarly, a clinical high-risk group has been identified among patients with acute promyelocytic leukemia, but the underlying molecular abnormalities remain unclear. FLT3 mutations frequently overlap in these favorable-risk AMLs, including core binding factor AML, and their prognostic impact is still controversial. As such, further risk stratification and treatment optimization based on various molecular abnormalities are warranted to improve the prognosis of favorable-risk AMLs. These molecular abnormalities are also considered therapeutic targets, and targeted therapies have been developed over the years. In recent years, several targeted agents have been approved and demonstrated to improve the prognosis of AML. However, resistance to targeted therapies is also a challenge. This Progress in Hematology features current trends and challenges in favorable-risk AML and FLT3 mutations that are frequently identified in these patients. [ABSTRACT FROM AUTHOR]

(1) Background: Relapsed/refractory (r/r) and secondary acute myeloid leukemia are highlighted by chemoresistance and poor outcomes. The aim of the study was to assess the efficacy and toxicity of fludarabine, cytarabine, and granulocyte-colony stimulation factor (FLAG) with or without idarubicin (-Ida) and to discuss novel therapies in this setting. (2) Methods: Clinical and cytogenetic data on 130 consecutive patients with r/r and secondary AML treated at our center were retrospectively analyzed. (3) Results: There were 48, 56, and 26 patients with relapsed, refractory, and secondary AML, respectively. The median age was 60 years. The overall response was achieved in 70% of patients. The median overall survival (OS) time for the whole group was 9.4 months. In total, 47% of patients proceeded to allogeneic hematopoietic stem cell transplantation (aHSCT) and these patients had significantly prolonged OS compared to the others (63 months vs. 4.2 months; p < 0.001). Among the variables, including age, FLT3 mutation status, European LeukemiaNet (ELN) 2022 classification risk, FLAG vs. FLAG-Ida, and aHSCT, a multivariate analysis revealed that only aHSCT significantly influenced overall survival. (4) Conclusions: FLAG(-Ida) chemotherapy remains an effective salvage chemotherapy for patients with r/r and secondary AML with a plan of proceeding to aHSCT. [ABSTRACT FROM AUTHOR]

FLT3 mutations are frequently identified in acute myeloid leukemia (AML). In particular, FLT3-ITD is known to be an indicator of a poor prognosis. FLT3 inhibitors have improved the treatment outcomes of AML patients with mutated FLT3. However, several drug-resistance mechanisms have been reported, and new clinical strategies to overcome drug resistance are needed. Heat shock protein (HSP) 90 is a molecular chaperone that mediates the correct folding and functionality of its client proteins, including FLT3. In the present study, we investigated the effects of an HSP90 inhibitor on FLT3 inhibitor-resistant AML cells. Using MOLM-13 (an AML cell line harboring FLT3-ITD), we established FLT3-selective inhibitor (FI-700)-resistant cell lines with an FLT3 N676K mutation. An HSP90 inhibitor (17-AAG) inhibited the growth of the cell lines, and combination treatment with FI-700 and 17-AAG showed synergistic inhibition. The underlying mechanism is thought to be as follows: HSP90 inhibits the association between HSP90 and FLT3, and thus reduces the phosphorylation of FLT3 and its downstream signaling proteins, which induces the consequent degradation of FLT3. In summary, we demonstrated that the HSP90 inhibitor could inhibit the cell growth of FLT3 inhibitor-resistant AML cells. Our results suggest that HSP90 is a promising molecular target in relapsed/refractory AML. [ABSTRACT FROM AUTHOR]

Background: Refractory/relapsed acute myeloid leukemia (R/R AML) has unsatisfactory outcomes even after allogeneic hematopoietic stem cell transplantation. Long-term survival is mainly influenced by complete remission (CR) rates after induction therapies. Objectives: To investigate CR/CR with incomplete hematologic recovery (CRi) rates and adverse events with a new induction therapy (bortezomib, homoharringtonine, and cytarabine [BHA]) for patients with R/R AML. Methods: We enrolled 21 patients with R/R AML (median age, 42 [range, 30-62] years), who received BHA for remission induction (bortezomib, 1.3 mg/m²/day on days 1 and 4; homoharringtonine, 4 mg/m²/day for 5 days, and cytarabine, 1.5 g/m2/day for 5 days). CR and adverse events were assessed. Results: After one course of BHA, the CR/CRi and partial remission rates were 38.1% and 14.3%, respectively, with an overall response rate (ORR) of 52.4% in 21 patients. 9 of 21 patients harbored FLT3-ITD or FLT3-TKD mutations, and achieved either CR/CRi or ORR of 66.7% (P=0.03) by comparison with that in R/R AML without FLT3 mutation. After induction therapy, consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation led to a one-year overall survival of 27.8% in all patients. One-year relapse-free survival was 50% in 8 patients who had achieved CR/CRi after one course of BHA. During induction, non-hematologic adverse events (grade 3/4) commonly were infection (90.5%), hypokalemia (14.4%), hypocalcemia (14.3%), and mucositis (9.5%). In patients achieving CR, the median time to neutrophil count >0.5x109/L and time to platelet count >20x109/L were 15 (13-17) days and 13 (13-18) days, respectively. Conclusion: BHA chemotherapy regimen was safe and tolerable to serve as an induction therapy for R/R AML, particularly with FLT3 mutation. The higher CR/ CRi rate will give a clue to determine a potentialeffectiveness of BHA for AML patients carrying FLT3 mutation in a further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: FLT3 gene mutations are among the most common genetic aberrations detected in AML and occur with a frequency of approximately 30%, mainly as internal tandem duplications (FLT3-ITD). As a novel finding, it has been reported that the specific insertion sites (IS) of FLT3-ITD exhibit marked heterogeneity in both biological and clinical features. Thus, the so-called non-juxtamembrane domain (non-JMD) FLT3-ITD insertions have been shown to be associated with worse clinical outcomes and resistance to both chemotherapy and tyrosine kinase inhibition. This present review summarizes our current knowledge of the biological and clinical impact of FLT3-ITD inserting at the non-JMD level. Recent evidence suggests that conformational changes depending on FLT3-ITD localization affect downstream signaling networks and the oncogenic potential. We propose that refined risk stratification guidelines integrating the negative prognostic impact of non-JMD FLT3-ITD are warranted. Overcoming therapy resistance in non-JMD-inserting FLT3-ITD-mutated AML may lead to promising treatment approaches. Mutations of the FLT3 gene are among the most common genetic aberrations detected in AML and occur mainly as internal tandem duplications (FLT3-ITD). However, the specific sites of FLT3-ITD insertion within FLT3 show marked heterogeneity regarding both biological and clinical features. In contrast to the common assumption that ITD insertion sites (IS) are restricted to the juxtamembrane domain (JMD) of FLT3, 30% of FLT3-ITD mutations insert at the non-JMD level, thereby integrating into various segments of the tyrosine kinase subdomain 1 (TKD1). ITDs inserted within TKD1 have been shown to be associated with inferior complete remission rates as well as shorter relapse-free and overall survival. Furthermore, resistance to chemotherapy and tyrosine kinase inhibition (TKI) is linked to non-JMD IS. Although FLT3-ITD mutations in general are already recognized as a negative prognostic marker in currently used risk stratification guidelines, the even worse prognostic impact of non-JMD-inserting FLT3-ITD has not yet been particularly considered. Recently, the molecular and biological assessment of TKI resistance highlighted the pivotal role of activated WEE1 kinase in non-JMD-inserting ITDs. Overcoming therapy resistance in non-JMD FLT3-ITD-mutated AML may lead to more effective genotype- and patient-specific treatment approaches. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: In acute myeloid leukemia, molecular genetics abnormalities, particularly NPM1 and FLT3 mutations, have a recognized prognostic role in the ELN risk classification and guide treatment decisions, especially since the availability of FLT3-targeted drugs. The NILG-AML 01/00 protocol uses a modified induction approach (ICE) and delivers the most active cytostatic agents at maximal doses in consolidation (a high dose of ARAC plus idarubicin) with autologous stem cell support. It calls for allogeneic transplant only in ELN high-risk patients including NPM1-wt FLT3-ITD-mutated patients. The results obtained from 171 patients showed that the median survival was not reached, and 5y-OS was 58% +/− 4. The prognostic influence of co-mutated FLT3 was overcome, and the efficacy of this treatment reduced the need for early consolidation with an allogeneic transplant in double-mutated patients, in their first complete remission. These data could represent the benchmark against which results of therapeutic programs using second-generation FLT3-targeted drugs should be compared. The prognosis of acute myeloid leukemia depends on genetic aberrations, particularly NPM1 and FLT3-ITD mutations. The targeted drugs' availability has renewed interest in FLT3 mutations, but the impact of these genetic alterations using these treatments is yet to be confirmed. Our objective was to evaluate the results obtained with the intensified NILG-AML 01/00 protocol (ClinicalTrials.gov Identifier: NCT 00400673) in 171 unselected patients (median age, 54.5 years, range 15–74) carrying the FLT3 (ITD or TKD) and/or NPM1 mutations. The CR rate and 5-y survival were 88.3% and 58% +/− 4, respectively, significantly higher in the NPM1-mutated (CR 93.9%, p: 0.0001; survival 71% +/− 6, p: 0.0017, respectively). In isolated ITD patients, the CR was lower (66.7%, p: 0.0009), and the 3 years-relapse-free survival worse (24%, p: <0.0002). The presence of ITD, irrespective of the allelic ratio, or TKD mutation, did not significantly affect the survival or relapse-free survival among the NPM1-co-mutated patients. Our data indicate that a high dose of ARAC plus idarubicin consolidation exerts a strong anti-leukemic effect in NPM1-mutated patients both with the FLT3 wild-type and mutated AML, while in the NPM1 wild-type and FLT3-mutated, the therapeutic effect remains unsatisfactory. New strategies incorporating target therapy with second-generation inhibitors will improve these results and their addition to this aggressive chemotherapeutic program merits testing. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the recent approval of some FLT3 inhibitors by drug regulatory agencies, treatment guidelines for FLT3-mutated AML still require allogeneic transplantation as a necessary procedure to treat the disease in first or second CR, due to the high relapse incidence related to the use of these drugs. The study of the heterogeneity of leukemogenesis and resistance mechanisms related to the use of FLT3 inhibitors, alone or in combination, represents one of the additional challenges in attempting to achieve the eradication of the mutated FLT3 leukemic clone. The analysis and knowledge of these pathways might drive future approach in this setting. FLT3 ITD and TKD mutations occur in 20% and 10% of Acute Myeloid Leukemia (AML), respectively, and they represent the target of the first approved anti-leukemic therapies in the 2000s. Type I and type II FLT3 inhibitors (FLT3i) are active against FLT3 TKD/ITD and FLT3 ITD mutations alone respectively, but they still fail remissions in 30–40% of patients due to primary and secondary mechanisms of resistance, with variable relapse rate of 30–50%, influenced by NPM status and FLT3 allelic ratio. Mechanisms of resistance to FLT3i have recently been analyzed through NGS and single cell assays that have identified and elucidated the polyclonal nature of relapse in clinical and preclinical studies, summarized here. Knowledge of tumor escape pathways has helped in the identification of new targeted drugs to overcome resistance. Immunotherapy and combination or sequential use of BCL2 inhibitors and experimental drugs including aurora kinases, menin and JAK2 inhibitors will be the goal of present and future clinical trials, especially in patients with FLT3-mutated (FLT3mut) AML who are not eligible for allogeneic transplantation. [ABSTRACT FROM AUTHOR]

(1) Background: The aim of our study was the complex assessment of WT1 variants and their expression in relation to chromosomal changes and molecular prognostic markers in acute myeloid leukemia (AML). It is the first multidimensional study in Polish AML patients; (2) Methods: Bone marrow aspirates of 90 AML patients were used for cell cultures (banding techniques and fluorescence in situ hybridization), and to isolate DNA (WT1 genotyping, array comparative genomic hybridization), and RNA (WT1 expression). Peripheral blood samples from 100 healthy blood donors were used to analyze WT1 rs16754; (3) Results: Allele frequency and distribution of WT1 variant rs16754 (A;G) did not differ significantly among AML patients and controls. Higher expression of WT1 gene was observed in AA genotype (of rs16754) in comparison with GA or GG genotypes—10,556.7 vs. 25,836.5 copies (p = 0.01), respectively. WT1 mutations were more frequent in AML patients under 65 years of age (p < 0.0001) and affected relapse-free survival (RFS). The presence of NPM1 or CEBPA mutations decreased the risk of WT1 mutation presence, odds ratio (OR) = 0.11, 95% CI 0.02–0.46, p = 0.002 or OR = 0.05, 95% CI 0.006–0.46, p = 0.002, respectively. We observed significantly higher WT1 expression in AML CD34+ vs. CD34−, −20,985 vs. 8304 (p = 0.039), respectively. The difference in WT1 expression between patients with normal and abnormal karyotype was statistically insignificant; (4) Conclusions: WT1 gene expression and its rs16754 variant at diagnosis did not affect AML outcome. WT1 mutation may affect RFS in AML. [ABSTRACT FROM AUTHOR]

Acute myeloid leukaemia (AML) is a haematopoietic malignancy with a dismal outcome. Consequently, risk stratification based on more effective prognostic biomarkers is crucial to make accurate therapy decisions. T cell receptor gamma alternative reading frame protein (TARP) has been reported in prostate and breast cancers, but its correlation with AML remains unclear. Differential expression of TARP mRNA in different AML subtypes was analysed using the UALCAN online platform. Its relationship with baseline clinical attributes, survival and efficacy were analysed based on three GSE1159, GSE425 and GSE6891 microarray datasets downloaded from Gene Expression Omnibus (GEO) and Oncomine databases. Quantitative real-time PCR was performed to determine mRNA levels of TARP in bone marrow mononuclear cells (BMMCs) isolated from AML patients. TARP was significantly overexpressed in AML patients. In AML, relatively low TARP expression was associated with the CBFβ-MYH11 fusion gene. The proportion of FLT3 mutations was significantly higher in non-adolescent and young adult (non-AYA, >39 years of age) AML patients who had high TARP levels but not in AYA (15–39 years) patients. High expression of TARP was related to poor outcome by univariate analysis but not by multivariate analysis and unsatisfactory therapeutic effects, which could be overcome by haematopoietic stem cell transplantation (HSCT). Our findings suggest that TARP might be a potential prognostic marker of AML and serve as a promising immunotherapeutic target. [ABSTRACT FROM AUTHOR]

FMS-like tyrosine kinase 3 (FLT3) is among the most common driver genes recurrently mutated in acute myeloid leukemia (AML), accounting for approximately 30% of cases. Activating mutations of the FLT3 receptor include internal tandem duplications (ITD) that map to the auto-inhibitory juxtamembrane (JM) domain or point mutations within the tyrosine kinase domain (TKD). Several FLT3 tyrosine kinase inhibitors have been developed in the last few years, but midostaurin is currently the only one approved for the treatment of newly diagnosed patients harboring FLT3 mutations. Here we describe for the first time a novel in-frame deletion in exon 14 (JM domain) of the FLT3 gene, that we identified in a young woman with CBFb-MYH11-positive AML. We demonstrated that this novel FLT3 variant is pathogenic, since it is responsible for constitutive activation of FLT3 receptor. Finally, ex-vivo studies demonstrated that this novel mutation is sensitive to midostaurin. [ABSTRACT FROM AUTHOR]

The prognostics implications of patients with acute myeloid leukemia harboring non-canonical FLT3 is unknown. The use of tyrosine kinase inhibitors in this patient population has not been previously reported. We report successful targeted therapy against non-ITD, non-D835 driver FLT3 alterations in two patient case studies with acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

Fms-like tyrosine kinase 3 (FLT3) mutation is one of the most common mutations in acute myeloid leukemia (AML). However, the effect of FLT3 mutation on survival is currently still controversial and the leukemogenic mechanisms are still under further investigation. The aim of our study is to identify differentially expressed genes (DEGs) in FLT3-mutant AML and to find crucial DEGs whose expression level is related to prognosis for further analysis. By mining the TCGA-LAML dataset, 619 differentially expressed lncRNAs (DElncRNAs) and 1,428 differentially expressed mRNAs (DEmRNAs) were identified between FLT3-mutant and FLT3-wildtype samples. Through weighted gene correlation network analysis (WGCNA) and the following Cox proportional hazards regression analysis, we constructed the prognostic risk models to identify the hub DElncRNAs and DEmRNAs associated with AML prognosis. The presence of both SH3TC2 divergent transcript (SH3TC2-DT) and SH3TC2 in respective prognostic risk models promotes us to further study the significance of this gene pair in AML. SH3TC2-DT and SH3TC2 were identified to be coordinately high expressed in FLT3-mutant AML samples. High expression of this gene pair was associated with poor survival. Using logistic regression analysis, we found that high SH3TC2-DT/SH3TC2 expression was associated with FLT3 mutation, high WBC count, and intermediate cytogenetic and molecular–genetic risk. AML with SH3TC2-DT/SH3TC2 high expression showed enrichment of transcripts associated with stemness, quiescence, and leukemogenesis. Our study suggests that the SH3TC2-DT/SH3TC2 gene pair may be a possible biomarker to further optimize AML prognosis and may function in stemness or quiescence of FLT3-mutant leukemic stem cells (LSCs). [ABSTRACT FROM AUTHOR]

Keywords: acute promyelocytic leukaemia; childhood leukaemia; Polycomb group (PcG) genes; FLT3 mutation EN acute promyelocytic leukaemia childhood leukaemia Polycomb group (PcG) genes FLT3 mutation e245 e248 4 06/18/20 20200615 NES 200615 I De novo i acute promyelocytic leukaemia (APL) is an aggressive subtype that accounts for 5-10% of all childhood acute myeloid leukaemia (AML). The results from our multivariate analysis, based on our molecular results, suggest that higher levels of the I BMI1 i gene transcripts and the I FLT3 i -ITD mutation were significantly more highly correlated in paediatric patients with APL than those with other AML subtypes. Acute promyelocytic leukaemia, childhood leukaemia, Polycomb group (PcG) genes, FLT3 mutation. [Extracted from the article]

Recent regulatory approval of midostaurin, a FLT3 targeting small molecular inhibitor, will likely lead to increased use of midostaurin in combination with intensive chemotherapy for patients with FLT3-mutant AML. Translation of clinical trial results into everyday practice has its challenges. This study compared the relevance of the trial population and practices studied in the midostaurin registration study (RATIFY) with real-world practice in terms of patient factors, chemotherapy, mutation-specific frequencies and clinical outcomes among patients with FLT3-mutant AML in the pre-midostaurin era (2010–2015) in Australia. We observed substantial diversity of chemotherapy regimens used in the community and limitations of the generalizability of eligibility criteria used in RATIFY (such as age and hyperleukocytosis). This study provides real-world historical data that may be used for comparison with future trial cohorts incorporating FLT3 inhibitors into the management of FLT3-mutant AML and highlights the inherent difficulties in translating clinical trial data into routine practice. [ABSTRACT FROM AUTHOR]

FLT3 mutations, characterized by an internal-tandem duplication or missense mutations in the tyrosine kinase domain, are observed in a third of patients with newly diagnosed acute myeloid leukemia. FLT3-ITD mutations are associated with high relapse rates and short overall survival with conventional chemotherapy. Several tyrosine kinase inhibitors targeting FLT3 have been developed in an effort to improve survival and therapeutic options. This review focuses on quizartinib, a second-generation FLT3 inhibitor that has demonstrated efficacy and safety as a single agent and in combination with chemotherapy. We discuss its clinical development as well as its place in the treatment of FLT3-mutated acute myeloid leukemia among the other FLT3 inhibtors currently available and its mechanisms of resistance. [ABSTRACT FROM AUTHOR]

The addition of midostaurin, a FLT3-inhibitor, to intensive chemotherapy (IC) was previously shown to improve outcome of younger patients with FLT3-mutated AML. The toxicity and efficacy of adding midostaurin to IC in patients not originally included in the RATIFY study or with intensified daunorubicin dosing are unknown. We conducted a retrospective, multi-center, historical-control study to characterize the safety and efficacy of adding midostaurin to IC in a "real-world" setting. Sixty-nine adult patients were included in the analysis (midostaurin n = 34, historical controls n = 35) with a mean follow-up of 18.4 (± 15) months. Median age of patients was 60 (range 26-82) years; 32% and 20% of patients were > 65 and 70 years, respectively. No differences in baseline characteristics were noted between the groups. Midostaurin was administered with 90 mg/m2 daunorubicin in 29% of patients; One-third of patients experienced dose reductions/interruptions during midostaurin therapy. Overall toxicity was comparable between the midostaurin and control groups.CR/CRi rates were higher in patients treated with midostaurin compared with controls (80% vs. 57%, p = 0.047) and significantly more patients in the midostaurin group were transplanted in first remission (95% vs. 68%, p = 0.04).Median OS and DFS were higher in the midostaurin vs. control group (not reached vs. 11 months (p = 0.085) and 13 vs. 6 months (p = 0.09), respectively). In our analysis, midostaurin was not associated with increased toxicity including in older patients, in those with secondary AML or when administered with intensified daunorubicin dosage. Higher remission rates in the midostaurin group and increased transplantation rates in first CR were associated with a trend towards better outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND: The search for effective therapeutic treatments for acute myeloid leukemia (AML) had little success in the past because the disease is heterogeneous and complex. Mutations, such as those in the FMS-like tyrosine kinase 3 (FLT3) gene, which are associated with poor outcomes and are present in approximately 30% of patients with AML, are an encouraging target for therapeutic approaches. Midostaurin is a multikinase inhibitor that targets the receptor tyrosine kinases FLT3 and CD117/KIT and is approved in combination with standard induction and consolidation chemotherapy for patients with newly diagnosed AML and FLT3 mutation, and as a single agent for advanced systemic mastocytosis. OBJECTIVE: To review the safety data for midostaurin as a single agent and in combination with standard chemotherapy or hypomethylating agents, important pharmacologic and pharmacokinetic data, and the efficacy data that supported the approval of each indication. DISCUSSION: Orally administered midostaurin is rapidly absorbed, distributed throughout the body, and metabolized by cytochrome P450 3A4. Midostaurin has demonstrated acceptable tolerability when administered as monotherapy and in combination with chemotherapy at a variety of doses. The clinical efficacy of midostaurin has been evaluated in many clinical trials. Treatment with midostaurin demonstrated a significant survival benefit in patients with newly diagnosed AML and FLT3 mutation, as well as improved outcomes in patients with advanced systemic mastocytosis. CONCLUSION: The approval of midostaurin has changed the treatment landscape for newly diagnosed patients with AML and FLT3 mutation, as well as those with advanced systemic mastocytosis. However, the drug is associated with challenges and limitations that clinicians need to consider for patient management. [ABSTRACT FROM AUTHOR]

Objectives: To assess real‐world treatment patterns and healthcare resource utilization (HRU) among patients with FLT3–mutated (FLT3mut) and FLT3–wild‐type (FLT3wt) acute myeloid leukemia (AML). Methods: Data were abstracted from medical charts of patients with AML from 10 countries. Patients were grouped based on their FLT3 mutation status, age (18‐64 or ≥65), and whether they were newly diagnosed (ND) or relapsed/refractory (R/R). Results: Charts of 1027 AML patients were included (183 FLT3mut 18‐64 ND; 136 FLT3mut ≥65 ND; 181 FLT3mut R/R; 186 FLT3wt 18‐64 ND; 159 FLT3wt ≥65 ND; 182 FLT3wt R/R). Substantial heterogeneity was observed in treatment patterns for AML. Among ND patients 18‐64, the most common initial treatment was standard‐to‐intermediate dose cytarabine‐based therapies (43.2% for FLT3mut and 55.9% for FLT3wt); among ND patients ≥65, the most common initial treatment was hypomethylating agent‐based therapies (36.0% and 47.2%). Among R/R patients, the most common initial treatment after R/R was best supportive care only (39.8% and 24.7%). HRU was substantial across cohorts during both event‐free and post‐event periods. Conclusions: Treatment patterns of AML were heterogeneous and FLT3mut AML was treated more aggressively than FLT3wt disease. HRU was substantial for all cohorts, particularly after relapse or treatment failure. [ABSTRACT FROM AUTHOR]

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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 asFLT3orKIT, 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 aKITmutation as well as in combination with standard intensive chemotherapy for adult patients with newly diagnosedFLT3-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 andFLT3-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 withFLT3mutations. By introduction of this new standard in AML withFLT3mutations, 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. [ABSTRACT FROM AUTHOR]

Wilms' tumor gene 1 (WT1) expression is a well-known predictor for relapse in acute myeloid leukemia. We monitored WT1 decrement along the treatment course to identify its significant role as a marker for residual disease in acute promyelocytic leukemia (APL) and tried to suggest its significance for relapse prediction. In this single center retrospective study, we serially measured PML-RARa and WT1 expression from 117 APL patients at diagnosis, at post-induction and post-consolidation chemotherapies, and at every 3 months after starting maintenance therapy. All 117 patients were in molecular remission after treatment of at least 2 consolidation chemotherapies. We used WT1 ProfileQuant™ kit (Ipsogen) for WT1 monitoring. High WT1 expression (>120 copies/104ABL1) after consolidation and at early period (3 months) after maintenance therapy significantly predicted subsequent relapse. All paired PML-RARa RQ-PCR were not detected except for one sample with early relapse. Patients with high WT1 expression at 3 months after maintenance therapy (n = 40) showed a significantly higher relapse rate (30.5 vs. 6.9%, P < 0.001) and inferior disease free survival (62.8 vs. 91.4%, P < 0.001). Multivariate analysis revealed that high peak leukocyte counts at diagnosis (HR = 6.4, P < 0.001) and high WT1 expression at 3 months after maintenance therapy (HR = 7.1, P < 0.001) were significant factors for prediction of relapse. Our data showed high post-remission WT1 expression was a reliable marker for prediction of subsequent molecular relapse in APL. In this high-risk group, early intervention with ATRA ± ATO, anti-CD33 antibody therapy, and WT1-specific therapy may be used for relapse prevention. Trial registration: Clinical Research Information Service (CRIS), KCT0002079 [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is the most frequent acute leukemia in adults, and has an unfavourable prognosis. 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 signifies a poorer prognosis, but also identifies an important target for therapy. FLT3 kinase inhibitors have now undergone clinical evaluations in phase I, II and III clinical trials; this review aims to highlight the role of FLT3 inhibitors as single agents and in combination with other anti-leukemia agents. [ABSTRACT FROM AUTHOR]

Acute myeloid leukaemia ( AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside (Ara-C)/daunorubicin induction (7+3) followed by three cycles of intermediate-dose Ara-C consolidation in 22 AML patients with activating FLT3 mutations. Sunitinib was added at predefined dose levels and as maintenance therapy for 2 years. At dose level 1, sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose-limiting toxicity ( DLT), prolonged haemotoxicity and hand-foot syndrome. At dose level −1, sunitinib 25 mg was restricted to days 1-7 of each chemotherapy cycle. One DLT was observed in six evaluable patients. Six additional patients were treated in an extension phase. Thirteen of 22 patients (59%; 8/14 with FLT3-internal tandem duplication and 5/8 with FLT3-tyrosine kinase domain) achieved a complete remission/complete remission with incomplete blood count recovery. For the 17 patients included at the lower dose level, median overall, relapse-free and event-free survival were 1·6, 1·0 and 0·4 years, respectively. Four out of five analysed patients with relapse during maintenance therapy lost their initial FLT3 mutation, suggesting outgrowth of FLT3 wild-type subclones. [ABSTRACT FROM AUTHOR]

FMS-like tyrosine kinase 3 ( FLT3) is the most frequently mutated gene in AML. Thirty percent of patients with acute myeloid leukemia (AML) harbor activating mutations in FLT3, either internal tandem duplication mutations in the juxtamembrane domain (FLT3-ITD) or point mutations in the tyrosine kinase domain (FLT3 TKD). Small molecule FLT3 inhibitors have emerged as an attractive therapeutic option in patients with FLT3 mutations; however, the clinical activity of early inhibitors was limited by a lack of selectivity, potency and unfavorable pharmacokinetic properties. Newer agents such as quizartinib have improved potency and selectivity associated with much higher bone marrow response rates; however, response duration is limited by the development of secondary resistance. We will review here a number of FLT3 inhibitors that have been evaluated in clinical trials and discuss challenges facing the use of these agents in AML. [ABSTRACT FROM AUTHOR]

The t(8;21)(q22;q22) is the most common translocation in acute myeloid leukemia (AML). We describe the clinicopathologic and cytogenetic profile of 117 patients with t(8;21) AML. There were 76 males and 88 adults. The median age was 26 years. Most patients (80%) had AML M2. Dysplasia was present in 68% of patients and eosinophilia in 18%. Eight patients had fewer than 20% blasts. Additional chromosomal aberrations were seen in 103 patients (88%) with loss of a sex chromosome (LSC) in 78 patients (66%) and deletion 9q in 21 (18%). The other recurrent abnormalities were trisomies 4, 8 and 15, monosomy 17 and deletion 7q (less than 5% each). Three- or four-way variant t(8;21) were seen in 6% of patients and 3% had tetraploidy. Aberrant expression of CD19 was seen in 54% of patients. FLT3 mutations were seen in 7.5% of patients (3/40) and c-KIT mutations in 6.6% (2/30). None had NPM1 or JAK2 V617F mutations. One patient had a granulocytic sarcoma. Complete remission was achieved in 96% of the 26 newly diagnosed patients after first induction. The median follow-up was 25 months (range 4-68). The overall survival was 69% at 31 months. [ABSTRACT FROM AUTHOR]

Tetraploidy and near-tetraploidy are rare in acute myeloid leukemia (AML), contrary to other hematological disease. In this paper we describe a case of a 52-year-old male with AML associated with tetraploidy, mutation in tyrosine kinase receptor FLT3, and very short survival. At presentation maculopapular rash with crustae, lymphadenopathy, and hepatosplenomegaly was diagnosed. The blasts comprised 80% of marrow nucleated cells (POX negative and PAS finely granular positive). Immunophenotyping done on marrow cells was (CD34, HLA DR, CD14, CD64, CD33, CD11b, and CD15) and correlated with the acute monoblastic leukemia. Detection of FLT3 mutation was done by polymerase chain reaction (PCR). Cytogenetic analysis show: 85-93, XXYY,inc(cp5)/46,XY. Based on these considerations, we suggest the detection of FLT3 mutations as a diagnostic procedure for all AML patients. [ABSTRACT FROM AUTHOR]

The tumor suppressor Gadd45α was earlier shown to be a repressed target of sustained receptor-mediated ERK1/2 signaling. We have identified Gadd45α as a downregulated gene in response to constitutive signaling from two FLT3 mutants (FLT3-ITD and FLT3-TKD) commonly found in AML, and a leukemogenic GM-CSF receptor trans-membrane mutant (GMR-V449E). GADD45A mRNA downregulation is also associated with FLT3-ITD+ AML. Sustained ERK1/2 signaling contributes significantly to receptor-mediated downregulation of Gadd45α mRNA in FDB1 cells expressing activated receptor mutants, and in the FLT3-ITD+ cell line MV4;11. Knockdown of Gadd45α with shRNA led to increased growth and survival of FDB1 cells and enforced expression of Gadd45α in FDB1 cells expressing FLT3-ITD or GMR-V449E resulted in reduced growth and viability. Gadd45α overexpression in FLT3-ITD+ AML cell lines also resulted in reduced growth associated with increased apoptosis and G1/S cell cycle arrest. Overexpression of Gadd45α in FDB1 cells expressing GMR-V449E was sufficient to induce changes associated with myeloid differentiation suggesting Gadd45α downregulation contributes to the maintenance of receptor-induced myeloid differentiation block. Thus, we show that ERK1/2-mediated downregulation of Gadd45α by sustained receptor signaling contributes to growth, survival and arrested differentiation in AML.Leukemia (2009) 23, 729–738; doi:10.1038/leu.2008.349; published online 8 January 2009 [ABSTRACT FROM AUTHOR]

FMS-like tyrosine kinase-3 (FLT3) is a new therapeutic target for acute myelocytic leukemia (AML), because FLT3 mutations are the most common genetic alterations in AML and are directly related to leukemogenesis. We studied cytotoxic interactions of a FLT3 inhibitor, PKC412, with eight conventional antileukemic agents (cytarabine, doxorubicin, idarubicin, mitoxantrone, etoposide, 4-hydroperoxy-cyclophosphamide, methotrexate and vincristine) using three leukemia cell lines carrying FLT3 mutations (MOLM13, MOLM14 and MV4-11) and five leukemia cell lines without FLT3 mutations (KOPB-26, THP-1, BALL-1, KG-1 and U937). PKC412 showed synergistic effects with all agents studied except methotrexate for FLT3-mutated cell lines in isobologram analysis. In contrast, PKC412 was rather antagonistic to most drugs, except for 4-hydroperoxy-cyclophosphamide and vincristine, in leukemia cell lines without FLT3 mutations. Cell-cycle analysis revealed that PKC412 induced G1 arrest in leukemia cell lines carrying FLT3 mutations, whereas it arrested cells in G2/M phase in the absence of FLT3 mutations, which may underlie the divergent cytotoxic interactions. These results suggest that the simultaneous administration of PKC412 and other agents except methotrexate is clinically effective against FLT3 mutation-positive leukemias, whereas it would be of little benefit for FLT3 mutation-negative leukemias. Our findings may be of help for the design of PKC412-based combination chemotherapy. [ABSTRACT FROM AUTHOR]

Relapse of FLT3‐mutated acute myeloid leukemia (AML) following allogeneic stem cell transplantation is associated with poor survival. The clinical utility of sorafenib monotherapy in this setting is described in a patient presenting as leukemia cutis. [ABSTRACT FROM AUTHOR]

Purpose: Activating Flt3 mutations are observed in about 30% of patients with acute myeloid leukaemia (AM L) and individual Flt3 mutations are applicable for minimal residual disease (MRD) analyses. Methods: We investigated the MRD status in four AML patients carrying different Flt3 mutations (three patients with Flt3 length mutations of the juxtamembrane do- main, one patient carrying a mutation of the Flt3 tyro- sine kinase domain, i.e. Flt3-TKD mutation) who underwent allogeneic peripheral blood stem cell transplantation (PBSCT). Residual leukaemia cells were retrospectively determined by real-time PCR at different time points. Results: We can demonstrate a good correlation between the course of MRD status and clinical events in all four investigated patients. Conclusion: These examples demonstrate the potential impact of Flt3 based M RD status not only after but also prior to allogeneic PBSCT. [ABSTRACT FROM AUTHOR]