PROGNOSTIC IMPACT OF IDH1 MUTATIONS IN AML PATIENTS RECEIVING STANDARD CHEMOTHERAPY

The prognostic impact of IDH1mut has been widely studied in newly diagnosed AML with contradictory results, suggesting adverse outcomes,7,14,19 no influence,3,8,27–33 or a favorable outcome in one study.15 A meta-analysis of 8 studies found a lower event-free survival (EFS) in patients with IDH1mut, but there were no differences in OS.17 However, two meta-analyses including 15 studies34 and 24 studies35 obtained significant associations between IDH1mut and lower OS, as well as a lower event-free survival and CR rate in the last meta-analysis.35 These associations were reproduced in the subset of CN-AML IDH1mut patients.34,35 Furthermore, the IDH1 single-nucleotide polymorphism rs11554137 was also related to a poor OS.35

The influence of these mutations in R/R AML remains scarcely reported. Mutation of IDH1 was an unfavorable factor for survival in a large cohort of 761 R/R AML treated with intensive salvage therapy.36 The main schemes employed were based on a high dose of Ara-C (HiDAC), used in 71.2% of the patients. Unfortunately, specific data regarding the outcomes of IDH1mut with each salvage scheme were not provided. The next large study analyzing the clinical outcomes of IDH mutations did not find any differences in the CR/CRi and the median OS (mOS) among IDH1mut, IDH2mut, and wild-type IDH (wtIDH) for AML induction or the first salvage therapy (S1) and the second or beyond salvage therapy (S2). This study employed at S1 and S2 schemes based on HiDAC (36% and 41%), hypomethylating agents (HMA) (32% and 27%), and low-dose Ara-C (24% and 3%). Specifically, IDH1mut showed a CR/CRi of 40% vs 41% and 36% vs 27% at S1 and S2 against wtIDH, respectively, and a mOS of 5.9 and 7.7 months at S1 and 4.0 and 4.8 months at S2, respectively.3 Lower survival rates were reported in a French cohort of 185 R/R AML patients treated with standard salvage therapies (intensive chemotherapy in 68%, azacitidine in 18%, and other therapies in 14%) comparing IDH1mut versus wtIDH and IDH2mut (mOS 5.9, 7.6, and 11 months; 3-year OS 8%, 19%, and 23%), whereas no differences were reported in CR (50%, 43%, and 52%, respectively).4Recently, the outcomes of R/R AML with IDH1mut from the UK NCRI AML trials treated with nontargeted therapy were analysed, showing mOS of 4.4 months, 1-year OS of 32%, 2-year OS of 17%. and remission rate of 23%. Age and AML subtypes (refractory, relapsed post-HSCT, second relapse, and relapsed within 1 year of remission) were not associated with differences in survival rates.37

NOVEL APPROACHES IN IDH1-MUTATED RELAPSED OR REFRACTORY AML

Several targeted therapy agents are currently under development for IDH1mut R/R AML patients, andare showing promising results.

Ivosidenib (AG-120)

Drug development and pharmacokinetics

Ivosidenib (AG-120) is the first oral selective small molecule inhibitor of the IDH1-R132mut, resulting in inhibition of mutant IDH1 enzyme and decreased D2HG levels. The efficacy, safety, and pharmacokinetics of ivosidenib were evaluated in Phase I/II clinical trial in patients with IDH1mutadvanced hematologic malignancies, including R/R AML [NCT02074839].38,39 Besides, this agent is being tested for advanced cholangiocarcinoma [NCT02989857], glioma [NCT03343197], and advanced solid tumors [NCT02073994]. In July of 2018, the FDA approved ivosidenib for the treatment of R/R AML patients with IDH1mut.40

The selected oral dose was 500 mg/24 hrs (maximum tolerated dose was not reached). It was rapidly absorbed (median 3 hrs to peak plasma concentration) and a steady state reached at 14 days. The steady-state mean apparent volume of distribution was 234 L and the protein bound was near 92–96%. CYP3A4 was the main way of metabolism, although 77% was excreted unchanged in the feces and 17% in the urine (10% unchanged), obtaining a clearance of 4.3 L/hr and a terminal elimination half-life of 93 hrs.38,41 A population pharmacokinetic model of ivosidenib has been recently performed, suggesting that no dose adjustments were needed according to the patient and disease conditions, and only the concomitant use of azoles (moderate/strong CYP3A4 inhibitors) was able to reduce ivosidenib clearance.42

Efficacy

The Phase I dose-escalation and dose-expansion clinical trial included 179 AML R/R IDH1mut patients treated with 500 mg of ivosidenib every 24 hrs in a 28-day cycle (cutoff date May 12, 2017;38 second cutoff date November, 201739) (Table 1). The primary endpoint of this study, CR or CRh, was achieved in 30.2% for an mCRD of 6.5 months (31.8% and 8.2 months at the second cutoff). In addition, the CR rate was 21.8% with an mCRD of 9.3 months (24.0% and 10.1 months at second cut-off) and overall response (OR) of 39.1% and mCRD of 6.5 months (41.9% and 6.5 months at second cutoff). The mOS in the first primary efficacy cohort of 125 patients treated with 500 mg/24 hrs was 8.8 and 9.0 months after a median follow-up of 14.8 and 15.3 months. Transfusion independence ≥56 days was achieved in 35% of patients with previous transfusion dependence and maintained in 56% of the patients who were transfusion-independent at baseline.

(To view a larger version of Table 1, click here.)

After ivosidenib therapy, 21% IDH1mut clearance was detected using digital PCR among the 34 patients who had CR or CRh38 (23%, 11 of 47 at the second cutoff).39 This subset of patients showed longer CRD (11.1 vs 6.5 months) and mOS (14.5 vs 10.2 months) than those without IDH1mutclearance. The role of the baseline comutated genes was also evaluated, and a significant association between CR or CRh and a lower comutational burden was found (P=0.02). However, no specific preexisting mutations were identified as predictors of CR or resistance, although mutations in receptor tyrosine–kinase pathway genes were enriched in patients without response.38

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