Madanat, Yazan F.

Introduction Patients (pts) with relapsed/refractory (R/R) myelodysplastic syndromes (MDS) have a poor prognosis and, until recently, lacked therapeutic options. Ivosidenib (IVO) is an oral, targeted, small-molecule inhibitor of mIDH1. In October 2023, IVO was granted FDA approval for the treatment of adult pts with mIDH1 R/R MDS on the basis of results from the pivotal AG120-C-001 MDS substudy (NCT02074839); IVO showed an acceptable safety profile and induced durable remissions, with a high rate (38.9%) of complete remissions (CR) per International Working Group (IWG) 2006 criteria (DiNardo et al. Blood Adv 2024; bloodadvances.2023012302.). Response criteria evolve to better reflect clinical benefit in specific pt populations and reduce interobserver variability. The updated IWG 2023 criteria for higher-risk MDS lowered the hemoglobin threshold for CR, added response categories for pts with <5% blasts or limited count recovery, and eliminated the marrow CR (mCR) category. Herein we analyze responses, transfusion independence (TI), and survival outcomes of pts treated with IVO according to IWG 2023 criteria. In addition, responses assessed per IWG 2023 and IWG 2006 criteria are compared. Methods Pts with mIDH1 R/R MDS who had received prior SOC therapy were eligible. Oral IVO 500 mg was administered daily on days 1-28 of 28-day cycles. Responses were assessed per IWG 2023 criteria, and a composite CR (CRc) category was included in the analysis, which comprises all CR categories: CR + CR equivalent (CRe) + CR with limited count recovery (CRL) + CR with partial hematologic recovery (CRh). Overall response rate (ORR) was defined as CR + mCR + partial remission (PR) per IWG 2006 criteria, and as CRc + PR + hematologic improvement (HI) per IWG 2023 criteria. For TI analysis, non-CRc was defined as HI + PR + no response (NR)/not evaluable + progressive disease. TI was defined as requiring no transfusion for ≥56 days. Results In total, 19 pts were enrolled (median age: 73 yr; prior hypomethylating therapy: 78.9%) and data from 18 efficacy-evaluable pts were analyzed. CR + PR rate (primary endpoint) per IWG 2006 was 38.9%, with all 7 (38.9%) responders having CR. CRc + PR rate per IWG 2023 was 66.7% (n=12), with all responders having CRc, including 5 (27.8%) pts with CR, 3 (16.7%) with CRe, and 4 (22.2%) with CRL (CR unilineage [CRLuni], n=2 [11.1%]; CR bilineage [CRLbi], n=2 [11.1%]); no pt had CRh or PR. ORR was 83.3% per IWG 2006, with 7 (38.9%) pts having CR and 8 (44.4%) mCR; 4 (22.2%) pts with mCR had HI. Per IWG 2023 criteria, the ORR was 72.2%, with 12 (66.7%) pts having CRc and 1 (5.6%) HI with neutrophil response. The 8 mCR per IWG 2006 criteria were reclassified as 1 CR, 4 CRL (2 CRLuni and 2 CRLbi), 1 HI, and 2 NR per IWG 2023. Median time to CRc was 1.58 mo. Median duration of CRc was not reached and Kaplan-Meier (KM) estimates at 3, 6, and 12 mo were 90.9%, 81.8%, and 68.2%, respectively. Five (CRc group n=4; non-CRc group n=1) of 7 (71.4%) and 3 (CRc, n=1; non-CRc, n=2) of 4 pts requiring red blood cell (RBC) and platelet transfusion at baseline, respectively, had TI. Median time to any (RBC/platelet) TI was 2.64 and 2.43 mo for pts with CRc and non-CRc, respectively. Moreover, 10 of 12 (83.3%) pts with CRc and 3 of 6 (50%) with non-CRc had or maintained TI during the study. Median duration of TI was not reached and KM estimates at 3 and 6 mo were 90.0% and 65.6%, respectively, for pts with CRc and 100% and 66.7% for non-CRc. Median event-free survival (EFS) was not reached for pts with CRc (n=12) or NR (n=5), and KM estimates at 1 yr were 68.2% and 53.3%, respectively. Median overall survival (OS) was not reached for pts with CRc and was 16.5 mo for pts with NR. For pts with CRc, OS KM estimates at 1, 3, and 5 yr were 90.9%, 51.1%, and 51.1%, respectively. For pts with NR, OS KM estimates were 75% at 1 yr and not estimable at 3 and 5 yr. For the pt with HI, the EFS estimate at 1 yr was 100% and OS estimates were 100% at 1, 3, and 5 yr. Conclusions IVO resulted in a high ORR (72.2%) according to IWG 2023 criteria, including a 66.7% CRc rate, despite the removal of the mCR category. Of 8 mCR per IWG 2006 criteria, 5 (62.5%) were reclassified as CRc per IWG 2023 criteria. By eliminating mCR and assessing response in a high-risk population with <5% blasts, IWG 2023 criteria accurately capture the clinical benefit of IVO in R/R MDS. While comparison of survival outcomes between IWG 2006 and IWG 2023 is limited by the small sample size, a similar trend with response-dependent EFS and OS outcomes was observed.

Background: Chromosomal rearrangements involving the KMT2A gene and mutations involving the nucleophosmin (NPM1) gene have been associated with response to menin inhibitors in multiple studies of acute myeloid leukemia (AML) patients characterized by these genetic alterations. Both alterations are more common in younger AML patients and those with NPM1 mutations historically perform better. However, the prevalence and outcomes of older (≥60 years) AML patients with these alterations who are treated with current therapies is less well understood. We present results from the Beat AML Master Trial (BAMT) that analyze the outcomes of this large, but less common subset of patients in an older AML population. Methods: Patients were consented and enrolled on this precision medicine-based Beat AML Master Trial (NCT03013998) from November 2016 to June 2024. Patients were included in this analysis if they harbor either the classic NPM1 mutation or a KMT2A rearrangement (over 10 different gene partners). Additionally, 2 patients with a NUP98 rearrangement were included with the KMT2A cohort as they are known to have similar biology in terms of menin dependence. These patients were treated with the following therapies: a sub-study specific targeted therapy for the dominant clone, venetoclax + hypomethylating agent (Ven/HMA), intensive chemotherapy (IC), alternative non-intensive therapy (NIT), or no therapy. Clinical/genetic characteristics and median overall survival (OS) were analyzed in each group separately. Overall survival (OS) was calculated from master consent and estimated using the Kaplan-Meier method. Results: Of 1096 AML patients enrolled on the BAMT, 246 patients had either an NPM1 (N=207, 18.9%) or KMT2A (N=39, 3.6%) genetic alteration. The baseline characteristics for the NPM1 cohort were median age 72 years (range: 60-92), 50% female, and ECOG performance status: 0-16%, 1-58%, 2-25% and 3-1%. Additional disease characteristics include treatment related AML at 11% and complex karyotype (≥3 abnormalities) at 3%. Median OS for the entire NPM1 cohort was 18.4 months (95% CI: 14.2-24.7). Patients were treated on a sub-study (35%), Ven/HMA (19%), IC (26%), NIT (8%) or no treatment (9%). Between treatment groups, median OS was 21 months (95% CI: 12.8-31.7) for those treated on a sub-study, 22 months (95% CI: 12.6-not reached (NR)) for Ven/HMA, 41.6 months (95% CI: 18.2-NR) for IC, and 6.3 months (95% CI: 1.3-23) for NIT, which was significantly different (p<0.0001). The baseline characteristics for the KMT2A cohort were median age 69 years (range: 60-88), 44% female, and ECOG performance status: 0-19%, 1-45%, 2-35% and 3-0%. Treatment related AML occurred in 23% of patients and complex karyotype in 31%. Median OS for the KMT2A cohort was 6.5 months (95% CI: 3.6-31.6). Patients were treated on a sub-study (38%), Ven/HMA (15%), IC (15%), NIT (15%), or no treatment (5%). Between treatment groups, median OS was 31.6 months (95% CI: 3.2-NR) for sub-study, 5.0 months (95% CI: 3.0-NR) for Ven/HMA, 12.7 months (95% CI: 4.9-NR) for IC, and 2.9 months (95% CI: 1.5-NR) for NIT, which was also significantly different (p<0.0001). Conclusions: In this cohort of older AML patients who possess NPM1 or KMT2A mutations, initial demographics and clinical characteristics upon presentation are as expected. Within each cohort and depending on the type of therapy received, there were interesting differences in survival. Median OS was the highest for the NPM1 cohort that received IC while the KMT2A cohort had the highest median OS when enrolled on a KMT2A targeted sub-study; a finding that supports precision-based medicine for this high-risk KMT2A group characterized by poor outcomes. As menin inhibitor combinations with induction chemotherapy or Ven/HMA move to the frontline setting, we anticipate seeing significant improvement in outcomes for AML patients in both of these genomic subsets. Further multivariable analysis will be performed to validate treatment effect on OS. Our analyses for these two cohorts also provide valuable outcome benchmarks for the design of future precision oncology studies that seek to improve survival in these subsets of older AML patients.

Introduction: Myelodysplastic syndromes (MDS) occur due to the acquisition of mutational events over time. Tobacco smoking is a risk factor for MDS and has been associated with distinct genetic mutations in solid cancers. We investigated the association between smoking intensity and duration and the number and types of genetic mutations in MDS using a large prospective cohort. Methods: The prospective NHLBI/NCI National MDS Natural History Study includes individuals with suspected or recently diagnosed MDS enrolled between June 2016-August 2023. Patient (Pt) bone marrow samples underwent central pathology review, resulting in diagnoses including MDS, MDS/myeloproliferative neoplasm overlap (MDS/MPN), or precursor conditions, such as clonal cytopenia of undetermined significance (CCUS). Self-reported smoking data were collected at enrollment. Smoking intensity (i.e., light, medium, and heavy) was defined per CDC definitions. Included mutations were those manually annotated to be pathogenic for MDS. Mutation frequency and prevalence, as well as associations with smoking history and other key covariates, were assessed using univariate tests of association and multivariable regression models for counts and proportions. Rates of disease progression were compared between groups using survival analysis methods for cumulative incidence incorporating non-disease death as a competing risk. Results: Of 1898 evaluable pts, 52% (N=979) had a history of cigarette smoking [MDS: 58% (252/436), MDS/MPN: 57% (52/91), CCUS: 57% (230/405)], and 18% still smoked at diagnosis. The mean ± SD cigarettes per day was 15.8 ± 12.5 and the mean ± SD smoking years was 29.8 ± 16.9 years. Compared to non-smokers, smokers were more often males (68% v 54%, p<0.001) in the 70-79 year age group (45% v 34%, p<0.001). Similar proportions of those with and without a smoking history had MDS (41% v 37%, respectively). Within MDS, there was no association between smoking and MDS prognostic risk per revised international prognostic scoring system. Compared to light smokers [1-10 pack-years (PY)], heavy smokers (30+ PY) were more often male (81% v 62%, p<0.001) and had higher rates of cardiovascular disease (38% v 20%, p<0.001). In univariate analyses, smokers and non-smokers had similar numbers of mutations (mean ± SD: 2.0 ± 2.7 in both groups). Pts with CCUS had the least number of mutations (1.5 ± 1.2), followed by MDS (2.3 ± 1.8), and MDS/MPN overlap (3.3 ± 1.8). Within disease groups, smokers and non-smokers had similar numbers of mutations. Mutation prevalence was higher among smokers v non-smokers in gene pathways for chromatin modification (15% v 11%, p<0.01) and RNA splicing (26% v 19%, p<0.001) and for individual genes ASXL1 (12% v 8%, p<0.01), SF3B1 (9% v 6%, p<0.05), U2AF1 (6% v 3%, p<0.05) and ZRSR2 (2% v 1%, p<0.05). In multivariable regression models, after adjustment for sex, age and disease group, smokers had significantly more mutations on average than non-smokers (2.0 v. 1.4, p=0.04). Moreover, the number of mutations increased significantly with PY smoked (p=0.006), and those at the 75th and 90th percentiles of PY had 1.8 and 3.5 times the number of mutations, respectively, compared to non-smokers, indicating a dose-response relationship. After adjustment, mutation prevalence increased with PY smoked in the gene pathways for chromatin modification and RNA splicing (p<0.03 for both) and for the genes ASXL1 and ETNK1 (p<0.05 in both cases). The five-year cumulative incidence of disease progression was significantly higher among long-term smokers compared to non-smokers/those with shorter smoking history (mean [95% CI] proportion progressed, 20+ years vs <20 years smoking: 27% [19%-36%] vs 18% [13%-24%], p < 0.05). Overall survival was significantly lower for smokers compared to non-smokers for CCUS pts [HR 1.91, 95% CI (1.03-3.55), p=0.04] but not for MDS [HR 1.21, 95% CI (0.53-1.30), p=0.41]. Conclusions: In this prospective, national cohort, tobacco smoking was associated with distinct genetic mutations related to MDS, suggesting smoking potentially contributes to its multi-step molecular pathogenesis. A dose-response relationship was also demonstrated, as was an association with progression and survival. Our data suggest that pts with a new MDS diagnosis who are also smokers should be counseled to stop smoking, as it appears to contribute to the acquisition of new genetic mutations that can lead to progression.

Abstract Although the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML aged ≥60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-, 11% intermediate-, and 78% had adverse-risk AML. ELN risk was prognostic for overall survival (OS) (P < .001) but did not stratify favorable- from intermediate-risk (P = .71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (n = 316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P < .05). A “mutation score” was calculated for each combination of these mutations, assigning adverse-risk patients to 2 risk groups: −1 to 0 points (“Beat-AML intermediate”) vs 1+ points (“Beat-AML adverse”). In the final refined risk classification, ELN favorable- and intermediate-risk were combined into a newly defined “Beat-AML favorable-risk” group, in addition to mutation scoring within the ELN adverse-risk group. This approach redefines risk for older patients with ND AML and proposes refined Beat-AML risk groups with improved discrimination for OS (2-year OS, 48% vs 33% vs 11%, respectively; P < .001), providing patients and providers additional information for treatment decision-making.

Abstract Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 patients with CCUS investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count of <100 × 109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the clonal cytopenia risk score (CCRS), which stratified patients into low- (score of <2.5 points), intermediate- (score of 2.5 to <5), and high-risk (score of ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high-risk (37.2%) groups, respectively, by the Gray test (P < .0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P = .005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

Mastocytosis is a heterogeneous group of disorders comprising cutaneous mastocytosis, systemic mastocytosis, and mast cell sarcoma. It is associated with a variety of symptoms related to the release of mast cell mediators and mast cell tissue infiltration. Referral to specialized centers with expertise in the management of mastocytosis and multidisciplinary collaboration with subspecialists (eg, allergists for the management of anaphylaxis and drug hypersensitivities, anesthesiologists for invasive procedures or surgery, high-risk obstetrician for pregnancy) is recommended. The NCCN Guidelines for Systemic Mastocytosis provide evidence- and consensus-based recommendations for the diagnosis and comprehensive care of patients with systemic mastocytosis. The multidisciplinary panel of experts convenes at least once a year to review requested changes to the guidelines from both internal and external entities as well as to discuss data on existing and new therapies. These NCCN Guidelines Insights focus on some of the recent updates to the guidelines.

Abstract Ivosidenib is a first-in-class mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor with efficacy and tolerability in patients with advanced mIDH1 hematologic malignancies, leading to approval in frontline and relapsed/refractory (R/R) mIDH1 acute myeloid leukemia. We report final data from a phase 1 single-arm substudy of once-daily ivosidenib in patients with R/R mIDH1 myelodysplastic syndrome (MDS) after failure of standard-of-care therapies. Primary objectives were to determine safety, tolerability, and clinical activity. The primary efficacy end point was the complete remission (CR) + partial remission (PR) rate. Nineteen patients were enrolled; 18 were included in the efficacy analysis. Treatment-related adverse events occurred in 8 (42.1%) patients, including a grade 1 QT interval prolongation in 1 (5.3%) patient and grade 2 differentiation syndrome in 2 (10.5%) patients. Rates of CR + PR and objective response (CR + PR + marrow CR) were 38.9% (95% confidence interval [CI], 17.3-64.3) and 83.3% (95% CI, 58.6-96.4), respectively. Kaplan-Meier estimates showed a 68.6% probability of patients in CR achieving a remission duration of ≥5 years, and a median overall survival of 35.7 months. Of note, 71.4% and 75.0% baseline red blood cell (RBC)- and platelet-transfusion-dependent patients, respectively, became transfusion independent (TI; no transfusion for ≥56 days); 81.8% and 100% of baseline RBC and platelet TI patients, respectively, remained TI. One (5.3%) patient proceeded to a hematopoietic stem cell transplant. In conclusion, ivosidenib is clinically active, with durable remissions and a manageable safety profile observed in these patients. This trial was registered at www.ClinicalTrials.gov as #NCT02074839.

Background: Acute myeloid leukemia (AML) therapy in older patients (age ≥ 60) has undergone a transformation with the introduction of multiple targeted therapies, which has allowed more patients to receive therapy than before. The most successful has been the combination of venetoclax + azacitidine (VA) which generated higher overall complete response rates in phase 2 studies than would be expected with azacitidine alone, leading to accelerated FDA approval on 21Nov2018. The VIALE-A phase 3 study confirmed the improved overall survival (OS, median 14.7 versus 9.6 months) of VA, leading to full FDA approval for marketing. This retrospective analysis provides real world data on the impact of baseline clinical and genomic markers of individuals receiving intensive chemotherapy versus VA. Methods: The precision medicine Beat AML Master Trial (NCT03013998) assigns patients to biomarker specific sub-study treatments based on targeted DNA sequencing and cytogenetics. However, a large subset of patients did not enroll on a sub-study, but were followed for off-study treatment and OS. From this subset, patients enrolled onward from 21Nov2018, when VA received accelerated approval, were examined for differences in clinical/genetic characteristics and OS in those receiving venetoclax + hypomethylating agent (V/HMA), any form of intensive chemotherapy (IC), alternative non-intensive therapy (NIT), or no therapy. The genetic mutations identified in this study are characterized by a variant allele frequency of 20%+, as defined in the trial for determining the dominant clone. The method of Kaplan-Meier was used to estimate OS, and the Cox model was fit to associate patient characteristics with OS. Results: From 21Nov2018, a total of 468 AML patients consented to the Beat AML trial and did not enroll to a sub-study. Treatment was chosen by the investigator based upon available clinical and genomic data. Of these 468 patients, 62 did not receive treatment, 2 had treatment data missing, 226 were treated with V/HMA, 112 with IC, and 66 with NIT. Demographics for all patients include median age 71 (60-90), 40% female, performance status (PS) (0-20%; 1-55%; 2-22%; 3-3%), median white blood cell (WBC) 4.1 (range 0.3-298.6), complex karyotype (CK) 20.6%, core binding factor (CBF) 7.8%, KMT2A-rearranged 3.6%, NPM1-mutated (m) 15.6%, IDH2m 14.6%, TP53m 13.2%, FLT3-ITD/TKD 12.9%, and NRASm/ PTPN11m/ KRASm/ NF1m/ CBLm 23.6%. Demographics that were significantly different (p<0.01) among the three groups (V/HMA, IC, and NIT) include age (younger in IC), PS (worse in NIT), AST/ALT (worse in NIT), CBF (more in IC), CK and TP53m (less in IC). Of the 404 patients who underwent treatment with V/HMA, IC, or NIT, 208 have died with those surviving having a median follow-up of 22.3 months. Figure 1 summarizes the OS of each treatment group. The median OS (95% CI) from time of initiating therapy is 13.6 (10.9-16.8) for V/HMA, 33.8 (20.7-not reached) for IC, and 11.6 (5.2-21.3) months for NIT. Univariable analysis for OS was significant at p<0.05 for increased age, WBC, PS, hemoglobin, CBF, CK, NPM1m, TP53m, TET2m and IC versus V/HMA. Multivariable analysis was significant at p<0.05 (hazard ratio) for increased age (1.14), PS (1.83), WBC (1.08), hemoglobin (0.91), and select genomic aberrations including CBF (0.37), NPM1m (0.35), and TP53m (2.1). Conclusions: These results from a large cohort of older AML patients treated with V/HMA, IC, or NIT show that their outcome is best defined by pre-treatment clinical features previously identified including age, performance status, WBC and hemoglobin along with limited genomic characteristics including CBF, NPM1m, and TP53m. While univariate analysis of OS favored IC over V/HMA and NIT, multivariable analysis supports that this advantage was most likely due to the favorable clinical and genomic features. The OS of V/HMA patients in this cohort is similar to that in the VIALE-A registration study of VA, providing further justification for this treatment for older AML patients deemed ineligible for intensive chemotherapy. Additionally, this data supports use of the patient cohort in this study for ongoing work in understanding and/or validating biomarkers associated with survival with V/HMA.

Background. Acute myeloid leukemia (AML) is a heterogenous disease that occurs primarily in older adults with a median age of 69 years at diagnosis. Most studies that characterize the genomic landscape of AML include younger adults with the majority of patients being younger than 60 years of age. We aimed to study the mutational landscape of newly diagnosed AML patients aged 60 years or older. Methods.Samples were collected from the multi-center Beat AML Master Trial (Burd, Nat Med 2020). Patients were enrolled between 2016 and 2023. Informed consent was obtained according to the Declaration of Helsinki. Patients diagnosed with non-APL AML and who were aged ≥ 60 years old were included. Patients underwent bone marrow aspiration and biopsy, cytogenetic analysis, FLT3-ITD ratio assessment (LeukoStrat CDx FLT3 Mutation Assay, Invivoscribe) and next generation sequencing (NGS) using FoundationOne®Heme(Foundation Medicine) to interrogate the entire coding region of 406 genes and select introns of 31 genes involved in rearrangements, as well as RNA sequencing to interrogate 265 genes known to be somatically altered in human hematological malignancies. The presence of multiple hotspot mutations within one gene in an individual patient was counted as one gene mutation. Patterns of co-occurrence between gene mutations were calculated using the Phi correlation coefficient. Statistical analyses were performed using R statistical software. P<0.01 was considered statistically significant. Results. A total of 1088 newly diagnosed AML patients were identified, of whom 1032 were 60 years or older. Patients had a median age of 72 years at time of diagnosis (range 60-92 years). Forty-two percent of the patients were female, most patients were non-Hispanic and 79% were Caucasian. NGS data were available for 1024 patients and mutations were identified in 461 different genes. Patients had a median number of 11.0 mutations (range 3.0 to 28.0). The most frequently mutated genes were DNMT3A (n=257; 25.1%), TP53(n=255; 24.9%), TET2 (n=243; 23.7%), RUNX1 (n=225; 22.0%), SRSF2 (n=221; 21.6%), ASXL1 (n=216; 21.1%), NPM1 (n=206; 20.1%), FLT3 (n=205; 20.0%), IDH2 (n=190; 18.6%), NRAS (n=208; 16.9%), PTPN11(n=104; 10.2%), STAG2 (n=101, 9.9% and IDH1 (n=99; 9.7%) (Figure 1A). FLT3-ITD was present in 98 (12.1%) of the 810 patients who were tested. Strongest significant co-occurrence was found between FLT3and NPM1 (n=103), STAG2 and ASXL1 (n=63), ASXL1 and RUNX1 (n=92), ASXL1 and SRSF2 (n=88), RUNX1 and SRSF2 (n=94), STAG2 and SRSF2 (n=51) and DNMT3A and NPM1 (n=92) (p<0.01). Pairwise negative correlations were observed between TP53 and NPM1 (n=6), TP53 and SRSF2 (n=17), and between NPM1 and RUNX1 (n=6) (p<0.01) (Figure 1B). The cytogenetic profiles and the full genomic landscape will be presented during the ASH meeting. Discussion. This is the largest study investigating the mutational profile in older adults with AML aged 60 years and older. Due to the 7-day screening period of the Beat AML study, patient selection was biased towards less-rapidly proliferative AML. We showed that the pattern of gene mutations was markedly different from other studies in AML that mainly included younger AML patients (Papaemmanuil, NEJM 2016; TCGA, NEJM 2013 ). The frequency of mutated TP53 was substantially higher in older AML patients, as was the occurrence of myelodysplasia-related gene mutations (e.g., SRSF2, RUNX1, ASXL1, STAG2, U2AF1, and SF3B1) and gene mutations in IDH1, IDH2 and TET2. In contrast, NPM1 mutation was less frequently mutated in older AML patients. Furthermore, we demonstrated that a large proportion (46%) of the AML patients older than 60 years of age do have a mutation that is potentially targetable for treatment ( FLT3 IDH1 IDH2 and NPM1). The high incidence of mutated TP53 and MDS-related gene mutations underscores the increased incidence of high-risk AML and the need for innovative personalized therapies in this older age group. Figure 1. A. Co-occurrence of the 15 most frequently mutated genes, and B. co-correlation between the 15 most frequently mutated genes. Blue indicates positive correlation, red indicated negative correlation. Only significant correlations (p<0.01) are shown.