selinexor and Leukemia--Myeloid--Acute

Patients with acute myeloid leukemia (AML) who achieve a morphologic complete remission still can have measurable residual disease (MRD) detected by multiparametric flow cytometry, molecular methods, or cytogenetics. Such patients with MRD have a high risk of disease recurrence over a short timeframe, but optimal treatment strategies are unknown. Outcomes with conventional treatment, including allogeneic hematopoietic cell transplantation, are worse than those for patients without MRD. Herein, the authors review current strategies, including novel clinical trials, targeted toward patients with MRD.

Topics: Aminopyridines; Aniline Compounds; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Azacitidine; Cytogenetic Analysis; Decitabine; Enzyme Inhibitors; Flow Cytometry; Hematopoietic Stem Cell Transplantation; Humans; Hydrazines; Immunologic Factors; In Situ Hybridization, Fluorescence; Lenalidomide; Leukemia, Myeloid, Acute; Molecular Diagnostic Techniques; Neoplasm, Residual; Nivolumab; para-Aminobenzoates; Protein Kinase Inhibitors; Pyrazines; Pyrrolidines; Recombinant Fusion Proteins; Remission Induction; Transplantation, Homologous; Triazines; Triazoles

Topics: Active Transport, Cell Nucleus; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Humans; Hydrazines; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Triazoles

Acute myeloid leukemia (AML) is the most common leukemia among the adult population and accounts for about 80% of all cases. Despite advancements in therapeutic regimens, the prognosis remains very poor, especially in the elderly population. Selinexor is a first-in-class, oral, small molecule Exportin-1 inhibitor that is being developed for the treatment of a variety of cancers, including AML. The efficacy and safety issues of selinexor in the treatment of AML are still the focus of attention. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of selinexor in the treatment of AML.. According to the search strategy, regardless of publication date or language, randomized controlled trials of selinexor for AML will be retrieved from 8 databases. First of all, the literature was screened according to the eligibility criteria, and use the Cochrane Collaboration's tool to assess the quality of the included literature. Then, using Rev Man 5.3 and STATA 14.2 software for traditional meta-analysis. Finally, the evaluation of the quality of the evidence and the strength of the recommendations will adopt the Grading of Recommendations, Assessment, Development, and Evaluation method.. This study will evaluate the efficacy and safety of selinexor for AML, thereby providing more evidence support for clinical decision-making in AML.. Our research will provide more references for the clinical medication of patients with AML.

Topics: Adult; Aged; Humans; Hydrazines; Leukemia, Myeloid, Acute; Meta-Analysis as Topic; Systematic Reviews as Topic; Triazoles

Prognosis for relapsed or refractory (R/R) acute myeloid leukemia (AML) despite salvage therapy is dismal. This phase I dose-escalation trial assessed the safety and preliminary clinical activity of selinexor, an oral exportin-1 (XPO1) inhibitor, in combination with FLAG-Ida in younger R/R AML patients. The aim was to find the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD). Fourteen patients were included, and selinexor dosage was 60 mg (3 patients), 80 mg (3 patients), and 100 mg (7 patients) weekly. No dose-limiting toxicities were reported. Grade ≥3 non-hematologic adverse events (AEs) occurred in 78.6% of patients. Two patients were non MTD evaluable due to early death, and overall, 3 out of 14 patients (21.4%) had fatal AEs. Five out of 12 (42%) response and MTD evaluable patients achieved a complete remission (CR; n=4) or CR with incomplete hematologic recovery (CRi, n=1), and 4 patients (33%) subsequently underwent allogeneic transplantation. The median overall survival (OS) and event-free survival (EFS) were 6.0 (range 0.9-19.3) and 1.1 months (range 0.7-19.3), respectively. Using selinexor 100 mg/weekly, CR/CRi rate of 66.7%, OS 13.6 months (range, 1.6-19.3), and EFS 10.6 months (range, 0.9-19.3). At last follow-up, 3 patients were alive. Selinexor 100 mg/weekly with FLAG-Ida combination in R/R AML showed acceptable tolerability and efficacy, establishing the RP2D of this regimen in future clinical trials. ClinicalTrials.gov Identifier: NCT03661515.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Granulocyte Colony-Stimulating Factor; Humans; Hydrazines; Idarubicin; Leukemia, Myeloid, Acute; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Treatment Outcome; Triazoles; Vidarabine

Induction chemotherapy results in complete remission (CR) rates of 20% to 50% among patients with poor-risk AML. Selinexor is an oral selective inhibitor of nuclear export with promising single-agent activity. By inhibiting the primary export protein, XPO1, selinexor localizes and activates tumor suppressor proteins in the nucleus and inhibits DNA damage repair, rationalizing combination with DNA-damaging agents.. This was a single-arm phase I clinical trial of selinexor combined with cytarabine and daunorubicin (7+3). Dose escalation was selinexor alone (3+3) with an expansion at the MTD. Cohorts 1 and 2 received 60 and 80 mg orally, respectively, twice weekly during induction. Consolidation cycles (≤ 2) with selinexor at induction dose plus 5+2 were allowed for patients who achieved CR. MTD and recommended phase II dose of selinexor were the primary endpoints.. Twenty-one patients with poor-risk AML were enrolled. All 21 patients were included in the safety evaluations and survival analyses (4 in each of 2 cohorts; 13 in the expansion); 8 (53%) of the 19 patients evaluable for response achieved CR/CRi. MTD was not reached. Selinexor 80 mg (orally, twice weekly) was used in the expansion phase. The most common grade 3/4 nonhematologic treatment-emergent adverse events were febrile neutropenia (67%), diarrhea (29%), hyponatremia (29%), and sepsis (14%). At median follow-up (28.9 months), 38% of patients were alive. Median overall survival was 10.3 months.. Selinexor plus 7+3 is a safe regimen for patients with newly diagnosed poor-risk AML and warrants further investigation in a larger clinical trial.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Hydrazines; Leukemia, Myeloid, Acute; Male; Maximum Tolerated Dose; Middle Aged; Patient Safety; Survival Rate; Tissue Distribution; Treatment Outcome; Triazoles

Topics: Adult; Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Cladribine; Cytarabine; Female; Filgrastim; Humans; Hydrazines; Leukemia, Myeloid, Acute; Male; Mice, Inbred C57BL; Middle Aged; Remission Induction; Treatment Outcome; Triazoles; Young Adult

Topics: Hematopoietic Stem Cell Transplantation; Humans; Hydrazines; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Transplantation Conditioning; Triazoles

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cytarabine; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Gastrointestinal Diseases; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Hydrazines; Idarubicin; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Progression-Free Survival; Recurrence; Salvage Therapy; Triazoles

The median overall survival of patients with high-risk myelodysplastic syndromes refractory to hypomethylating agents is less than 6 months. Currently, no standard therapy for such patients exists. Preclinical studies have shown that inhibition of the nuclear export protein exportin 1 (XPO1) causes nuclear accumulation of p53 and disruption of NF-κB signalling, both relevant targets for myelodysplastic syndromes. We therefore aimed to assess the safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents.. We did a single-centre, single-arm, phase 2 trial at the Memorial Sloan Kettering Cancer Center in the USA. We included patients 18 years or older with high-risk myelodysplastic syndromes or oligoblastic acute myeloid leukaemia (defined as blasts ≥20% but ≤30%) refractory to hypomethylating agents and with an Eastern Cooperative Oncology Group performance status score of 0-2. Eligible patients received 3-week long cycles of oral selinexor (60 mg twice per week for 2 weeks, followed by 1 week off). The primary outcome was overall response rate. Complete remission, partial remission, marrow complete remission, or haematological improvement were included in the response categories for assessing the primary endpoint. The activity analysis included all patients who completed at least one full-scheduled post-treatment disease assessment. All patients who were given selinexor were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT02228525.. Between Sept 23, 2014, and March 13, 2018, 25 patients were enrolled on this study. The median follow-up was 8·5 months (IQR 3·1-12·2). Two patients did not meet the full eligibility criteria after baseline assessment; therefore, 23 patients were evaluable for activity assessment. In the 23 evaluable patients, overall response rate was 26% (95% CI 10-48) in six patients with marrow complete remission, with an additional 12 patients (52%, 95% CI 31-73) achieving stable disease. The most common grade 3 or 4 adverse events were thrombocytopenia (eight [32%] of 25 patients) and hyponatraemia (five [20%]). There were no drug-related serious adverse events and no treatment-related deaths.. Selinexor showed responses in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. Adverse events were manageable with supportive care implementation. Further studies are needed to compare selinexor with supportive care alone, and to identify patient subgroups that might benefit the most from selinexor treatment.. Karyopharm Therapeutics.

Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Azacitidine; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Hydrazines; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Patient Safety; Prognosis; Survival Rate; Triazoles

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Cytarabine; Drug Resistance, Neoplasm; Female; Galectins; Hepatitis A Virus Cellular Receptor 2; Humans; Hydrazines; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; T-Lymphocyte Subsets; Treatment Failure; Triazoles

Selinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8, or 10 doses of selinexor in a 21- or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only nonhematological grade 3/4 AE, occurring in >5% of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (∼35 mg/m

Topics: Adult; Blast Crisis; Bone Marrow Cells; Disease-Free Survival; Female; Humans; Hydrazines; Leukemia, Myeloid, Acute; Male; Middle Aged; Survival Rate; Triazoles

Relapse in patients with acute myeloid leukemia (AML) is common and is associated with a dismal prognosis. Treatment options are limited and the understanding of molecular response patterns is still challenging. We analyzed the clonal response patterns of 15 patients with relapsed/refractory AML treated with selinexor in a phase II trial (SAIL). DNA was analyzed at three time points and showed a decline of mutated alleles in FLT3, SF3B1, and TP53 under SAIL treatment. Overall survival (OS) was similar between patients with declining versus persisting clones. We show an interesting long-term course of a patient who relapsed after allogeneic stem cell transplantation (alloHCT) with SF3B1- and SRSF2-mutated AML and received selinexor as maintenance treatment for 4 years. Measurable residual disease (MRD) remained detectable for 2 weeks after donor lymphocyte infusion (DLI) in this patient and then remained negative under selinexor maintenance treatment. Selinexor was tolerated well and was stopped after 4 years of SAIL treatment. We present an exploratory study and identify subclonal patterns of patients treated with selinexor.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Prognosis; Recurrence

Topics: Antineoplastic Agents; Apoptosis; Azacitidine; Cell Line, Tumor; Eukaryotic Initiation Factor-4E; Humans; Karyopherins; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins c-myc; Signal Transduction

Acute myeloid leukemia (AML) is a heterogeneous disease with variable patient responses to therapy. Selinexor, an inhibitor of nuclear export, has shown promising clinical activity for AML. To identify the molecular context for monotherapy sensitivity as well as rational drug combinations, we profile selinexor signaling responses using phosphoproteomics in primary AML patient samples and cell lines. Functional phosphosite scoring reveals that p53 function is required for selinexor sensitivity consistent with enhanced efficacy of selinexor in combination with the MDM2 inhibitor nutlin-3a. Moreover, combining selinexor with the AKT inhibitor MK-2206 overcomes dysregulated AKT-FOXO3 signaling in resistant cells, resulting in synergistic anti-proliferative effects. Using high-throughput spatial proteomics to profile subcellular compartments, we measure global proteome and phospho-proteome dynamics, providing direct evidence of nuclear translocation of FOXO3 upon combination treatment. Our data demonstrate the potential of phosphoproteomics and functional phosphorylation site scoring to successfully pinpoint key targetable signaling hubs for rational drug combinations.

Topics: Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Hydrazines; Leukemia, Myeloid, Acute; Proteome; Proto-Oncogene Proteins c-akt; Triazoles; Tumor Suppressor Protein p53

NPM1 is the most frequently mutated gene in adults with acute myeloid leukemia (AML). The interaction between mutant NPM1 (NPM1c) and exportin-1 (XPO1) causes aberrant cytoplasmic dislocation of NPM1c and promotes the high expression of homeobox (HOX) genes, which is critical for maintaining the leukemic state of NPM1-mutated cells. Although there is a rationale for using XPO1 inhibitors in NPM1-mutated AML, selinexor administered once or twice per week did not translate into clinical benefit in patients with NPM1 mutations. Here, we show that this dosing strategy results in only a temporary disruption of the XPO1-NPM1c interaction, limiting the efficacy of selinexor. Because the second-generation XPO1 inhibitor eltanexor can be administered more frequently, we tested the antileukemic activity of prolonged XPO1 inhibition in NPM1-mutated AML models. Eltanexor caused irreversible HOX downregulation, induced terminal AML differentiation, and prolonged the survival of leukemic mice. This study provides essential information for the appropriate design of clinical trials with XPO1 inhibitors in NPM1-mutated AML.

Topics: Animals; Antineoplastic Agents; Gene Expression Regulation, Leukemic; Karyopherins; Leukemia, Myeloid, Acute; Mice; Nuclear Proteins; Nucleophosmin

NPM1 is the most frequently mutated gene in cytogenetically normal acute myeloid leukemia (AML). In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation. Finally, we show that XPO1 inhibition relocalizes NPM1c to the nucleus, promotes differentiation of AML cells, and prolongs survival of Npm1-mutated leukemic mice. We describe an exquisite dependency of NPM1-mutant AML cells on NPM1c, providing the rationale for the use of nuclear export inhibitors in AML with mutated NPM1.

Topics: Aged; Animals; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cytoplasm; Down-Regulation; Exportin 1 Protein; Female; Gene Expression Regulation, Leukemic; Homeodomain Proteins; Humans; Hydrazines; Karyopherins; Leukemia, Myeloid, Acute; Mice; Mutation; Nuclear Proteins; Nucleophosmin; Proteolysis; Receptors, Cytoplasmic and Nuclear; Triazoles; Xenograft Model Antitumor Assays

The antiapoptotic Bcl-2 family proteins play critical roles in resistance to chemotherapy in acute myeloid leukaemia (AML). The Bcl-2-selective inhibitor ABT-199 (Venetoclax) shows promising antileukaemic activity against AML, though Mcl-1 limits its antileukaemic activity. XPO1 is a nuclear exporter overexpressed in AML cells and its inhibition decreases Mcl-1 levels in cancer cells. Thus, we hypothesized that the XPO1-selective inhibitor KPT-330 (Selinexor) can synergize with ABT-199 to induce apoptosis in AML cells through down-regulation of Mcl-1. The combination of KPT-330 and ABT-199 was found to synergistically induce apoptosis in AML cell lines and primary patient samples and cooperatively inhibit colony formation capacity of primary AML cells. KPT-330 treatment decreased Mcl-1 protein after apoptosis initiation. However, binding of Bim to Mcl-1 induced by ABT-199 was abrogated by KPT-330 at the same time as apoptosis initiation. KPT-330 treatment increased binding of Bcl-2 to Bim but was overcome by ABT-199 treatment, demonstrating that KPT-330 and ABT-199 reciprocally overcome apoptosis resistance. Mcl-1 knockdown and overexpression confirmed its critical role in the antileukaemic activity of the combination. In summary, KPT-330 treatment, alone and in combination with ABT-199, modulates Mcl-1, which plays an important role in the antileukaemic activity of the combination.

Topics: Adult; Aged; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; Exportin 1 Protein; Female; Gene Expression Regulation, Neoplastic; Humans; Hydrazines; Karyopherins; Leukemia, Myeloid, Acute; Male; Middle Aged; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Receptors, Cytoplasmic and Nuclear; Sulfonamides; Triazoles

Acute myeloid leukemia (AML) is a clonal hematologic malignant disease of developing myeloid cells that have acquired aberrant survival, uncontrolled proliferation and a block in normal hematopoietic cell differentiation. Standard chemotherapy often induces remissions in AML patients, but the disease frequently relapses due to incomplete targeting of leukemia-initiating cells (LICs), emphasizing the need for novel effective treatments. Exportin 1 (XPO1)-mediated nuclear export, which is inhibited by the drug selinexor, is an attractive new therapeutic target in AML. Selinexor has shown impressive activity in Phase I/II clinical trials for AML. Here we report the anti-leukemic efficacy and tolerability of KPT-8602, a second-generation XPO1 inhibitor. KPT-8602 demonstrates substantially reduced brain penetration compared to selinexor, with resultant attenuation of the central nervous system mediated side effects of anorexia and weight loss. Due to its improved tolerability profile, KPT-8602 can be given daily compared to the two or three times weekly regimen of selinexor, and exhibits greater anti-leukemic efficacy against both leukemic blasts and LICs in AML patient-derived xenograft models. Importantly, normal hematopoietic stem and progenitor cell (HSPC) frequency is not significantly reduced by KPT-8602, providing a therapeutic window for elimination of relapse-driving LICs while sparing normal HSPCs. These findings strongly endorse clinical testing of KPT-8602 in patients with relapsed and refractory AML.

Topics: Active Transport, Cell Nucleus; Animals; Antineoplastic Agents; Blast Crisis; Carcinogenesis; Exportin 1 Protein; Hematopoietic Stem Cells; Heterografts; Humans; Hydrazines; Karyopherins; Leukemia, Myeloid, Acute; Mice; Receptors, Cytoplasmic and Nuclear; Triazoles

Currently available combination chemotherapy for acute myeloid leukemia (AML) often fails to result in long-term remissions, emphasizing the need for novel therapeutic strategies. We reasoned that targeted inhibition of a prominent nuclear exporter, XPO1/CRM1, could eradicate self-renewing leukemia-initiating cells (LICs) whose survival depends on timely XPO1-mediated transport of specific protein and RNA cargoes. Using an immunosuppressed mouse model bearing primary patient-derived AML cells, we demonstrate that selinexor (KPT-330), an oral antagonist of XPO1 that is currently in clinical trials, has strong activity against primary AML cells while sparing normal stem and progenitor cells. Importantly, limiting dilution transplantation assays showed that this cytotoxic activity is not limited to the rapidly proliferating bulk population of leukemic cells but extends to the LICs, whose inherent drug resistance and unrestricted self-renewal capacity has been implicated in the difficulty of curing AML patients with conventional chemotherapy alone.

Topics: Animals; Exportin 1 Protein; Humans; Hydrazines; Immunosuppression Therapy; Karyopherins; Leukemia, Myeloid, Acute; Mice; Neoplastic Stem Cells; Receptors, Cytoplasmic and Nuclear; Triazoles; Xenograft Model Antitumor Assays

Selinexor, a selective inhibitor of XPO1, is currently being tested as single agent in clinical trials in acute myeloid leukemia (AML). However, considering the molecular complexity of AML, it is unlikely that AML can be cured with monotherapy. Therefore, we asked whether adding already established effective drugs such as topoisomerase (Topo) II inhibitors to selinexor will enhance its anti-leukemic effects in AML.. The efficacy of combinatorial drug treatment using Topo II inhibitors (idarubicin, daunorubicin, mitoxantrone, etoposide) and selinexor was evaluated in established cellular and animal models of AML.. Concomitant treatment with selinexor and Topo II inhibitors resulted in therapeutic synergy in AML cell lines and patient samples. Using a xenograft MV4-11 AML mouse model, we show that treatment with selinexor and idarubicin significantly prolongs survival of leukemic mice compared with each single therapy.. Aberrant nuclear export and cytoplasmic localization of Topo IIα has been identified as one of the mechanisms leading to drug resistance in cancer. Here, we show that in a subset of patients with AML that express cytoplasmic Topo IIα, selinexor treatment results in nuclear retention of Topo IIα protein, resulting in increased sensitivity to idarubicin. Selinexor treatment of AML cells resulted in a c-MYC-dependent reduction of DNA damage repair genes (Rad51 and Chk1) mRNA and protein expression and subsequent inhibition of homologous recombination repair and increased sensitivity to Topo II inhibitors. The preclinical data reported here support further clinical studies using selinexor and Topo II inhibitors in combination to treat AML. Clin Cancer Res; 22(24); 6142-52. ©2016 AACR.

Topics: Active Transport, Cell Nucleus; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Nucleus; DNA Damage; DNA Repair; DNA Topoisomerases, Type II; Drug Resistance, Neoplasm; Exportin 1 Protein; Female; Humans; Hydrazines; Karyopherins; Leukemia, Myeloid, Acute; Mice; Mice, SCID; Proto-Oncogene Proteins c-myc; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Topoisomerase II Inhibitors; Triazoles

The prognosis of acute myeloid leukemia (AML) is poor, highlighting the need for novel treatments. Hypomethylating agents, including decitabine are used to treat elderly AML patients with relative success. Targeting nuclear export receptor (exportin 1 [XPO1]) is a novel approach to restore tumor suppressor (TS) function in AML. Here, we show that sequential treatment of AML blasts with decitabine followed by selinexor (XPO1 inhibitor) enhances the antileukemic effects of selinexor. These effects could be mediated by the re-expression of a subset of TSs (CDKN1A and FOXO3A) that are epigenetically silenced via DNA methylation, and cytoplasmic-nuclear trafficking is regulated by XPO1. We observed a significant upregulation of CDKN1A and FOXO3A in decitabine- versus control-treated cells. Sequential treatment of decitabine followed by selinexor in an MV4-11 xenograft model significantly improved survival compared with selinexor alone. On the basis of these preclinical results, a phase 1 clinical trial of decitabine followed by selinexor in elderly patients with AML has been initiated.

Topics: Active Transport, Cell Nucleus; Animals; Antineoplastic Agents; Azacitidine; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Decitabine; DNA Methylation; DNA Modification Methylases; Exportin 1 Protein; Forkhead Box Protein O3; Forkhead Transcription Factors; Humans; Hydrazines; Karyopherins; Leukemia, Myeloid, Acute; Mice; Mice, Inbred NOD; Mice, SCID; Receptors, Cytoplasmic and Nuclear; Triazoles; Tumor Cells, Cultured; Up-Regulation