Abstract
Purpose:
The development of targeted therapeutics has revolutionized treatment for elderly patients with acute myeloid leukemia (AML). Two “doublet” regimens are approved in the frontline setting for intensive-chemotherapy (IC) ineligible AML: Venetoclax (VEN) in combination with hypomethylating agent (HMA) therapy, and azacitidine (AZA) plus ivosidenib (IVO) specifically for IDH1-mutated AML. While both regimens have improved AML outcomes, most patients will either not respond to frontline therapy or relapse, with dismal salvage outcomes.
Methods:
We herein report on 60 newly diagnosed IC-ineligible patients treated at our institution with “triplet” regimens for IDH-mutant AML. Patients received either AZA+VEN+IVO on NCT03471260 (IDH1-mutated patients only), or oral decitabine+VEN+IVO/enasidenib (ENA) on NCT04774393 (arms for IDH1 and IDH2-mutant disease, respectively).
Results:
The triplet regimens were well tolerated with low early mortality (n=1 (2%) in 60-days), and a similar safety profile to HMA + VEN and IDHi doublet regimens. The composite complete remission rate (CRc) was 92% (55/60), with overall response rate (ORR) of 95% (57/60). With median follow up of 27.4 months, the median overall survival (OS) has not yet been reached. 2-year OS was 69% with a 2-year cumulative incidence of relapse of 24%. Patients with treated-secondary AML (tsAML) experienced inferior outcomes with a CRc of 71% (12/17) and a 2-year OS of 34%; 2-yr OS was 84% in patients without tsAML. Nineteen patients (32%) transitioned to stem cell transplant (SCT), and 51% remain on study.
Conclusions:
Given the excellent outcomes of IDH-triplet therapy for newly diagnosed, IC-ineligible IDH-mutant AML, further prospective studies comparing IDH-triplet versus doublet regimens are warranted.
Introduction:
The treatment landscape for patients with acute myeloid leukemia (AML) has transformed over the past decade, with over a dozen new therapeutic options and increasingly individualized, targeted approaches based on the underlying genomic profile leading to improved AML clinical outcomes.1,2
Approximately 20% of AML is characterized by the presence of an isocitrate dehydrogenase-1 (IDH1) or isocitrate dehydrogenase-2 (IDH2) mutation.3,4 Mutant selective IDH inhibitors, including the IDH2 inhibitor enasidenib, and the IDH1 inhibitors ivosidenib and olutasidenib, are FDA-approved as single-agents in the relapsed setting for AML harboring the respective IDH mutation.5–7 In addition, for patients with newly diagnosed IDH1-mutated AML who are ineligible for standard intensive chemotherapy (IC), the combination of azacitidine and ivosidenib is approved as a front-line lower intensity combination, improving response rates and survival compared to azacitidine alone.8,9
Importantly, for patients with newly diagnosed and IC-ineligible AML of all underlying genomics, one of the most meaningful recent advances to AML therapy has been the approval of the BCL2 inhibitor venetoclax, in combination with hypomethylating agent (HMA) therapy, now considered the frontline standard of care for most older patients world-wide.10,11
Although outcomes for patients with IDH-mutated AML have improved, the majority of patients will still relapse, and outcomes in the relapsed setting remain dismal.12–14 Preclinical and clinical data has demonstrated synergy between IDH inhibitors and venetoclax, suggesting a role for treatment combinations incorporating both novel therapeutics.15,16 We previously reported on the safety and efficacy of ivosidenib and venetoclax, with or without the addition of azacitidine, and demonstrated a composite remission rate (CRc) over 90% in a small cohort (n=14) of patients with newly diagnosed IDH1-mutated AML.17 Furthermore, responses appeared deeper and more durable in patients receiving the “triplet” over the ivosidenib + venetoclax small molecule “doublet”, with flow MRD-negative CRc rates 75% vs 50%, and 24-month OS 75% vs 58%.
In this pooled clinical trial analysis, we report on the outcomes of sixty patients with newly diagnosed IDH mutated AML, not eligible for intensive chemotherapy, treated on a frontline triplet regimen containing a hypomethylating agent, venetoclax, and IDH inhibitor.
Methods:
Patients and Study Treatment:
All adults with newly diagnosed IC-ineligible IDH1 or IDH2 mutated AML, treated at the University of Texas MD Anderson Cancer Center on a frontline “IDH triplet” clinical trial from October 2019 – May 2024 were included. Patients received either azacitidine (AZA) + venetoclax + ivosidenib on NCT03471260 (IDH1-mutated patients only), or oral decitabine (DEC-C) + venetoclax + either ivosidenib or enasidenib on NCT04774393 (arms for IDH1 and IDH2 mutant disease, respectively).
Receipt of prior venetoclax or ivosidenib on NCT03471260 was excluded, whereas prior venetoclax, IDHi or HMA therapy for treatment of an antecedent hematologic disorder (i.e. treated secondary AML (tsAML)) was allowed on NCT04774393. The studies were conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonization. Protocols and amendments were approved by the competent authorities and the local Institutional Review Board. All patients or their legal guardians provided informed consent.
Patients in both trials were admitted to the hospital for cycle 1 therapy, including a three-day venetoclax ramp up to mitigate the risk for tumor lysis syndrome (TLS). Venetoclax was administered from days 1–14 per treatment cycle in both studies. Ivosidenib and enasidenib are continuous once daily medications, beginning on C1D14 of the AZA+VEN+IVO study and beginning on C1D8 on the DEC-C+VEN+IVO/ENA study and continuing thereafter. AZA was given for 7 days per treatment cycle and oral DEC-C for 5 days. Standard antibacterial, antifungal, and antiviral prophylaxis was recommended in all patients for cycle 1, and in subsequent cycles in the setting of persistent neutropenia. Dosing regimens including venetoclax dose modifications with/without concomitant CYP3A inhibitors for each protocol is provided in Supplemental Table 1. Use of G-CSF was permitted once patients were in remission to expedite count recovery. In subsequent cycles, prophylactic G-CSF could be administered after completion of HMA and VEN therapy for ANC <1000 cells/μL at the discretion of the treating physician.
Outcome Measures:
The dual primary objectives of both investigator-initiated trials were to determine the safety and efficacy of the treatment combinations. Safety was measured by CTCAE v5.0 criteria and also included 30 and 60-day all-cause mortality. Efficacy was measured by composite complete remission (CRc) within the first 5 cycles of study therapy, defined as complete remission (CR), CR with incomplete hematological recovery (CRi), and CR with partial hematological recovery (CRh). The objective response rate (ORR) was also annotated, including CR + CRi + CRh + partial remission (PR) + morphologic remission free state (MLFS).
Overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR) and duration of remission (DOR) were assessed by the Kaplan-Meier method, with log-rank tests to compare among patient subgroups. EFS was defined as lack of CRc response (with the event at time of protocol discontinuation), relapse, or death from any cause. CIR and DOR were censored at stem cell transplant (SCT).
MRD was assessed locally via multiparameter flow cytometry (FC) with 10−4 sensitivity. MRD by FC was determined at best response and assessed at each remission marrow. Mutations were assessed by an in-house 81-gene next generation sequencing (NGS) panel (limit of detection: 2% variant allele frequency (VAF)), at baseline and at relapse.
Statistical analyses were performed using R version 4.3.2 (Vienna, Austria).
Results:
From October 2019 to May 2024, 60 patients with newly diagnosed IC-ineligible IDH1 or IDH2 mutated AML were enrolled with median follow up time of 27.4 months (95% CI: 21.4 – 36.2). Demographic information is provided in Table 1. Median age at enrollment was 71 (range 62–87), and 55% of patients were ≥ 70 years. 27% (n=16) patients were treated on AZA + VEN + IVO, and 73% (n=44) patients were treated on DEC-C + VEN + IVO/ENA; including n=21 IVO-treated patients, and n=23 ENA-treated patients. There were four patients with both IDH1 and IDH2 co-existing clones; in three of the four cases, the IDH1 clone was larger so they received IVO, whereas in one case the IDH2 clone was larger so they received ENA.
Table 1.
Total Cohort Demographics and Characteristics
| Variable | Overall1 (n=60) |
|---|---|
| Age | 71 (62 – 87) |
| Female sex | 24 (40%) |
| White | 55 (92%) |
| DAC + VEN + ENA | 23 (52%) |
| Therapy-related | 4 (7%) |
| Adverse | 47 (78%) |
| Adverse | 4 (7%) |
| Signaling mutation2 | 20 (33%) |
| SCT | 19 (32%) |
Median (min, max); n (%)
Including FLT3, JAK2, KIT, KRAS, NF1, NRAS, PTPN11
The AML was characterized as de novo in 58% (n=35), therapy-related in 7% (n=4), and secondary to antecedent hematologic disorder in 35% (n=21); including n=15 patients with prior MDS and n=6 patients with prior MPN. 17 of the 21 patients with secondary AML arising from MDS or MPN had received prior therapy and were considered treated secondary AML (tsAML), representing 28% of the entire AML cohort.
By ELN 2022, 78% (n=47) patients were considered adverse risk, primarily related to MDS-associated mutations. By ELN 2024, 7% (n=4) patients were considered adverse risk due to concurrent TP53 mutation, 22% (n=13) intermediate due to concurrent signaling mutations including FLT3-ITD, NRAS or KRAS, and the remaining 72% (n=43) were favorable risk. NPM1 mutations were present in 22% (n=13) patients. Full genomic mutational profiles are depicted in Supplemental Figure 1.
Responses were assessed within the first 5 cycles of study treatment and included a CRc rate of 92% (n=55) and ORR of 95% (n=57) (Table 2; Supplemental Figure 2). Median time to first and best response were 27 days and 61 days, respectively. Median number of cycles to best response was 2 (range 1–5). Patients with IDH1-mutated AML had CRc rate of 86%, with 81% attaining MRD negative disease, and patients with IDH2-mutated AML had CRc rate of 100%, with 95% attaining MRD negative disease status. CRc was 100% in all 4 cases of therapy-related AML. Responses in patients having received prior therapy for an antecedent hematologic malignancy (i.e. tsAML) were lower, with CRc of 71%, compared to a CRc rate of 98% in enrolled patients without tsAML. Only one patient (TP53-mutated) had received prior venetoclax for a previous MDS diagnosis; this patient did not respond.
Table 2.
Clinical Outcomes of the Frontline Cohort1
| All (n=60) | Non-tsAML (n=43) | tsAML (n=17) | IDH1mut (n=37) | IDH2mut (n=23) | |
|---|---|---|---|---|---|
| 2-year OS | 69 (57 – 83) | 84 (73 – 97) | 34 (16 – 71) | 72 (57 – 90) | 67 (49 – 91) |
| 2-year EFS | 67 (56 – 81) | 79 (66 – 93) | 34 (21 – 73) | 72 (58 – 88) | 62 (44 – 87) |
| 2-year CIR2 | 24 (6 – 39) | 20 (0 – 36) | 38 (0 – 65) | 26 (0 – 46) | 22 (0 – 43) |
| 30-day mortality | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| 60-day mortality | 1 (2) | 0 (0) | 1 (6) | 0 (0) | 1 (4) |
| CRc3 | 55 (92) | 42 (98) | 13 (71) | 32 (86) | 23 (100) |
| ORR | 57 (95) | 43 (100) | 14 (82) | 34 (92) | 23 (100) |
| MRD negativity | 45 (87) | 35 (88) | 10 (83) | 25 (81) | 20 (95) |
% (95% CI); n(%)
Censored at SCT
Within 5 cycles of treatment
By multiparameter flow cytometry at best response, sensitivity 10−4 (excluding inadequate samples or unknown)
Early mortality was reassuringly low; with 2% (n=1) 60-day mortality and no 30-day mortality (Table 2). With a median follow up time of 27.4 months, median OS has not been reached (Supplemental Figure 3). 2-year OS was 69% and 2-year EFS was 67%, with a 2-year CIR of 24% (Table 2). Survival outcomes in IDH1 and IDH2 mutated patients were similar, with 2-yr OS of 72% in IDH1-mutated and 67% in IDH2-mutated AML (Figure 1), although direct comparisons between IDH1 and IDH2-mutated patients are limited given the relatively small and heterogenous cohorts. Outcomes were inferior in patients with tsAML, with a 2-yr OS of 34%, whereas patients without tsAML experienced a 2-yr OS of 84%, with 2-yr CIR of 20% (Figure 2). Overall survival was not significantly different when evaluated by age (2-yr OS 83% vs 71% for age < 70 and age ≥ 70, respectively), or whether the patient received SCT (Supplemental Figure 4), although follow-up will be required to determine whether outcomes will remain comparable over time. Patients who transitioned to SCT were on average younger (median age 68 vs 74, p=0.001) but otherwise there were no other significant differences in baseline characteristics (Supplemental Table 2). Patients with positive MRD by flow at best response trended towards worse OS and EFS (Supplemental Figure 5), although this was not statistically different, likely given the small numbers of patients with residual positive MRD. A landmark analysis performed at the median time to SCT (4.2 months, range 2.7–8.8 months) in NPM1-wildtype AML demonstrated a 2-yr OS of 77% vs 69% in those who did and did not proceed to SCT (Supplemental Figure 6).
Figure 1. Survival Outcomes with IDH inhibitor triplets in newly diagnosed IDH1 and IDH2 mutant AML.
Survival outcomes were calculated using the Kaplan Meier method for patients with IDH1 mutant AML (blue) and IDH2 mutant AML (yellow). Censored events are marked. For the four patients with both IDH1 and IDH2 mutations, they were categorized by which targeted inhibitor they received. (A) Overall survival (OS). (B) Event free survival (EFS) with events defined as non-response, relapse, or death. (C) Cumulative incident of relapse (CIR) censored at stem cell transplant or death of other causes.
Figure 2. Patients with tsAML experience worse outcomes.
Survival outcomes were calculated using the Kaplan Meier method for patients with tsAML (red) and non-tsAML (blue). Censored events are shown. (A) Overall survival (OS). (B) Event free survival (EFS) with events defined as non-response, relapse, or death. (C) Cumulative incident of relapse (CIR) censored at stem cell transplant or death of other causes.
Patients received a median of 5 cycles of therapy (range 1–52) and 51% (n=21) of patients who did not undergo SCT remain on study (Supplemental Table 3). Reasons for treatment discontinuation included SCT (49%), relapse (23%), patient choice (10%), lack of response (8%), or death (5%). For patients that did not transition to SCT, the median number of cycles received was 8 (range 1–52). The median duration of cycle 1 was 39 days (range 27–79), with median ANC recovery (> 500 cells/μL) by day 34 and platelet recovery (>50K/μL) by day 20. Once in remission, red cell or platelet transfusions were infrequent (16% required red cell transfusions, 12% platelet transfusions in subsequent remission cycles). Venetoclax and HMA therapy duration were often attenuated once in remission at the discretion of the treating physician and principal investigator, often in the setting of MRD negative remission and/or delayed count recovery or adverse events with previous cycles (Supplemental Table 4). In cycle 3, the median days of venetoclax received was 7 (IQR 7–14) with 4 days of DEC-C (IQR 3–5) or 7 days of AZA (IQR 7–7). By cycle 6+, the HMA was on average administered for 3 days with DEC-C (IQR 3–5) or 5 days of AZA (IQR 5–7) with 7 days of venetoclax (IQR 5–7). The IDH inhibitor was always given continuously and only stopped for side effects in rare circumstances. The median cycle duration remained 5 weeks for subsequent “maintenance” cycles (Supplemental Table 4).
Non-hematologic adverse events (AEs) were common, occurring in 77% of patients with 43% of events grade ≥ 3 (Table 3). Infectious AEs were most common, occurring in 42% of patients (37% grade ≥ 3) (Supplemental Table 5). Other common non-hematologic AEs included hyperbilirubinemia (27%, 5% grade ≥ 3, primarily in ENA-treated patients due to UGT1A1 metabolism), diarrhea (20%, 2% grade ≥ 3), transaminitis (15%, 2% grade ≥ 3), and acute kidney injury, constipation, and nausea (13% each, all grade 1–2). Differentiation syndrome was reported in 5% of patients (3% grade ≥ 3), QTC prolongation in 3% (2% grade ≥ 3), and one event of grade 3 TLS occurred (2%).
Table 3.
Non-Hematologic Adverse Events
| Event1 | All Grades n (%) | Grade ≥3 n (%) |
|---|---|---|
| All | 46 (77) | 26 (43) |
| Infectious | 25 (42) | 22 (37) |
| All (non-infectious) | 36 (60) | 12 (20) |
| Hyperbilirubinemia | 16 (27) | 3 (5) |
| Diarrhea | 12 (20) | 1 (2) |
| Transaminitis | 9 (15) | 1 (2) |
| Acute kidney injury | 8 (13) | 0 (0) |
| Constipation | 8 (13) | 0 (0) |
| Nausea | 8 (13) | 0 (0) |
| Vomiting | 5 (8) | 1 (2) |
| Hypokalemia | 4 (7) | 0 (0) |
| Differentiation syndrome | 3 (5) | 2 (3) |
| Fatigue | 3 (5) | 0 (0) |
| Cough | 2 (3) | 0 (0) |
| Hyperphosphatemia | 2 (3) | 1 (2) |
| Hyperuricemia | 2 (3) | 0 (0) |
| QTc prolongation | 2 (3) | 1 (2) |
| Abdominal pain | 1 (2) | 1 (2) |
| Alopecia | 1 (2) | 0 (0) |
| Arthralgias | 1 (2) | 0 (0) |
| Hypomagnesemia | 1 (2) | 0 (0) |
| Hypocalcemia | 1 (2) | 0 (0) |
| Rash | 1 (2) | 0 (0) |
| Tumor lysis syndrome | 1 (2) | 1 (2) |
At least possibly related while on protocol
Outcomes for key genomic subsets were evaluated with a focus on NPM1, K/NRAS, and TP53 mutated patients (Supplemental Figure 7). There was no difference in OS, EFS, or DOR for patients based on the presence or absence of NPM1 or K/NRAS mutations. Patients (n=4) with TP53 mutations had inferior overall outcomes. While CRc occurred in 3 of 4, relapse was universal with mDOR of 10.9 months and OS of only 2.2, 9.1, 10.9, and 15.2 months.
10 patients relapsed after achieving an initial response on study, with all patients undergoing repeat mutational assessment within one month of documented relapse (Figure 3). Of the n=6 IDH1 relapses, only one patient had a remaining IDH1 mutation at relapse; 5 were no longer detectable at a VAF of ≥ 2%. Of the n=4 IDH2 relapses, 2 patients had persistently detected IDH2 at relapse. None of the four IDH1 and IDH2 dual mutated patients relapsed on triplet therapy, and none of the three patients with repeat NGS panels in remission had persistent IDH1 or IDH2 mutations detected. There was no clear mutational pattern associated with resistance; emerging mutations included 2 patients with a new RUNX1 mutation detected, 1 patient with a new FLT3-ITD, and 1 patient with a new KRAS mutation. No new IDH mutations were detected at relapse, and 4 patients had no new emerging mutations detected at time of relapse.
Figure 3. Mutational landscape at relapse.
Mutations were assessed by an in house 81-gene next generation sequencing (NGS) panel (limit of detection: 2% variant allele frequency (VAF)) at baseline and at relapse. The oncoprint displays mutations in the 10 patients that relapsed based on if they were cleared (purple), persistent (blue), or emergent (yellow) from baseline to relapse.
Discussion:
In this largest report to date on patients with newly diagnosed, IC-ineligible IDH1 and IDH2-mutant AML treated with “triplet” trials incorporating a hypomethylating agent, venetoclax, and IDH-inhibitor, we confirm excellent clinical outcomes, with an expected and well-tolerated safety profile. The CRc rate among all enrolled patients was 92%, with 87% of responding patients attaining MRD negative status by flow cytometry. Furthermore, responses were durable, with a 2-yr cumulative incidence of relapse of only 24%, and 2-yr overall survival of 72% (IDH1) and 67% (IDH2), with a median OS that has not yet been reached. These results compare favorably to the responses seen with both approved doublet regimens for IDH1-mutated AML, with AZA+VEN resulting in a CRc of 67% in the VIALE-A trial and AZA+IVO providing a CRc of 53% in the AGILE trial.8,14 We identified two subgroups with inferior outcomes: patients with tsAML and/or TP53 co-mutated AML. Notably however, despite the inferior outcomes compared to the de novo IDH-mutated AML patients in this analysis, it is important to recognize that the IDH-mutated tsAML patients fared quite well compared to tsAML expectations, for instance a large recent analysis of tsAML outcomes reported a CRc rate of 26% and mOS of only 5 months.18 Patients with tsAML were excluded from both the pivotal VIALE-A and AGILE trials and so experience of IDH-mutated tsAML patients was previously limited.
The safety profile of the IDH-inhibitor triplet regimens was consistent with expectations of an HMA + venetoclax doublet regimen, with no new safety signals identified. For instance, cycle durations over the first 3 cycles lasted an average of 35–39 days, similar to HMA + venetoclax doublets, and infectious complications were the most common AEs (occurring in 42% of patients).10 Despite the recognized myelosuppression and myelosuppressive-related complications with HMA + venetoclax based regimens, early mortality with IDH-triplet therapy was very low. Importantly, IDHi-related AEs such as differentiation syndrome were less frequent than what is reported with IDHi monotherapy, which is likely explained by the concurrent HMA+VEN regimen preventing unconstrained differentiation.19,20 The largely well-tolerated nature of this treatment is also reflected in the fact that ~50% of patients remain on study therapy at the time of data cut, with some patients remaining on protocol treatment for over 5 years.
In these studies, attenuated “maintenance” cycles were often administered after a deep remission was obtained, to minimize periods of cytopenias and to improve long-term tolerability. The average patient on study after cycle 6 received 3 days of DEC-C or 5 days of AZA, 7 days of venetoclax, and continuous IVO or ENA, with cycles administered every 35 days, and often with GCSF support.
While these two trials were not designed for direct comparisons, there were notably no significant differences in outcomes between the parental AZA triplet and the all-oral DEC-C triplet. A “total oral” frontline regimen for IDH-mutant AML may be particularly appealing, as patients typically experience significant burden from frequent appointments related to infusions or injections.
Mechanisms of relapse were varied and included emergence of signaling mutations in a minority of patients (i.e. KRAS, FLT3-ITD), and emergence of RUNX1 mutations in two patients. Of substantial importance, 50% of the IDH2 mutated relapses and 83% of the IDH1 mutated relapses no longer had evidence of the IDH clone at relapse (at VAF cutoff of 2%), suggesting deep suppression or possibly extinction of the IDH-clone with IDH-triplet therapy in many patients. Furthermore, no emergent IDH mutations or IDH isoform switching was identified at relapse. More detailed analyses of relapse samples and clonal trajectories with single-cell sequencing approaches are ongoing.
In summary, these data demonstrate excellent outcomes of IDH-triplet therapy in the treatment of newly diagnosed, IC-ineligible IDH-mutant AML. Enrollment on these trials are ongoing (NCT03471260 and NCT04774393), with expansion to additional clinical sites to augment enrollment and confirm generalizability among academic settings. Prospective studies comparing IDH-triplet versus doublet regimens are warranted.
Supplementary Material
Context Summary:
Key Objective
To evaluate the efficacy of frontline “triplet” regimens for patients with isocitrate dehydrogenase (IDH) mutated acute myeloid leukemia (AML) ineligible for intensive chemotherapy as part of two ongoing clinical trials.
Knowledge Generated
Treatment with a triplet regimen containing a hypomethylating agent (HMA), venetoclax, and either ivosidenib or enasidenib resulted in a composite complete remission rate of 92% with a median overall survival that has not been reached.
Relevance (written by Charles Craddock):
Novel triplets incorporating venetoclax, a HMA and an IDH-inhibitor-either ivosidenib or enasidenib- are well tolerated and result in notable response rates in patients with newly diagnosed IDH mutated AML. Planned randomized trials will be important in order to determine the ability of these novel combinations to improve patient outcomes in IDH-1 and IDH-2 mutated AML.
Funding Statement:
This research is supported in part by the MD Anderson Cancer Center Leukemia Support Grant (CA100632).
CDD is funded by the Leukemia and Lymphoma Society, Grant/Award Number: AWD00006066; V Foundation Lloyd Family Clinical Scholar Award, Grant/Award Number: D2018 – 013. JMP is supported by a T32 Training Grant (CA009666).
Footnotes
Previous Publication: This earlier version of the data presented in this manuscript was previously presented as a poster presentation at the 2024 Annual Meeting of the American Society of Hematology (ASH).
Data sharing:
The study data is not publicly available to respect participant confidentiality. Requests for sharing of deidentified data should be directed to the corresponding author.
References:
- 1.Kantarjian H et al. Current status and research directions in acute myeloid leukemia. Blood Cancer J 14, 163 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.DiNardo CD, Erba HP, Freeman SD & Wei AH Acute myeloid leukaemia. The Lancet vol. 401 2073–2086 Preprint at 10.1016/S0140-6736(23)00108-3 (2023). [DOI] [PubMed] [Google Scholar]
- 3.Bataller A et al. Targetable genetic abnormalities in patients with acute myeloblastic leukemia across age groups. American Journal of Hematology vol. 99 Preprint at 10.1002/ajh.27236 (2024). [DOI] [PubMed] [Google Scholar]
- 4.Patel KP et al. Acute myeloid leukemia with IDH1 or IDH2 mutation: Frequency and clinicopathologic features. Am J Clin Pathol 135, (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Stein EM et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130, (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.DiNardo CD et al. Durable Remissions with Ivosidenib in IDH1 -Mutated Relapsed or Refractory AML. New England Journal of Medicine 378, (2018). [DOI] [PubMed] [Google Scholar]
- 7.de Botton S et al. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. Blood Adv 7, (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Montesinos P et al. Ivosidenib and Azacitidine in IDH1 -Mutated Acute Myeloid Leukemia. New England Journal of Medicine 386, (2022). [DOI] [PubMed] [Google Scholar]
- 9.De Botton S et al. Updated efficacy and safety data from the AGILE study in patients with newly diagnosed acute myeloid leukemia treated with ivosidenib + azacitidine compared to placebo + azacitidine. Journal of Clinical Oncology 41, (2023). [Google Scholar]
- 10.DiNardo CD et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. New England Journal of Medicine 383, (2020). [DOI] [PubMed] [Google Scholar]
- 11.Pratz KW et al. Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia. Am J Hematol 99, (2024). [DOI] [PubMed] [Google Scholar]
- 12.DiNardo CD et al. Outcomes of patients with IDH1-mutant relapsed or refractory acute myeloid leukemia receiving ivosidenib who proceeded to hematopoietic stem cell transplant. Leukemia 35, (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Wang F et al. Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia. Nat Commun 12, 2607 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Pollyea DA et al. Impact of Venetoclax and Azacitidine in Treatment-Naïve Patients with Acute Myeloid Leukemia and IDH1/2 Mutations. Clinical Cancer Research 28, (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Gruber E et al. Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells. Cell Rep 40, (2022). [DOI] [PubMed] [Google Scholar]
- 16.Cathelin S et al. Enasidenib-induced differentiation promotes sensitivity to venetoclax in IDH2-mutated acute myeloid leukemia. Leukemia 36, (2022). [DOI] [PubMed] [Google Scholar]
- 17.Lachowiez CA et al. A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies. Blood Cancer Discov 4, (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Senapati J et al. Outcomes of Patients With Treated Secondary Acute Myeloid Leukemia: A High-Risk Subtype That Warrants an Independent Prognostic Designation. Am J Hematol 100, 249–259 (2025). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Montesinos P et al. Differentiation syndrome associated with treatment with IDH2 inhibitor enasidenib: pooled analysis from clinical trials. Blood Adv 8, 2509–2519 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Issa GC, Stein EM & DiNardo CDD How I Treat: Differentiation Therapy in Acute Myeloid Leukemia. Blood blood.2024024008 (2024) doi: 10.1182/blood.2024024008. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The study data is not publicly available to respect participant confidentiality. Requests for sharing of deidentified data should be directed to the corresponding author.