IDH1/2 inhibitor Ivosidenib/Enasidenib combined with intensive chemotherapy is well tolerated in newly treated AML patients

The “7+3” intensive induction chemotherapy regimen of cytarabine combined with daunorubicin is a more effective treatment regimen for patients with acute myeloid leukemia (AML), which can improve the patient’s progression-free survival (PFS) and overall survival ( OS).

About 20% of AML patients have IDH1/2 gene mutations.
Ivosidenib (AG-120) and Enasidenib (AG-221) are inhibitors that target IDH1/2, and have been approved by the FDA as a single-agent treatment for relapsed or refractory AML.

A phase I study evaluated the efficacy and safety of Ivosidenib/Enasidenib combined with intensive chemotherapy in newly-treated AML patients with IDH1/2 mutations.

The main results of the research are summarized as follows for the reference of readers.

The key point Ivosidenib/Enasidenib combined induction therapy and intensive chemotherapy during consolidation therapy are safe in newly-treated AML patients with IDH1/2 mutations.

Ivosidenib has a complete remission (CR)/complete remission with incomplete blood count recovery (CRi)/complete remission (CRp) with incomplete platelet count recovery in newly-treated AML patients.
The rate is 77%, and Enasidenib is 74%.

Research methods The study included newly-treated AML patients aged ≥18 years, ECOG score 0-2, and IDH1/2 mutations, who received 500mg/day Ivosidenib/Enasidenib combined with cytarabine (200mg/m2/day, total 7 Day) and daunorubicin (60mg/m2/day for 3 days) induction therapy.

Patients who achieve at least partial remission (PR) after induction therapy can receive 4 cycles of cytarabine or 1 cycle of mitoxantrone/etoposide combined with Ivosidenib/Enasidenib for consolidation therapy, and those who are still in remission after the completion of consolidation therapy Patients can continue to receive Ivosidenib/Enasidenib single-drug maintenance treatment until an intolerable adverse event occurs or receive hematopoietic stem cell transplantation (HSCT).
Patients receiving HSCT will stop Ivosidenib/Enasidenib treatment.

Results of the study A total of 60 patients received Ivosidenib combined with induction chemotherapy, and 93 patients received Enasidenib combined with induction chemotherapy.

 The median age of patients in the Ivosidenib group was 62.
5 years.

Nine patients (15%) received 2 cycles of induction therapy, 35 patients (58%) received consolidation therapy, and 19 patients (32%) received Ivosidenib maintenance therapy.

By the end of the data, 47 patients (78%) had stopped Ivosidenib treatment, mainly due to HSCT (28 cases), and 13 patients were still undergoing Ivosidenib maintenance treatment.

 The median age of patients in the Enasidenib group was 63.
0 years.

2 patients received Enasidenib and died due to adverse events on the 8th day, 22 patients (24%) received 2 cycles of induction therapy, 46 patients (49%) received consolidation therapy, and 24 patients (26%) received Enasidenib Maintenance treatment.

As of the data cutoff, 81 patients (87%) had stopped enasidenib treatment, mainly due to HSCT (43 cases), and 12 patients were still undergoing Enasidenib maintenance treatment.

01 Safety The adverse reactions observed during the induction therapy and consolidation therapy of the combined regimen are similar to those observed with the "7+3" regimen alone.

The 30-day and 60-day mortality rates of patients in the Ivosidenib group were 5% and 10%, and those in the Enasidenib group were 5% and 9%.

Thirteen patients in the Ivosidenib group died (including the follow-up period), of which 7 patients (54%) died during treatment (within 28 days after the last treatment); 31 patients in the Enasidenib group died, of which 13 patients (42%) Died during treatment.

All deaths were not related to Ivosidenib and Enasidenib.
The main causes of death were respiratory failure, lung infection, intracranial hemorrhage, and sepsis caused by disease progression and complications.

 The treatment of Ivosidenib and Enasidenib does not affect the recovery time of patients with neutrophil count (ANC) and platelet count.

The median time for ANC (>500/μL) and platelet count (>50,000/μL) to recover during induction therapy in the Ivosidenib group was 28 days; the median time to recover ANC and platelet count during induction therapy in the Enasidenib group was 34 days And 29 days.

02 Efficacy The overall CR/CRi/CRp rate of patients in the Ivosidenib group was 68%, 77% in the Enasidenib group; the CR/CRi/CRp rate in the Ivosidenib group was 55% after induction therapy, and the rate in the Enasidenib group was 72%.

 At a median follow-up of 9.
3 months (range: 0.
4-32.
1 months) in the Ivosidenib group, the 12-month OS rate was 78%, and the median OS was not reached.

At a median follow-up of 14.
5 months (range: 0.
5-31.
8 months) in the Enasidenib group, the 12-month OS rate was 76%, and the median OS was 25.
6 months (95%CI: 25.
5 months-NE).

Research conclusions Ivosidenib/Enasidenib combined with intensive chemotherapy induction therapy and consolidation therapy are well tolerated in newly-treated AML patients with IDH1/2 mutations.
The efficacy of this combination will be further verified in a subsequent phase III randomized study. Reference: Eytan M.
Stein, Courtney D.
DiNardo, Amir T.
Fathi, et al.
Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study.
Blood (2021) 137 (13): 1792 –1803.
.
https://doi.
org/10.
1182/blood.
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