Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial.

BACKGROUND: Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity. METHODS: KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50-1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41. FINDINGS: From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50-1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4-30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission. INTERPRETATION: Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing. FUNDING: Kura Oncology.

A Multicenter Analysis of Allogeneic Transplant Outcomes in Adults with Philadelphia-like B-cell Acute Lymphoblastic Leukemia in First Complete Remission.

BACKGROUND: Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subset of B-cell ALL with a poor prognosis with conventional therapies. Diagnostic challenges and lack of standardized treatment protocols contribute to suboptimal outcomes. Additionally, while allogeneic hematopoietic cell transplantation (HCT) is frequently recommended in adults with Ph-like ALL given its high-risk nature, data supporting its role remains limited. OBJECTIVE: We conducted a multicenter retrospective study evaluating outcomes of adult patients undergoing HCT in first complete remission (CR1) for Ph-like ALL compared to Philadelphia chromosome positive ALL (Ph-pos) and other B-cell Philadelphia negative (Ph-neg) ALL. STUDY DESIGN: Data was collected from from five academic centers across the US, focusing on HCT outcomes for patients with ALL. Patients undergoing HCT in CR1 between 2006 and 2021 were included. RESULTS: Among 673 patients, 83 (12.3%) had Ph-like ALL, while 271 (40.3%) had Ph-pos and 319 (47.4%) had Ph-neg ALL. Outcomes following HCT in CR1 for Ph-like ALL were comparable to Ph-neg ALL, with no significant differences in 3-year overall survival (66% vs 59%, p=0.1), progression-free survival (59% and 54%, p=0.1), or relapse rates (22% vs 20%, p=0.7). In contrast, Ph-pos ALL had superior outcomes; 3-year OS (75%, p<0.001), PFS (70%, p=0.001) and relapse (12%, p=0.003), this is likely attributed to tyrosine kinase inhibitor therapy. CONCLUSION: Our study suggests that HCT, coupled with effective 2nd line therapies can possibly mitigate the poor prognosis associated with Ph-like ALL and offers promising outcomes for patients with Ph-like ALL.

Randomized Phase III SIERRA Trial of 131I-Apamistamab Before Allogeneic Hematopoietic Cell Transplantation Versus Conventional Care for Relapsed/Refractory AML.

PURPOSE: Older patients with relapsed or refractory AML (RR AML) have dismal prognoses without allogeneic hematopoietic cell transplantation (alloHCT). SIERRA compared a targeted pretransplant regimen involving the anti-CD45 radioconjugate 131I-apamistamab with conventional care. METHODS: SIERRA (ClinicalTrials.gov identifier: NCT02665065) was a phase III open-label trial. Patients age ≥55 years with active RR AML were randomly assigned 1:1 to either an 131I-apamistamab-led regimen before alloHCT or conventional care followed by alloHCT if initial complete remission (CR)/CR with incomplete platelet recovery (CRp) occurred. Initial response was assessed 28-56 days after alloHCT in the 131I-apamistamab group and 28-42 days after salvage chemotherapy initiation; patients without CR/CRp or with AML progression could cross over to receive 131I-apamistamab followed by alloHCT. The primary end point was durable complete remission (dCR) lasting 180 days after initial CR/CRp. Secondary end points were overall survival (OS) and event-free survival (EFS), assessed hierarchically in the intention-to-treat (ITT) population. RESULTS: The ITT population included 153 patients (131I-apamistamab [n = 76]; conventional care [n = 77]). In total, 44/77 conventional care arm patients crossed over and 40/77 (52%) received 131I-apamistamab and alloHCT, with six patients (13.6%) experiencing a dCR. In the ITT population, the dCR rate was significantly higher with 131I-apamistamab (17.1% [95% CI, 9.4 to 27.5]) than conventional care (0% [95% CI, 0 to 4.7]; P < .0001). The OS hazard ratio (HR) was 0.99 (95% CI, 0.70 to 1.41; P = .96), and the EFS HR was 0.23 (95% CI, 0.15 to 0.34), with HR <1 favoring 131I-apamistamab. Grade ≥3 treatment-related adverse events occurred in 59.7% and 59.2% of the 131I-apamistamab and conventional care groups, respectively. CONCLUSION: The 131I-apamistamab-led regimen was associated with a higher dCR rate than conventional care in older patients with RR AML. 131I-apamistamab was well tolerated and could address an unmet need in this population.

Surrogates of Endothelial Injury Predict Survival After Post-transplant Cyclophosphamide.

Post-transplant cyclophosphamide (PT-Cy) is becoming the standard of care for preventing graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplant (alloHCT). Cyclophosphamide is associated with endothelial injury. We hypothesized that the endothelial activation and stress index (EASIX) score, being a marker of endothelial dysfunction, will predict non-relapse mortality (NRM) in alloHCT patients receiving PT-Cy for GVHD prophylaxis. We evaluate the prognostic ability of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and EASIX scores, and report other factors influencing survival, in patients with hematologic malignancies undergoing alloHCT and receiving PT-Cy-based GVHD prophylaxis. Adult patients with hematologic malignancies who underwent alloHCT and received PT-Cy for GVHD prophylaxis at the three Mayo Clinic locations were included in this study. We retrospectively reviewed the Mayo Clinic database and the available electronic medical records to determine the patient, disease, and transplant characteristics. An HCT-CI score of ≥3 was considered high. The EASIX score was calculated from labs available between day -28 (of alloHCT) to the day of starting conditioning and analyzed on log2 transformed values. A log2-EASIX score ≥2.32 was considered high. The cumulative incidence of NRM was determined using competing risk analysis, with relapse considered as competing risk. Overall survival (OS) from transplant was determined using Kaplan-Meier and log-rank methods. Cox-proportional hazard method was used to evaluate factors impacting survival. A total of 199 patients were evaluated. Patients with a high log2-EASIX score had a significantly higher cumulative incidence of NRM at 1 year after alloHCT (34.5% versus 12.3%, P = .003). Competing risk analysis showed that a high log2-EASIX score (HR 2.92, 95% CI 1.38 to 6.17, P = .005) and pre-alloHCT hypertension (HR 2.15, 95% CI 1.06 to 4.36, P = .034) were independently predictive of 1 year-NRM. Accordingly, we combined the two factors to develop a composite risk model stratifying patients in low, intermediate, and high-risk groups: 111 (55.8%) patients were considered low-risk, 76 (38.2%) were intermediate and 12 (6%) were high-risk. Compared to patients in the low-risk group, the intermediate (HR 2.38, 95% CI 1.31 to 4.33, P = .005) and high-risk (HR 5.77, 95% CI 2.31 to 14.39, P < .001) groups were associated with a significantly inferior 1-year OS. Multiorgan failure (MOF) was among the common causes of NRM (14/32, 43.8%) particularly among patients with prior pulmonary comorbidities [7 (50%) patients]. Our study shows that EASIX score is predictive of survival after PT-Cy. The novel EASIX-HTN composite risk model may stratify patients prior to transplant. MOF is a common cause of NRM in patients receiving PT-Cy, particularly among patients with pulmonary comorbidities.

Beat-AML 2024 ELN-refined risk stratification for older adults with newly diagnosed AML given lower-intensity therapy.

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.

Risk Prediction for Clonal Cytopenia: Multicenter Real-World Evidence.

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 CCUS patients 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 <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 <2.5 points), intermediate- (score 2.5-<5), and high-risk (score ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high- (37.2%) risk groups, respectively, by Gray's 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.

FLT3 inhibitors potentially improve response rates in acute myeloid leukemia harboring t(6;9)(DEK::NUP214): The Mayo Clinic experience.

Not available.

Final phase 1 substudy results of ivosidenib for patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome.

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.

The impact of cytotoxic therapy on the risk of progression and death in clonal cytopenia(s) of undetermined significance.

ABSTRACT: Clonal cytopenia of undetermined significance (CCUS) is defined by a myeloid driver mutation in the context of otherwise unexplained cytopenia. CCUS has an inherent risk of progressing to myeloid neoplasm. However, it is unknown how exposure to previous cytotoxic therapy may impact the risk of progression and survival. We stratified patients with CCUS by prior exposure to DNA-damaging therapy. Of 151 patients, 46 (30%) had received cytotoxic therapy and were classified as therapy-related CCUS (t-CCUS), whereas 105 (70%) had de novo CCUS. A lower proportion of t-CCUS had hypercellular marrows (17.8% vs 44.8%, P = .002) but had higher median bone marrow blast percentages. After a median follow-up of 2.2 years, t-CCUS had significantly shorter progression-free survival (PFS, 1.8 vs 6.3 years; hazard ratio [HR], 2.1; P = .007) and median overall survival (OS; 3.6 years vs not reached; HR, 2.3; P = .007) compared with CCUS. Univariable and multivariable time-to-event analyses showed that exposure to cytotoxic therapy independently accounted for inferior PFS and OS. Despite the similarities in clinical presentation between CCUS and t-CCUS, we show that exposure to prior cytotoxic therapies was an independent risk factor for inferior outcomes. This suggests that t-CCUS represents a unique clinical entity that needs more stringent monitoring or earlier intervention strategies.

Efficacy of Autologous and Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Promyelocytic Leukemia: Results of a Systematic Review and Meta-Analysis.

Despite therapeutic advances for acute promyelocytic leukemia (APL) with the emergence of all-trans retinoic acid, arsenic trioxide, and gemtuzumab-ozogamycin, approximately 10% of patients still experience disease relapse, typically occurring within 24 to 36 months following completion of front-line treatment. Traditionally, both allogeneic (allo) and autologous (auto) hematopoietic cell transplantation (HCT) have been considered reasonable treatment options for relapsed APL; however, no randomized controlled studies have been conducted comparing allo-HCT and auto-HCT in patients with relapsed APL. We performed a systematic review/meta-analysis to assess the totality of evidence pertaining to allo-HCT or auto-HCT in relapsed APL. Our search identified 1158 references, of which 23 met our inclusion criteria. While acknowledging the limitations of comparing these 2 treatment modalities indirectly, based on results from separate meta-analyses, it appears that pooled rates of event-free survival (71% versus 54%), progression-free survival (63% versus 43%), and overall survival (82% versus 58%) are higher after auto-HCT. This difference can be explained in part by the higher risk of pooled nonrelapse mortality (NRM) in patients undergoing allo-HCT (29% versus 5%), owing to inherent risks associated with this modality. In the absence of a randomized prospective clinical trial comparing allo-HCT and auto-HCT, our results show that both modalities are acceptable in patients with relapsed APL. The higher pooled NRM rate with allo-HCT is an important consideration when choosing this option. Additionally, the comparable pooled relapse rate for auto-HCT and allo-HCT (24% versus 23%) provides a rationale for evaluating post-HCT consolidative strategies to mitigate this risk.

Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms.

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P<0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P=0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P=0.02), whereas melphalan-based conditioning was associated with a decreased relapse risk (HR 0.02, P=0.01). We conclude that mBCOR is a high-risk feature across MDS/AML, and that alloSCT improves survival in this population.

Treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN): focus on the use of tagraxofusp and clinical considerations.

BPDCN is an aggressive myeloid malignancy with a poor prognosis. It derives from the precursors of plasmacytoid dendritic cells and is characterized by CD123 overexpression, which is seen in all patients with BPDCN. The CD123-directed therapy tagraxofusp is the only approved treatment for BPDCN; it was approved in the US as monotherapy for the treatment of patients aged ≥2 years with treatment-naive or relapsed/refractory BPDCN. Herein, we review the available data supporting the utility of tagraxofusp in treating patients with BPDCN. In addition, we present best practices and real-world insights from clinicians in academic and community settings in the US on how they use tagraxofusp to treat BPDCN. Several case studies illustrate the efficacy of tagraxofusp and discuss its safety profile, as well as the prevention, mitigation, and management of anticipated adverse events.

A prospective study of the relationship between illness perception, depression, anxiety, and quality of life in hematopoietic stem cell transplant patients.

AIM: The aim of study was to investigate whether depression and anxiety symptoms and illness perception prior to hematopoietic stem cell transplantation (HSCT) predict health related quality of life (HRQOL) at Day 100 and 1 year following HSCT. METHODS: A total of 205 patients who underwent HSCT (N = 127 autologous transplants, N = 78 allogeneic transplants) were included in this prospective study. Baseline assessment was assessed prior to transplantation and post HSCT data were collected at Day 100 and 1 year. At baseline we assessed depressive symptoms (Patient Health Questionnaire-9), anxiety symptoms (Generalized Anxiety Disorder-7), illness perception (Brief Illness Perception Questionnaire), and HRQOL (Functional Assessment of Cancer Therapy-BMT). RESULTS: Patients who expressed a greater level of concern about the severity, course, and ability to exert control over one's illness (i.e., illness perception) and who reported a greater level of depression and anxiety symptoms prior to HSCT reported lower HRQOL at both Day 100 and 1 year posttransplant, with a similar degree of association observed at the two follow-up time points. CONCLUSIONS: Our findings suggest that pretransplant perceptions about their illness and negative mood are significant predictors of HRQOL following HSCT. Illness perception, depression, and anxiety are potentially modifiable risk factors for less than optimal outcome after HCSCT and intervention strategies should be explored.

Loneliness, immunological recovery patterns, and health-related quality of life (HRQOL) outcomes in patients receiving hematopoietic stem cell transplantation.

PURPOSE: Loneliness may compromise health-related quality of life (HRQOL) outcomes and the immunological impacts of loneliness via neuroendocrinological mechanisms likely have consequences for patients who have undergone a hematopoietic stem cell transplantation (HSCT). RESEARCH APPROACH AND MEASURES: Loneliness (pre-transplant), immunological recovery (Day 30, Day 100, 1-year post-transplant), and HRQOL (Day 100, 1 year) were measured in a sample of 205 patients completing a HSCT (127 autologous, 78 allogenic). RESULTS: Greater levels of pre-transplant loneliness predicted poorer HRQOL at Day 100 and 1-year follow-up. Loneliness also was associated with higher absolute neutrophil to absolute lymphocyte (ANC/ALC) ratios in the entire sample at Day 30, which in turn was associated with Day 100 HRQOL. CONCLUSIONS: Findings demonstrate that pretransplant loneliness predicts HRQOL outcomes and associates with inflammatory immunological recovery patterns in HSCT patients. The balance of innate neutrophils to adaptive lymphocytes at Day 30 present a distinct profile in lonely individuals, with this immunity recovery profile predicting reduced HRQOL 100 days after the transplant. Addressing perceptions of loneliness before HSCT may be an important factor in improving immunological recovery and HRQOL outcomes.

Venetoclax and hypomethylating agent combination therapy in newly diagnosed acute myeloid leukemia: Genotype signatures for response and survival among 301 consecutive patients.

Venetoclax + hypomethylating agent (Ven-HMA) is currently the standard frontline therapy for older/unfit patients with newly diagnosed acute myeloid leukemia (ND-AML). Our objective in the current retrospective study of 301 adult patients (median age 73 years; 62% de novo) with ND-AML was to identify molecular predictors of treatment response to Ven-HMA and survival; European LeukemiaNet (ELN) genetic risk assignment was favorable 15%, intermediate 16%, and adverse 69%. Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients. In multivariable analysis, inclusive of mutations only, "favorable" predictors of CR/CRi were NPM1 (86% vs. 56%), IDH2 (80% vs. 58%), and DDX41 (100% vs. 58%) and "unfavorable" TP53 (40% vs. 67%), FLT3-ITD (36% vs. 63%), and RUNX1 (44% vs. 64%) mutations; significance was sustained for each mutation after adjustment for age, karyotype, and therapy-related qualification. CR/CRi rates ranged from 36%, in the presence of unfavorable and absence of favorable mutation, to 91%, in the presence of favorable and absence of unfavorable mutation. At median follow-up of 8.5 months, 174 deaths and 41 allogeneic stem cell transplants (ASCT) were recorded. In multivariable analysis, risk factors for inferior survival included failure to achieve CR/CRi (HR 3.4, 95% CI 2.5-4.8), adverse karyotype (1.6, 1.1-2.6), TP53 mutation (1.6, 1.0-2.4), and absence of IDH2 mutation (2.2, 1.0-4.7); these risk factors were subsequently applied to construct an HR-weighted risk model that performed better than the ELN genetic risk model (AIC 1661 vs. 1750): low (n = 130; median survival 28.9 months), intermediate (n = 105; median 9.6 months), and high (n = 66; median 3.1 months; p < .001); survival in each risk category was significantly upgraded by ASCT. The current study identifies genotype signatures for predicting response and proposes a 3-tiered, CR/CRi-based, and genetics-enhanced survival model for AML patients receiving upfront therapy with Ven-HMA.