Mutations in the isocitrate dehydrogenase gene (IDH1/2) are present in approximately 20% of patients with acute myeloid leukemia (AML), with a higher incidence in older patients.1 The prognostic impact of IDH1/2 mutations is context-dependent, given their frequent association with diploid or other intermediate-risk karyotype, FLT3-internal tandem duplications (ITD) and NPM1 mutations.2 Three IDH inhibitors are currently Food and Drug Administration-approved for IDH-mutated AML; ivosidenib and olutasidenib (IDH1 inhibitors) and enasidenib (IDH2 inhibitor). Ivosidenib ± azacitidine is approved for frontline therapy and all three IDH inhibitors for relapsed/refractory disease. Complete remission with (CR) or without (CRi) blood count recovery rates in newly diagnosed IDH-mutated AML patients treated with ivosidenib or enasidenib were reported at 42.4%,3 and 21%,4 respectively; the corresponding CR/CRi rate in the relapsed/refractory setting were 30.4% and 26.6%.5,6 Hypomethylating agent and venetoclax combination therapy (HMA-Ven) is also a therapeutic consideration for elderly/unfit IDH-mutated AML.7 There is limited comparative data on the outcomes of patients treated with IDH inhibitors versus HMA-Ven. We have previously described our experience with HMA-Ven in treatment-naïve and relapsed/refractory AML and identified molecular predictors of response and survival.8,9 In the current study, our primary objective was to determine the impact of mutations and karyotype on response and survival in IDH-mutated AML patients receiving IDH1/2 inhibitor monotherapy in routine clinical practice and retrospectively compare the findings with those of IDH-mutated patients treated with HMA-Ven.
The current study includes a total of 59 consecutive patients with IDH-mutated AML treated with single-agent IDH1/2 inhibitor (ivosidenib or enasidenib), outside of clinical trials, at the Mayo Clinic (Rochester MN, Jacksonville FL, Scottsdale, AZ), between 2017 and 2023. Study patients were retrospectively recruited after Institutional Review Board approval. Cytogenetic and molecular studies were performed at the time of diagnosis by conventional karyotype and next-generation sequencing (NGS) of a 42-gene panel, respectively. Four-gene panel NGS (FLT3, IDH1/2 and TP53) was obtained at relapse. Disease risk and response were assessed according to the 2022 European LeukemiaNet (ELN) criteria.10 Timing of response assessment was based on treating physician discretion. Determinants of treatment response were assessed by Χ2 or Fisher’s exact test for nominal data and Wilcoxon rank sum test for continuous variables. Overall survival was calculated from the time of initiation of IDH1/2 inhibitor to last follow-up or death without censoring for transplant and evaluated by the Kaplan–Meier method. Analyses were performed using JMP Pro 16.0.0 software package, SAS Institute, Cary, NC.
A total of 59 patients with IDH-mutated AML (median age 74 years, range 54-91; 59% males; 54% secondary or therapy-related) received ivosidenib (n=16) or enasidenib (n=43), of which 11 (19%) and 48 (81%) patients were treated in the frontline and relapsed/refractory setting, respectively. Patients with relapsed/refractory disease had received either one (n=24), two (n=15), three (n=6), or four (n=3) prior therapies which included cytarabine + ida-rubicin (7+3) (n=24), HMA-Ven (n=11), mitoxantrone, etoposide, cytarabine (MEC) (n=5), liposomal daunorubicin/cytarabine (n=4), cladribine, cytarabine, granulocyte colony-stimulating factor (G-CSF), mitoxantrone (CLAG-M)/fludarabine, cytarabine, G-CSF, idarubicin (FLAG-IDA) (n=4), and 7+3+ midostaurin (n=3). Seven patients had relapsed following allogeneic hematopoietic stem cell transplant (alloHSCT). ELN cytogenetic risk was evaluable in 57 patients and included intermediate (75%, n=43) or adverse (25%, n=14) risk. Mutations detected included DNMT3A in 22 patients (37%), SRSF2 in 21 (36%), RUNX1 in 15 (25%), ASXL1 in 12 (20%), BCOR in seven (12%), NPM1 in seven (12%), K/NRAS in six (10%), FLT3-ITD in six (10%), and TP53 in four (7%). A comparison of IDH1- versus IDH2-mutated patients revealed a higher incidence of RUNX1 mutations (44% vs. 19%; P=0.05) and adverse karyotype (50% vs. 14%; P=0.01) in IDH1-mutated patients. Treatment-emergent toxicities included differentiation syndrome (n=17), hyperbilirubinemia (n=11), and Qtc prolongation (n=6); treatment was discontinued due to toxicity in six patients. Table 1 provides information regarding patient characteristics at the time of initiation of IDH inhibitor, response rates, and overall outcome.
Fifteen (25%) patients achieved CR (n=10; 17%) or CRi (n=5; 8%); median time to response was 2.2 months (range, 1.0-7.1) and median response duration 3.6 months (range, 1.0-33). In addition, two (3%) patients experienced partial remission and eight (14%) hematological improvement. Measurable residual disease (MRD) assessement was performed in a subset of patients; MRD negativity was confirmed in three (75%) of four patients, evaluable by multiparametric flow cytometry, and in one (17%) of six patients, evaluable by IDH mutation analysis. Among the 15 patients with CR/CRi, relapse was documented in four (27%), and six (40%) patients were bridged to alloHSCT.
Table 1.Clinical characteristics at time of treatment initiation with single agent IDH1/2 inhibitor for 59 patients with acute myeloid leukemia stratified by achievement of complete response or complete response with incomplete count recovery.
Four of the five remainder patients are alive and in continuing response for a median duration of 22.2 months (range, 2.1-44.4), while one patient in ongoing response for 6.9 months, has died from sepsis. An additional two patients, one with hematological response and one non-responder, proceeded to alloHSCT following HMA-Ven and cladribine-cytarabine-Ven, respectively. CR/CRi rates were higher with IDH2 versus IDH1 mutation (33% vs. 6%; P=0.02). Among IDH2-mutated patients, CR/CRi was more likely with R140 versus R170 mutation (14/34, 41% vs. 0/6, 0%; P=0.02). In addition, CR/CRi rates were higher with BCOR mutation (CR/CRi 71% vs. 19%; P=0.01), and RUNX1 mutation (47% vs. 18%; P=0.03); CR/CRi rates were lower in the presence of ELN adverse karyotype (7% vs. 33%; P=0.04), ASXL1 (8% vs. 30%; P=0.09) or TP53 mutations (0% vs. 27%; P=0.12). Multivariable analysis confirmed superior response in the presence of BCOR (P=0.01; overall response to odds ratio [OR]=19.5) or RUNX1 mutations (P=0.04; OR 5) and inferior response in the presence of ELN adverse karyotype (P=0.01; OR=13.5). CR/CRi rates were not significantly different in the frontline versus relapsed/refractory setting (27% vs. 25%; P=0.88), de novo versus secondary AML (22% vs. 29%; P=0.55), presence or absence of NPM1 (43% vs. 23%; P=0.28), FLT3-ITD (33% vs. 25%; P=0.65), DNMT3A (36% vs. 19%; P=0.14), TET2 (25% vs. 25%; P=1.0), SRSF2 (24% vs. 26%; P=0.83), or K/NRAS (33% vs. 25%; P=0.65) mutations (Table 2). Response was also not influenced by IDH mutation variant allele frequency (median-38%; range, 5-50; P=0.38) and number of prior therapies (P=0.86). Only one (9%) of 11 patients previously treated with HMA-Ven (n=8, frontline HMA-Ven) responded to IDH inhibitor therapy compared to 14 of 48 (29%) patients without prior HMA-Ven exposure (P=0.13).
Table 2.Predictors of complete response or complete response with incomplete count recovery and post-treatment survival in 59 patients with acute myeloid leukemia treated with IDH1/2 inhibitor monotherapy.
At a median follow-up of 9.5 months (range, 0.4-70), from initiation of IDH inhibitor, 43 (73%) patients have died and eight (14%) underwent alloHSCT. Median survival following IDH inhibitor therapy was 10.4 months (range, 3.4-33.1) and superior in IDH2- versus IDH1-mutated patients (13.1 vs. 5.1 months; P<0.01), in the presence versus absence of CR/CRi (not reached [NR] vs. 9.3 months; P<0.01) and in patients receiving alloHSCT (NR vs. 9.5 months; P<0.01). The survival differences in IDH1- versus IDH2-mutated patients remained significant after accounting for karyotype, mutations, response and alloHSCT. Univariate survival analysis identified adverse karyotype (P=0.04), absence of BCOR (P=0.01) and absence of RUNX1 mutations (P=0.05) as predictors of inferior survival. Multivariable analysis, adjusted for alloHSCT, confirmed the survival impact of BCOR and RUNX1 mutations and adverse karyotype; corresponding hazard ratio (HR) and 95% confidence interval (CI) were HR=4.8, 95% CI: 1.4-16.5; HR=2.4, 95% CI: 1.1-5.4; HR=3.2, 95% CI: 1.5-6.7 (Table 2). A three-tiered survival model was subsequently generated by using HR-weighted risk point assignment; two points for absence of BCOR mutation and one point each for absence of RUNX1 mutation and presence of adverse karyotype, resulting in high (4 points, n=7; median survival 2.4 months), intermediate (2-3 points, n=45, median 11 months) and low (0–1 point, n=5; median NR) risk categories (P<0.01; Figure 1A). The aforementioned observations were confirmed when survival analysis was restricted to IDH2-mutated patients; the small number of IDH1-mutated patients precluded similar analysis.
Response rates and survival in the 59 IDH-mutated patients treated with IDH inhibitors were retrospectively compared to IDH-mutated Mayo Clinic patients treated with HMA-Ven (n=32; median age 69 years; treatment-naïve n=20 and relapsed/refractory n=12); CR/CRi rates were not different in HMA-Ven treated frontline versus relapsed/refractory patients (70% vs. 75%; P=0.76). Similarly, CR/CRi rates were comparable in IDH inhibitor-treated frontline versus relapsed/refractory patients (27% vs. 25%; P=0.87). CR/CRi rates were superior with HMA-Ven compared to IDH inhibitor (72% vs. 25%; P<0.01) while survival was similar between the two treatment regimens (17.8 vs. 10.4 months; P=0.24; Figure 1B). CR/CRi with HMA-Ven was higher in the presence of SRSF2 mutation (100% vs. 65%; P=0.03) while not influenced by adverse karyotype (63% vs. 73%; P=0.59) or RUNX1 (57% vs. 76%; P=0.34) or BCOR mutations (100% vs. 69%; P=0.14).
The current study confirms activity of IDH inhibitor mono-therapy in treatment-naïve and relapsed/refractory IDH-mutated AML3-6 and unveils unique molecular predictors of response and survival. The study also provides comparative information in IDH-mutated patients treated with HMA-Ven. Salient observations include the favorable impact of BCOR and RUNX1 mutations on IDH inhibitor treatment response and survival and were most apparent in IDH-2 mutated patients. In previously reported enasidenib clinical trials, responses were negatively affected by the presence of FLT3 (overall response rate [ORR] 8.3%) or NRAS (ORR 29%) mutations, and high co-mutational burden (≥ 6 vs. ≤3 mutations; ORR 31% vs. 55%);11 in addition, as was the case in the current study, adverse karyo-type was associated with inferior response (ORR 18% vs. 46%) and survival (ORR 7 vs. 9.3 months).11 In ivosidenibtreated patients, treatment response was lower in the presence of receptor tyrosine kinase pathway mutations (CR/CRh 7% vs. 43%) and higher with JAK2 mutation (CR/CRh 64% vs. 32%).12
Figure 1.Overall survival in patients with IDH1/2-mutated acute myeloid leukemia. (A) Overall survival in 57 patients with acute myelod leukemia (AML) treated with IDH inhibitor, stratified by hazard ratio (HR)-weighted scoring system, absence of BCOR mutation, HR=4.8, 95% confidence interval (CI): 1.4-16.5; presence of adverse karyotype, HR=3.2, 95% CI: 1.5-6.7; and absence of RUNX1 mutation, HR=2.4, 95% CI: 1.1-5.4, allocating 2 adverse points for absence of BCOR mutation, 1 adverse point for adverse karyotype, and 1 adverse point for absence of RUNX1 mutation. Median overall survival stratified by low risk (0-1 points), intermediate risk (2-3 points) and high risk (4 points) is shown. (B) Overall survival in 91 patients with IDH-mutated AML treated with either IDH inhibitor (N=59) or hypomethylating agent + venetoclax (N=32). alloHSCT: allogeneic stem cell transplantation; RR: relapsed refracto-ryrefractory; yr: years.
The observations from the current study are particularly relevant in light of the adverse prognosis assigned to BCOR and RUNX1 mutations, in the latest ELN 2022 risk stratification, which was, however, derived from intensively treated patients.10 Our findings differ from a prior study on IDH-mutated AML patients treated with IDH inhibitors (n=60), in which RUNX1 mutation was associated with inferior CR rate, in addition, among patients in whom pre-treatment and relapsed samples were analyzed (n=18), BCOR and RUNX1 mutations were frequently acquired at the time of relapse in four and three cases, respectively.13 The discrepancies stem from key differences in the study populations, unlike the current study, the former study included patients with myelodysplastic syndrome and chronic myelomonocytic leukemia (n=5) and was enriched with patients harboring complex karyotype (22% vs. 11%).13 It should be noted that response prediction is different than survival prediction and frequency of mutations at time of relapse might actually suggest that a higher proportion of patients with the specific mutations achieved response and thus were at risk for relapse. In other words, one has to respond first, in order to relapse. Regardless, the current study provides a practical prognostic model for use in IDH-mutated patients with AML receiving IDH inhibitor therapy. The study also suggests superiority of HMA-Ven to IDH inhibitor, in IDH-mutated AML, irrespective of karyotype or mutational profile. The favorable responses seen with HMA-Ven were also evident in a prior study of 81 IDH1/2-mutated AML patients treated with HMA-Ven with reported CR/CRi rate of 79%.14 Recently, “doublet therapy” with IDH inhibitor + HMA and “triplet therapy” with IDH inhibitor + Ven + HMA have garnered interest due to higher responses with composite CR rates of 53%,15 and 90%,16 respectively. Nonetheless, controlled studies are needed to determine the optimal combination therapy and associated molecular determinants of response and survival.
Footnotes
- Received June 11, 2023
- Accepted July 27, 2023
Correspondence
Disclosures
No conflicts of interest to disclose.
Contributions
KM, NG and AT designed the study, collected data, performed analysis and co-wrote the paper. MA, OK and MP collected data. AA, HA, KHB, AM, AS, MH, MRL, WH, MS, MMP, AP, TB, JF, JP, LS and CA contributed patients. All authors reviewed and approved the final draft of the paper.
Data-sharing statement
Data will be shared upon reasonable request to the corresponding author.
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