主要目的：对比 HMPL-306 与挽救性化疗方案在伴IDH1或IDH2突变的 R/R AML患者中的总体生存情况次要目的：对比 HMPL-306与挽救性化疗在伴IDH1或IDH2突变的 R/R AML患者中的其他疗效；评价 HMPL-306与挽救性化疗在伴IDH1或IDH2突变的 R/R AML患者中的安全性；评价 HMPL-306在伴IDH1或IDH2突变的R/R AML患者中的药代动力学（PK）特征

开始日期2024-04-26

申办/合作机构

和记黄埔医药（上海）有限公司

NCT04522895 / Completed临床2期IIT

IDH2-Post-Allo-Trial: Enasidenib As Consolidation or Salvage Therapy for Patients with IDH2 Mutated AML or MDS Following Allogeneic Blood Stem Cell Transplantation

This is a prospective, open label, single arm, multi-centre phase II trial aiming to evaluate the safety and efficacy of Enasidenib (investigational product) as prophylactic consolidation in patients with IDH2-mutated MDS, CMML and AML in remission after allo-SCT.

开始日期2020-08-27

申办/合作机构

Heinrich-Heine-Universität Düsseldorf

[+1]

NCT03515512 / Completed临床1期IIT

A Phase I Study of IDH2 Inhibition Using Enasidenib as Maintenance Therapy for IDH2-mutant Myeloid Neoplasms Following Allogeneic Stem Cell Transplantation

This research study is studying a targeted therapy drug as a possible treatment for IDH2 mutant acute myeloid leukemia or chronic myelomonocytic leukemia while undergoing hematopoietic stem cell transplantation.
The drug involved in this study is:
-Enasidenib.

开始日期2018-07-17

申办/合作机构

The General Hospital Corp.

[+1]

100 项与 IDH2突变急性髓系白血病相关的临床结果

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100 项与 IDH2突变急性髓系白血病相关的转化医学

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0 项与 IDH2突变急性髓系白血病相关的专利（医药）

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项与 IDH2突变急性髓系白血病相关的文献（医药）

2024-01-23·Blood Advances

A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML

Article

作者: Mao, Hsiaoyin Charlene ; Olin, Rebecca L. ; Chervin, Jordan ; Mims, Alice S. ; Vergilio, Jo-Anne ; Borate, Uma ; Marcus, Sonja ; Patel, Prapti ; Yocum, Ashley O. ; Cai, Sheng F. ; Lin, Tara ; Stefanos, Mona ; Dunbar, Andrew J. ; Li, Yan ; Burd, Amy ; Druggan, Franchesca ; Blum, William G. ; Chen, Timothy L. ; Schiller, Gary J. ; Byrd, John C. ; Huang, Ying ; Lance, Jennie R. ; Heerema, Nyla A. ; Litzow, Mark ; McNulty, Samantha N. ; Foster, Matthew C. ; Rosenberg, Leonard ; Kovacsovics, Tibor ; Shoben, Abigail ; Boyiadzis, Michael ; Druker, Brian J. ; Collins, Robert H. ; Druley, Todd ; Baer, Maria R. ; Levine, Ross L. ; Foran, James M. ; Stein, Eytan M. ; Stock, Wendy

AbstractEnasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998.

2024-01-01·Cancer Science

Phospholipid metabolic adaptation promotes survival of IDH2 mutant acute myeloid leukemia cells

Article

作者: Arima, Yuichiro ; Wang, Yuxin ; Morishima, Tatsuya ; Takizawa, Hitoshi ; Suda, Toshio ; Chin, Desmond Wai Loon ; Takahashi, Koichi ; Tokunaga, Kenji ; Matsuoka, Masao

AbstractGenetic mutations in the isocitrate dehydrogenase (IDH) gene that result in a pathological enzymatic activity to produce oncometabolite have been detected in acute myeloid leukemia (AML) patients. While specific inhibitors that target mutant IDH enzymes and normalize intracellular oncometabolite level have been developed, refractoriness and resistance has been reported. Since acquisition of pathological enzymatic activity is accompanied by the abrogation of the crucial WT IDH enzymatic activity in IDH mutant cells, aberrant metabolism in IDH mutant cells can potentially persist even after the normalization of intracellular oncometabolite level. Comparisons of isogenic AML cell lines with and without IDH2 gene mutations revealed two mutually exclusive signalings for growth advantage of IDH2 mutant cells, STAT phosphorylation associated with intracellular oncometabolite level and phospholipid metabolic adaptation. The latter came to light after the oncometabolite normalization and increased the resistance of IDH2 mutant cells to arachidonic acid‐mediated apoptosis. The release of this metabolic adaptation by FDA‐approved anti‐inflammatory drugs targeting the metabolism of arachidonic acid could sensitize IDH2 mutant cells to apoptosis, resulting in their eradication in vitro and in vivo. Our findings will contribute to the development of alternative therapeutic options for IDH2 mutant AML patients who do not tolerate currently available therapies.

2023-07-05·American journal of clinical pathology

Clinicopathologic Features of IDH2 R172-Mutated Myeloid Neoplasms.

Article

作者: Bailey, Nathanael G ; Davis, Adam R ; Aggarwal, Nidhi ; Canady, Briana C

OBJECTIVESIDH1 and IDH2 are among the most commonly mutated genes in myeloid neoplasms (MNs). It has been proposed that IDH2 R172 mutations (mR172) define a molecular subtype of acute myeloid leukemia (AML), but the clinicopathologic features of AML with mR172 have not been fully described.METHODSWe retrospectively identified and characterized all mR172 MNs with increased blasts in our archive for comparison to a similar number of MNs with IDH2 R140 (mR140) and IDH1 R132 (mR132) mutations (n = 39).RESULTSmR172 cases had lower leukocyte counts and bone marrow cellularity than did non-mR172 cases. mR172 MNs often displayed blasts with highly invaginated, cleaved nuclei and typically expressed CD34, HLA-DR, CD117, and CD13 but often with diminished CD33. mR172 cases often had co-occurring mutations in myelodysplasia-associated genes and/or an adverse karyotype. Despite frequent adverse-risk genetic changes, in our cohort mR172 cases had significantly improved overall survival vs non-mR172 cases (P = .01), and we validated that mR172 was associated with improved survival in an independent large data set.CONCLUSIONSWe show that MNs with mR172 represent a morphologically and phenotypically distinct subtype, which in our cohort exhibited relatively favorable survival that is not captured in current AML risk assignment.