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How Acute myeloid leukaemia (AML) Clinical Landscape is transforming for IDH1 or IDH2 mutated patients? Key comments from ASH 2022

IDHI Mutation AML

Acute myeloid leukaemia is a genetically heterogeneous hematologic malignancy in which approximately 8% and 12% of acute myeloid leukemias harbour an IDH1 or IDH2 mutation, respectively. 

A generally inferior outcome is seen with IDH1 mutations and a relatively favourable prognosis may be seen with IDH2 mutations

The recent discovery of recurrent IDH mutations in cancer led to the rapid development of small molecule targeted inhibitors, which effectively inhibit the 2HG oncometabolite and promote the restoration of normal myeloid differentiation

Treatment algorithm for AML with mutated IDH1 or IDH2

Treatment Algorithm for AML with mutated IDH1/IDH2
Treatment Algorithm for AML with mutated IDH1/IDH2 IDH: Isocitrate Dehydrogenase; HMA: Hypomethylating agent; IDHi: IDH inhibitor; Allo-HSCT: Allogenic hematopoietic stem cell transplant; MRD: minimal residual disease

FDA Approved therapies for AML with IDH1/IDH2 mutation

  1. AG221 (enasidenib) Mutant IDH2 inhibitor; relapsed / refractory AML (2017)
  2. AG120 (ivosidenib) Mutant IDH1 inhibitor; relapsed / refractory AML (2018)
  3. Ivosidenib approved for newly diagnosed AML not eligible for intensive therapy (2019)
  4. Olutasidenib approved for R/R AML with IDH1 mut (2022)
TherapyIDHIFA (enasidenib)REZLIDHIA (Olutasidenib) +/-Azacitidine TIBSOVO (ivosidenib)TIBSOVO (ivosidenib)
Dosage; N100 mg daily; N=199150 mg twice; N=147500 mg daily; N=28500 mg daily; N=174
Patient SegmentR/R AML with IDH2 mutR/R AML with IDH1 mutNewly diagnosed with IDH1 mutR/R AML with IDH1 mut
Phase; Trial statusPhase ½; Approved 2017 (US)Phase ½; Approved 2022(US)Phase 1; Approved (2019, 2018) (US)Phase 1; Approved (2019, 2018) (US)
ResultsCR (19%); mDOR (8 mos)CRh (4%); mDOR (9.6 mos)CR/CRh (23%); mDOR (8.2 mos)CR (32%); mDOCR (28.1)CRh (2.7%); oDOCRh (28.5 mos)CR+CRh (35%); mDOCR + CRh (25.9 mos)CR (28.6%); mDOCR (NE)CRh (14.3%); DOCRh (15.7 mos)CR+CRh (42.9%); mDOCR + CRh (NE)CR (24.7%); mDOCR (10.1)CRh (8%); mDOCRh (3.6 mos)CR+CRh (32.8%); mDOCR + CRh (8.2 mos)

Other important therapies for AML with IDH1/IDH2 mutation

TherapyMOASponsorComments from ASH 2022
Gemtuzumab (Mylotarg)Anti-CD33PfizerGemtuzumab + Standard Induction Chemotherapy Improves Outcomes in Intermediate Risk Cytogenetic AML 
Venetoclax + EnasidenibBcl2-i+ IDH2-iM.D AndersonCRC rate overall: 72% (ND: 100%, R/R: 53%)
Azacitidine + HAG regimenDNA methylation-iServierA cost-effective 1L with high efficacy and well tolerance for elderly/unfit AML, especially ND AML patients.
Venetoclax + ivosidenibBcl2-i+ IDH1-iM.D AndersonAn effective regimen for the treatment of IDH mutated AML with high response rates including MRD-negative CRC, most notably in de novo patients and R/R pts without prior VEN exposure
Venetoclax + AzacitidineBcl2-I + DNA methylation iAbbVie/GenetechMedian OS was reached at the final analysis, at 19.9 mo in the Ven+Aza group
Ivosidenib + AzacitidineIDH1-i + DNA methylation iServierIt showed significant clinical benefit as compared with placebo and azacitidine in this difficult-to-treat population

Key Takeaway points in AML with mutated IDH1/IDH2

Personalised therapies have taken a key role in AML marked by the development of oral, potent, small molecule and mutant-specific IDH1 and IDH2 inhibitors.

Different combinations with standard anti-leukaemia therapies (i.e., intensive chemotherapy, hypomethylating agents), rational combinations (venetoclax) and agents targeted against AML resistance pathways (i.e., FLT3, RAS, other RTK pathway inhibitors). Additionally, second-generation and “pan” IDH1/IDH2 inhibitors are also under development which has shown the promise for improved outcomes in patients with IDH-mutated AML

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