EHA 2018 | IDH mutant inhibitors in AML

Isocitrate dehydrogenase (IDH) mutations occur in approximately 20% of AML patients and the prevalence increases with patient age. IDH enzymes catalyze the conversion of isocitrate to α-Ketoglutarate (αKG). However, mutations in IDH1/2 lead to a reverse reaction of αKG to the oncometabolite D-2-Hydroxyglutarate (D-2HG). The accumulation of 2HG competitively inhibits αKG, thus leading to alterations in TET2-dependent hydroxymethylation, chromatin modification, activation of the hypoxic response, and increased dependence on BCL2. IDH inhibitors bind with the mutant IDH1 or IDH2 catalytic active site thus preventing the oncogenic reduction of αKG to D-2HG.¹

At the 23^rd Congress of the European Hematology Association (EHA), there was an oral session focused on IDH mutant inhibitors in acute myeloid leukemia (AML).

Daniel Pollyea from the University of Colorado School of Medicine, Aurora, CO, gave the first two talks at this session. The speaker first presented data from a phase I dose escalation and expansion study (NCT02074839), evaluating ivosidenib monotherapy in patients with advanced hematologic malignancies with an IDH1 mutation. The efficacy and safety data obtained from the cohorts of R/R AML patients (primary efficacy population) receiving ivosidenib (500 mg once daily) with at least 6 months of follow-up were presented during this talk. The results of this study have been previously reported by the AGP here. The results of the study showed that “in this high-risk, molecularly defined R/R AML patient population, ivosidenib induced durable remissions and was well tolerated”. Additionally, ivosidenib induced IDH1 mutational clearance in bone marrow mononuclear cells BMMCs in 23% of patients with best overall response of CR+CRh.

Next, Daniel Pollyea presented data on the clinical outcomes of older patients with previously untreated mIDH2 AML who were treated with enasidenib monotherapy in the AG221-C-001 study (NCT01915498). This phase I/II dose escalation study is evaluating efficacy and safety of enasidenib monotherapy in patients with advanced hematologic malignancies with mIDH2.

In the AG221-C-100 study, 39 patients (median age = 77 years, range: 58–87) with previously untreated mIDH2 AML who were unfit for standard treatment were enrolled. Patients on the dose escalation phase were administered 50–650 mg/day enasidenib, and all patients in the expansion phase received enasidenib 100 mg/day, continuous 28-Day treatment cycles. The data cut-off was 1^st September 2017.

Most frequent treatment-related Treatment-Emergent Adverse Events (TEAEs) any grade occurring in ≥ 10% of patients were hyperbilirubinemia (31%) and nausea (23%). Two patients discontinued treatment due to treatment-related TEAE of cardiac tamponade and thrombocytopenia respectively. Serious treatment-related TEAEs was reported > 1 patient including IDH differentiation syndrome (n = 4) and tumor lysis syndrome (n = 2).

With a median follow-up of 8.4 months (range, 0.5–4.3), the overall response rate (ORR) was 31% (12/39) with a complete remission (CR) rate of 18% (7/9). Median overall survival (OS) and event-free survival (EFS) for the entire cohort were 11.3 and 5.7 months respectively. Compared to non-responders, responders had a better EFS (2.83 vs not reached, respectively) and OS (5.69 vs not reached, respectively).

Dr. Pollyea concluded that enasidenib monotherapy “was generally well tolerated by older patients with newly diagnosed mIDH2 AML”. Additionally, enasidenib monotherapy was associated with encouraging response rate in older AML patients with mIDH2. The presenter further concluded that the use of enasidenib for older patients with newly diagnosed mIDH2 AML who are unfit to receive standard therapy is a “promising strategy”.

The final talk on mutant IDH inhibitors was given by Courtney DiNardo from The University Texas MD Anderson Cancer Center, Houston, TX. Courtney DiNardo presented results from the phase Ib portion of an ongoing phase Ib/II study (NCT02677922) of mIDH inhibitors (enasidenib or ivosidenib) in combination with azacitidine (AZA) in patients with newly diagnosed AML.

A total of 29 newly diagnosed patients with mIDH were treated with enasidenib (n = 6, median age = 68 years) or ivosidenib (n = 23, median age = 76 years) in combination with AZA. mIDH2 patients received enasidenib in dose-escalation cohorts of 100 (n = 3) or 200 mg (n = 3) and mIDH1 patients received ivosidenib 500 mg once daily, each in continuous 28-Day cycle. All patients were administered subcutaneous AZA (75 mg/m²/day x 7 Days/cycle). At data cut-off of 15^th March 2018, 19 patients in the enasidenib (n = 2) and ivosidenib (n = 17) arm remained on the study.

In the ivosidenib/azacitidine arm, most common TEAEs any grade were nausea (n = 14), anemia (n = 14), and thrombocytopenia (n = 11). Most common treatment-related TEAEs included nausea (n = 12), vomiting (n = 7), QT interval prolongation (n = 6) and fatigue (n = 5). Serious events were reported in > 2 patients of febrile neutropenia and IDH differentiation syndrome (n = 3). Two deaths occurred on study due to sepsis and AML progression respectively, neither was treatment-related.

In the enasidenib/azacitidine arm, most common TEAEs any grade were hyperbilirubinemia (n = 5), abdominal pain, nausea, vomiting, pyrexia (n = 4 each). Nausea (n = 4) was the only treatment-related TEAE. Serious events were reported in > 1 patient of hyperbilirubinemia (n = 2) and pyrexia (n = 2).

The ORR in the ivosidenib/azacitidine and enasidenib/azacitidine arm was 78% (18/23) and 67% (4/6) respectively. Interestingly, 7 of 21 patients in the ivosidenib/azacitine arm achieved IDH1 mutation clearance including five (50%) patients in morphological CR. Three of 6 patients in the enasidenib/azcitidine arm achieved IDH2 mutation clearance including two (66%) patients in morphological CR.

Dr. DiNardo concluded by stating that ivosidenib or enasidenib plus azacitidine combination is “well tolerated” in patients with newly diagnosed AML. Additional, response rates seen with these combination regimens were “promising” with IDH mutational clearance observed in patients who attained a morphological CR.