scholarly journals The role of enasidenib in the treatment of mutant IDH2 acute myeloid leukemia

2018 ◽  
Vol 9 (7) ◽  
pp. 163-173 ◽  
Author(s):  
Iman Abou Dalle ◽  
Courtney D. DiNardo
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
The United States ◽  
Dna Hypermethylation ◽  
Induced Differentiation ◽  
Recurrent Mutations ◽  
Isocitrate Dehydrogenase 2 ◽  
Differentiation Block ◽  
Acute Myeloid

Recurrent mutations affecting cellular metabolism and epigenetic regulation are implicated in the pathogenesis of acute myeloid leukemia (AML). Isocitrate dehydrogenase 2 ( IDH2) gene mutations are described in 12% of patients with AML and 5% of patients with myelodysplastic syndromes. IDH2 enzyme is involved in the Krebs cycle, catalyzing α-ketoglutarate from isocitrate. Mutant IDH2 enzymes acquire a neomorphic enzymatic activity with the ability to produce 2-hydroxyglutarate from α-ketoglutarate, inhibiting multiple α-ketoglutarate-dependent dioxygenase reactions; leading to aberrant DNA hypermethylation and differentiation block in myeloid precursors and ultimately promoting leukemogenesis. Enasidenib (formerly AG-221) is an oral small molecule selective targeted inhibitor of the mutant IDH2 enzyme, approved in August 2017 by the United States Food and Drug Administration for the treatment of patients with relapsed or refractory (R/R) IDH2-mutated AML. Preclinical studies showed the effectiveness of enasidenib in inhibiting the production of 2-hydroxyglutarate with high potency, and alleviating the mutant IDH2-induced differentiation block. In the original AG221-001 phase I/II trial, patients with R/R AML were treated with enasidenib single agent therapy at escalating doses up to 650 mg daily, with the 100 mg dose level identified to be safe and effective for further evaluation. Overall, 113 patients were treated in the dose-escalation and 126 in the dose-expansion cohorts. The overall response rate for R/R patients was 40%, including a complete remission of 19%. At a median follow up of 7.7 months, the median overall survival was 9.3 months, and reached 19.7 months in responders. Enasidenib was well tolerated, although adverse events of clinical interest include indirect hyperbilirubinemia and IDH-inhibitor-induced differentiation syndrome, which can be life threatening if not identified and treated promptly. Ongoing clinical trials evaluating enasidenib in combination with intensive chemotherapy and hypomethylating agents in newly diagnosed AML, and in rational combinations for R/R AML patients are underway.

A Novel Path for ATRA Differentiation Therapy in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3727-3727
Author(s):  
Jean-Emmanuel Sarry ◽  
Helena Boutzen ◽  
Christian Récher
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Negative Regulator ◽  
Granulocytic Differentiation ◽  
Induced Differentiation ◽  
Idh1 R132h ◽  
Recurrent Mutations ◽  
Idh Mutations ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is characterized by accumulation of malignant blasts with impaired differentiation programs due to recurrent mutations, among which IDH mutations occur in 15% of AML patients. These mutations lead to a block in erythroid commitment while they may also bias hematopoietic differentiation to myeloid lineage. Interestingly, Lyn tyrosine kinase is required for erythroid differentiation and we have observed a reduction of Lyn expression in the presence of IDH1-R132H mutation. It is also a negative regulator of ATRA-induced granulocytic differentiation. Accordingly, we hypothesized that IDH mutations may sensitize AML cells to ATRA-induced differentiation. Here, we report that clinically achievable doses of ATRA are sufficient to trigger differentiation specifically on AML cell lines, primary patient samples and xenograft mice models carrying IDH1 mutation as observed by an increase in CD11b expression, granulocytic enzyme activity and morphologic changes in May-Grunwald-Giemsa staining. We also showed that ATRA-induced terminal granulocytic differentiation increases apoptosis while decreases proliferation and colony formation specifically in IDH1 mutant cells. Moreover, inhibition of IDH1-R132H activity reduced ATRA-sensitivity while increasing expression of IDH mutation correlated with highest ATRA sensitivity. Furthermore, treatment with a cell-permeable form of the oncometabolite specifically produced by the mutant (eg. 2-HydroxyGlutarate) sensitized AML cells to ATRA-induced differentiation. Finally, because ATRA-induced differentiation triggers a transient increase of Lyn activation, its association with Lyn inhibitors synergistically increased ATRA-induced differentiation of IDH mutant blasts. In summary, our results showed that IDH mutations by producing 2-HG sensitized leukemic blasts to ATRA and that this synergizes with Lyn inhibition. Since 2HG concentration reaches millimolar in AML patient serum and is 100-fold higher in IDH mutated patients than in non-mutated ones, we would predict a strong efficacy and specificity of ATRA. Furthermore, as IDH mutations are systematically conserved at relapse, this therapeutic strategy might be promising to achieve a long-term remission specifically for this AML patient subgroup. Disclosures No relevant conflicts of interest to declare.

scholarly journals Acute myeloid leukemia with IDH1 and IDH2 mutations: 2021 treatment algorithm

2021 ◽  
Vol 11 (6) ◽  
Author(s):  
Ghayas C. Issa ◽  
Courtney D. DiNardo
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Efficacy ◽  
Myeloid Leukemia ◽  
Hematologic Malignancy ◽  
Single Agent ◽  
Treatment Algorithm ◽  
Recurrent Mutations ◽  
Idh1 And Idh2 Mutations ◽  
Mutant Idh1 ◽  
Acute Myeloid

AbstractAcute myeloid leukemia is a genetically heterogeneous hematologic malignancy; approximately 20% of AML harbors a mutation in the isocitrate dehydrogenase (IDH) genes, IDH1 or IDH2. These recurrent mutations in key metabolic enzymes lead to the production of the oncometabolite 2-hydroxyglutarate, which promotes leukemogenesis through a block in normal myeloid differentiation. Since this discovery, selective oral inhibitors of mutant IDH1 and IDH2 have subsequently been developed and are now approved as single agent therapy, based on clinical efficacy observed within the original first-in-human trials. The investigation of IDH inhibitors in combination with standard therapies such as azacytidine, with intensive chemotherapy, and with other small molecule targeted therapies in rational combinations are currently under evaluation to further improve upon clinical efficacy.

scholarly journals Thyroiditis: A Rare Manifestation of Enasidenib-Induced Differentiation Syndrome

2020 ◽  
Vol 13 (2) ◽  
pp. 583-587
Author(s):  
Pavan Annamaraju ◽  
Swathi Gopishetty ◽  
Naga Goparaju ◽  
Matthew Beasey ◽  
Vamsi Kota ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Pleural Effusion ◽  
Isocitrate Dehydrogenase ◽  
Myeloid Leukemia ◽  
Induced Differentiation ◽  
Common Presentation ◽  
Isocitrate Dehydrogenase 2 ◽  
Rare Manifestation ◽  
Idh2 Mutation ◽  
Acute Myeloid

Enasidenib is an FDA-approved isocitrate dehydrogenase 2 (IDH2) inhibitor, which is used in the treatment of acute myeloid leukemia (AML). We present a case of AML with an IDH2 mutation treated with a regimen of enasidenib and 5-azacitidine, where thyroiditis was noted to be a part of differentiation syndrome. The patient is a 77-year-old woman with IDH2-mutated AML who had initially been started on 100 mg of enasidenib and then presented with dyspnea and was diagnosed with pleural effusion – a common presentation with enasidenib – but was also noted to have thyroiditis. She was started on steroids, but due to continued hyperbilirubinemia and thyroiditis, her dose of enasidenib was reduced to half, which resulted in clinical improvement. This case demonstrates thyroiditis as one of the rare manifestations in the treatment of AML with enasidenib-induced differentiation syndrome.

scholarly journals FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

2021 ◽  
Vol 11 (5) ◽  
Author(s):  
Naval Daver ◽  
Sangeetha Venugopal ◽  
Farhad Ravandi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Prognostic Significance ◽  
Treatment Algorithm ◽  
Molecular Testing ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Acute Myeloid

AbstractApproximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

scholarly journals mIDH-associated DNA hypermethylation in acute myeloid leukemia reflects differentiation blockage rather than inhibition of TET-mediated demethylation

Cell Stress ◽  
2017 ◽  
Vol 1 (1) ◽  
pp. 55-67 ◽  
Author(s):  
Laura Wiehle ◽  
Günter Raddatz ◽  
Stefan Pusch ◽  
Julian Gutekunst ◽  
Andreas von Deimling ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Dna Hypermethylation ◽  
Acute Myeloid

scholarly journals Single-agent and combination biologics in acute myeloid leukemia

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 548-556 ◽  
Author(s):  
Guillaume Richard-Carpentier ◽  
Courtney D. DiNardo
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Gemtuzumab Ozogamicin ◽  
Targeted Agents ◽  
Newly Diagnosed ◽  
Rational Drug ◽  
Genomic Characterization ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by recurrent genetic, epigenetic, and metabolic abnormalities. As a result of our increasing knowledge of the underlying biology of AML leading to rational drug development, several new targeted agents have been recently added to our therapeutic arsenal. The BCL2 inhibitor venetoclax in combination with low-dose cytarabine (LDAC) or hypomethylating agents (HMAs) is safe and effective in older patients with newly diagnosed AML ineligible for intensive chemotherapy. Glasdegib, a hedgehog pathway inhibitor, may be used in combination with LDAC for the same indication and improves survival compared with LDAC alone. In newly diagnosed, fit, older patients with therapy-related AML or AML with myelodysplasia-related changes, the liposome-encapsulated combination of daunorubicin and cytarabine (CPX-351) has shown superiority over the 7 + 3 regimen. The presence of an IDH1 or IDH2 mutation can be effectively targeted by ivosidenib or enasidenib, respectively. Gemtuzumab ozogamicin improves event-free survival in CD33+ patients with favorable or intermediate-risk cytogenetics. With new targeted agents available, comprehensive genomic characterization of AML at diagnosis and relapse is increasingly necessary to select optimal treatment. Herein, we review the new single-agent and combination biologics (omitting FLT3 inhibitors, which are discussed separately) and provide recommendations on how to best use and manage patients on these regimens in clinical practice.

Alternative polyadenylation dysregulation contributes to the differentiation block of acute myeloid leukemia

Blood ◽  
2021 ◽  
Author(s):  
Amanda G Davis ◽  
Daniel T. Johnson ◽  
Dinghai Zheng ◽  
Ruijia Wang ◽  
Nathan D. Jayne ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Alternative Polyadenylation ◽  
Hematopoietic Stem ◽  
Global Trends ◽  
Protein Levels ◽  
Mtorc1 Signaling ◽  
Differentiation Block ◽  
Acute Myeloid

Post-transcriptional regulation has emerged as a driver for leukemia development and an avenue for therapeutic targeting. Among post-transcriptional processes, alternative polyadenylation (APA) is globally dysregulated across cancer types. However, limited studies have focused on the prevalence and role of APA in myeloid leukemia. Furthermore, it is poorly understood how altered poly(A) site (PAS) usage of individual genes contributes to malignancy or whether targeting global APA patterns might alter oncogenic potential. In this study, we examined global APA dysregulation in acute myeloid leukemia (AML) patients by performing 3' Region Extraction And Deep Sequencing (3'READS) on a subset of AML patient samples along with healthy hematopoietic stem and progenitor cells (HSPCs) and by analyzing publicly available data from a broad AML patient cohort. We show that patient cells exhibit global 3' untranslated region (UTR) shortening and coding sequence (CDS) lengthening due to differences in PAS usage. Among APA regulators, expression of FIP1L1, one of the core cleavage and polyadenylation factors, correlated with the degree of APA dysregulation in our 3'READS dataset. Targeting global APA by FIP1L1 knockdown reversed the global trends seen in patients. Importantly, FIP1L1 knockdown induced differentiation of t(8;21) cells by promoting 3'UTR lengthening and downregulation of the fusion oncoprotein AML1-ETO. In non-t(8;21) cells, FIP1L1 knockdown also promoted differentiation by attenuating mTORC1 signaling and reducing MYC protein levels. Our study provides mechanistic insights into the role of APA in AML pathogenesis and indicates that targeting global APA patterns can overcome the differentiation block of AML patients.

scholarly journals Treatment patterns in patients with acute myeloid leukemia in the United States: a cross-sectional, real-world survey

2019 ◽  
Vol 35 (5) ◽  
pp. 927-935 ◽  
Author(s):  
Bruno C. Medeiros ◽  
Bhavik J. Pandya ◽  
Anna Hadfield ◽  
James Pike ◽  
Samuel Wilson ◽  
...  
Keyword(s):  
United States ◽  
Acute Myeloid Leukemia ◽  
Real World ◽  
Myeloid Leukemia ◽  
The United States ◽  
Treatment Patterns ◽  
Cross Sectional ◽  
World Survey ◽  
Acute Myeloid

Quizartinib in the treatment of FLT3-internal-tandem duplication-positive acute myeloid leukemia

2019 ◽  
Vol 15 (34) ◽  
pp. 3885-3894 ◽  
Author(s):  
Shilpa Paul ◽  
Adam J DiPippo ◽  
Farhad Ravandi ◽  
Tapan M Kadia
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Tyrosine Kinase Domain ◽  
Missense Mutations ◽  
Internal Tandem Duplication ◽  
Acute Myeloid

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.

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