IDH2 mutation is associated with favorable outcome among older adults with newly diagnosed acute myeloid leukemia treated with hypomethylating agent-based therapy

Abstract

Mutations of isocitrate dehydrogenase (IDH) are recurrent in newly diagnosed acute myeloid leukemia (AML) and their prevalence increases with age. The prognostic impact of IDH mutations in AML remains controversial. IDH inhibitors generally have a favorable side-effect profile, making them an attractive option for older patients. This retrospective analysis aimed to describe the prevalence and prognostic impact of IDH mutations in a large cohort of newly diagnosed AML patients aged ≥60 years enrolled in the Beat AML clinical trial. A total of 1,023 patients were included. IDH mutations were detected in 28% of patients, including 9.7% with IDH1mut, 18.9% with IDH2mut, and 1.0% with mutations in both IDH1 and IDH2. IDH mutations frequently co-occurred with DNMT3A (38%), NPM1 (35%), and SRSF2 (34%) mutations. In patients treated with intensive chemotherapy, IDH mutations were not prognostic for overall survival (OS) (P=0.76), while OS was longer for patients with IDH2mut compared to IDHwt in patients treated with hypomethylating agent (HMA)-based therapy (median OS, 18.5 vs. 10.2 months, P<0.001). IDH1 was not significant for outcome. IDH2 remained prognostic for OS after exclusion of patients receiving an IDH inhibitor (hazard ratio=0.60, 95% confidence interval: 0.41-0.89). Outcomes with TP53 or myelodysplasia-related gene mutations were also better with an IDH co-mutation (P=0.043, and P=0.006, respectively). In patients treated with HMA plus venetoclax (N=243), IDHmut was not prognostic (P=0.42). The high prevalence of IDHmut and favorable impact in patients treated with HMA-based therapy supports studies investigating the addition of targeted therapies to HMA-based regimens for older patients with IDH-mutant AML; mut: mutated; wt: wild-type.

Introduction

Alterations in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of acute myeloid leukemia (AML).¹ Isocitrate dehydrogenase (IDH) is involved in cellular metabolism, histone demethylation, and DNA modification.^2,3 IDH1 and IDH2 are homodimeric nicotinamide adenine dinucleotide phosphate (NADP)-dependent enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate in the cytoplasm and mitochondria, respectively.⁴ The vast majority of IDH1 mutations in AML occur at arginine 132 (R132), while IDH2 mutations typically occur at arginine 140 (R140) or arginine 172 (R172).⁵ These mutations occur within the conserved, active site of the enzyme, resulting in a partially reversed reaction that reduces α-ketoglutarate to 2-hydroxyglutarate. Accumulation of the oncometabolite 2-hydroxyglutarate interferes with α-ketoglutarate-dependent enzymes such as Tet methylcytosine dioxygenase 2 (TET2)-dependent DNA hydroxymethylation, histone demethylation and hypoxia-inducible factor-1α activation leading to impaired hematopoietic differentiation and enhanced proliferation.^3,6-8

IDH mutations were first identified in AML in 2008 and have since been found to be among the most common recurrently mutated genes in AML.⁹ The prognostic impact of IDH1 and IDH2 mutations remains controversial, and may be influenced by cytogenetic context (i.e., normal karyotype) and the presence of other molecular abnormalities (i.e., NPM1, FLT3-ITD) in patients treated with intensive chemotherapy.^10-13 In patients receiving lower-intensity treatment, recent studies have reported particularly favorable outcomes with incorporation of venetoclax-based therapies for patients with IDH1 and IDH2 mutations.¹⁴

IDH inhibitors are small molecules that bind within the IDH enzymatic active site blocking aberrant 2-hydroxyglutarate production and inducing myeloid differentiation and enhanced proliferation.¹⁵ Although they can lead to differentiation syndrome, they generally have a favorable side-effect profile, making them an attractive option, particularly for older patients. While IDH mutations are known to occur more frequently in older AML patients, only a few studies have reported on the prevalence of IDH mutations in patients 60 years or older. We aimed to describe the incidence and prognostic impact of IDH mutations in patients with newly diagnosed AML aged 60 years or older in a large cohort of AML patients treated on the Beat AML clinical trial.

Methods

Study cohort

Eligible patients were adults aged 60 years or older with newly diagnosed AML who met the screening criteria for enrollment in the Beat AML trial (NCT03013998) and provided consent before 10 May, 2023.¹⁶ Informed consent was obtained in accordance with the Declaration of Helsinki. The study was approved by institutional review boards. Details of treatments received are provided in Online Supplementary Table S1.

Details of genomic analysis have been reported previously.¹⁶ Cytogenetic analysis from diagnostic assessment was centrally reviewed and reported in accordance with the International System for Human Cytogenomic Nomenclature.¹⁷ Complex karyotype was defined by the presence of ≥3 unrelated chromosome abnormalities. Normal karyotype was defined by the detection of no chromosome abnormalities in a minimum of at least 20 metaphases analyzed. Cytogenetics were centrally reviewed (NH). IDH molecular testing was performed by next-generation sequencing using FoundationOne Heme (Foundation Medicine).¹⁸ A mutation was considered present at any detectable variant allele frequency.

Statistical analysis

The patients’ characteristics are summarized using the median (range) for continuous variables and frequency (percentage) for categorial variables. The Student t test or Wilcoxon rank sum test and χ² or Fisher exact test were used to compare continuous or categorial variables, respectively. Statistical significance was defined by a P<0.05. Patients with an IDH mutation outside the active site (N=11) were excluded from the outcome analysis. Patients with active site mutations in both IDH1 and IDH2 (N=6) were included in analyses that evaluated the impact of IDH^mut on outcome but were excluded from sub-analyses for IDH1 or IDH2. Patients with a mutation in both an active site of one and an inactive site in the other were assigned based on their mutation in the active site. As an example, a patient with mutated IDH1-R132C and IDH2-V406L was assigned to IDH1. Overall survival (OS) was estimated using the Kaplan-Meier method from the date of trial inclusion until death. OS was censored for date of allogeneic hematopoietic stem cell transplantation (HSCT) or last follow-up. Group differences were calculated using the log-rank test. Cox proportional hazard models were used to describe the relative risk of each variable on death over time from the date of trial inclusion. Statistical analyses were conducted in RStudio, version 4.2.3.

Results

Patients’ characteristics and prevalence of IDH mutations

We identified a total of 1,023 patients with newly diagnosed AML who were 60 years or older at the date of trial inclusion. Patients had a median age of 72 (range, 60-92) years. The majority were non-Hispanic White (82%), and 42% were female (Table 1). There were 282 (28%) patients identified with an IDH mutation. Ninety-nine (9.7%) patients had IDH1-mutated (IDH1^mut) AML, with nearly all IDH1 mutations at the active site, IDH1-R132 (N=90/99, 91%), including R132C (N=46), R132H (N=33), R132G (N=6), and R132S (N=5). The remaining nine mutations were outside the active sites at A353D (N=1), D38N (N=1), D220G (N=1), F32V (N=2), F355S (N=1), M318T (N=1), and V294M (N=2). There were 193 (19%) IDH2 mutations identified with nearly all being point mutations at active sites, including IDH2-R140 (N=144 [75%]: R140W [N=6], R140Q [N=136], R140L [N=2]) or IDH2-R172 (N=43 [22%]: R172K [N=43]).

The remaining six IDH2 mutations were at inactive residues: A22V, D225N, E429K, I98T, V406L, Y179D. Six patients had mutations in the active sites of both IDH1 and IDH2, and four patients had a mutation in the active site of IDH1 (N=2) or IDH2 (N=2) as well as a mutation in the inactive site of the other.

The prevalence of IDH mutations was fairly stable among patients 60 years and older according to age groups (Figure 1A). A significantly greater proportion of patients with IDH^mut were female, compared to patients with wildtype IDH (IDH^wt) (48% vs. 40%, P=0.045), and were classified as favorable risk by 2022 European LeukemiaNet criteria (24% vs. 12%, P<0.001) (Table 1).

IDH associated with mutations and cytogenetics

The most commonly co-occurring mutations with IDH^mut compared to IDH^wt were DNMT3A (38% vs. 20%, P<0.001), NPM1 (35% vs. 14%, P<0.001), and SRSF2 (34% vs. 17%, P<0.001) (Figure 1B). Genes that were observed in IDH^wt compared to IDH^mut included TP53 (31% vs. 10%, respectively, P<0.001) and TET2 (28% vs. 11%, respectively, P<0.001). ASXL1, KRAS, NRAS, WT1, RUNX1 and FLT3 were all not statistically associated with IDH mutations.

Table 1.Baseline characteristics of the study patients (N=1,023).

IDH^mut was more frequently associated with a normal karyotype compared to IDH^wt (41% vs. 26%, P<0.001), while complex karyotype (34% in IDH^wt vs. 11% in IDH^mut, P<0.001) and core-binding factor (CBF) (4% IDH^wt vs. 0.7% in IDH^mut, P=0.035) cytogenetic abnormalities were significantly more commonly detected in patients with IDH^wt (Figure 1B). Only one patient with CBF-AML had an active site IDH2 mutation, a second patient had a non-pathogenic mutation, IDH2-A22V.

Figure 1.IDH mutations in older patients with acute myeloid leukemia. (A) The prevalence of IDH mutations in acute myeloid leukemia according to age. (B) Co-occurring mutations and karyotypes in patients with mutated IDH (IDH^mut) (red) and wild-type IDH (IDH^wt) (blue). Significant associations with P<0.05 are denoted with an asterisk (*).

IDH mutations and clinical outcome

A total of 1,002/1,023 (98.0%) patients were eligible for outcome analysis; ineligibility was due to lack of follow-up data (N=10) or an IDH mutation outside the active site (N=11). Of the 1,002 patients, 187 were treated with intensive chemotherapy, 705 were treated with lower-intensity therapy and 96 patients received supportive care or therapy regimen was unknown (N=14). Ninety-eight patients were treated with an IDH inhibitor (ivosidenib [N=24] or enasidenib [N=74]). One hundred forty-six (14.6%) patients proceeded with allogeneic HSCT. A summary of the various treatment regimens is shown in Online Supplementary Table S1.

Among patients treated with intensive chemotherapy, IDH^mut patients (N=50) and IDH^wt patients (N=137) had a similar median OS of 23.5 and 22.4 months, respectively (P=0.76) with a hazard ratio (HR) of death of 1.09 (95% confidence interval 95% CI:]: 0.64-1.83) (Online Supplementary Figure S1A, Online Supplementary Table S2). Analysis by type of IDH mutation did not show a difference between IDH1^mut versus IDH2^mut compared to IDH^wt (Figure 2A, Online Supplementary Table S2). One patient was excluded from the analysis due to the presence of active site mutations in both IDH1 and IDH2. Seventy (37%) patients treated with intensive chemotherapy proceeded with allogeneic HSCT. When comparing IDH^mut patients (N=195) to IDH^wt patients (N=510) among those treated with any lower-intensity therapy regimen (N=705), IDH^mut was statistically associated with a higher survival probability compared to IDH^wt (HR=0.63, 95% CI: 0.51-0.78), with a median OS of 15.6 versus 10.2 months (P<0.001) for IDH^mut and IDH^wt, respectively (Online Supplementary Figure S1B). The prognostic impact was mainly driven by IDH2 (N=133) compared to IDH^wt (HR=0.56, 95% CI: 0.44-0.72), whereas IDH1^mut (N=58) was not significantly prognostic (HR=0.84, 95% CI: 0.60-1.18) (Online Supplementary Table S3). Given that most patients treated with lower-intensity therapy received a hypomethylating agent (HMA)-based regimen (N=666/705, 94.5%), we then performed a similar analysis restricted to patients treated with HMA-based therapy. Survival analysis showed a median OS of 16.7 versus 10.2 months (P<0.001) for IDH^mut (N=179) versus IDH^wt (N=487), respectively (Online Supplementary Figure S1C). Analysis by IDH subtypes showed that IDH2^mut was associated with a hazard ratio of 0.55 (95% CI: 0.43-0.72) for death compared to IDH^wt, irrespective of IDH2 mutation subtype (Table 2), with a median OS of 18.5 versus 10.2 months for IDH2^mut versus IDH^wt, respectively (Figure 2B). IDH1^mut was not significant for survival outcome. Seventy patients (10.5%) treated with HMA-based therapy received allogeneic HSCT; IDH1^mut (N=9), IDH2^mut (N=17), IDH^wt (N=44). IDH^mut was a favorable prognostic factor among the patients receiving a HSCT (P=0.043); numbers were too small to evaluate the impact of IDH1^mut or IDH2^mut.

After exclusion of patients also receiving a IDH inhibitor as part of their treatment regimen (N=84), IDH2 (N=57) remained favorably associated with outcome (HR=0.60, 95% CI: 0.41-0.89) compared to IDH^wt. In patients treated with HMA in combination with venetoclax (N=243), OS was similar for IDH^mut and IDH^wt patients (P=0.42), irrespective of whether the mutation was in IDH1 or IDH2.

Survival in patients with IDH mutations and karyotype abnormalities

IDH mutations frequently co-occur with normal karyotype and less frequently with a complex karyotype.^19,20 When we analyzed IDH mutations in patients with cytogenetically normal AML (N=203), IDH^mut was associated with a longer OS (median OS 21.1 vs. 15.8 months, P=0.035) compared to IDH^wt among those receiving HMA-based therapy (IDH1: HR=0.78, 95% CI: 0.43-1.40; IDH2: HR=0.65, 95% CI: 0.42-1.00). No significant prognostic impact of IDH was found in patients receiving intensive chemotherapy (N=90). In patients with complex cytogenetics (N=209), IDH^mut (N=23) was associated with a superior OS compared to IDH^wt (N=186) (median OS 10.9 vs. 6.9 months, P=0.05). Numbers were too small to investigate the effect of IDH in CBF-AML or KMT2A-rearranged AML.

Figure 2.Kaplan-Meier survival analysis for overall survival stratified by IDH mutation. (A, B) Overall survival analysis in patients treated with intensive chemotherapy (A) and hypomethylating agent-based therapy (B). Patients with a mutation in both IDH1 and IDH2 were excluded from the analysis. mut: mutated; wt: wild-type.

Clinical impact of IDH in combination with NPM1, TP53 or myelodysplasia-related gene mutations

With 35% of patients having a co-occurring NPM1 mutation, previous studies have shown that IDH mutations with NPM1-mutant and FLT3-ITD-negative molecular status have been associated with particularly favorable outcomes, while others showed worse outcomes in subsets of patients with NPM1- and IDH-mutated AML.^11,21 We, therefore, analyzed whether the favorable outcome associated with IDH in patients receiving HMA-based therapy further improved in the presence of a NPM1 mutation in FLT3-ITD-negative AML. IDH^mut (N=47) did not prolong OS compared to IDH^mut (N=27) in patients with NPM1-mutant and FLT3-ITD-negative AML (HR=0.82, 95% CI: 0.44-1.56) (Table 2).

OS for patients with TP53-mutant AML treated with HMA-based therapy improved when co-mutated with IDH, with a median OS of 10.2 versus 6.9 months for IDH^mut (N=20) and IDH^wt (N=167) patients, respectively (P=0.043) (Online Supplementary Figure S2A). Among these 20 TP53-mutant AML patients with an IDH mutation, nine were treated with an IDH inhibitor, with a trend towards longer OS time for patients treated with an IDH inhibitor (P=0.058) (Online Supplementary Figure S2B).

Like TP53 mutations, myelodysplasia-related mutations, including ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2, are common in older patients with AML and are associated with dismal outcomes. When co-mutated with IDH (N=116), the median OS improved compared to that of patients with myelodysplasia related-gene mutations and wild-type IDH (N=267) from 10.6 months to 16.7 months in patients treated with HMA-based therapy (P=0.006) (Online Supplementary Figure S2C). The effect was mostly driven by IDH2 (HR=0.64, 95% CI: 0.47-0.88). Half of the patients (N=58/116) were treated with an IDH inhibitor, which resulted in an improved median OS compared to that of patients who did not receive treatment with an IDH inhibitor (median OS 17.6 vs. 14.1 months, P=0.029) (Online Supplementary Figure S2D).

Discussion

In this study we present a large, retrospective analysis of more than 1,000 patients 60 years and older with newly diagnosed AML enrolled in the Beat AML clinical trial (NCT03013998) describing the incidence and prognostic impact of IDH mutations. IDH mutations were found in 28% of patients overall and in 36% of patients with a normal karyotype, with IDH2 mutations occurring in 19% of patients and accounting for approximately two-thirds of the IDH mutations. This is concordant with other cohorts focused on older patients with AML reporting IDH mutations in 21% to 28% of patients.^22-25 We observed a significantly favorable prognostic association between IDH2 mutations and survival in patients treated with HMA-based therapy.

The impact of IDH mutations on outcome has been studied extensively in the setting of intensive treatment and remains controversial.^12,13,26-29 In contrast, the importance of IDH mutations for outcome in patients treated with lower-intensity therapies has been studied much less.^30,31 IDH1 and IDH2 mutations are associated with older age at presentation and patients are often ineligible for intensive therapy due to poor performance status or co-morbidities. Instead, most older patients are offered epigenetic/lower-intensity treatments, making evaluation of the prognostic impact of IDH mutations in this group relevant.

Table 2.Univariate analysis for IDH-mutated patients treated with hypomethylating agent-based therapy (N=666).^†

For patients with untreated newly diagnosed IDH-mutated AML who are ineligible for intensive chemotherapy, the phase III randomized VIALE-A clinical trial performed a subgroup analysis showing superior OS with azacitidine+venetoclax versus azacitidine alone with a median OS of 19.9 months versus 6.2 months (P<0.001), and 35% of the responders who survived ≥2 years had an IDH mutation.^23,32 The phase III AGILE clinical trial evaluated ivosidenib in combination with azacitidine in a relatively similar cohort of patients with IDH1-mutated newly diagnosed AML who were ineligible for intensive chemotherapy, showing significant clinical benefit of the addition of ivosidenib as compared with azacitidine alone.³³ After a median follow-up of 15.1 months, the median OS was 24.0 months compared to 7.9 months. Both trials showed most benefit for patients 75 years and older. The phase II/Ib Beat AML substudy applied a risk-adapted approach to assess the efficacy of enasidenib monotherapy for patients 60 years of age or older with newly diagnosed AML in whom genomic profiling demonstrated that mutant IDH2 was the dominant leukemia clone.³⁴ The study showed an overall response rate of 46%, demonstrating the efficacy of enasidenib monotherapy in upfront treatment of IDH2^mut AML. For patients with relapsed/refractory IDH1^mut AML, olutasidenib has shown efficacy in combination with azacitidine with overall response rates exceeding 50%,^35,36 and enasidenib showed meaningful improved event-free survival and overall response rates as compared to conventional care regimens in relapsed/refractory IDH2^mut AML, but did not improve OS with a median OS of 6.5 versus 6.2 months (P=0.23).³⁷

In addition to the observation that an IDH2 mutation was a favorable prognostic indicator in patients treated with HMA-based therapy overall, IDH2^mut remained prognostic in normal karyotype AML, and IDH^mut did not abrogate the favorable prognostic impact of patients with NPM1-mutant FLT3-ITD wild-type AML. Among patients with TP53-mutant AML and AML with myelodysplasia-related gene mutations, which are both associated with extremely poor outcomes, IDH^mut was associated with prolonged OS, particularly in subsets of patients receiving an IDH inhibitor. It is unclear why, in our cohort, IDH2^mut AML did not show favorable survival in patients treated with venetoclax, as IDH mutations generally show high sensitivity to venetoclax therapy.³⁸ We did not find a high frequency of co-occurring mutations in TP53 or kinase pathway genes, which have been linked to inferior responses to venetoclax.

The discovery of targetable mutations has expanded the therapeutic landscape of AML, particularly of IDH^mut AML. While IDH inhibitors can lead to differentiation syndrome, they generally have a favorable side-effect profile, making them an attractive option for older patients either alone or in combination with HMA-based therapy. Combinations of HMA and IDH inhibitors have shown encouraging results in frontline older AML patients with the combination an HMA and venetoclax being particularly effective in IDH^mut AML, and ivosidenib may be preferred over venetoclax in IDH1^mut AML. The major limitations of our study are its retrospective design, the relatively small number of patients treated with HMA with venetoclax as a significant proportion of the patients were consented prior to the approval of venetoclax in November 2018, and a potential selection bias as Beat AML study had separate IDH^mut study arms.

In summary, our study demonstrates that IDH2 mutations have a favorable prognosis in patients with newly diagnosed AML who are 60 years or older and are treated with HMA-based therapy. The data support studies investigating the addition of targeted therapies to lower-intensity therapy regimens for older patients with IDH-mutated AML.

Footnotes

• Received July 24, 2025
• Accepted October 27, 2025

Correspondence

°Current address: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

Y.F. Madanat yazan.madanat@utsouthwestern.edu

Disclosures

ET has participated in advisory boards and/or consulting for Abbvie, Astellas, Daiichi-Sankyo, Servier and Rigel and has received research funding from Prelude Therapeutics, Schrodinger, Incyte and AstraZeneca. EMS has served on the advisory boards of Astellas Pharma, AbbVie, Genentech, Daiichi Sankyo, Novartis, Amgen, Seattle Genetics, Syros Pharmaceuticals, Syndax Pharmaceuticals, Agios Pharmaceuticals and Celgene and is an equity holder in Auron Therapeutics. TLL has received research funding from Biopath Holdings, Astellas Pharma, Celyad, Aptevo Therapeutics, Cleave Biosciences, Ciclomed, Jazz Pharmaceuticals and Kura Oncology and serves on the advisory boards of Servier, Syndax and Daiichi Sankyo. MRB has received institutional funding from AbbVie, Ascentage, Astellas, Curadev, Gilead, Kura and Takeda. WGB has served on advisory boards of AbbVie and Syndax and has received research funding from ImmuneOnc, Meryx and Nkarta. OO has served on the advisory boards of Servier, Rigel, AbbVie and Incyte and on a data safety monitoring board for Threadwell Therapeutics. JFZ has received honoraria for advisory board participations and/or consultancy from AbbVie, Astellas, AstraZeneca, Crossbow Therapeutics, Daiichi Sankyo, Foghorn, Genmab, Ipsen, Jazz, Johnson & Johnson, Neogenomics, Novartis, Relmada, Rigel, Sellas, Servier, Shattuck Labs, Sumitomo Pharma and Syndax and has received research funding from AbbVie, Arog, Ascentage, AstraZeneca, Auron Therapeutics, Daiichi Sankyo, Faron, Jazz, Loxo, Newave, Novartis, Sellas, Servier, Shattuck Labs, Stemline, Sumitomo Pharma and Zentalis. RLO has received research funds from Cellectis and consulted for Actinium, Astellas, AbbVie, Rigel and Servier. CCS has received research funds from AbbVie, BMS, Erasca, Revolution Medicines and Zentalis and served on advisory boards for AbbVie, Genentech and Astellas. GJS has commercial interests in BMS, Amgen and J&J; he has received fees from AbbVie, Agios, Amgen, Astellas, BMS, Incyte, Janssen, Jazz, Karyopharm, Kite, Pharmacyclics, Sanofi/Genzyme and Stemline and has received research funds from AbbVie, Actinium, Actuate, Arog, Astellas, AltruBio, AVM Bio, BMS/ Celgene, Celator, Constellation, Daiichi-Sankyo, Deciphera, Delta-Fly, Forma, FujiFilm, Gamida, Genentech-Roche, Glycomimetics, Geron, Incyte, Karyopharm, Kiadis, Kite/Gilead, Kura, Marker, Mateon, Onconova, Pfizer, PrECOG, Regimmune, Samus, Sangamo, Sellas, Stemline, Syros, Takeda, Tolero, Trovagene, Agios, Amgen, Jazz, Orca, Ono-UK and Novartis. MS has been a consultant for Eilean Therapeutics. BJD has interests in Cepheid, Labcorp, Nemucore Medical Innovations, Novartis and the RUNX1 Research Program; has SAB and stock in Aptose Biosciences, Blueprint Medicines, Enliven Therapeutics, Iterion Therapeutics, GRAIL and Recludix Pharma; is on the Board of Directors and has stock in Amgen and Vincerx Pharma; is on the Board of Directors of Burroughs Wellcome Fund and CureOne (inactive); is a member of the Joint Steering Committee of Beat AML LLS; is a member of an advisory committee for the Multicancer Early Detection Consortium; is a founder of VB Therapeutics; has sponsored research agreements with AstraZeneca, DELiver Therapeutics, Immunoforge, Terns, Enliven Therapeutics (inactive) and Recludix Pharma (inactive); has received clinical trial funding from Novartis and AstraZeneca; receives royalties from patent 6958335 (Novartis exclusive license) and OHSU and Dana-Farber Cancer Institute (one Merck exclusive license, one CytoImage, Inc. exclusive license, one DELiver Therapeutics non-exclusive license, and one Sun Pharma Advanced Research Company non-exclusive license); and holds US Patents 4326534, 6958335, 7416873, 7592142, 10473667, 10664967 and 11049247. RLL is on the supervisory board of Qiagen; is a scientific advisor to Imago, Mission Bio, Syndax, Zentalis, Ajax, Bakx, Auron, Prelude, C4 Therapeutics and Isoplexis for which he receives equity support; receives research support from Ajax and Abbvie; has consulted for Incyte, Janssen, Morphosys and Novartis; and has received honoraria from AstraZeneca and Kura for invited lectures and from Gilead for grant reviews. UMB has been a consultant for Genentech, Daiichi Sankyo, Takeda, Pfizer, AbbVie/Genentech and Novartis. ASM has served on the advisory boards of AbbVie/Genentech, Novartis, Ryvu Therapeutics, Rigel Therapeutics, Treadwell Therapeutics and Foghorn Therapeutics. JCB is a current equity holder in Lomond Therapeutics Inc (a publicly traded company) and Eilean Therapeutics and is a member of the Board of Directors or advisory committees of Lomond, Newave, Eilean, Kartos and Orange Grove. YFM has received honoraria/consulting fees from BMS, Kura Oncology, BluePrint Medicines, Geron, OncLive, MD Education, VJHemOnc and Medscape Live; has participated in advisory boards and received honoraria from Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology, SOBI, Rigel Pharmaceuticals, Geron, Cogent Biosciences and Novartis; and has received travel reimbursement from Blueprint Medicines, MD Education and Morphosys: none of these relationships were related to this work.

Contributions

FWH and YFM performed the research and wrote the manuscript. YH, RLW, RTS, ET, EMS, TLL, MRB, VHD, WGB, MLA, WS, OO, JFZ, RLO, CCS, GJS, EKC, SVH, NAH, TC, MM, MS, SGM, LR, BJD, RLL, AB, AOY, UMB, ASM, JCB and YFM collected and assembled data, and were involved in the care of patients. All authors reviewed the manuscript and approved the final version.

Funding

The study was sponsored by the Leukemia & Lymphoma Society. Funding for the trial was made possible by the Harry T. Mangurian Foundation, many other donors and the sites that enabled resources for rapid turnaround for cytogenetic analysis and other monitoring requirements for patients. Sub-studies in this trial were supported by pharmaceutical sponsors. We thank the pharmaceutical sponsors who paid the cost of performing the specific sub-studies with their investigational drugs.