Clinical pharmacokinetics and pharmacodynamics of ivosidenib in Chinese patients with relapsed or refractory IDH1-mutated acute myeloid leukemia.

PURPOSE: This study aimed to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of ivosidenib in Chinese patients with relapsed or refractory acute myeloid leukemia (R/R AML) carrying the mIDH1 mutation. METHODS: A bridging study (NCT04176393) was conducted involving 29 Chinese patients who received a daily dose of ivosidenib 500 mg in 28-day cycles. Plasma concentrations of ivosidenib and D-2-hydroxyglutarate (2-HG) were measured before and after treatment. Non-compartmental analysis (NCA) was employed to evaluate the PK, and an established population pharmacokinetic (popPK) model developed from non-Chinese patients was externally validated. RESULTS: The findings revealed comparable PD effects of ivosidenib in Chinese patients with mIDH1 R/R AML. After adjusting for concomitant drug effects, PK characteristics were similar between Chinese and non-Chinese patients. Furthermore, the popPK model offered additional insights into the possible causes of the apparent ethnic difference in PK exposure. CONCLUSION: The study indicates that ivosidenib can be used effectively in Chinese patients, and the observed ethnic differences in PK exposure can be explained by concomitant drug effects. The popPK model contributes to a better understanding and optimization of personalized dosing in Chinese patients with mIDH1 R/R AML.

Ivosidenib: A Review in Advanced Cholangiocarcinoma.

Ivosidenib (Tibsovo®), a first-in-class, oral small molecule, potent and selective inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), is approved in the EU and USA for the treatment of adults with pretreated, advanced, mIDH1 cholangiocarcinoma (CCA). It is presumed to exert its cytostatic effects in this setting by suppressing 2-hydroxyglutarate, an oncometabolite produced by mIDH1 that impairs cellular differentiation and promotes tumorigenesis. In the multinational phase 3 ClarIDHy study in patients with pretreated, advanced mIDH1 CCA, monotherapy with ivosidenib once daily significantly prolonged progression-free survival (PFS) and almost doubled the disease control rate compared with placebo. Moreover, it had a favourable effect on overall survival (OS), which was also significantly prolonged after correcting for a high rate of crossover from the placebo group (permitted by the trial protocol). Ivosidenib treatment preserved health-related quality of life (HRQOL) relating to physical function, pain and appetite loss/eating and was generally well tolerated, with the most common treatment-emergent adverse events being low-grade diarrhoea, nausea and fatigue. Thus, ivosidenib represents a novel and valuable targeted therapy for the subset of patients with pretreated, advanced CCA tumors harbouring mIDH1.

Cholangiocarcinoma (CCA) is often diagnosed at an advanced stage when the prognosis is poor due to limited treatment options, including standard-of-care (palliative) chemotherapy. Around 40% of patients with CCA have a tumor that can be targeted for treatment due to the presence of a molecular abnormality implicated in tumor formation and/or maintenance. One such abnormality (present in ≈14% of patients with intrahepatic CCA), is a mutated form of the isocitrate dehydrogenase 1 (IDH1) enzyme ('mutant IDH1') that inappropriately catalyses the production of 2-hydroxyglutarate (2-HG), an oncometabolite that promotes tumorigenesis. Ivosidenib (Tibsovo^®), a first-in-class, small molecule, oral inhibitor of mIDH1, exerts a cytostatic (stabilizing) effect on mIDH1 CCA tumors, presumably by suppressing the production of 2-HG. Compared with placebo, ivosidenib resulted in a statistically significant, near-doubling of progression-free survival and, similarly, a near doubling of the disease control rate in a pivotal study in patients with pretreated, advanced, mIDH1 CCA. Overall survival was also significantly improved after controlling for the high rate of crossover. Health-related quality of life was maintained and ivosidenib treatment was generally well tolerated. Ivosidenib represents a novel and valuable targeted therapy for patients with advanced mIDH1 CCA tumors.

Repurposing FDA-Approved Drugs for Temozolomide-Resistant IDH1 Mutant Glioma Using High-Throughput Miniaturized Screening on Droplet Microarray Chip.

To address the challenge of drug resistance and limited treatment options for recurrent gliomas with IDH1 mutations, a highly miniaturized screening of 2208 FDA-approved drugs is conducted using a high-throughput droplet microarray (DMA) platform. Two patient-derived temozolomide-resistant tumorspheres harboring endogenous IDH1 mutations (IDH1mut ) are utilized. Screening identifies over 20 drugs, including verteporfin (VP), that significantly affected tumorsphere formation and viability. Proteomics analysis reveals that nuclear pore complex may be a potential VP target, suggesting a new mechanism of action independent of its known effects on YAP1. Knockdown experiments exclude YAP1 as a drug target in tumorspheres. Pathway analysis shows that NUP107 is a potential upstream regulator associated with VP response. Analysis of publicly available genomic datasets shows a significant correlation between high NUP107 expression and decreased survival in IDH1mut astrocytoma, suggesting NUP107 may be a potential biomarker for VP response. This study demonstrates a miniaturized approach for cost-effective drug repurposing using 3D glioma models and identifies nuclear pore complex as a potential target for drug development. The findings provide preclinical evidence to support in vivo and clinical studies of VP and other identified compounds to treat IDH1mut gliomas, which may ultimately improve clinical outcomes for patients with this challenging disease.

Novel Therapies in Myelodysplastic Syndrome: Where Do Venetoclax and Isocitrate Dehydrogenase Inhibitors Fit in?

ABSTRACT: Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic stem cell disorders with treatment approaches tailored to the presence of cytopenias, disease risk, and molecular mutation profile. In higher-risk MDSs, the standard of care are DNA methyltransferase inhibitors, otherwise referred to as hypomethylating agents (HMAs), with consideration for allogeneic hematopoietic stem cell transplantation in appropriate candidates. Given modest complete remission rates (15%-20%) with HMA monotherapy and median overall survival of approximately 18 months, there is much interest in the investigation of combination and targeted treatment approaches. Furthermore, there is no standard treatment approach in patients with progression of disease after HMA therapy. In this review, we aim to summarize the current evidence for the B-cell lymphoma-2 inhibitor, venetoclax, and a variety of isocitrate dehydrogenase inhibitors in the treatment of MDSs along with discussing their potential role in the treatment paradigm of this disease.

Mutant Isocitrate Dehydrogenase 1 Expression Enhances Response of Gliomas to the Histone Deacetylase Inhibitor Belinostat.

Histone deacetylase inhibitors (HDACis) are drugs that target the epigenetic state of cells by modifying the compaction of chromatin through effects on histone acetylation. Gliomas often harbor a mutation of isocitrate dehydrogenase (IDH) 1 or 2 that leads to changes in their epigenetic state presenting a hypermethylator phenotype. We postulated that glioma cells with IDH mutation, due to the presence of epigenetic changes, will show increased sensitivity to HDACis. This hypothesis was tested by expressing mutant IDH1 with a point alteration-converting arginine 132 to histidine-within glioma cell lines that contain wild-type IDH1. Glioma cells engineered to express mutant IDH1 produced D-2-hydroxyglutarate as expected. When assessed for response to the pan-HDACi drug belinostat, mutant IDH1-expressing glioma cells were subjected to more potent inhibition of growth than the corresponding control cells. Increased sensitivity to belinostat correlated with the increased induction of apoptosis. Finally, a phase I trial assessing the addition of belinostat to standard-of-care therapy for newly diagnosed glioblastoma patients included one patient with a mutant IDH1 tumor. This mutant IDH1 tumor appeared to display greater sensitivity to the addition of belinostat than the other cases with wild-type IDH tumors based on both standard magnetic resonance imaging (MRI) and advanced spectroscopic MRI criteria. These data together suggest that IDH mutation status within gliomas may serve as a biomarker of response to HDACis.

Metronomic Temozolomide in Heavily Pretreated Patients With Recurrent Isocitrate Dehydrogenase Wild-type Glioblastoma: A Large Real-Life Mono-Institutional Study.

AIMS: Glioblastoma (GBM) is the most common primary malignant brain tumour in adults and frequently relapses. The aim of this study was to assess the efficacy and safety of metronomic temozolomide (TMZ) in the recurrent GBM population. MATERIALS AND METHODS: All patients treated at our centre between September 2013 and March 2021 were retrospectively reviewed. The main inclusion criteria were first-line therapy with the Stupp protocol, relapse after the first or subsequent line of therapy, treatment with a metronomic TMZ schedule (50 mg/m2 continuously) and histological diagnosis of isocitrate dehydrogenase wild-type GBM according to World Health Organization 2016 classification. RESULTS: In total, 120 patients were enrolled. The median follow-up was 15.6 months, the median age was 59 years, Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0-2 in 107 patients (89%). O6-methylguanine-DNA-methyltransferase (MGMT) was methylated in 66 of 105 (62%) evaluable patients. The median number of prior lines of treatment was 2 (range 1-7). Three (2%) patients showed a partial response; 48 (40%) had stable disease; 69 (57%) had progressive disease. The median overall survival from the start of metronomic TMZ was 5.4 months (95% confidence interval 4.3-6.4), whereas the median progression-free survival (PFS) was 2.6 months (95% confidence interval 2.3-2.8). At univariate analysis, MGMT methylated and unmethylated patients had a median PFS of 2.9 and 2.1 months (P = 0.001) and a median overall survival of 5.6 and 4.4 months (P = 0.03), respectively. At multivariate analysis, the absence of MGMT methylation (hazard ratio = 2.3, 95% confidence interval 1.3-3.9, P = 0.004) and ECOG-PS ≤ 2 (hazard ratio = 0.5, 95% confidence interval 0.3-0.9, P = 0.017) remained significantly associated with PFS, whereas ECOG-PS ≤ 2 (hazard ratio = 0.4, 95% confidence interval 0.3-07, P = 0.001) was the only factor associated with overall survival. The most common grade 3-4 toxicities were haematological (lymphopenia 10%, thrombocytopenia 3%). CONCLUSIONS: Rechallenge with metronomic TMZ is a well-tolerated option for recurrent GBM, even in pretreated patients. Patients with methylated MGMT disease and good ECOG-PS seem to benefit the most from this treatment.

Single-center, observational study of AML/MDS-EB with IDH1/2 mutations: genetic profile, immunophenotypes, mutational kinetics and outcomes.

OBJECTIVE: IDH1/2 mutations, intervening in epigenetic procedures, are frequently encountered in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Knowledge of the genetics, immunophenotypes, and mutational kinetics of IDH1/2-mutated AML can contribute to the understanding of AML clonal architecture and inform therapeutics and monitoring. METHODS: We retrospectively analyzed 50 IDH1/2-mutated AML/MDS-EB cases of our institution, to identify recurrent co-mutations, immunophenotypes, patterns of co-variance of IDH1/2 allele burdens with those of recurrent co-mutations, frequency of persistent IDH1/2 mutation as clonal hematopoiesis of indeterminate potential (CHIP) in remission and response to hypomethylating agents. RESULTS: Most frequently co-mutated genes were DNMT3A, SRSF2 and NPM1. Most cases with co-existent IDH1/2 and NPM1 mutations (11/13) showed an 'APL-like' immunophenotype (CD34-HLADR-). Allele burdens of mutated IDH1/2 were identical to mutated SRSF2 allele burdens at diagnosis and remission, but not always to mutated NPM1 allele burden in remission. We show persistence of significant mutIDH1/2 allele burden in approximately one-fourth of patients with deep remissions. IDH1/2 mutations were significantly more frequent among responders to first-line HMA-based regimens than among non-responders, in patients treated for myeloid neoplasms with excess blasts. CONCLUSIONS: IDH1/2 mutations are most frequently accompanied by DNMT3A, SRSF2 and NPM1 mutations. NPM1-IDH1/2 mutated AML has a mature phenotype possibly amenable to differentiation therapies. IDH1/2 and SRSF2 mutations probably arise at the same developmental stage of the disease, as their allele burdens covariate. IDH1/2 mutation represents CHIP in a substantial proportion of cases and is therefore no reliable residual disease marker. The preferential presence of IDH1/2 mutations among HMA-responders could inform therapeutic decisions if confirmed in larger series.

PRMT1 driven PTX3 regulates ferritinophagy in glioma.

Mutations in the Krebs cycle enzyme IDH1 (isocitrate dehydrogenase (NADP(+)) 1) are associated with better prognosis in gliomas. Though IDH1 mutant (IDH1R132H) tumors are characterized by their antiproliferative signatures maintained through hypermethylation of DNA and chromatin, mechanisms affecting cell death pathways in these tumors are not well elucidated. On investigating the crosstalk between the IDH1 mutant epigenome, ferritinophagy and inflammation, diminished expression of PRMT1 (protein arginine methyltransferase 1) and its associated asymmetric dimethyl epigenetic mark H4R3me2a was observed in IDH1R132H gliomas. Reduced expression of PRMT1 was concurrent with diminished levels of PTX3, a key secretory factor involved in cancer-related inflammation. Lack of PRMT1 H4R3me2a in IDH1 mutant glioma failed to epigenetically activate the expression of PTX3 with a reduction in YY1 (YY1 transcription factor) binding on its promoter. Transcriptional activation and subsequent secretion of PTX3 from cells was required for maintaining macroautophagic/autophagic balance as pharmacological or genetic ablation of PTX3 secretion in wild-type IDH1 significantly increased autophagic flux. Additionally, PTX3-deficient IDH1 mutant gliomas exhibited heightened autophagic signatures. Furthermore, we demonstrate that the PRMT1-PTX3 axis is important in regulating the levels of ferritin genes/iron storage and inhibition of this axis triggered ferritinophagic flux. This study highlights the conserved role of IDH1 mutants in augmenting ferritinophagic flux in gliomas irrespective of genetic landscape through inhibition of the PRMT1-PTX3 axis. This is the first study describing ferritinophagy in IDH1 mutant gliomas with mechanistic details. Of clinical importance, our study suggests that the PRMT1-PTX3 ferritinophagy regulatory circuit could be exploited for therapeutic gains.Abbreviations: 2-HG: D-2-hydroxyglutarate; BafA1: bafilomycin A1; ChIP: chromatin immunoprecipitation; FTH1: ferritin heavy chain 1; FTL: ferritin light chain; GBM: glioblastoma; HMOX1/HO-1: heme oxygenase 1; IHC: immunohistochemistry; IDH1: isocitrate dehydrogenase(NADP(+))1; MDC: monodansylcadaverine; NCOA4: nuclear receptor coactivator 4; NFE2L2/Nrf2: NFE2 like bZIP transcription factor 2; PTX3/TSG-14: pentraxin 3; PRMT: protein arginine methyltransferase; SLC40A1: solute carrier family 40 member 1; Tan IIA: tanshinone IIA; TCA: trichloroacetic acid; TEM: transmission electron microscopy; TNF: tumor necrosis factor.

Mutations de l'ADN dans les cholangiocarcinomes : cibler IDH1 et autres mutations.

DNA mutations in cholangiocarcinoma: targeting IDH1 and other mutations Biliary tract cancers (BTC) are rare cancers with a poor prognosis, particularly at the metastatic stage, with a 5-year survival rate not exceeding 7%. Two lines of chemotherapy are currently recommended in France, with cisplatin-gemcitabine and 5 FU-oxaliplatin as first and second-line treatment respectively, allowing a median survival of approximately one year. However, many studies have shown that BTC, and more particularly intrahepatic cholangiocarcinoma, have a high somatic alteration rate (mutations, fusions, or amplifications). Some of these alterations are potential therapeutic targets. To date, only ivosidenib and pemigatinib, targeting IDH1 mutations and FGFR2 fusions respectively, are approved in France for pre-treated patients with these molecular alterations. Many other potentially targetable alterations are found in BTC, including mutations in genes involved in DNA repair, BRAF, HER2 and the recently exploited KRASG12C mutation. This review will focus on targetable mutations in BTC and develop the main molecules that can be used in BTC with these actionable alterations, offering new therapeutic perspectives for these patients, with the ultimate goal of improving their prognosis.

Real-World Data on Ivosidenib in Patients with Previously Treated Isocitrate Dehydrogenase 1-Mutated Intrahepatic Cholangiocarcinomas: An Early Exploratory Analysis.

BACKGROUND: The results of the phase III ClarIDHy trial have led to US FDA approval of ivosidenib as a therapeutic option for patients with locally advanced or metastatic cholangiocarcinoma (CCA) harboring isocitrate dehydrogenase 1 (IDH1) mutations. OBJECTIVE: In this study, we report the first real-world experience including eight patients with previously treated locally advanced or metastatic IDH1-mutated CCA treated with ivosidenib. PATIENTS AND METHODS: Patients treated with ivosidenib as second and third line for advanced CCA were collected with the aim of evaluating the survival outcomes. A molecular study has been performed by next-generation sequencing assay. RESULTS: After a median follow up of 9.4 months, median progression-free survival (PFS) from the start of treatment with ivosidenib was 4.4 months (95% confidence interval [CI] 3.3-5.8), whereas median overall survival (OS) was not reached. The disease control rate was 62.5%, with two patients achieving a partial response (25%); 12.5% of patients experienced a treatment-related adverse event (AE), but no grade 3 or higher AEs were reported. The observed grade 2 AEs were prolonged QT interval and hypomagnesemia (25% of the sample). Molecular profiling was performed on six of eight patients, highlighting TP53, BAP1, CDKN2A and CDKN2B as the most common co-altered genes in these patients. CONCLUSION: Efficacy outcomes were consistent with those reported in the ClarIDHy trial. Real-world experiences on larger samples are needed in order to confirm our results.

Grossamide attenuates inflammation by balancing macrophage polarization through metabolic reprogramming of macrophages in mice.

Macrophages exhibited different phenotypes in response to environmental cues. To meet the needs of rapid response to stimuli, M1-activated macrophages preferred glycolysis to oxidative phosphorylation (OXPHOS) in mitochondria to quickly produce energy and obtain ample raw materials to support cell activation at the same time. Activated macrophages produced free radicals and cytokines to eradicate pathogens but also induced oxidative damage and enhanced inflammation. Grossamide (GSE), a lignanamide from Polygonum multiflorum Thunb., exhibited notable anti-inflammatory effects. In this study, the potential of GSE on macrophage polarization was explored. GSE significantly down-regulated the levels of M1 macrophage biomarkers (Cd32a, Cd80 and Cd86) while increased the levels of M2 indicators (Cd163, Mrc1 and Socs1), showing its potential to inhibit LPS-induced M1 polarization of macrophages. This ability has close a link to its effect on metabolic reprogramming of macrophage. GSE shunted nitric oxide (NO) production from arginine by up-regulation of arginase and down-regulation of inducible nitric oxide synthase, thus attenuated the inhibition of NO on OXPHOS. LPS created three breakpoints in the tricarboxylic acid cycle (TCA) cycle of macrophage as evidenced by down-regulated isocitrate dehydrogenase, accumulation of succinate and the inhibited SDH activity, significantly decreased level of oxoglutarate dehydrogenase expression and its substrate α-ketoglutarate. Thus GSE reduced oxidative stress and amended fragmented TCA cycle. As a result, GSE maintained redox (NAD+/NADH) and energy (ATP/ADP) state, reduced extracellular acidification rate and enhanced the oxygen consumption rate. In addition, GSE decreased the release of inflammatory cytokines by inhibiting the activation of the LPS/TLR4/NF-κB pathway. These findings highlighted the central role of immunometabolism of macrophages in its functional plasticity, which invited future study of mode of action of anti-inflammatory drugs from viewpoint of metabolic reprogramming.

Isocitrate dehydrogenase 2 inhibitor enasidenib synergizes daunorubicin cytotoxicity by targeting aldo-keto reductase 1C3 and ATP-binding cassette transporters.

Targeting mutations that trigger acute myeloid leukaemia (AML) has emerged as a refined therapeutic approach in recent years. Enasidenib (Idhifa) is the first selective inhibitor of mutated forms of isocitrate dehydrogenase 2 (IDH2) approved against relapsed/refractory AML. In addition to its use as monotherapy, a combination trial of enasidenib with standard intensive induction therapy (daunorubicin + cytarabine) is being evaluated. This study aimed to decipher enasidenib off-target molecular mechanisms involved in anthracycline resistance, such as reduction by carbonyl reducing enzymes (CREs) and drug efflux by ATP-binding cassette (ABC) transporters. We analysed the effect of enasidenib on daunorubicin (Daun) reduction by several recombinant CREs and different human cell lines expressing aldo-keto reductase 1C3 (AKR1C3) exogenously (HCT116) or endogenously (A549 and KG1a). Additionally, A431 cell models overexpressing ABCB1, ABCG2, or ABCC1 were employed to evaluate enasidenib modulation of Daun efflux. Furthermore, the potential synergism of enasidenib over Daun cytotoxicity was quantified amongst all the cell models. Enasidenib selectively inhibited AKR1C3-mediated inactivation of Daun in vitro and in cell lines expressing AKR1C3, as well as its extrusion by ABCB1, ABCG2, and ABCC1 transporters, thus synergizing Daun cytotoxicity to overcome resistance. This work provides in vitro evidence on enasidenib-mediated targeting of the anthracycline resistance actors AKR1C3 and ABC transporters under clinically achievable concentrations. Our findings may encourage its combination with intensive chemotherapy and even suggest that the effectiveness of enasidenib as monotherapy against AML could lie beyond the targeting of mIDH2.

IDH1 inhibitor-induced neutrophilic dermatosis in a patient with acute myeloid leukemia.

Ivosidenib is an oral inhibitor of mutant Isocitrate dehydrogenase 1 (IDH1). It is approved for treatment of patients with relapsed or refractory IDH1-mutated acute myeloid leukemia (AML) and patients with newly diagnosed IDH1-mutated AML who are 75 years or older or those who are ineligible to receive intensive chemotherapy. While generally well tolerated, differentiation syndrome has been reported in 15-20% of patients. Here, we report a case of acute febrile neutrophilic dermatosis or Sweet's syndrome in conjunction with the use of ivosidenib for the treatment of relapsed AML. We discuss the clinical presentation of this rare entity, review relevant literature, and comment on its association with differentiation syndrome.

Pharmacokinetic/Pharmacodynamic Evaluation of Ivosidenib or Enasidenib Combined With Intensive Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed IDH1/2-Mutant Acute Myeloid Leukemia.

Mutant isocitrate dehydrogenase 1/2 (mIDH1/2) proteins catalyze production of the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib and enasidenib are oral inhibitors of mIDH1 and mIDH2, respectively. An open-label phase 1 study is evaluating the safety and efficacy of ivosidenib or enasidenib combined with intensive induction and consolidation chemotherapy in adult patients with newly diagnosed mIDH1/2 acute myeloid leukemia (AML; NCT02632708). In this population, we characterized the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships for ivosidenib and enasidenib. Patients received continuous oral ivosidenib 500 mg once daily or enasidenib 100 mg once daily combined with chemotherapy. Serial blood samples were collected for measurement of the concentrations of the mIDH inhibitors. 2-HG concentrations were measured in both plasma and bone marrow aspirates. Samples were collected from 60 patients receiving ivosidenib and 91 receiving enasidenib. For both drugs, exposures at steady state were higher than after single doses, with mean accumulation ratios (based on area under the plasma concentration-time curve from time 0 to 24 hours) of 2.35 and 8.25 for ivosidenib and enasidenib, respectively. Mean plasma 2-HG concentrations were elevated at baseline. After multiple ivosidenib or enasidenib doses, mean trough plasma 2-HG concentrations decreased to levels observed in healthy individuals and were maintained with continued dosing. There was a corresponding reduction in bone marrow 2-HG concentrations. When combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML, ivosidenib and enasidenib demonstrated PK/PD profiles similar to those when they are given as single agents. These findings support the dosing of ivosidenib or enasidenib in combination with intensive chemotherapy for the treatment of patients with newly diagnosed mIDH1/2 AML.

Synergy between TMZ and individualized multimodal immunotherapy to improve overall survival of IDH1 wild-type MGMT promoter-unmethylated GBM patients.

The prognosis of IDH1 wild-type MGMT promoter-unmethylated GBM patients remains poor. Addition of Temozolomide (TMZ) to first-line local treatment shifted the median overall survival (OS) from 11.8 to 12.6 months. We retrospectively analyzed the value of individualized multimodal immunotherapy (IMI) to improve OS in these patients. All adults meeting the criteria and treated 06/2015-06/2021 were selected. Thirty-two patients (12f, 20m) had a median age of 47 y (range 18-69) and a KPI of 70 (50-100). Extent of resection was complete (11),

Assessment of Transporter-Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients With Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome.

As a first-in-class, selective, potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation. An in vitro study showed that enasidenib at clinically relevant concentrations has effects on multiple drug metabolic enzymes and transporters, including inhibition of P-glycoprotein, breast cancer resistance protein, organic anion transporter (OAT) P1B1, and OATP1B3 transporters. Therefore, a drug-drug interaction study was conducted to assess the impact of enasidenib at steady state on the pharmacokinetics of several probe compounds in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome, including the probes herein described in this article, digoxin and rosuvastatin. Results from 8 patients (all Asian) with a mean age of 67.1 years showed that following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), digoxin's (0.25 mg) area under the plasma concentration-time curve from time 0 to 30 days was 1.2-fold (90% confidence interval, 0.9-1.6), compared with digoxin alone. Following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), rosuvastatin's (10 mg) area under the plasma concentration-time curve from time 0 to infinity was 3.4-fold (90% confidence interval, 2.6-4.5) compared with rosuvastatin alone. These results should serve as the basis for dose recommendations for drugs that are substrates of P-glycoprotein, breast cancer resistance protein, OATP1B1, and OATP1B3 transporters, when used concomitantly with enasidenib.

In Situ Sprayed Starvation/Chemodynamic Therapeutic Gel for Post-Surgical Treatment of IDH1 (R132H) Glioma.

Complete resection of isocitrate dehydrogenase 1 (IDH1) (R132H) glioma is unfeasible and the classic post-surgical chemo/radiotherapy suffers from high recurrence and low survival rate. IDH1 (R132H) cells are sensitive to low concentrations of glucose and high concentrations of reactive oxygen species (ROS) due to inherent metabolism reprograming. Hence, a starvation/chemodynamic therapeutic gel is developed to combat residual IDH1 (R132H) tumor cells after surgery. Briefly, glucose oxidase (GOx) is mineralized with manganese-doped calcium phosphate to form GOx@MnCaP nanoparticles, which are encapsulated into the fibrin gel (GOx@MnCaP@fibrin). After spraying gel in the surgical cavity, GOx catalyzes the oxidation of glucose in residual IDH1 (R132H) cells and produces H2 O2 . The generated H2 O2 is further converted into highly lethal hydroxyl radicals (•OH) by a Mn2+ -mediated Fenton-like reaction to further kill the residual IDH1 (R132H) cells. The as-prepared starvation/chemodynamic therapeutic gel shows much higher therapeutic efficacy toward IDH1 (R132H) cells than IDH1 (WT) cells, and achieves long-term survival.

Successful Treatment of Cytogenetically Normal Acute Myeloid Leukemia With Ten-Eleven Translocation 2-Isocitrate Dehydrogenase 2 and Additional Sex Comb-like 1-Nucleophosmin Co-mutations by HLA Haploidentical Stem Cell Transplantation: A Case Report and Literature Review.

The presence of recurrent gene mutations is increasingly important in acute myeloid leukemia (AML) and sheds new insights into the understanding of leukemogenesis, prognostic evaluation, and clinical therapeutic efficacy. Until now, ten-eleven translocation 2 (TET2) and isocitrate dehydrogenase 2 (IDH2) mutations were reported to be mutually exclusive in AML patients. Similarly, nucleophosmin (NPM1) and additional sex comb-like 1 (ASXL1) mutations were rarely coexisted in AML. A 47-year-old man diagnosed with high-risk AML presented simultaneous mutations of TET2-IDH2 and NPM1-ASXL1 revealed by next-generation sequencing. After successful treatment with chemotherapy followed by HLA haploidentical transplantation, he achieved a clinical complete remission without evidence of overt graft-versus-host disease. This case highlights that HLA haploidentical transplantation might be a safe and feasible therapy for AML patients who are characterized by TET2-IDH2 and NPM1-ASXL1 co-mutations.