Efficacy and tolerability of isocitrate dehydrogenase inhibitors in patients with acute myeloid leukemia: A systematic review of clinical trials

Aiman, Wajeeha; Ali, Muhammad Ashar; Basit, Muhammad Abdul; Omar, Zainab; Suleman, Muhammad; Hassan, Muhammad Umair; Jamil, Taimoor; Anwar, Muhammad Saad; Shafique, Zubair; Dhanesar, Gurneel; Faisal, Muhammad Salman; Akerman, M; Maroules, Michael; Anwer, Faiz

doi:10.1016/j.leukres.2023.107077

Cited by 6 publications

(5 citation statements)

References 29 publications

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“…Given that conventional chemotherapy is still the standard AML treatment, the need for new targeted therapies, especially against various AML subtypes like those involving HOXA9, remains imperative. Among the newly approved or evaluated treatments, 2 , 3 differentiation therapies have indeed proved effective in the clinic such as the mitochondrial protein IDH2 (isocitrate dehydrogenase‐2) inhibitor enasidenib (AG221, Celgene), 5 , 38 the IDH1 inhibitor Ivosidenib (AG‐120, Agios), 5 , 39 lysine‐specific demethylase 1 (LSD1) inhibitors 40 , 41 such as tranylcypromine and analogs 32 , 42 or ORY‐1001, 3 , 43 , 44 , 45 or the DOT1L inhibitor pinometostat (EPZ‐5676) 7 , 17 , 46 , 47 known to downregulate HOXA9 expression. 48 More recently the Menin/MLL inhibitor revumenib (SNDX‐5613) showed promising results against the HOXA9‐dependant MLL subtypes of AML, 6 , 49 but it also led to resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Among approved or clinically tested targeted therapies are FLT3‐mutated, P53‐mutated, IDH‐mutated or BCL2 inhibitors, cereblon E3‐ligase modulators, and monoclonal antibodies (anti‐CD33, CD123 ± CD3, CD47, CTLA4, PD‐1, or TIM3) 3,4 . Additionally, the development of small molecule inhibitors aiming to induce AML cell differentiation to mirror the success of all‐trans ‐retinoic‐acid (ATRA/Tretinoïne/Vesanoid®) and arsenic trioxide (ATO/Trisenox®) targeting the PML‐RARα fusion transcription factor in acute promyelocytic leukemia (APL, AML‐M3) is an attractive strategy leading to the development of IDH1 (Ivosidenib/AG‐120/Tibsovo®) or IDH2 (Enasidenib/AG‐221/Idhifa®) mutants inhibitors, or epigenetic modulators against the menin/MLL interaction like Revumenib/SNDX‐5613, Ziftomenib/KO‐539 or JNJ‐6617, or targeting DOT1L histone methyltransferase (Pinometostat/EPZ‐5676) 5–7 …”

Section: Introductionmentioning

confidence: 99%

“…3,4 Additionally, the development of small molecule inhibitors aiming to induce AML cell differentiation to mirror the success of all-trans-retinoic-acid (ATRA/Tretinoïne/Vesanoid®) and arsenic trioxide (ATO/Trisenox®) targeting the PML-RARα fusion transcription factor in acute promyelocytic leukemia (APL, AML-M3) is an attractive strategy leading to the development of IDH1 (Ivosidenib/AG-120/Tibsovo®) or IDH2 (Enasidenib/AG-221/Idhifa®) mutants inhibitors, or epigenetic modulators against the menin/MLL interaction like Revumenib/SNDX-5613, Ziftomenib/KO-539 or JNJ-6617, or targeting DOT1L histone methyltransferase (Pinometostat/EPZ-5676). [5][6][7] While transcription factors play a key role in regulating the expression of oncogenic-associated genes, the direct targeting of these factors by antitumor molecules remains limited. 8,9 Notably, HOXA9 emerges as a crucial transcription factor in AML, exhibiting overexpression in ~70% of AML cases, including NPM1-mutated, MLL-rearranged, NUP98-NSD1, MYST3-CREBBP, RUNX1-EVI1, and EZH2-mutated AMLs.…”

Section: Introductionmentioning

confidence: 99%

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Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9‐dependent AML

Lambert,

Jambon,

Bouhlel

et al. 2024

HemaSphere

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The mainstay of acute myeloid leukemia (AML) treatment still relies on traditional chemotherapy, with a survival rate of approximately 30% for patients under 65 years of age and as low as 5% for those beyond. This unfavorable prognosis primarily stems from frequent relapses, resistance to chemotherapy, and limited approved targeted therapies for specific AML subtypes. Around 70% of all AML cases show overexpression of the transcription factor HOXA9, which is associated with a poor prognosis, increased chemoresistance, and higher relapse rates. However, direct targeting of HOXA9 in a clinical setting has not been achieved yet. The dysregulation caused by the leukemic HOXA9 transcription factor primarily results from its binding activity to DNA, leading to differentiation blockade. Our previous investigations have identified two HOXA9/DNA binding competitors, namely DB1055 and DB818. We assessed their antileukemic effects in comparison to HOXA9 knockdown or cytarabine treatment. Using human AML cell models, DB1055 and DB818 induced in vitro cell growth reduction, death, differentiation, and common transcriptomic deregulation but did not impact human CD34+ bone marrow cells. Furthermore, DB1055 and DB818 exhibited potent antileukemic activities in a human THP‐1 AML in vivo model, leading to the differentiation of monocytes into macrophages. In vitro assays also demonstrated the efficacy of DB1055 and DB818 against AML blasts from patients, with DB1055 successfully reducing leukemia burden in patient‐derived xenografts in NSG immunodeficient mice. Our findings indicate that inhibiting HOXA9/DNA interaction using DNA ligands may offer a novel differentiation therapy for the future treatment of AML patients dependent on HOXA9.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9‐dependent AML

Lambert,

Jambon,

Bouhlel

et al. 2024

HemaSphere

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“…Specific inhibitors of the epigenetic regulators IDH 1/2 and EZH2 are becoming available. Ivosidenib and enasidenib, IDH1 and 2 inhibitors, have been approved and licensed for AML ( 64 ). Tazemetostat is the first EZH2 inhibitor approved by the FDA and targets both wild-type and mutant EZH2 inducing cell cycle arrest.…”

Section: Epigenetic Therapiesmentioning

confidence: 99%

Epigenetics in myeloproliferative neoplasms

Greenfield

McMullin

2023

Front. Oncol.

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The myeloproliferative neoplasms (MPNs) are a group of acquired clonal disorders where mutations drive proliferative disease resulting in increased blood counts and in some cases end-stage myelofibrosis. Epigenetic changes are the reversible modifications to DNA- and RNA-associated proteins that impact gene activity without changing the DNA sequence. This review summarizes mechanisms of epigenetic changes and the nucleosome. The drivers and epigenetic regulators in MPNs are outlined. In MPNs, distinct patterns of epigenetic dysregulation have been seen in chronic and in advanced phases. Methylation age and histone modification are altered in MPNs and by further treatment. The alterations found in methylation age in MPNs and with treatment are discussed, and the changes in histone modification with Janus kinase (JAK) inhibition are evaluated. Currently available therapeutic areas where the epigenome can be altered are outlined. Thus, we review the current knowledge and understanding of epigenetics in MPN and consider further management options. Understanding the epigenome and its alteration in MPNs and epigenetic changes associated with the progression of disease will lead to advances in therapeutic options.

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“…As a background, IDH1/2 mutations occur in 2–4% of MF patients in chronic or accelerated phase disease [ 42 ] and approximately 19% in MPN-BP [ 43 ]. IDH inhibitors as monotherapy or combined with other chemotherapy have shown impressive activity in IDH-mutated AML, both in the upfront and relapsed/refractory setting [ 44 ]; reported overall (ORR) and complete (CR) response rates with ivosidenib [ 45 ] or enasidenib [ 46 ] monotherapy were approximately 40% and 20%, respectively, and in combination with chemotherapy ranged from 63 t% to 89% for ORR and 47% to 68% for CR [ 44 ].…”

Section: Introductionmentioning

confidence: 99%

Blast phase myeloproliferative neoplasm: contemporary review and 2024 treatment algorithm

2023

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Leukemic transformation in myeloproliferative neoplasms (MPN), also referred to as “blast-phase MPN”, is the most feared disease complication, with incidence estimates of 1–4% for essential thrombocythemia, 3–7% for polycythemia vera, and 9–13% for primary myelofibrosis. Diagnosis of MPN-BP requires the presence of ≥20% circulating or bone marrow blasts; a lower level of excess blasts (10–19%) constitutes “accelerated phase” disease (MPN-AP). Neither “intensive” nor “less intensive” chemotherapy, by itself, secures long-term survival in MPN-BP. Large-scale retrospective series have consistently shown a dismal prognosis in MPN-BP, with 1- and 3-year survival estimates of <20% and <5%, respectively. Allogeneic hematopoietic stem cell transplant (AHSCT) offers the possibility of a >30% 3-year survival rate and should be pursued, ideally, while the patient is still in chronic phase disease. The value of pre-transplant bridging chemotherapy is uncertain in MPN-AP while it is advised in MPN-BP; in this regard, we currently favor combination chemotherapy with venetoclax (Ven) and hypomethylating agent (HMA); response is more likely in the absence of complex/monosomal karyotype and presence of TET2 mutation. Furthermore, in the presence of an IDH mutation, the use of IDH inhibitors, either alone or in combination with Ven-HMA, can be considered. Pre-transplant clearance of excess blasts is desired but not mandated; in this regard, additional salvage chemotherapy is more likely to compromise transplant eligibility rather than improve post-transplant survival. Controlled studies are needed to determine the optimal pre- and post-transplant measures that target transplant-associated morbidity and post-transplant relapse.

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Efficacy and tolerability of isocitrate dehydrogenase inhibitors in patients with acute myeloid leukemia: A systematic review of clinical trials

Cited by 6 publications

References 29 publications

Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9‐dependent AML

Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9‐dependent AML

Epigenetics in myeloproliferative neoplasms

Blast phase myeloproliferative neoplasm: contemporary review and 2024 treatment algorithm

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