[Wednesday Reading] Professor Liu Qifa: Based on AML, looking forward to the future, comprehensively analyzing the impact of IDH mutation on the development and treatment of AML

Introduction Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are prevalent in a variety of myeloid malignancies
.

Mutant IDH proteins block cell differentiation by competitively inhibiting α-ketoglutarate (α-KG)-dependent dioxygenase
.

Small-molecule inhibitors of mutant IDH1 and IDH2 in histone and DNA demethylation have been developed and progressed in various stages of clinical trials
.

Recently, a review published in "Nature Reviews Clinical Oncology" (impact factor 66.
675), a sub-journal of Nature, introduced in detail the biological characteristics of IDH mutations, the prognosis in various related tumors, and the correlation of IDH mutation-targeted drug therapy.
The research data of tumor and the treatment of potential pathogenesis of tumor are rich in content 1
.

As the first-in-class IDH1 mutation inhibitor avonib is expected to benefit Chinese AML patients, Professor Liu Qifa, director of the Institute of Hematology of Southern Medical University, was invited to give a wonderful presentation on IDH mutation in acute myeloid leukemia (AML).
Read and comment! Professor Liu Qifa Chief Physician, Professor, Doctoral Supervisor Dean of the Institute of Hematology, Southern Medical University, Director of the Institute of Hematology, Director of the Department of Hematology, Nanfang Hospital, Member of the Asia-Pacific Hematology Association, Vice Chairman of the Chinese Medical Association Hematology Branch, Chinese Medical Association Blood Head of the Infections Group of the Academic Society, Vice President of the Hematology Branch of the Chinese Geriatrics Association, Vice Chairman of the Cell Research and Treatment Branch of the Chinese Research Hospital Association, Standing Committee Member of the Hematologist Branch of the Chinese Medical Doctor Association Deputy Chairman, Chief Expert of Hematology Tumors in Guangdong Province, has been engaged in the diagnosis and treatment of hematological tumors and related basic research work since graduating from university in 1983.
He used to conduct leukemia molecular biology research work as a visiting researcher at Tokyo Autonomous Medical University in Japan..

He has made great achievements in the fields of molecular pathogenesis of leukemia, tumor immunotherapy, hematopoietic stem cell transplantation, and infection prevention and control in immunocompromised people
.

He has presided over 1 national key research and development plan, 3 863 plans, 9 national natural science projects including 1 key project and more than 20 provincial and ministerial research projects
.

Relevant research achievements have won 1 second prize of National Science and Technology Progress Award, 2 first prizes and 5 second prizes of provincial and ministerial scientific and technological achievements
.

He has published more than 200 papers in core journals at home and abroad, including: Lancet Oncol, JCO, PNAS, Blood and Leukemia and other SCI journals more than 100
.

Core takeaways • Mutations in IDH1 or IDH2 lead to the accumulation of the metabolite D-2-hydroxyglutarate (D-2HG), which has profound effects on the cellular epigenetics, differentiation patterns, and metabolic profile of AML
.

• The incidence, early-onset nature of IDH mutations, and the consistent expression of mutated proteins in AML cells make them an attractive therapeutic target in AML
.

• The roles of mutant IDH1 and IDH2 in AML development and progression may be transient or dynamic and context-dependent
.

• IDH mutational status at disease relapse can provide insight into the mechanism of relapse
.

In AML, inhibition of mutated IDH1 or IDH2 produces resistance mutations that restore D-2HG production
.

Biological properties of IDH mutations in AML Approximately 20% of AML patients have somatic mutations in IDH1 (R132C and R132H) or IDH2 (R172 and R140) (Figure 1)
.

The novel activity of the IDH mutant enzyme is to convert α-KG to the metabolite D-2HG, which consumes NADPH and generates NADP+
.

Heterozygous status is necessary for D-2HG production, whereas IDH mutations are almost always heterozygous
.

The presence of mutant IDH subunits in the enzyme complex favors the closed conformation and confers high affinity to NADPH for the reduction of α-KG to D-2HG
.

The exact mechanism by which IDH mutations cause disease remains unclear, but the structural similarity of D-2HG and α-KG leads to competitive inhibition
.

Thus, in IDH-mutant AML, pathways utilizing α-KG as a substrate are disrupted, resulting in epigenetic dysregulation of histone and DNA methylation, chromatin remodeling, blockade of cell differentiation, and other transformative effects
.

Figure 1.
IDH mutations are involved in different tumor types, including blood domain AML.
Development of IDH mutation inhibitors in AML.
IDH mutations often occur in the early stages of AML and are specifically expressed in cells, making them attractive therapeutic targets
.

IDH mutation small molecule inhibitors, IDH mutation-directed immunotherapy and drugs targeting IDH mutation-induced metabolic disorders are the current research hotspots
.

The unique structural and functional features of IDH mutations facilitate the discovery of small molecule inhibitors (Fig.
2)
.

AGI-5198, the first molecule to effectively inhibit mutations in IDH1, observed a 90% reduction in D-2HG production in its in vitro assays, but its overall pharmacokinetic and pharmacodynamic properties prevented it from successfully entering clinical applications
.

A series of chemical optimizations resulted in an IDH1 mutation inhibitor (evonib, also known as AG-120), an IDH2 mutation inhibitor (Enasidenib, AG-221), and IDH1 and IDH2 mutations with better pharmacological properties A dual inhibitor of (Vorasidenib, AG-881)
.

These inhibitors stabilize mutant enzymes in the open inactive conformation by binding to the allosteric site and preventing the conformational change required for catalysis
.

Figure 2.
Discovery of Small Molecule Inhibitors IDH-mutant AML01 Prognosis and Biology AML is the most common acute leukemia in adults and is characterized by uncontrolled proliferation of poorly differentiated myeloid cells leading to immature myeloid cells or primitive cell accumulation
.

The 5-year overall survival (OS) rate of AML patients is approximately 40-50%, although the prognosis gradually deteriorates with age and the appearance of relapsed and/or refractory (R/R) disease, and the 5-year OS rate can be reduced to 5-10%
.

A meta-analysis of data from 33 studies involving 12,747 patients with AML elucidates the prognostic value of IDH mutations
.

The subgroup of IDH-1 mutant AML patients had better OS (HR 1.
17; 95% CI 1.
05-1.
31) and event-free survival (EFS) rates (HR 1.
29; 95% CI 1.
07-1.
56) compared with IDH wild-type patients.
was worse, and the complete response (CR) rate was lower (RR 1.
21; 95% CI 1.
02-1.
44)
.

Interestingly, although IDH2-R172 mutation patients had a lower CR rate (RR 2.
14; 95% CI 1.
61-2.
85), patients with IDH2 (R172 and R140) mutations showed a favorable trend in OS (HR 0.
78; 95% CI 95% CI) 0.
66–0.
93)
.

Although this analysis was comprehensive and acknowledged the heterogeneity among these studies, other studies did not find an effect of IDH mutation on AML prognosis
.

These differences may reflect differences in patient populations, the role of co-mutations, or differences in genetic subgroups selected for analysis
.

02IDH Inhibitors in Ivornib (IDH1 Inhibitor) Table 1.
Ivoribib-Related Studies Monotherapy in R/R AML: A phase I study of ivonib monotherapy in patients with IDH1-mutant AML included 258 patients with IDH1-mutated hematological malignancies, of which 179 patients had R/R AML
.

Ivornib was generally tolerated despite grade ≥3 TRAEs (most commonly QT prolongation [7.
8%], differentiation syndrome [3.
9%], and decreased platelet count [3.
4%]) in 20.
7% of patients Sex is good
.

Among 125 patients with R/R AML who received 500 mg ivonib daily and were followed up for at least 6 months, the objective response rate (ORR) was 41.
6%, and the CR+ with partial hematologic recovery (CR/CRh) rate was 30.
4%, CR rate was 21.
6%, median OS was 8.
8 months, median OS was not reached in patients who achieved CR or CRh (median follow-up time was 14.
3 months), except for CR or CRh, patients who achieved objective response The median OS was 9.
3 months, compared with only 3.
9 months for patients without remission
.

In addition, 21% of patients with CR or CRh had clear IDH1 mutations in bone marrow mononuclear cells (BMMCs) at one or more time points, and this feature was associated with better responses: 28% of 25 patients with CR achieved IDH1 mutation clearance, but not in patients who did not achieve CR
.

These findings paved the way for FDA approval of ivonib for the treatment of patients with IDH1-mutated R/R AML
.

Monotherapy for newly diagnosed AML: A phase I study of ivonib monotherapy in patients with newly diagnosed IDH1-mutant AML enrolled 34 patients with grade ≥3 TRAE in a subgroup of patients not eligible for standard intensive induction chemotherapy The incidence of differentiation syndrome was 38%, the incidence of differentiation syndrome was 9%, and the incidence of QT interval prolongation was 6%
.

CR/CRh rate was 42.
4% (CR rate was 30.
3%), ORR was 54.
5%, and median OS was 12.
6 months
.

Longitudinal assessment of IDH1 VAF was performed in 30 of these patients, and mutational clearance of BMMC was observed in 64.
3% of patients with CR or CRh compared with 0% in patients without CR or CRh (P< 0.
001)
.

These data support FDA approval of ivonib as first-line treatment in this subset of patients
.

Despite the small cohort size, these data suggest that newly diagnosed AML patients respond better to ivonib compared with R/R AML patients
.

Therefore, the timing of ivonib treatment and the selection of the benefit population are also very important
.

Combination chemotherapy for newly diagnosed AML: A phase I study of evonib or Enasenib combined with induction and consolidation chemotherapy in newly diagnosed IDH-mutant AML patients observed similar TRAEs with the combination regimen as monotherapy, in patients receiving evonib CR rates at the end of induction therapy were 55% and 47%, respectively, and CR/CRh rates were 72% and 63%, respectively, in 60 patients who received enasidenib and 91 patients who received enasidenib, which were used to treat primary AML.
Patients had better overall responses than those with secondary AML
.

Thirty-nine percent of CR or CRh patients cleared IDH1 mutations in BMMC and 23% cleared IDH2 mutations
.

The 12-month OS rate of more than 75% in both treatment groups was better than data in other studies, and this advantage was more pronounced in elderly patients
.

Therefore, the combination of a mutant IDH inhibitor with intensive induction chemotherapy and consolidation chemotherapy is a promising treatment for patients with IDH-mutant AML
.

Combination of demethylating agents in newly diagnosed AML: a phase I/II trial in newly diagnosed IDH1-mutant AML patients showed that ivonib combined with azacitidine induced leukemia cell differentiation and apoptosis with an ORR of 78.
3 %, the CR rate was 60.
9%
.

These promising findings prompted the Phase III AGILE trial (NCT03173248) of ivonib plus azacitidine versus placebo plus azacitidine
.

An update was presented at the December 2021 ASH meeting of the AGILE study, a pivotal Phase III study evaluating ivonib combined with azacitidine in first-line treatment of newly diagnosed IDH1-mutant AML patients, and its results showed that it was comparable to placebo Compared with azacitidine combined with azacitidine, ivonib combined with azacitidine can significantly improve EFS (HR=0.
33, P=0.
0011), reduce the risk of recurrence, progression or death after remission by 67%, and significantly prolong OS (24.
0 months vs 7.
9 months, P=0.
0005), significantly improved CR rate (47.
2% vs 14.
9%, P<0.
0001), CR/CRh rate (52.
8% vs 17.
6%, P<0.
0001) and ORR (62.
5% vs 18.
9 %, P<0.
0001), the patient's disease remission was transformed into a survival benefit, and all subgroups had the same benefit in EFS and OS, and the infection rate was significantly lower (28.
2% vs 49.
3%), and no treatment-related death occurred.

.

Combination with BCL-2 Inhibitors for R/R AML: A Phase I/II Trial of Ivornib in Combination with Veneclax in Patients with IDH1 Mutant Hematological Malignancies is Underway (NCT03471260), Promising Observation in R/R AML Patients to promising preliminary efficacy and safety
.

In fact, as more and more data from preclinical and clinical studies are accumulated, the development of therapies that exploit IDH mutations will become a reality
.

Enasidenib (IDH2 Inhibitor) Enasidenib, optimized from the lead compound AGI-6780, is an oral, selective and potent IDH2 inhibitor that reduces D-2HG levels, reverses histone methylation patterns, and is in vitro Cell differentiation was induced in both in vivo AML models
.

In mice transplanted with IDH2-R140Q-mutated human AML primary cells, the drug was well tolerated and reduced intracellular D-2HG levels below detectable limits in the transplanted cells, and the transplanted cells Begin to express differentiation markers, including CD11b, CD14, CD15 and CD24
.

On day 38, >60% of human AML cells had differentiated
.

Correspondingly, KIT-expressing immature human AML cells were reduced, and the proportion of AML blasts was reduced by 2-35-fold
.

Directions for future research Differentiation arrest is a consistent feature of IDH mutant AML, and IDH mutant inhibitors can effectively induce differentiation
.

However, apoptosis and cell death were rarely observed with IDH mutant inhibitors, highlighting the importance of combination therapy for maximum therapeutic benefit
.

Furthermore, IDH mutations occur early in the onset of AML, but most current trials are conducted in patients with advanced disease, and given that D-2HG changes as the tumor evolves, it is also critical to explore the timing of targeted therapy for IDH
.

Experts commented that the function of IDH1 as a metabolic enzyme was known to the public earlier, but its mutation in tumors has not been discovered for a long time
.

It was not until 2008 that IDH1 mutation-driven tumor progression first entered people’s field of vision.
Since then, multiple studies have shown that IDH1 mutation in AML patients3 is associated with poor prognosis: compared with IDH wild-type patients, IDH1-mutant AML patients have sub- The cohort had worse OS and EFS rates and lower CR rates
.

IDH1 mutation is involved in the occurrence and development of AML, not only has a prognostic role in AML, but also can be used as a therapeutic target for AML
.

Ivornib is the world's first widely used small molecule inhibitor targeting IDH1 mutations in the world, and has achieved significant efficacy in multiple previous studies in the treatment of IDH1-mutated AML patients
.

For newly diagnosed IDH1-mutant AML patients, the good efficacy and safety of ivonib not only showed in the AG120-C-001 clinical study4, but also in combination with azacitidine in a phase Ib The study also showed good safety and efficacy5 and was further validated in the phase III study AGILE, reported at the ASH annual meeting,6 and AG120 evaluating ivonib in combination with standard induction and consolidation regimens In the Phase I study of -221-C-001, CR+ incomplete hematologic recovery (CRi)/incomplete platelet recovery (CRp) remission rates and 1-year OS rates both showed encouraging data7
.

For patients with R/R IDH1-mutant AML, the efficacy of ivonib has been demonstrated in a multicenter, single-arm, open-label phase I clinical trial (AG120-C-001)4.
The CS3010-101 study, the first bridging registration trial in R/R AML patients, also demonstrated its excellent efficacy and favorable safety profile
.

Based on the above breakthrough clinical trial results, ivonib has been approved for use in IDH1-mutant AML patients abroad.
Patients with relapsed or refractory AML
.

It is expected that researchers will continue to explore the potential of IDH1 mutation-related therapeutic strategies and enrich the treatment options for AML patients
.

References: 1.
Pirozzi CJ, Yan H.
The implications of IDH mutations for cancer development and therapy.
Nat Rev Clin Oncol.
2021 Oct;18(10):645-661.
2.
Parsons DW, et al.
An integrated genomic analysis of human glioblastoma multiforme.
Science.
2008;321(5897):1807-1812.
3.
Mardis ER, et al.
Recurring mutations found by sequencing an acute myeloid leukemia genome.
N Engl J Med.
2009 Sep 10;361(11):1058- 1066.
4.
Roboz GJ, Dinardo CD, et al.
Blood, 2020, 135(7): 463-471.
5.
DiNardo CD, et al.
Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia.
J Clin Oncol .
2021 Jan 1;39(1):57-65.
6.
Pau Montesinos, et al.
Oral on ASH 2021 (697).
https://ash.
confex.
com/ash/2021/webprogram/Paper147805.
html7.
Eytan M .
Stein, et al.
Poster on ASH 2021 (1276).
https://ash.
confex.
com/ash/2021/webprogram/Paper146507.
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