IDHIFA is an isocitrate dehydrogenase-2 inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDAapproved test

For patients with IDH1 or IDH2 mutant AML, ivosidenib or enasidenib, respectively, or HMAs alone are recommended.

This open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 inhibitor, with conventional care regimens (CCR) in patients aged ≥60 years with late-stage, mutant-IDH2 acute myeloid leukemia (AML) relapsed/refractory (R/R) to 2 or 3 prior AML-directed therapies....Enasidenib provided meaningful benefits in EFS, TTF, ORR, HI, and RBC-TI in this heavily pretreated older mutant-IDH2 R/R AML population.

...Previously untreated AML (de novo or secondary) defined according to World Health Organization (WHO) criteria, excluding acute promyelocytic leukemia (APL) [AML with t(15;17)], with locally documented IDH1 and/or IDH2 gene mutation...

Patients were eligible for maintenance therapy irrespective of conditioning, if in complete remission (CR) at day +30 post-HCT, had ECOG PS ≤2 and adequate marrow function….The 1 and 2-year overall survival and LFS were 100% resulting in high 1 and 2-year CRFS of 93% and 87%, respectively. (Fig 1b). In conclusion, post-HCT maintenance therapy with enasidenib is safe and feasible with highly favorable survival outcomes in mIDH2 AML.

Enasidenib significantly improved the response rates in patients with mIDH-2 AML....Ivosedanib significantly improved the response rates and survival rates in patients with mIDH-1 AML. Olutasidenib was also effective in patients with R/R mIDH-1 AML. More randomized double-blind multicenter clinical trials are needed to confirm these results.

At three-year follow-up, ENAm continues to be a safe and well-tolerated therapy in ND patients ≥ 60 years old with IDH2m AML both alone and with the risk-adapted addition of AZA. CR/CRi rates are high (48%, adjusted 95% CI 30.3-60.5) and remissions are durable (11.1 months, 95% CI 5.6-41.4).

...post-HCT enasidenib maintenance therapy was safe and well-tolerated, resulting in favorable survival outcomes in AML patients carrying IDH2 mutations.

Of 128 eligible patients, 87 received ENA and 41 received other 1L R/R therapy. Compared with other 1L therapies, ENA was associated with higher ORR (74% versus 34%, P<0.01; adjusted odds ratio, 11.72 [95% CI, 2.8-49.1], P<0.01), longer median PFS (8 versus 3 months, after a median follow-up of 9 and 7 months, respectively; adjusted HR, 0.31 [95% CI, 0.19-0.53], P<0.01), and longer median OS (9 versus 6 months; adjusted HR, 0.31 [95% CI, 0.18-0.53], P<0.01). This is the fi rst real-world study to demonstrate superior OS, PFS, and ORR benefits for older patients with R/R IDH2-mutated AML treated with ENA versus other 1L therapies.

After a median follow-up of 9 and 6 months, median PFS was 8 months in enasidenib-treated patients and 5 months in patients receiving other 1 L RR therapy, respectively (adjusted HR=0.36, 95% CI: 0.23-0.57, p < 0.01)…Results from this real-world study confirm the effectiveness of enasidenib among patients with IDH2-mutated RR AML and demonstrate that hospitalizations were significantly lower vs. other 1 L RR treatment in clinical practice.

The composite complete remission rate (CRc) [complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)] was 100% in ND AML, and 58% in R/R AML….ENA + AZA was a well-tolerated, and effective therapy for elderly pts with IDH2mut ND AML as well as pts with R/R AML. The addition of VEN to ENA + AZA appears to improve outcomes in R/R IDH2mutAML.

Combination enasidenib plus azacitidine was well tolerated and significantly improved overall response rates compared with azacitidine monotherapy, suggesting that this regimen can improve outcomes for patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia.

Multicenter retrospective study including patients with IDH2-mut AML and MDS treated in Spain (2017-2020) with ENA outside of Clinical trial...The overall response rate (ORR) was 47% (N=9), 6 patients (31%) achieved complete response (CR)....The results of this study confirm both the effectiveness and the good drug tolerability reported with ENA in the Phase II study.

Using Mayo Clinic's cohort of AML patients, we provide a real-world look at outcomes forIDH2mutated RR-AML patients treated with enasidenib….Complete response (CR) was achieved in 4 (30.7%) patients by cycle 2 and 2 of those patients (50%)…

CR/partial response/morphologic leukemia-free state rate was higher among patients treated with enasidenib versus other 1L RR therapies (77% vs 52%; P < 0.01)....median PFS was 8.4 and 4.8 months (adjusted HR = 0.36, 95% CI 0.23–0.57; P < 0.01), and median OS was 11.0 and 6.4 months (adjusted HR = 0.37, 95% CI 0.22–0.60; P < 0.01)...this large real-world cohort study confirm the effectiveness of 1L RR enasidenib among patients with IDH2-mutated AML.

Nine IDH2 mutated pts were considered for analysis: 4 (44%) cases were de novo AML,...All pts completed at least one cycle of ENA with a median number of 5 cycles (range 1-16). Median OS from AML diagnosis and from the beginning of ENA was 28 mo (range 3-65), and 15 mo (range 1-27) respectively; median PFS was 13 mo (range 1-14).

...this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML...In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance...

Combining ENA + AZA resulted in significantly improved response rates and durations, and was generally well-tolerated in older patients with mIDH2 ND-AML.

Azacitidine (75 mg/m2 days 1-7) was added to enasidenib for patients not achieving a complete remission or complete remission with incomplete hematologic recovery (CR/CRi) by cycle 5....Five pts with inadequate response to monotherapy proceeded to the phase 1b portion of the study with enasidenib in combination with azacitidine. The combination was generally well tolerated...

 ENA + AZA was associated with significantly improved complete remission and overall response rates and significant mIDH2 VAF reductions compared with AZA-only. 

After 18 months of surveillance, repeat bone marrow evaluation for new-onset pancytopenia revealed relapsed AML with evidence of IDH2 mutation at codon 140,...The decision was made to increase the enasidenib dose to 200 mg daily. With follow up for another 5 months on the escalated dose, the patient achieved hematologic complete response (hCR)...

The patient was treated with induction chemotherapy and failed to respond. Repeat bone marrow evaluation showed primary refractory disease with positive IDH2 mutation at codon 140 with a variant frequency of 40.7%. Treatment with 100 mg enasidenib was started. The patient maintained a partial response for 6 months, then peripheral blasts counts started to gradually increase. The decision was made to increase enasidenib dose to 200 mg daily, which improved peripheral blasts within one month of escalated dose therapy. [Figure 3] The patient maintained a response to therapy for another 3 months before she relapsed.

Our preliminary evidence indicates that the addition of ATRA to treatments with IDH2 inhibitor may lead to further improvements or increases in response rates in IDH2-mutant AML patients who do not appear to benefit from treatments with IDH2 inhibitor alone.

AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models.