Addition of IDH inhibitors to standard chemotherapy improves outcomes in leukemia subtype
ATLANTA — Ivosidenib or enasidenib used in combination with standard induction therapy provided encouraging response rates and appeared well tolerated among patients with acute myeloid leukemia, according to findings presented at the ASH Annual Meeting and Exposition.
The addition of ivosidenib (AG-120, Agios) or enasidenib (Idhifa; Celgene, Agios) to induction chemotherapy provided particularly promising results among patients with secondary AML, many of whom received treatment with hypomethylating agents.
“Mutations in IDH1 or IDH2 are seen in approximately 15% to 20% of patients with AML. Ivosidenib and enasidenib are oral inhibitors of mutant IDH1 and IDH2 proteins, respectively,” Eytan M. Stein, MD, hematologic oncologist at Memorial Sloan Kettering Cancer Center, said during a presentation. “Given the single-agent activity of ivosidenib and enasidenib in relapsed and refractory AML, the safety and efficacy of these agents are being explored in earlier lines of therapy, in combination with standard induction and consolidation regimens.”
Stein and colleagues enrolled patients with newly diagnosed IDH1-mutated or IDH2-mutated AML in this open-label, multicenter, phase 1 study. All patients received standard induction chemotherapy (daunorubicin 60 mg/m2 per day or idarubicin 12 mg/m2 per day for 3 days with cytarabine 200 mg/m2 for 7 days). Patients with IDH1 mutations also received ivosidenib 500 mg once per day; patients with IDH2 mutations also received enasidenib 100 mg once per day.
Following induction therapy, patients could be treated with up to four cycles of consolidation chemotherapy with continued used of the IDH inhibitor. Individuals were eligible for up to 4 cycles of consolidation chemotherapy after induction while therapy with the IDH inhibitor continued.
Patients who completed consolidation chemotherapy or were not eligible for such treatment could continue maintenance therapy with ivosidenib or enasidenib for up to 2 years from initial induction. The researchers also allowed patients to withdraw at any point for allogeneic hematopoietic stem cell transplant, although those individuals did not continue maintenance therapy after transplant.
In total, 65 patients received treatment; 27 received ivosidenib and 38 received enasidenib. The median age was 60 years (range, 24-76) in the ivosidenib arm and 63 years (range, 32-76) in the enasidenib arm. Half of the patients with IDH2 mutations (n = 19; 50%) had secondary AML that developed after myelodysplastic syndrome, another antecedent hematologic disorder or exposure to genotoxic injury, compared with 33% (n = 9) of patients with IDH1 mutations.
Ivosidenib and enasidenib used in combination with induction chemotherapy both appeared well tolerated. The most common nonhematologic treatment-related adverse events of grade 3 or higher during induction therapy, regardless of attribution, included febrile neutropenia (56%), increased alanine aminotransferase (11%), increased aspartate aminotransferase (11%) and colitis (11%) among patients receiving ivosidenib and febrile neutropenia (63%), hypertension (11%), colitis (8%) and maculopapular rash (8%) among patients treated with enasidenib. One dose-limiting toxicity — persistent grade 4 thrombocytopenia without leukemia — occurred on day 42 in a patient who received daunorubicin/cytarabine plus enasidenib.
Median time to absolute neutrophil count recovery ( 500/µL) was 28 days for patients treated with ivosidenib and 34 days for patients treated with enasidenib. Platelet recovery (> 50,000/µL) occurred at 28 days for patients receiving ivosidenib and 33 days for patients receiving enasidenib. Patients treated with enasidenib who developed secondary AML experienced extended time to platelet count recovery (median, 50 days).
Researchers evaluated 23 patients in the ivosidenib arm for efficacy. A complete response, complete response with incomplete blood count recovery or complete response with incomplete platelet recovery was reached in 86% of patients (n = 12 of 14) with de novo AML and 44% of patients (n = 4 of 9) with secondary AML. Researchers evaluated 37 patients treated with enasidenib for efficacy. A complete response, complete response with incomplete blood count recovery or complete response with incomplete platelet recovery was attained in 67% of patients (n = 12 of 18) with de novo AML and 58% of patients (n = 11 of 19) with secondary AML.
Patients in the enasidenib arm were more likely than patients in the ivosidenib arm to be treated with at least one cycle of consolidation therapy and undergo HSCT (enasidenib, 14 vs. 7 patients; ivosidenib, 8 vs. 6 patients). Patients treated with ivosidenib demonstrated mortality rates of 7% on both days 30 and 60; patients treated with enasidenib demonstrated mortality rates of 5% of day 30 and 8% on day 60.
“Preliminary response data are consistent with expectations for induction chemotherapy in newly diagnosed patients with mutations in IDH1 or IDH2,” Stein said. “The prolonged platelet recovery observed [among] patients with IDH2-mutated secondary AML may reflect the reduced hematopoietic reserve [among] patients with secondary AML. An alternative dosing schedule for enasidenib is being explored to see if delayed platelet recovery can be mitigated.” – by Julia Ernst, MS
Stein EM, et al. Abstract 726. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Stein reports an advisory board role with GlaxoSmithKline; consultant roles with Agios Pharmaceuticals, Celgene Corporation, Novartis and Pfizer; research funding from Agios Pharmaceuticals, Celgene Corporation, Constellation Pharmaceuticals, GlaxoSmithKline, Novartis and Seattle Genetics; and travel expenses from Celgene Corporation and Pfizer. Please see the abstract for all other authors’ relevant financial disclosures.