Phase Ib/2 Study of Oral Decitabine/Cedazuridine (ASTX727) and Venetoclax in Combination with the Targeted Mutant IDH1 Inhibitor Ivosidenib or the Targeted Mutant IDH2 Inhibitor Enasidenib in IDH Mutated Acute Myeloid Leukemia

Atluri, Himachandana; Maiti, Abhishek; Sasaki, Koji; Daver, Naval; Alvarado, Yesid; Hossain, Md Feroz; Wang, Xuemei; Pemmaraju, Naveen; Takahashi, Koichi; Borthakur, Gautam; Ferrajoli, Alessandra; Short, Nicholas J.; Abbas, Hussein A.; Ravandi, Farhad; Jabbour, Elias; Andreeff, Michael; Kantarjian, Hagop; Konopleva, Marina; DiNardo, Courtney D.

doi:10.1182/blood-2022-164986

Cited by 12 publications

(8 citation statements)

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“…A phase 2 study is currently underway (NCT03471260). Preliminary data of a phase 1b/2 trial of triplet therapy with decitabine/cedazuridine, venetoclax, and ivosidenib showed encouraging response rates and tolerability in newly diagnosed and relapsed patient populations [ 72 ].…”

Section: Targeting Idh1 - Ivosidenibmentioning

confidence: 99%

“…Nonetheless, the lack of OS benefit with enasidenib despite the use of a suboptimal control arm without the inclusion of venetoclax raises concern for the role of enasidenib monotherapy in R/R AML. Enasidenib is currently being evaluated as combination therapy for R/R IDH2 -mutated AML in phase 1b/2 studies with venetoclax (NCT04092179) and decitabine/cedazuridine with venetoclax (NCT04774393), with preliminary data presented at ASH 2023 showing feasibility and favorable outcomes with both combinations [ 72 , 83 ].…”

Section: Targeting Idh2 – Enasidenibmentioning

confidence: 99%

“…Further randomized data are needed to assess azacitidine and enasidenib compared to or in combination with venetoclax in newly diagnosed patients unfit for standard induction therapy. As above, a phase 1b/2 study of enasidenib with decitabine/cedazuridine and venetoclax is ongoing, with promising preliminary data in newly diagnosed patients [ 72 ].…”

Section: Targeting Idh2 – Enasidenibmentioning

confidence: 99%

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Management of isocitrate dehydrogenase 1/2 mutated acute myeloid leukemia

Fruchtman,

Avigan,

Waksal

et al. 2024

Leukemia

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The emergence of next generation sequencing and widespread use of mutational profiling in acute myeloid leukemia (AML) has broadened our understanding of the heterogeneous molecular basis of the disease. Since genetic sequencing has become a standard practice, several driver mutations have been identified. Accordingly, novel targeted therapeutic agents have been developed and are now approved for the treatment of subsets of patients that carry mutations in FLT3, IDH1, and IDH2 [1, 2]. The emergence of these novel agents in AML offers patients a new modality of therapy, and shifts treatment paradigms toward individualized medicine. In this review, we outline the role of IDH mutations in malignant transformation, focus in on a novel group of targeted therapeutic agents directed toward IDH1- and IDH2-mutant AML, and explore their impact on prognosis in patients with AML.

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Section: Targeting Idh1 - Ivosidenibmentioning

confidence: 99%

Section: Targeting Idh2 – Enasidenibmentioning

confidence: 99%

Section: Targeting Idh2 – Enasidenibmentioning

confidence: 99%

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Management of isocitrate dehydrogenase 1/2 mutated acute myeloid leukemia

Fruchtman,

Avigan,

Waksal

et al. 2024

Leukemia

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“…A trial of an all-oral triplet of decitabine-cedazuridine, venetoclax and ivosidenib or enasidenib is currently ongoing 59,88 (Clini calTr ials. gov identifier NCT04774393).…”

Section: Emerging Combinatorial Approaches In Clinical Trialsmentioning

confidence: 99%

Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease

Jen,

Kantarjian,

Kadia

et al. 2024

Br J Haematol

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SummaryThe treatment landscape of acute myeloid leukaemia (AML) is evolving rapidly. Venetoclax in combination with intensive chemotherapy or doublets or triplets with targeted or immune therapies is the focus of numerous ongoing trials. The development of mutation‐targeted therapies has greatly enhanced the treatment armamentarium, with FLT3 inhibitors and isocitrate dehydrogenase inhibitors improving outcomes in frontline and relapsed/refractory (RR) AML, and menin inhibitors showing efficacy in RR NPM1mut and KMT2A‐rearranged AML. With so many new drugs approved, the number of potential combinatorial approaches to leverage the maximal benefit of these agents has increased dramatically, while at the same time introducing clinical challenges, such as key preclinical and clinical data supporting the development of combinatorial therapy, how to optimally combine or sequence these novel agents, how to optimise dose and duration to maintain safety while enhancing efficacy, the optimal duration of therapy and the role of measurable residual disease in decision‐making in both intensive and low‐intensity therapy settings. In this review, we will outline the evidence leading to the approval of key agents in AML, their on‐label current approvals and how they may be optimally combined in a safe and deliverable fashion to further improve outcomes in AML.

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“…In the R/R cohort, the CRc rate was 53%. MRD-negative CRc by flow cytometry was achieved in 42% [69].…”

Section: Experimental Non-immunotherapeutic Approaches For R/r Amlmentioning

confidence: 99%

Non-Immunotherapy Approaches for Relapsed or Refractory AML: An Update for 2024

Buchrits,

Wolach

2023

Acta Haematol

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Background: Relapsed or refractory (R/R) acute myeloid leukemia (AML) is a challenging, high-risk, clinical scenario with a dismal outcome. Recent insights on the genetic, epigenetic, and metabolic events that drive clonal progression and the advent of novel therapies resulted in the incorporation of several new targeted therapies, alone or in combination, in the R/R setting with the aim of improving response rates and survival. Herein we review current challenges and future opportunities with non-immunotherapeutic approaches to treat R/R AML. Summary: Inhibitors of FLT3 and IDH 1/2 are now FDA-approved for patients with R/R disease and corresponding mutations. These agents are also used in combination with intensive and low-intensity platforms in an attempt to improve response and survival. Several targeted agents are currently being tested alone or in combination in early-phase trials. These include drugs that target apoptotic pathways, drugs that interfere with key survival pathways of the R/R leukemic cell as well as therapies aimed towards the leukemia marrow microenvironment. Menin inhibitors are a promising class of active drugs in NPM1 and KMT2A-rearranged AML. Key-messages: Several new targeted therapies, immunologic and non-immunologic are being studied and are moving through pre-clinical and clinical pipelines. Significant remaining challenges include the development of synergistic combination therapies tailored to the specific biology and clinical context of the patient, and re-defining the role and timing of allogeneic transplantation in patients with R/R disease.

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Phase Ib/2 Study of Oral Decitabine/Cedazuridine (ASTX727) and Venetoclax in Combination with the Targeted Mutant IDH1 Inhibitor Ivosidenib or the Targeted Mutant IDH2 Inhibitor Enasidenib in IDH Mutated Acute Myeloid Leukemia

Cited by 12 publications

References 0 publications

Management of isocitrate dehydrogenase 1/2 mutated acute myeloid leukemia

Management of isocitrate dehydrogenase 1/2 mutated acute myeloid leukemia

Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease

Non-Immunotherapy Approaches for Relapsed or Refractory AML: An Update for 2024

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