ASH 2024: Select Abstracts of Key Advances in AML

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Welcome to our comprehensive review of the latest AML research from the 2024 ASH Annual Meeting. Below, you will find summaries of key abstracts highlighting advancements in treatment strategies, clinical outcomes, and innovative therapies in acute myeloid leukemia. Click on any title in the bulleted list to read the full abstract summary.

Abstract #1569

Measurable Residual Disease Detection on Day 30 Post Hematopoietic Stem Cell Transplantation Predicts Clinical Outcome in Acute Myeloid Leukemia

Authors: Sze Pui Tsui, Ho-Wan Ip, Stephen Lam, et al.

Background: Post-HSCT relapse remains one of the greatest challenges in AML management. While the role of measurable residual disease (MRD) in predicting relapse following chemotherapy is well established, its value when detected early after hematopoietic stem cell transplantation (HSCT) has not been thoroughly investigated. This study examines the impact of MRD positivity at Day 30 post-HSCT on leukemia-free survival (LFS) and overall survival (OS).

Study Overview and Results: In this retrospective analysis, 123 AML patients who underwent allogeneic HSCT—79 with myeloablative conditioning and 44 with reduced-intensity conditioning—were evaluated for MRD using droplet digital PCR targeting nine recurrent mutation hotspots, including NPM1, DNMT3A, IDH1/2, FLT3, and NRAS. MRD positivity was observed in 30% of patients at Day 30 post-HSCT.

Patients with MRD positivity had significantly worse outcomes compared to MRD-negative patients. Leukemia-free survival (LFS) was notably shorter for MRD-positive patients, with a median of 20.8 months versus 110 months for MRD-negative patients (p=0.00044). Similarly, overall survival (OS) was significantly reduced, with MRD-positive patients achieving a median OS of 45.6 months compared to 144.7 months for MRD-negative patients (p=0.0039).

Subgroup analysis demonstrated that MRD positivity was highly predictive of relapse risk regardless of mutation type. For patients with NPM1-positive AML, MRD positivity increased the risk of relapse more than five-fold (HR 5.2, p<0.001), while patients with non-NPM1 mutations also faced an increased risk (HR 2.34, p=0.02). Multivariate analysis confirmed MRD positivity as the strongest predictor of both LFS (HR 2.85, p=0.0025) and OS (HR 2.67, p=0.0097), underscoring its prognostic significance.

Relevance: This study underscores the importance of early MRD assessment at Day 30 post-HSCT as a powerful prognostic tool for AML patients. The significant association between MRD positivity and poor survival outcomes highlights a critical window for intervention. Patients identified as MRD-positive early after transplant could benefit from intensified monitoring, preemptive treatment strategies, or enrollment in clinical trials to address their elevated relapse risk. These findings emphasize the evolving role of MRD detection in personalizing post-HSCT care to improve long-term outcomes in AML.

Link to Abstract: Abstract 1569

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Abstract #225

Prognostic Value of Measurable Residual Disease (MRD) in AML Treatment with Venetoclax in Combination with Hypomethylating Agents: Validation of the ELN 2021 MRD Recommendations

Authors: Carlos Jimenez-Vicente, Aina Cardus, Guillermo Ramil López, et al.

Background: The prognostic significance of measurable residual disease (MRD) in AML patients undergoing intensive chemotherapy is well established. However, its role in patients treated with venetoclax-based low-intensity regimens remains less clear. This multicenter study validates the ELN 2021 MRD recommendations in AML patients treated with venetoclax and hypomethylating agents (VenHMA).

Study Overview and Results: This retrospective study included 251 AML patients treated with VenHMA across five centers in Spain between March 2019 and January 2024. MRD was assessed using reverse-transcription quantitative PCR (RT-qPCR) for patients with NPM1-mutated AML and multiparameter flow cytometry (MFC) for others.

Among the 251 patients, 89 were evaluable for MRD response. The median age was 73 years, and most patients had either AML with myelodysplasia-related features (42.7%) or NPM1-mutated AML (37.1%). Venetoclax-based therapy was used as frontline treatment in 74.1% of patients and in relapsed/refractory (R/R) settings for the remainder.

MRD negativity was strongly associated with improved survival outcomes. Patients achieving MRD negativity experienced significantly longer leukemia-free survival (LFS) and overall survival (OS). In landmark analyses, MRD-negative patients had a median LFS of 16.8 months compared to 6.2 months for MRD-positive patients (p<0.001). Similarly, MRD negativity correlated with prolonged OS, with a median OS of 20.4 months versus 8.1 months for MRD-positive patients (p<0.001). Multivariate analysis confirmed MRD negativity as an independent predictor of both LFS (HR 0.45, p=0.002) and OS (HR 0.51, p=0.005), regardless of baseline characteristics.

Relevance: This study highlights the prognostic value of MRD assessment in AML patients receiving venetoclax and hypomethylating agents. Achieving MRD negativity was associated with significantly improved survival, reinforcing the importance of MRD monitoring in this patient population. These findings validate the ELN 2021 MRD recommendations and suggest that MRD-directed strategies could help refine treatment decisions, optimize response assessment, and identify patients who may benefit from intensified therapy or novel agents. For community hematologists, incorporating MRD monitoring into routine practice for AML patients receiving venetoclax-based therapy could improve outcomes and inform clinical decision-making.

Link to Abstract: Abstract 225

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Abstract #1396

A Randomized Placebo-Controlled Phase 1 Trial in Healthy Volunteers Investigating the Safety, Pharmacokinetics, and Pharmacodynamics of a Novel FLT3/IRAK4 Inhibitor, Lomonitinib (ZE46-0134)

Authors: John C. Byrd, Amy Burd, Brian Ledwith, et al.

Background: Lomonitinib is a highly selective pan-FLT3/IRAK4 inhibitor designed to target FLT3 mutations, a major driver in FLT3-mutated AML, while also inhibiting IRAK4, a potential escape pathway. Preclinical studies demonstrated superior efficacy to gilteritinib in FLT3-ITD and FLT3 gatekeeper mutations and suggested minimal toxicity. This first-in-human Phase 1 study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of lomonitinib in healthy volunteers.

Study Overview and Results: In this single-center, randomized, double-blind, placebo-controlled Phase 1 trial, healthy volunteers received lomonitinib in a loading strategy followed by a maintenance dose. A total of 24 subjects participated in multiple ascending dose (MAD) cohorts, with lomonitinib administered as 50–100 mg on Day 1 (loading dose) followed by 10–20 mg QD on Days 2–7. Additional participants assessed lomonitinib in combination with itraconazole, a CYP3A4 inhibitor, and in the presence of proton pump inhibitors (PPIs).

Lomonitinib was well tolerated across all dosing cohorts, with no treatment-related adverse events reported. PK analysis confirmed dose-proportional increases in systemic exposure and rapid attainment of steady-state concentrations (by Day 4) with the loading dose strategy. Importantly, neither PPIs nor CYP3A4 inhibitors significantly influenced lomonitinib’s PK profile. PD assessments demonstrated FLT3 target engagement at doses of ≥10 mg, aligning with therapeutic levels predicted in preclinical studies.

Relevance: Lomonitinib’s favorable safety, pharmacokinetic, and pharmacodynamic profiles support its potential as a next-generation FLT3/IRAK4 inhibitor for FLT3-mutated AML. The unique loading strategy, enabling rapid therapeutic levels, distinguishes it from other FLT3 inhibitors with longer half-lives and narrower therapeutic indices. These findings pave the way for ongoing Phase 1B trials in patients with relapsed/refractory FLT3-mutated AML. If efficacy and safety are confirmed in AML patients, lomonitinib may address resistance mechanisms and improve outcomes in this challenging patient population.

Link to Abstract: Abstract 1396

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Abstract #217

A Phase II Randomized Trial Comparing Low-Dose Cytarabine and Venetoclax +/- Midostaurin in Non-Adverse Cytogenetic Risk Acute Myeloid Leukemia: The ALLG AMLM25 INTERVENE Trial

Authors: Chong Chyn Chua, Blake Hsu, Anoop K. Enjeti, et al.

Background: In older, unfit patients with AML, combining low-dose cytarabine (LDAC) and venetoclax (Ven) has become a common frontline option. However, myelosuppression remains a challenge when FLT3 inhibitors like gilteritinib are added. This study explores whether sequential addition of midostaurin (MIDO), a shorter half-life FLT3 inhibitor, to LDAC and venetoclax (LVM regimen) improves outcomes without exacerbating toxicity in non-adverse cytogenetic risk AML.

Study Overview and Results: The Phase II ALLG AMLM25 INTERVENE trial randomized 124 newly diagnosed AML patients (age ≥60) unfit for intensive chemotherapy to receive either LVM (LDAC, venetoclax, and midostaurin sequentially) or LV (LDAC + venetoclax alone). Median follow-up was 13.4 months, with a median patient age of 74 years (81% ≥70 years).

  • The CR/CRi rate was significantly higher in the LVM arm (57%) compared to LV (38%) by the end of 4 cycles.
  • Among FLT3-ITD positive patients, MRD negativity by PCR-NGS was achieved in 72% with LVM versus 47% with LV.
  • Median overall survival (OS) favored the LVM arm, though it did not reach statistical significance (median OS: 15.8 months vs. 11.4 months; HR 0.75, p=0.09).

Treatment-related toxicities were manageable. The sequential use of midostaurin reduced the risk of prolonged myelosuppression compared to concurrent administration seen in prior studies.

Relevance: The INTERVENE trial demonstrates that the sequential addition of midostaurin to LDAC and venetoclax improves response rates and MRD negativity without exacerbating toxicity in older, unfit AML patients with non-adverse cytogenetics. These findings highlight an effective and tolerable triplet regimen that could serve as a new treatment option, particularly for patients with FLT3-ITD mutations. For clinicians, this approach addresses a critical need for improved frontline strategies in this challenging patient population while balancing efficacy and safety.

Link to Abstract: Abstract 217

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Abstract #450

A Retrospective Analysis of Intensive Chemotherapy vs. Venetoclax/Hypomethylating Agents for Patients Aged 60-75 with Favorable-Risk, NPM1-Mutated AML

Authors: Andrew Zale, Alexander J. Ambinder, Venkata Preetam Sandeep Kaduluri, et al.

Background: NPM1-mutated AML without FLT3-ITD is classified as favorable-risk, and intensive chemotherapy (IC) remains the standard of care. However, older patients face greater morbidity from IC, leading to increased use of venetoclax with hypomethylating agents (Ven/HMA). This retrospective analysis compares survival outcomes between IC and Ven/HMA in patients aged 60-75 with favorable-risk NPM1-mutated AML.

Study Overview and Results:
This analysis included 55 patients aged 60-75 with favorable-risk NPM1-mutated AML treated at Johns Hopkins. Of these, 36 (64%) received IC, while 19 (35%) were treated with Ven/HMA. Both groups had comparable baseline characteristics, including performance status, WBC, and molecular profiles. Patients in the IC group were younger (mean age 66.1 vs. 69.6 years, p=0.005) and were more likely to receive treatment before venetoclax approval.

The median overall survival (OS) was 6.2 years for IC and 4.9 years for Ven/HMA, with no statistically significant difference between groups (p=0.523). Patients undergoing allogeneic stem cell transplant (alloHCT) in first remission had improved outcomes regardless of initial therapy. Notably, among the 7 Ven/HMA-treated patients who underwent alloHCT, none relapsed, and only 1 died from non-relapse mortality, achieving excellent survival outcomes.

Multivariate analysis showed that higher baseline WBC was associated with worse OS, while transplant in first remission was linked to improved survival (p=0.01). Although Ven/HMA-treated patients were less likely to undergo alloHCT (37% vs. 69%), those who did achieved durable remissions.

Relevance: This study provides real-world evidence supporting the comparable efficacy of Ven/HMA to IC in older patients with favorable-risk, NPM1-mutated AML. The findings suggest that Ven/HMA is a viable alternative to IC in patients aged 60-75, particularly for those deemed unfit for intensive therapy. Importantly, outcomes are optimized when patients achieve remission and proceed to alloHCT. These results offer valuable guidance for clinicians navigating treatment decisions in this patient population, balancing efficacy, safety, and patient fitness.

Link to Abstract: Abstract 450

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Abstract #61

Single-Cell Multiomics Unveils Venetoclax-Resistant Monocytic Differentiation and Immune Evasion in TP53 Mutant AML Clones

Authors: Edward Ayoub, PhD, David Lehotzky, PhD, Li Li, MD, PhD, et al.

Background: TP53 mutations are present in 8-30% of AML cases and are associated with poor prognosis and therapy resistance. This study employs single-cell multiomics to identify mechanisms underlying resistance to venetoclax-based therapies and immune evasion in TP53-mutated AML clones.

Study Overview and Results: Researchers analyzed 52 longitudinal single-cell RNA sequencing (scRNA-seq) samples from 26 TP53-mutated AML patients and incorporated single-cell DNA/protein sequencing (scDNA+protein) and mass cytometry (CyTOF) in a subset of patients.

The analysis revealed that resistant TP53-mutated AML clones exhibit monocytic differentiation as a key escape mechanism. Pre-treatment CD34+ blasts transitioned to post-treatment CD16+ monocytic cells, indicating loss of stemness and resistance to venetoclax. Proteomic profiling further showed upregulation of anti-apoptotic markers, including BCL-XL and Ki67, and decreased immune surveillance markers such as HLA-DR.

Unexpectedly, TP53 mutations were detected in T cells and natural killer (NK) cells, correlating with T-cell exhaustion and immune evasion. This novel finding underscores the broader impact of TP53 mutations beyond leukemic cells. Additionally, MYC and PLK4 were identified as potential therapeutic targets, warranting further translational investigation.

Relevance: This study provides critical insights into venetoclax resistance in TP53-mutated AML, identifying monocytic differentiation and T-cell exhaustion as mechanisms of treatment failure. The detection of TP53 mutations in immune cells represents a paradigm shift, highlighting the complexity of resistance and immune escape. For clinicians, these findings reinforce the need for novel strategies to target resistant clones and enhance immune surveillance in TP53-mutated AML.

Link to Abstract: Abstract 61

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Abstract #372

Modified Dual CLL1-CD15 and CLL1-CD16 iCAR-T Cells for Mitigating Granulocytopenia Toxicities in the Treatment of Acute Myeloid Leukemia

Authors: Rui Zhang, Yifan Zhao, Mingfeng Zhao.

Background: CLL1-targeted CAR-T cell therapy has emerged as a promising strategy for AML but is limited by severe granulocytopenia due to CLL1 expression on neutrophils. To address this toxicity, the authors developed dual CLL1-CD15 and CLL1-CD16 inhibitory CAR (iCAR) T cells incorporating novel inhibitory domains to selectively spare neutrophils while maintaining anti-leukemic activity.

Study Overview and Results: Researchers designed CLL1-CD15 iCAR constructs incorporating inhibitory domains (PD-1, CSK, PD-1/2B4, PD-1/BTLA) and evaluated their ability to minimize neutrophil toxicity while maintaining cytotoxicity against AML blasts. The PD-1/2B4 combination demonstrated superior performance, reducing exhaustion, enhancing activation, and improving cytotoxicity toward CD15-negative tumor cells.

Building on these results, a CLL1-CD16 iCAR structure with a truncated VHH recognition domain was developed. CLL1-CD16 iCAR-T cells showed:

  • Enhanced elimination of CD16-negative AML blasts while minimizing cytotoxicity to CD16-positive neutrophils.
  • Sustained activation and cytotoxicity in the presence of AML blasts, neutrophils, and other iCAR-T cells.
  • Improved survival in xenograft AML models, with reduced incidence of granulocytopenia compared to traditional CLL1 CAR-T cells.

Relevance: This study presents an innovative approach to overcome granulocytopenia-related toxicities associated with CLL1 CAR-T therapy. By integrating dual inhibitory elements and optimizing target specificity, CLL1-CD16 iCAR-T cells achieve precise targeting of AML blasts while sparing neutrophils. These findings provide a foundation for clinical trials of CLL1-CD16 iCAR-T therapy in refractory/relapsed AML, offering a safer and more effective immunotherapy option for patients with limited treatment alternatives.

Link to Abstract: Abstract 372

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Abstract #216

Phase I/II Study of the All-Oral Combination of Revumenib (SNDX-5613) with Decitabine/ Cedazuridine (ASTX727) and Venetoclax (SAVE) in R/R AML

Authors: Ghayas C. Issa, Branko Cuglievan, Naval Daver, et al.

Background: Revumenib, an oral menin inhibitor, has demonstrated efficacy in KMT2A-rearranged (KMT2Ar) and NPM1-mutated AML, particularly in combination with venetoclax-based regimens. This Phase I/II trial (SAVE) explores the efficacy and safety of the all-oral combination of revumenib, venetoclax, and decitabine/cedazuridine (ASTX727) in relapsed/refractory (R/R) AML patients.

Study Overview and Results: A total of 26 patients (median age 35 years, range 12–79) with R/R AML or myeloid mixed-phenotype leukemia (MPAL) were enrolled. Molecular profiles included KMT2Ar (42%), NPM1 mutations (38%), and NUP98 rearrangements (20%). Most patients (65%) had prior venetoclax exposure, and 42% had undergone prior allogeneic hematopoietic stem cell transplant (HSCT).

  • The overall response rate (ORR) was 88% (23/26), with CR/CRh achieved in 58% of patients.
  • Among responders, 74% achieved MRD negativity by flow cytometry, with the highest MRD-negative rates observed in KMT2Ar and NPM1-mutated subsets.
  • 12 patients (46%) proceeded to HSCT, and 3 resumed maintenance revumenib post-HSCT, with 2 patients maintaining remission.
  • At a median follow-up of 6.6 months, 6-month relapse-free survival was 59%, and overall survival was 74%.

The regimen was well tolerated, with common Grade ≥3 adverse events including febrile neutropenia (46%), lung infections (42%), and QT prolongation (8%). Differentiation syndrome occurred in 8% of patients and resolved with steroids.

Relevance: The SAVE regimen demonstrates high remission rates and encouraging MRD-negative responses in heavily pretreated R/R AML patients with KMT2Ar and NPM1 mutations. The all-oral nature of this combination makes it an attractive option for outpatient treatment, addressing a significant unmet need in AML care. For clinicians, the results highlight the potential of combining menin inhibition with venetoclax and hypomethylating agents as a highly active and tolerable therapeutic strategy, with promising outcomes, particularly for patients who proceed to HSCT.

Link to Abstract: Abstract 216

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Abstract #212

Bleximenib Dose Optimization and Determination of RP2D from a Phase 1 Study in Relapsed/Refractory Acute Leukemia Patients with KMT2A and NPM1 Alterations

Authors: Emma Searle, MD, PhD, Christian Recher, MD, PhD, Maher Abdul-Hay, MD, et al.

Background: KMT2A rearrangements (KMT2Ar) and NPM1 mutations are common in acute leukemias and associated with poor outcomes, particularly in relapsed/refractory (R/R) disease. Bleximenib (JNJ-75276617) is a potent menin-KMT2A inhibitor being evaluated as monotherapy in patients with KMT2Ar or NPM1-mutated R/R acute leukemia (AL). This Phase 1 trial identifies the recommended Phase 2 dose (RP2D) and evaluates safety, pharmacokinetics (PK), and preliminary efficacy.

Study Overview and Results: A total of 121 patients with R/R acute leukemia (AML, n=108; ALL, n=6; other, n=7) were treated across multiple dose levels (45 mg BID, 90/100 mg BID, 150 mg BID) in 28-day cycles. Median patient age was 61 years, with KMT2Ar detected in 60% of patients and NPM1 mutations in 40%. The median number of prior therapies was 2, and 25% had undergone prior allogeneic transplant.

  • The RP2D was determined to be 90/100 mg BID based on overlapping PK exposures and manageable safety profiles.
  • Treatment-related adverse events (TRAEs) occurred in 58% of patients, most commonly differentiation syndrome (13%), neutropenia (12%), and thrombocytopenia (11%). Grade ≥3 differentiation syndrome occurred in 7% of patients, including two fatal events.
  • Clinical activity was observed in heavily pretreated patients, with composite response rates (CR/CRh) of 28% in KMT2Ar and 33% in NPM1-mutated subsets. Responses were durable, with several patients achieving measurable residual disease (MRD) negativity.

Relevance: This study establishes the RP2D of bleximenib and demonstrates promising clinical activity in heavily pretreated R/R AML patients with KMT2Ar or NPM1 mutations. Differentiation syndrome remains a significant but manageable toxicity with appropriate monitoring and dose adjustments. For clinicians, these findings position bleximenib as a potentially impactful therapy in a difficult-to-treat AML subset, paving the way for future Phase 2/3 studies to confirm efficacy and safety.

Link to Abstract: Abstract 212

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Abstract #968

Favorable Outcomes in Newly Diagnosed Pediatric AML with Gemtuzumab Ozogamicin and Risk-Stratified Therapy: Results from the International Phase III MyeChild 01 Trial

Authors: Brenda Gibson, André Baruchel, Andrew Moore, et al.

Background: Gemtuzumab ozogamicin (GO), a CD33-targeted antibody-drug conjugate, has shown survival benefits when added to intensive chemotherapy in pediatric AML. The MyeChild 01 trial is an international Phase III study investigating the efficacy and safety of 1 versus 3 doses of GO when combined with risk-stratified induction therapy in children with AML, high-risk myelodysplastic syndrome (MDS), or isolated myeloid sarcoma.

Study Overview and Results: A total of 515 pediatric patients were enrolled across multiple countries (UK, France, Australia, New Zealand, Ireland, Switzerland). Patients were randomized to receive either 1 dose or 3 doses of GO (3 mg/m²) during the first induction course with mitoxantrone and cytarabine (MA). Risk stratification following induction therapy was based on cytogenetics, molecular features, measurable residual disease (MRD), and remission status.

  • Of the 472 evaluable patients, 142 were classified as high-risk (HR) and received FLA-Ida (fludarabine, cytarabine, idarubicin) for Course 2, followed by allogeneic hematopoietic stem cell transplantation (HSCT).
  • Event-free survival (EFS) and overall outcomes will be presented in detail, with preliminary results suggesting favorable survival in both GO arms.
  • The addition of GO was well tolerated, with manageable toxicity profiles similar to prior pediatric AML studies.

Patient characteristics included a median age of 10 years and a median white cell count (WCC) of 14 x 10⁹/L. Most patients (96%) had de novo AML, and extramedullary disease was reported in 16%.

Relevance: The MyeChild 01 trial confirms the feasibility and efficacy of incorporating gemtuzumab ozogamicin into frontline induction therapy for pediatric AML, with favorable survival outcomes. Risk-stratified therapy, including MRD-driven decision-making and allocation to HSCT for high-risk patients, optimizes treatment for this population. These findings provide a foundation for refining pediatric AML protocols and further establishing GO as a key component of intensive chemotherapy regimens.

Link to Abstract: Abstract 968

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Abstract #4286

A Phase I Study to Evaluate the Safety and Tolerability of Gemtuzumab Ozogamicin and Midostaurin When Used in Combination with Standard Cytarabine and Daunorubicin Induction for Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia

Authors: Uma Borate, Kaitlyn M. Dvorak-Kornaus, Qiuhong Zhao, et al.

Background: FLT3 mutations occur in 25-30% of AML cases and are associated with aggressive disease. While midostaurin combined with cytarabine and daunorubicin (7+3) has become the standard of care for FLT3-mutated AML, CD33-directed therapy with gemtuzumab ozogamicin (GO) may provide additional benefit due to high CD33 expression on FLT3-mutated blasts. This Phase I study evaluates the safety and tolerability of GO when added to standard induction therapy and midostaurin in newly diagnosed (ND) FLT3-mutated, CD33+ AML patients.

Study Overview and Results: This open-label trial enrolled 21 patients with newly diagnosed FLT3-mutated, CD33+ AML. Patients received cytarabine (100 mg/m², Days 1-7), daunorubicin (60–90 mg/m², Days 1-3), midostaurin (50 mg BID, Days 8-21), and escalating doses of GO (3 mg/m²) administered on Days 1, 4, and 7 across four dose levels (DL1-DL4).

  • Composite CR (CR/CRi) was achieved in 76% of patients (16/21).
  • Eleven patients (52%) proceeded to allogeneic hematopoietic cell transplantation (HSCT).
  • Dose-limiting toxicities (DLTs) were observed primarily in DL3 (gastrointestinal toxicity with reduced midostaurin administration) and one hematologic DLT in DL2 (inadequate count recovery by Day 42). No DLTs were seen in DL1 or DL4.
  • The most common toxicities included nausea (79%), diarrhea (74%), and Grade 3+ cytopenias (WBC decrease: 58%; platelet count decrease: 53%).
  • At a median follow-up of 367 days, overall survival (OS) rates were 79% at 6 months, 65% at 1 year, and 39% at 2 years.

Relevance: This Phase I study demonstrates that the addition of gemtuzumab ozogamicin to standard induction therapy with midostaurin is well tolerated in newly diagnosed FLT3-mutated, CD33+ AML patients. The favorable CR rates and tolerable toxicity profile suggest that incorporating CD33-targeted therapy may enhance outcomes in this high-risk population without exacerbating treatment-related toxicity. These results provide a foundation for further evaluation of this combination in larger, prospective trials.

Link to Abstract: Abstract 4286

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Abstract #2907

Gemtuzumab-Based Induction Chemotherapy Combined with Midostaurin for FLT3-Mutated Patients: Results from the Patient-Reported Outcome Measures from the NCRI AML19V2 ‘Midotarg Pilot’

Authors: Joanna Canham, Ian Thomas, Nigel H. Russell, et al.

Background: The AML19 v2 ‘Midotarg’ pilot explored the addition of midostaurin (MIDO) to gemtuzumab ozogamicin (GO) and daunorubicin/cytarabine (DA) induction chemotherapy in FLT3-mutated AML. While the clinical outcomes demonstrated safety and promising survival results, this analysis focuses on patient-reported outcomes (PROs) to evaluate quality of life (QoL) during and after treatment.

Study Overview and Results: A total of 196 patients were enrolled, including 77 FLT3-mutated patients who received either DAGO1m (single dose of GO + MIDO) or DAGO2m (two doses of GO + MIDO). PROs were assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire at baseline, prior to treatment courses, and at 3, 6, 9, and 12 months post-trial entry.

  • Global QoL scores improved significantly for all patients over time, increasing from 47 to 71 prior to Course 2 and remaining stable through 12 months.
  • No statistically significant differences in global QoL were observed between the DAGO1m/DAGO2m groups and the non-midostaurin groups.
  • Specific domains showed transient differences during treatment, including dyspnea scores that were significantly lower at 6 months in the midostaurin-treated group (19 vs. 32, p=0.001). Insomnia scores were also improved in the midostaurin group at both 6 months (21 vs. 34, p=0.002) and 9 months (19 vs. 33, p=0.002).
  • At 12 months, once all patients were off treatment, no significant differences were seen across any QoL domains.

Importantly, there were no significant differences in the proportion of patients experiencing clinically meaningful QoL deterioration at any time point between treatment arms.

Relevance: The AML19 Midotarg pilot demonstrates that combining gemtuzumab ozogamicin with midostaurin in FLT3-mutated AML improves clinical outcomes without compromising patient-reported quality of life. While transient differences in symptom burden were noted during treatment, these effects resolved post-treatment. These findings provide valuable insights into balancing efficacy and patient experience in the management of FLT3-mutated AML, supporting the broader integration of this combination therapy into frontline regimens.

Link to Abstract: Abstract 2907

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Abstract #1508

Venetoclax-Based Therapy Versus Intensive Chemotherapy Followed By Allogeneic-Stem Cell Transplantation for High-Risk Elderly Acute Myeloid Leukemia

Authors: Alexandre Iat, Jan Philipp Bewersdorf, Julia Gilhodes, et al.

Background: High-risk elderly AML patients (aged 60–74) often face poor outcomes with standard intensive chemotherapy (IC) followed by allogeneic stem cell transplantation (allo-SCT). While venetoclax (VEN)-based regimens are effective in IC-ineligible patients, their role as frontline therapy for "fit" elderly AML patients remains underexplored. This study compares VEN-based therapy followed by allo-SCT with IC in high-risk patients.

Study Overview and Results: In this international retrospective study, 86 newly diagnosed AML patients with adverse-risk cytogenetics (per ELN 2022) were treated with either VEN-based regimens (n=20) or IC (n=66). VEN regimens included VEN with hypomethylating agents (HMA) or cladribine-fludarabine. Both groups had comparable baseline cytogenetics and mutational profiles, with 25% harboring TP53 mutations.

  • Overall Response Rate (ORR): VEN group 90% vs. IC group 78.7% (p=0.338).
  • Complete Remission (CR) Rates: VEN group 90% vs. IC group 80.3% (p=0.505).
  • Allo-SCT in CR/CRi: 50% of VEN-treated patients vs. 72.7% of IC-treated patients (p=0.101).
  • Median Overall Survival (OS): 20 months (VEN) vs. 19 months (IC) (p=0.508).

VEN-treated patients experienced comparable outcomes to IC-treated patients in terms of OS and relapse-free survival (RFS). Interestingly, VEN patients had fewer relapses after allo-SCT (35% vs. 31.8%), despite older age and longer times to transplantation.

Relevance: VEN-based therapy offers a promising alternative to IC for high-risk elderly AML patients eligible for allo-SCT, achieving comparable survival and response rates with potentially reduced toxicity. For clinicians, these findings support the integration of VEN regimens into treatment paradigms, particularly for older patients who may not tolerate IC.

Link to Abstract: Abstract 1508

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Abstract #733

Efficacy and Safety of Uproleselan Combined with Chemotherapy Vs. Chemotherapy Alone in Relapsed/Refractory Acute Myeloid Leukemia: Findings from an International Phase 3 Trial

Authors: Daniel J. DeAngelo, MD, PhD, Andre C. Schuh, MD, FRCPC, Brian A. Jonas, MD, PhD, et al.

Background: Uproleselan, an E-selectin antagonist, disrupts leukemia survival pathways and enhances chemotherapy sensitivity. Early-phase studies demonstrated its potential to improve outcomes in relapsed/refractory (R/R) AML. This Phase 3 trial evaluates uproleselan combined with chemotherapy versus chemotherapy alone in R/R AML patients.

Study Overview and Results: The trial enrolled 388 R/R AML patients (median age 58 years) randomized 1:1 to receive either uproleselan or placebo alongside chemotherapy (MEC or FAI regimens). Patients had a median of one prior therapy, and 33% had primary refractory AML. The primary endpoint was overall survival (OS), with key secondary endpoints including CR/CRh rates and measurable residual disease (MRD) negativity.

  • Median OS: Uproleselan 13.0 months vs. placebo 12.3 months (p=0.39). However, in primary refractory AML, OS significantly improved with uproleselan: 31.2 months vs. 10.1 months (p=0.004).
  • MRD Negativity: Achieved by 67.1% of uproleselan-treated patients versus 61.5% in placebo-treated patients.
  • CR/CRh Rates: Higher with uproleselan (46.4%) versus placebo (41.2%).
  • Patients undergoing allo-SCT post-treatment demonstrated longer OS with uproleselan (Not Reached) compared to placebo (24.8 months).

The treatment was well tolerated, with Grade ≥3 oral mucositis rates comparable between arms (7.2%).

Relevance: Uproleselan represents a significant step forward in the treatment of R/R AML, particularly for primary refractory patients who traditionally face dismal outcomes. By targeting the E-selectin pathway, uproleselan enhances chemotherapy’s impact while maintaining a manageable safety profile. The observed survival benefit in primary refractory patients and those undergoing allo-SCT post-treatment underscores its potential to redefine therapy in these high-risk subgroups. Furthermore, its ability to deepen responses and increase MRD negativity highlights its utility in achieving durable remissions. For clinicians, uproleselan offers a promising option to incorporate into current regimens, particularly for patients at high risk of treatment failure.

Link to Abstract: Abstract 733

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Abstract #2883

Clinical Outcomes Using Frontline “Triplet” Regimens for Newly Diagnosed IDH-Mutated Acute Myeloid Leukemia (AML): A Pooled Analysis of Two Phase Ib/2 Clinical Trials

Authors: Jennifer Marvin-Peek, MD, Himachandana Atluri, MD, Nicholas J. Short, MD, et al.

Background: Mutations in isocitrate dehydrogenase (IDH) genes occur in approximately 20% of AML cases and are associated with distinct pathophysiology and treatment challenges. Triplet regimens combining hypomethylating agents (HMA), venetoclax (VEN), and IDH inhibitors (IDHi) aim to prevent resistance and relapse by targeting multiple pathways simultaneously. This pooled analysis evaluates outcomes in newly diagnosed (ND), IDH-mutated AML patients treated with frontline triplet regimens.

Study Overview and Results: This analysis included 50 patients treated with either azacitidine (AZA) + VEN + ivosidenib (IVO) or oral decitabine/cedazuridine (ASTX727) + VEN + IVO/enasidenib (ENA). The median patient age was 71 years. Adverse-risk disease accounted for 72%, and 24% had secondary AML (tsAML).

  • Overall Response Rate (ORR): 96% (48/50).
  • Composite CR (CR/CRh/CRi) Rate: 92% (46/50).
  • Measurable Residual Disease (MRD) Negativity: Achieved in 78% (36/46) of evaluable patients.
  • Median Duration of Remission (DOR): 27 months.
  • 2-Year Overall Survival (OS): 82% (95% CI: 70–95%).

Notably, patients with tsAML had significantly worse outcomes compared to non-tsAML, with a median OS of 11 months versus not reached. Relapse occurred in 21% of responders, but most relapsed patients no longer had detectable IDH mutations, indicating a shift in clonal dynamics.
The triplet regimens were well tolerated, with a 30-day mortality of 0% and Grade ≥3 non-hematologic adverse events in 10% of patients.

Relevance: This study highlights the potential of frontline triplet regimens combining HMA, VEN, and IDHi to achieve deep, durable responses in newly diagnosed IDH-mutated AML, including high rates of MRD negativity. These findings underscore the utility of targeting multiple pathways simultaneously to reduce relapse risk, particularly in IDH-mutated disease. For clinicians, these data offer evidence to support triplet therapies as a promising option for patients ineligible for intensive chemotherapy, though secondary AML remains a therapeutic challenge requiring further innovation.

Link to Abstract: Abstract 2883

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Abstract #63

Abundance of Relapse-Predictive Cells Can be Estimated at Diagnosis and Is Strongly Associated with Outcome in Pediatric AML

Authors: Mohammad Javad Najaf Panah, MS, Alexandra McLean Stevens, MD, Michael Krueger, et al.

Background: Despite advancements in risk assessment for pediatric AML (pAML), relapse rates remain high among patients classified as low risk by cytogenetic (cyto) and measurable residual disease (MRD) criteria. This study uses single-cell RNA sequencing (scRNA-seq) to identify relapse-predictive cell subclones at diagnosis and evaluate their association with chemoresistance and clinical outcomes.

Study Overview and Results: The study analyzed diagnosis-relapse pairs from 13 pediatric AML cases using scRNA-seq to identify subclones. These findings were validated with public RNA-seq data from 870 FLT3-ITD-negative cases. Five relapse-predictive subclones (R1-R5) were identified, and their aggregate abundance (T) at diagnosis was strongly associated with outcomes:

  • Patients with T ≥7% had a 3-year OS of 54.4%, compared to 79.6% in patients with T <7% (p<10^-15).
  • Incorporating T abundance into current risk models improved outcome predictions, particularly for patients with conflicting cyto and MRD risk categories.
  • Multivariate analysis confirmed T abundance as an independent prognostic factor (HR 1.3, p=3.69e-05).

Patient-derived xenograft (PDX) models validated the chemoresistant nature of R subclones, with R cell populations enriched for oxidative phosphorylation, MYC targets, and genes co-expressed with FLT3 and CDK6. Additionally, the R5 subclone exhibited sensitivity to tamibarotene, a retinoic acid receptor agonist, suggesting a potential therapeutic target.

Relevance: This study introduces a novel method for refining pAML risk stratification by integrating relapse-predictive cell abundance into diagnostic algorithms. For clinicians, these findings underscore the importance of identifying chemoresistant subclones early to guide therapy intensification and consider novel agents like tamibarotene. This approach could reduce relapse rates and improve survival in pediatric AML, offering actionable insights into the biology of high-risk disease.

Link to Abstract: Abstract 63

Reference: Panah MJN, et al. Abundance of Relapse-Predictive Cells Can be Estimated at Diagnosis and Is Strongly Associated with Outcome in Pediatric AML. Blood. 2024;144 (Supplement 1):63. doi: https://doi.org/10.1182/blood-2024-206142

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Abstract #4255

Phase 1 Safety and Efficacy of Tuspetinib Plus Venetoclax Combination Therapy in Study Participants with Relapsed or Refractory Acute Myeloid Leukemia (AML) Support Exploration of Triplet Combination Therapy of Tuspetinib Plus Venetoclax and Azacitidine for Newly Diagnosed AML

Authors: Naval Daver, MD, Kyoo Hyung Lee, MD, PhD, Pau Montesinos, MD, et al.

Background: Tuspetinib (TUS) is an oral kinase inhibitor targeting multiple pathways implicated in AML progression, including FLT3, JAK1/2, and mutant KIT. This Phase 1 study evaluates TUS as monotherapy and in combination with venetoclax (VEN) for relapsed/refractory (R/R) AML. It aims to inform future development of triplet regimens incorporating TUS with VEN and hypomethylating agents (HMAs) in newly diagnosed AML.

Study Overview and Results: The study enrolled 93 patients for TUS monotherapy (dose escalation: 20–200 mg) and 79 patients for TUS + VEN combination therapy (40/80 mg TUS with 400 mg VEN daily). Key findings include:

  • In the monotherapy (80 mg TUS) group, the composite CR (CRc) was 26.3% overall, 37.5% in FLT3-mutated AML, and 35.7% in VEN-naïve patients. Responses in FLT3-mutated patients included 33.3% CRc in prior FLT3 inhibitor-treated patients.
  • In the combination therapy (TUS + VEN) group, the median age was 69 years; 73% had FLT3 wild-type AML, 75% were prior VEN-treated. Objective responses were observed across cohorts, with lower-than-expected rates of febrile neutropenia (26.6%).

TUS + VEN demonstrated a manageable safety profile with no TUS-related serious adverse events or dose-limiting toxicities.

Relevance: Tuspetinib offers a novel therapeutic approach for addressing resistance mechanisms in R/R AML, particularly in FLT3-mutated and VEN-naïve populations. The results pave the way for triplet combinations, leveraging TUS to enhance VEN and HMA efficacy in newly diagnosed AML. For clinicians, this study highlights TUS as a promising candidate for optimizing combination strategies, particularly for patients with limited therapeutic options.

Link to Abstract: Abstract 4255

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Abstract #1007

Updated Results from a Phase II Study of Vibecotamab, a CD3-CD123 Bispecific T-Cell Engaging Antibody, for MDS or CMML After Hypomethylating Agent Failure and in MRD-Positive AML

Authors: Daniel Nguyen, MD, PhD, Farhad Ravandi, MBBS, Nicholas J. Short, MD, et al.

Background: CD123 is highly expressed on leukemic stem cells, making it an attractive therapeutic target in myeloid neoplasms, including AML, MDS, and CMML. Vibecotamab is a CD3-CD123 bispecific T-cell engaging antibody that has shown clinical activity in AML. This Phase II study evaluates vibecotamab in MDS/CMML following hypomethylating agent (HMA) failure and in MRD-positive AML.

Study Overview and Results: The study enrolled 37 patients: 19 with MDS/CMML and 18 with AML in MRD-positive remission. Vibecotamab was administered in a ramp-up dosing schedule in 28-day cycles.

  • In the MDS/CMML Cohort, the overall response rate (ORR) was 68%, with 63% achieving marrow complete remission (mCR) and 5% achieving hematologic improvement (HI). Median duration of response was 5.2 months and responses were observed across all risk levels, including TP53-mutated patients.
  • In the AML MRD Cohort, MRD negativity was achieved in 28% of patients, all after one cycle. Median overall survival was 10.3 months and responses were independent of CD123 expression levels.

The treatment was well tolerated, with no new safety signals. Most relapses occurred after protocol completion, highlighting the need for maintenance strategies.

Relevance: Vibecotamab demonstrates promising activity in MDS/CMML following HMA failure and MRD-positive AML, two high-risk populations with limited therapeutic options. Its efficacy across diverse genetic and cytogenetic subtypes supports its potential as a valuable addition to the therapeutic arsenal in myeloid malignancies. For clinicians, these results highlight the importance of incorporating novel immunotherapies targeting CD123 into current treatment paradigms, with future studies needed to optimize maintenance strategies and combination regimens.

Link to Abstract: Abstract 1007

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Abstract #1564

Demographics, Characteristics, Survival and Outcomes in Older, Untreated, Acute Myeloid Leukemia Patients with NPM1 Mutations or KMT2A rearrangements from the Beat AML Master Clinical Trial

Authors: Uma Borate, MD, Rina Li Welkie, MPH, Ying Huang, MS, MA, et al.

Background: While NPM1 mutations and KMT2A rearrangements are associated with specific responses to menin inhibitors, their prevalence and clinical outcomes in older AML patients (≥60 years) remain underexplored. This study analyzes the outcomes of this subset of patients enrolled in the Beat AML Master Trial (BAMT), with a focus on treatment regimens and overall survival (OS).

Study Overview and Results: From 1,096 patients enrolled, 246 harbored either an NPM1 mutation (n=207) or KMT2A rearrangement (n=39). Patients were stratified by treatment modality: sub-study targeted therapies, venetoclax + hypomethylating agent (Ven/HMA), intensive chemotherapy (IC), non-intensive therapy (NIT), or no treatment.

In the NPM1 mutation cohort, the median age was 72 years, and 26% of patients had an ECOG performance status of ≥2. The overall median OS was 18.4 months (95% CI: 14.2–24.7), with outcomes varying significantly by treatment modality. Patients receiving sub-study targeted therapies or Ven/HMA had a median OS of 21 months and 22 months, respectively. Intensive chemotherapy resulted in the best outcomes, with a median OS of 41.6 months, while non-intensive therapies were associated with a much poorer median OS of 6.3 months.

In the KMT2A rearrangement cohort, the median age was 69 years, with 35% of patients having an ECOG performance status of ≥2 and 31% exhibiting complex karyotypes. This cohort showed an overall median OS of 6.5 months (95% CI: 3.6–31.6). Survival outcomes were poorest in patients receiving non-intensive therapies, and high-risk cytogenetic features further diminished responses.

For both cohorts, intensive chemotherapy achieved superior survival compared to non-intensive options, but the choice of therapy often depended on ECOG status and patient fitness.

Relevance: This study highlights the need for personalized approaches in older AML patients with NPM1 mutations or KMT2A rearrangements. Intensive chemotherapy offers a survival advantage in fit patients, while venetoclax-based therapies provide an effective alternative for those with limited fitness. These findings underscore the importance of genetic profiling and fitness-based stratification to guide therapy selection, ensuring optimal outcomes in this challenging population.

Link to Abstract: Abstract 1564

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Abstract #3585

AUTX703, a Novel and Potent KAT2A and KAT2B Protein Degrader, Induces Differentiation and Offers Survival Advantage in a Primary Human AML Xenograft Model

Authors: Hélène Duparc, PhD, James Neef, BS, Janany Kandiah, MS, et al.

Background: Differentiation therapy aims to reverse the block in cellular maturation in AML, enabling leukemic cells to progress into non-proliferative, mature cell states. This study investigates AUTX703, a first-in-class oral protein degrader targeting KAT2A and KAT2B, epigenetic enzymes implicated in leukemic stem cell plasticity and differentiation arrest in AML.

Study Overview and Results: Using a primary AML xenograft model and patient-derived AML blasts, AUTX703 demonstrated potent activity across preclinical systems:

  • In AML cell lines, AUTX703 degraded KAT2A/KAT2B with DC50 <0.1nM, inducing monocytic differentiation markers (CD86) and growth inhibition (GI50 at 1nM).
  • Ex vivo treatment of AML CD34+ blasts showed significant differentiation and growth inhibition (GI50 <1nM), confirmed by increases in CD11b expression and granulocytic markers.
  • In an AML xenograft model, AUTX703 improved survival over 8 weeks with a dose-dependent reduction in peripheral blasts and well-tolerated safety profile.

The compound’s ability to induce myeloid differentiation was consistent across genetically diverse AML subtypes. A Phase 1 clinical trial is planned to evaluate its safety and efficacy in AML patients.

Relevance: AUTX703 represents a novel therapeutic avenue in AML by leveraging differentiation therapy through targeted protein degradation. For clinicians, this approach could address the unmet need for therapies targeting leukemic stem cells and differentiation arrest, especially in patients unresponsive to standard cytotoxic therapies. The preclinical findings provide a strong foundation for the forthcoming clinical trials, offering hope for improved outcomes in this challenging disease.

Link to Abstract: Abstract 3585

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Last modified: December 20, 2024

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