作者: Wang, Tony J C ; Chang, Eric L ; McClelland Iii, Shearwood ; Chao, Samuel T ; Chang, Eric L. ; Milano, Michael T. ; Chiang, Veronica L.S. ; Shiue, Kevin ; Lehrer, Eric J. ; Knisely, Jonathan P.S. ; Pollom, Erqi L. ; Knisely, Jonathan P S ; Chundury, Anupama ; McGranahan, Tresa M. ; Milano, Michael T ; Lehrer, Eric J ; Tom, Martin C ; Tom, Martin C. ; Breen, William G. ; Breen, William G ; Palmer, Joshua D ; Palmer, Joshua D. ; Nagpal, Seema ; McGranahan, Tresa M ; McClelland III, Shearwood ; Chiang, Veronica L S ; Saeed, Hina ; Chao, Samuel T. ; Pollom, Erqi L ; Wang, Tony J.C.

The ARS brain committee recommends that vorasidenib may be appropriate for recurrent or residual IDH-mutant grade 2 oligodendroglioma or astrocytoma. Vorasidenib is usually not appropriate for completely resected grade 2 oligodendroglioma or astrocytoma, any grade 3 oligodendroglioma or astrocytoma, or combined with radiotherapy and/or chemotherapy for any grade 2-3 glioma.

2024-11-01·Expert Review of Hematology

A review of the isocitrate dehydrogenase inhibitors in management of adult patients with AML and MDS

Review

作者: Norman, Mallory ; Shallis, Rory ; Podoltsev, Nikolai ; Eighmy, William ; Stahl, Maximilian ; Yamartino, Katelyn ; Mendez, Lourdes ; Zeidan, Amer M. ; Gerstein, Rachel

INTRODUCTION:

The development of oral therapies impacts the management of acute myeloid leukemia and myelodysplastic syndromes, especially for targetable mutations including IDH1/2.

AREAS COVERED:

We discuss IDH1/2 activity and inhibitor therapy in various settings, including monotherapy, combination therapy with hypomethylating agents, and other approaches.

EXPERT OPINION:

Olutasidenib, enasidenib, and ivosidenib are approved for relapsed AML. Ivosidenib is approved for relapsed MDS and alone or with azacitidine in newly diagnosed AML. However, unanswered questions exist. In newly diagnosed AML, ivosidenib + azacitidine shows a survival benefit compared to azacitidine, but it is unknown whether ivosidenib + azacitidine demonstrates improved survival compared to ivosidenib. Ivosidenib + azacitidine demonstrated a survival benefit not seen with enasidenib + azacitidine. It is unclear whether newly diagnosed AML should be treated with azacitidine + ivosidenib or azacitidine + venetoclax. Azacitidine + venetoclax shows excellent response rates in IDH mutated disease. Retrospective data show low response rates of IDH inhibitor therapy post-venetoclax whereas HMA + venetoclax retains activity post IDH inhibition. The role of IDH inhibition post-transplant is unclear. Single-arm studies show post-transplant maintenance is safe; however, randomized trials are needed. Similarly, IDH inhibitors can be combined with chemotherapy however randomized studies are needed.

2024-10-01·INTERNATIONAL JOURNAL OF HEMATOLOGY

Advances in pathogenesis research and challenges in treatment development for acute myeloid leukemia

Review

作者: Yamaguchi, Hiroki

Acute myeloid leukemia (AML) develops when hematopoietic stem cells acquire chromosomal and genetic abnormalities, transforming into leukemia stem cells (LSCs) and further gaining driver mutations. Advances in genomic analysis have identified numerous new gene mutations involved in AML development. Recent research has shown that individuals with germline mutations in genes like DDX41 and CEBPA develop AML upon acquiring additional somatic mutations, and the latest WHO classification separates AML with such mutations into distinct disease groups. LSCs are regulated by different metabolic processes than normal stem cells, contributing to drug resistance and relapse. LSCs rely on oxidative phosphorylation (OXPHOS) metabolism for energy production, and venetoclax inhibits this process, affecting LSCs. Resistant LSCs show enhanced glycolysis, which suggests that targeting both OXPHOS and glycolysis is crucial. While targeted therapies like FLT3, BCL-2, and IDH inhibitors have shown efficacy, resistance remains an issue, highlighting the need for new treatment strategies. CAR-T cell therapy is an emerging immunotherapy that shows particular promise for targeting CD123 and CLL-1, with acceptable toxicity. Future developments in CAR-T cell therapy and other immunotherapies are anticipated to improve AML treatment outcomes.

项与 IDH2 inhibitors (Zhejiang Meton) 相关的新闻（医药）

2024-08-06

·FiercePharma

Servier snags FDA approval for Voranigo, the first targeted therapy for a common type of brain tumor

This marks the first FDA approval of a systemic therapy for patients with grade 2, IDH-mutant gliomas. Servier has expanded its IDH drug armamentarium with the FDA approval for an IDH1/2 dual inhibitor. The approval represents the first major treatment advance in low-grade brain cancer in more than two decades.The new FDA approval is for Servier’s Voranigo, or vorasidenib, for adult and children ages 12 and older with low-grade glioma with a susceptible IDH1 or IDH2 mutation. As the FDA noted in its press release, this marks the first approval of a systemic therapy for this type of grade 2 IDH-mutant brain cancer, which includes oligodendrogliomas and astrocytomas.Servier obtained Voranigo through its $2 billion acquisition of Agios Pharmaceuticals’ oncology business in 2021. Royalty Pharma, which earlier this year acquired a stake in Agios’ royalty payments for Voranigo, has projected the drug could reach more than $1 billion in annual peak sales in the U.S.Gliomas are the most common primary malignant brain tumors in adults, and IDH1 or IDH2 mutations are present in nearly all grade 2 diffuse gliomas in adults. By Royalty’s estimates, there are around 1,500 new diagnoses for these two IDH-mutant gliomas each year in the U.S.Current therapeutic interventions for these patients are more than 20 years old and are all used off label, Islam Hassan, M.D., senior medical director at Servier, noted in an interview with Fierce Pharma ahead of Tuesday’s FDA decision.Before Voranigo, Servier already has the IDH1 inhibitor Tibsovo and the IDH2 inhibitor Idhifa. Although doctors have been using the two meds off-label because of the lack of treatment options, neither was approved for brain cancer.Voranigo, for its part, was designed to penetrate the blood-brain barrier to be effective against brain tumors, Hassan explained. In a phase 3 trial coded INDIGO, Voranigo significantly reduced the risk of tumor progression or death by 61% compared with placebo among patients with residual or recurrent grade 2 IDH-mutant glioma. These patients had undergone no previous treatment other than surgery.In addition, Voranigo also showed a statistically significant benefit in delaying the need for the next treatment, slashing the risk for further treatment by 74% in the study.The trial is ongoing to gather overall survival data. Still, Hassan argued that the progression-free survival data are just as important, because these tumors will continue to grow and penetrate the brain and may develop into high-grade disease.Besides the Voranigo monotherapy regimen, Servier has been evaluating the IDH inhibitor alongside Merck’s immunotherapy Keytruda in recurrent or progressive IDH1-mutant gliomas. While anti-PD-1 antibody drugs like Keytruda have been largely unsuccessful in brain tumors, Hassan pointed to a previous study in which patients received Voranigo and Keytruda before surgery. In tissues collected from surgery, Servier noticed some changes in the immune microenvironment that Hassan said warrant further development of this combination.Servier is also testing Voranigo alongside the chemotherapy temozolomide in high-grade IDH-mutant glioma. As Hassan noted, these patients with grade 4 gliomas are typically excluded from other clinical trials.The FDA approval triggers a $200 million milestone payment from Servier to Agios, plus a $905 million payment from Royalty to Agios in exchange for a 15% royalty on U.S. net sales of up to $1 billion for the therapy.