EHA 2024: Select Abstracts of Key Advances in AML

Welcome to our comprehensive review of the latest AML research from the 29th European Hematology Association Congress, held in June 2024. 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 #P565

FLAG Regimen, Combined with Gemtuzumab (FLAG-GO) Results in Better Optimal Molecular Response and Outcomes, Compared to Combination with Idarubicin (FLAG-IDA) in Untreated Core Binding Factor AML

Authors: Gautam Borthakur, Farhad Ravandi, Tapan Kadia, Courtney DiNardo, et al

Background: Optimal molecular response (OMR) is a critical parameter impacting outcomes in core-binding factor acute myeloid leukemia (CBF AML). The addition of gemtuzumab ozogamicin (GO) to the FLAG regimen (fludarabine, GCSF, cytarabine) has been associated with improved molecular and clinical outcomes compared to FLAG combined with idarubicin (IDA).

Study Overview and Results: This phase 2 trial monitored OMR and survival outcomes in newly diagnosed CBF-AML patients treated with FLAG-GO versus FLAG-IDA. A total of 179 patients were treated, with 85 receiving FLAG-GO and 94 receiving FLAG-IDA. The study found that OMR at the end of induction and consolidation was significantly higher in the FLAG-GO cohort (61% and 83%) compared to the FLAG-IDA cohort (41% and 56%). Overall survival at six years was 80% for FLAG-GO and 70% for FLAG-IDA, while relapse-free survival at six years was 76% for FLAG-GO and 58% for FLAG-IDA.

Relevance: These findings suggest that the FLAG-GO regimen leads to higher optimal molecular response rates and improved long-term outcomes in patients with de novo CBF AML compared to FLAG-IDA. For practicing oncologists, this supports the use of FLAG-GO as a preferred induction/consolidation regimen for better patient outcomes.

Link to Abstract: Abstract P565

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Abstract #P441

Clinical and Molecular Characteristics of AML Patients with an Exceptional Response to Ivosidenib

Authors: Justin M. Watts,  Prapti A Patel,  Sung Choe,  Xiaofei Bai,  Dylan M Marchione,  Eytan Stein

This study investigates the clinical and molecular characteristics of IDH1-mutant relapsed/refractory AML patients who exhibited exceptional responses to ivosidenib (IVO), defined as a duration of response (DOR) greater than 12 months. Among 179 patients treated with IVO 500mg daily, 13 patients (7.3% of the cohort) achieved exceptional responses, with a median DOR of 42.6 months. The study found that these patients commonly had low mutational burdens, lacked receptor tyrosine kinase (RTK) pathway mutations, and often had co-mutations associated with clonal hematopoiesis, such as DNMT3A, ASXL1, SRSF2, and JAK2. Additionally, these patients frequently had intermediate-risk cytogenetics and a high rate of IDH1 R132C mutations.

Relevance: For practicing oncologists, these findings underscore the potential of ivosidenib to achieve durable remissions in a subset of IDH1-mutant AML patients, highlighting the importance of genetic profiling in identifying patients who may benefit most from this therapy.

Link to Abstract: Abstract P441

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Abstract #P1373

Olutasidenib as Bridge-to-Transplant Treatment in Patients with Relapsed/Refractory mIDH1 Acute Myeloid Leukemia (AML)

Authors: Stéphane De Botton, Christian Récher, Daniela Cilloni, Jordi Esteve Reyner, et al

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative for AML patients at high risk of relapse, but achieving remission in relapsed/refractory (R/R) AML is challenging. Olutasidenib (OLU), an FDA-approved treatment for R/R mIDH1 AML, has shown promise in enabling previously ineligible patients to proceed to HSCT.

Study Overview and Results: This study reports on the characteristics and outcomes of patients treated with olutasidenib who then underwent allogeneic HSCT. In the Phase 2 trial, 153 patients with R/R mIDH1 AML received OLU monotherapy, and 16 proceeded to HSCT. Among these, 75% achieved complete remission or CR with partial hematologic recovery (CR/CRh). The overall survival probability was 94% at 12 months and 61% at 24 months.

Relevance: These findings suggest that olutasidenib is effective in achieving remission and serving as a bridging strategy to allogeneic HSCT in patients with R/R mIDH1 AML. For practicing oncologists, olutasidenib offers a valuable option for improving the eligibility of high-risk AML patients for potentially curative transplantation.

Link to Abstract: Abstract P1373

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Abstract #P1377

Long Term Efficacy Results of the SIERRA Trial: A Phase 3 Study of 131I-Apamistamab-Led Allogeneic Hematopoietic Cell Transplantation Versus Conventional Care in Older Patients with Active, R/R AML

Authors: James M Foran, Boglarka Gyurkocza, Rajneesh Nath, Stuart Seropian, et al

Background: Older patients with relapsed or refractory (R/R) AML often cannot tolerate intensive treatments and are ineligible for curative allogeneic hematopoietic cell transplantation (HCT). Iomab-B (131I-apamistamab), an anti-CD45 radioimmunoconjugate, delivers high-dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells with reduced off-target toxicity. This study investigates the long-term efficacy of Iomab-B-led conditioning followed by HCT in older patients with active R/R AML.

Study Overview and Results: In the SIERRA trial, 153 patients aged ≥55 years with active R/R AML were randomized to receive either Iomab-B-based conditioning followed by HCT or physician's choice of conventional care (CC). Among evaluable patients, 74.6% on the Iomab-B arm achieved initial CR/CRp compared to 6.3% on the CC arm. The median overall survival (OS) was significantly longer in the Iomab-B arm (6.3 months) compared to the CC arm (4.0 months). The Iomab-B regimen was well tolerated, with lower rates of sepsis and mucositis compared to standard HCT.

Relevance: These findings demonstrate that Iomab-B-led conditioning followed by HCT significantly improves remission rates and overall survival in older patients with R/R AML. For practicing oncologists, Iomab-B offers a promising option for enabling HCT in a patient population traditionally not considered eligible, potentially leading to better long-term outcomes.

Link to Abstract: Abstract P1377

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Abstract #P580

A Multicenter Real-World Analysis of Gemtuzumab Ozogamicin in the First-Line Treatment of CBF-AML

Authors: Philippe J. Muller, Sven Zukunft, Barbora Weinbergerová, Jiří Šrámek, et al

Background: Gemtuzumab ozogamicin (GO) added to cytarabine and daunorubicin significantly improved event-free survival (EFS) in the ALFA-0701 trial, leading to its approval for AML treatment. Although limited data exist on its use in core-binding factor AML (CBF-AML), a meta-analysis showed that GO addition significantly reduces relapse risk and improves overall survival (OS) in AML patients with favorable cytogenetics.

Study Overview and Results: This registry-based analysis compared outcomes of CBF-AML patients treated with intensive chemotherapy plus GO versus intensive therapy alone. The study included 265 patients, with similar baseline characteristics between the GO and non-GO cohorts. Composite complete remission rates were comparable (88.8% vs. 88.1%). After a median follow-up of 2.2 years for the GO cohort and 5.5 years for the non-GO cohort, 2-year EFS was 59% for GO and 47.6% for non-GO. OS was significantly better in the GO cohort (90.4% vs. 79.5%).

Relevance: These findings suggest that adding GO to frontline chemotherapy improves overall survival in CBF-AML patients, despite a longer platelet recovery time. For practicing oncologists, this real-world data supports the use of GO in first-line treatment of CBF-AML to enhance patient outcomes by reducing the risk of relapse.

Link to Abstract: Abstract P580

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Abstract #P544

Venetoclax Plus Azacitidine Cytarabine Aclarubicin and G-CSF (VA-CAG Regimen) for Newly Diagnosed Patients with Acute Myeloid Leukemia: Update of a Prospective Multicenter Phase 2 Clinical Trial

Authors: Xiaoping Li,  Yanling Jin,  Qiurong Zhang, et al

Background: The combination of venetoclax, a BCL-2 inhibitor, with hypomethylating agents like azacitidine has shown promise in AML treatment. Adding cytarabine, aclarubicin, and G-CSF (CAG regimen) to this combination could enhance efficacy, particularly for newly diagnosed AML patients.

Study Overview and Results: This phase 2 trial explored the VA-CAG regimen for newly diagnosed AML patients. The study enrolled 67 patients, achieving a 98.5% overall response rate, with 94% achieving complete remission (CR). The regimen showed a high rate of MRD negativity (82.5%) and an acceptable safety profile, with common adverse events being neutropenia and thrombocytopenia.

Relevance: These results highlight the VA-CAG regimen as an effective and safe treatment option for newly diagnosed AML patients, particularly those who are young and fit, offering high remission rates and a good safety profile.

 Link to Abstract: Abstract P544

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Abstract #P623

Reduced Dose FLAG-Mitoxantrone and Low Dose Venetoclax Induces Deep Remissions and High Rate of Transition to Successful Allogeneic Stem Cell Transplantation in Relapsed/Refractory AML

Authors: Ahmad Ibrahim, Kamal Al Zahran, Ahmad Khalil, Ali Youssef, et al

Background: Venetoclax combined with FLAG-Ida (G-CSF, Fludarabine, Cytarabine, Idarubicin) is an effective therapy for relapsed/refractory (R/R) AML, associated with deep remissions and high rates of transition to successful allogeneic hematopoietic stem cell transplantation (AHSCT). Lowering the cytarabine dose and shortening the duration of venetoclax administration can reduce hematological and infectious toxicities. FLAG-Mitoxantrone (Mitox) has also been effective and well-tolerated as a salvage regimen for R/R AML.

Study Overview and Results: This pilot study evaluated the efficacy of reduced dose FLAG-Mitox combined with low-dose venetoclax (Ven) in R/R AML patients, followed by AHSCT when feasible. Among 30 patients treated, 77% achieved composite complete remission (CRc), and 60% underwent AHSCT in second CR. The 2-year overall survival (OS) and relapse-free survival (RFS) were significantly higher in patients who underwent AHSCT compared to those who did not (75% vs. 25% and 67% vs. 20%, respectively).

Relevance: These findings suggest that the reduced dose FLAG-Mitox and Ven regimen is highly effective in inducing deep remissions and enabling successful transition to AHSCT in R/R AML patients. For practicing oncologists, this regimen offers a promising salvage therapy that improves outcomes and increases the likelihood of long-term remission.

Link to Abstract: Abstract P623

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Abstract #P615

Real-World Experience Using CPX-351 for AML-MRC and Therapy-Related Myeloid Neoplasms

Authors: Daniele Avenoso, Catherine Quinlan, Sara Lozano Cerrada, Ahmed Butt, et al

Background: AML secondary to myelodysplastic syndromes (AML-MRC) or prior chemo/radiotherapy (t-AML) is associated with poor prognosis and high rates of chemo-refractoriness. In patients aged >60, the CPX-351 regimen showed superior overall survival compared to standard of care in a prospective randomized clinical trial.

Study Overview and Results: This study reports the efficacy of CPX-351 followed by allogeneic hematopoietic stem cell transplant (allo-HSCT) in AML-MRC and t-AML patients treated across five centers. Among 110 patients, the overall response rate to CPX-351 was 69%, with 60% achieving complete remission (CR). Allo-HSCT was offered to 50% of patients, leading to significantly improved overall survival (OS) in both AML-MRC and t-AML groups. Median OS was 18 months, with transplanted patients showing markedly better outcomes compared to non-transplanted patients.

Relevance: These findings support the use of CPX-351 as an effective induction therapy for high-risk AML, particularly when followed by allo-HSCT, which offers a substantial survival benefit. For practicing oncologists, this combination provides a viable treatment strategy for improving outcomes in AML-MRC and t-AML patients, especially those over 60 years old.

Link to Abstract: Abstract P615

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Abstract #PB2448

Improving Bone Marrow Microenvironment in Acute Myelogenous Leukemia Elderly Patients (AML) Through 2 Months of Pre-Induction with Azacitidine and Venetoclax

Author: Maher Salamoon

Background: Acute Myelogenous Leukemia (AML) is a heterogeneous disease traditionally treated with standard chemotherapy (3+7), which carries a high risk of mortality during the induction phase, especially in elderly patients. Recent treatments targeting FLT-3 and Bcl-2 have been combined with chemotherapy, but the induction mortality rate remains high. This study explores a new treatment method aimed at improving the bone marrow microenvironment to reduce induction mortality in elderly AML patients.

Study Overview and Results: This study included 20 elderly AML patients (aged 60-72, median age 66), excluding those with M3 AML. They underwent a pre-induction phase involving Azacitidine (75mg/m² for five consecutive days each month) and Venetoclax (200 mg daily) for two months. Bone marrow aspirations were performed monthly and compared with a control group of 30 similar-aged patients. Results showed a median blast clearance of 36% after the first month and 50% after the second month. Additionally, 75% of patients achieved normalization of white blood cell counts, and 90% achieved normalization of platelet counts. The mortality rate in the study group was 10%, compared to 60% in the control group. Patients achieving complete response (15 out of 20) proceeded with a (5+2) induction protocol followed by four consolidation cycles. The one-year progression-free survival (PFS) was 60%, and the overall survival (OS) at two years was also 60%.

Relevance: This study highlights the potential benefits of a pre-induction regimen with Azacitidine and Venetoclax in elderly AML patients, demonstrating significant improvements in bone marrow blast clearance, normalization of blood counts, and reduced induction mortality. For practicing oncologists, these findings suggest a promising approach to improve outcomes in this high-risk patient group. Implementing this regimen could lead to better management of elderly AML patients, reducing induction-phase mortality and enhancing overall survival.

Link to Abstract: Abstract PB2448

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Abstract #PB2449

Pre-Induction with Four Weekly High-Dose Cytarabine Reduces Mortality Rate and Prolongs Progression-Free Survival in Acute Myelogenous Leukemia (AML): A Comparative Study

Authors: Maher Salamoon, Mehdi Balti

Background: Acute myelogenous leukemia (AML) remains one of the most challenging and lethal diseases, regardless of morphologic subtype and risk category. Traditional induction therapy, such as the standard (3+7) regimen, has limited success, prompting the need for innovative approaches to improve response and survival rates.

Study Overview and Results: This study aimed to evaluate the role of pre-induction with weekly high-dose Cytarabine on response rate and relapse-free survival. Conducted at Al Bairouni University Cancer Center in Damascus, Syria, the study involved 100 AML patients. Group I (50 patients) received the standard (3+7) regimen, while Group II (50 patients) received pre-induction with 3 grams of Cytarabine on days 1, 8, 15, and 28, followed by the standard (3+7) regimen. Both groups underwent consolidation chemotherapy. Results showed that the response rate was significantly higher in Group II (62% vs. 45%, p=0.05). Group II also exhibited a lower mortality rate (15% decrease, p=0.03), better progression-free survival (PFS) (89 months vs. 13 months, p=0.05), and a better toxicity profile with shorter hospital stays post-induction (18 days vs. 25 days, median).

Relevance: This study demonstrates that pre-induction with high-dose Cytarabine can significantly improve outcomes in AML patients by enhancing response rates, reducing mortality, and prolonging progression-free survival. For community oncologists, this suggests a viable strategy to improve patient management and survival outcomes in AML. Implementing this pre-induction regimen could lead to better patient prognoses and a more efficient use of hospital resources.

Link to Abstract: Abstract PB2449

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Abstract #PB2502

Real-World Use of Venetoclax + Azacitidine in Elderly (>70 Years) Chemotherapy-Ineligible Untreated Acute Myeloid Leukemia Patients: A Second Level Hospitals Experience

Authors: Rosalia de la Puerta Paula, Carolina Villegas Da Ros, Aima Lancharro Anchel, et al 

Background: Acute myeloid leukemia (AML) presents significant challenges, particularly in elderly patients, with a 5-year survival rate of less than 10% for those over 60. In 2018, the BCL-2 inhibitor venetoclax (Ven) combined with azacitidine (Aza) was approved for newly diagnosed AML patients aged ≥75 or those ineligible for intensive chemotherapy.

Study Overview and Results: This retrospective analysis, conducted from January 2020 to February 2024, included 29 elderly AML patients from three second-level hospitals in Spain. Patients received azacitidine combined with venetoclax as first-line treatment. The primary endpoint was overall survival (OS), and the secondary endpoint was OS related to response rate (CR) after the first treatment cycle. Data were analyzed using Kaplan-Meier methodology, with follow-up until the last recorded event.

The majority of patients (68.9%) had favorable or intermediate-risk AML. The most common mutations were NPM1 and BCOR. At the end of the follow-up, 41.4% achieved complete response (CR or CRi). The median OS (mOS) was 26.9 months, with patients achieving CR in the first month showing a longer OS of 31 months. Cytopenias occurred in 51.7% of patients, and neutropenic fever in 65.5%. Patients received between 1 and 37 treatment cycles.

Relevance: This study demonstrates the significant benefit of azacitidine plus venetoclax in elderly, chemotherapy-ineligible AML patients, achieving a median OS of 26.9 months. Notably, patients who achieved CR in the first month had an even longer OS of 31 months. These findings underscore the importance of this regimen in improving outcomes for a population with limited treatment options.

Link to Abstract: Abstract PB2502

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Abstract #PB2505

Hypomethylating Agents + Venetoclax Therapy in Late Elderly AML: "To Be or Not to Be" Well Effective?

Authors: Lorenzo Rizzo, Marta Riva, Silvia Ferrari, Cosimo De Giorgio, et al 

Background: Acute myeloid leukemia (AML) significantly affects the elderly, with about one-third of patients being over 75 years old. Since 2020, the combination of hypomethylating agents (HMA) with venetoclax has enhanced the efficacy of less-intensive therapeutic options. Real-world data on this combination's effectiveness in the late elderly population remains limited.

Study Overview and Results: This retrospective study evaluated the feasibility, tolerance, safety, and efficacy of HMA + venetoclax in AML patients aged over 75 years, treated at a single center from 2020 onward. The study included 26 patients with a median age of 80.3 years. Patients received either azacitidine + venetoclax (58%) or decitabine + venetoclax (42%), with a total of 2 to 31 treatment cycles per patient. The best response (BR) included complete response (CR) in 25% of patients, and 37.5% achieved BR after two cycles. The only significant factor influencing response was previous HMA treatment. Median event-free survival (EFS) and overall survival (OS) were 5.8 and 6.3 months, respectively. Risk class and BR type were significant predictors of OS.

Relevance: This study highlights the feasibility and effectiveness of HMA + venetoclax in elderly AML patients, even in those over 75 years old. Despite the limitations of a retrospective analysis, the approach appears viable, with meaningful response rates and improved long-term survival. The study also emphasizes the importance of first-line treatment, as the loss of response or progression often leads to rapid patient death. Further prospective studies are needed to confirm the superiority of HMA + venetoclax regimens over best supportive care in this population.

Link to Abstract: Abstract PB2505

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Abstract #PB2516

Prognostic Role of C-Reactive Protein, Albumin, and the Glasgow Prognostic Score in Elderly Patients with Acute Myeloid Leukemia Not Suitable for Intensive Treatment: A Retrospective Study

Authors: Verena Petermichl, Matthias Weber, Lukas Graf, Yannick Gerth, et al

Background: In acute myeloid leukemia (AML), prognosis is traditionally determined by cytogenetic aberrations and mutations as defined by the European Leukemia Net (ELN). However, these criteria often place the majority of elderly patients in the adverse risk category, limiting their prognostic utility. C-reactive protein (CRP) and albumin levels have been shown to add prognostic information independently from the ELN2017 risk classification. This study investigates the prognostic value of these biomarkers when the ELN2022 classification is applied.

Study Overview and Results: This retrospective study reviewed clinical data from AML patients (excluding acute promyelocytic leukemia) diagnosed at our hospital between 2016 and 2021. The Glasgow Prognostic Score (GPS) was determined based on CRP and albumin levels. Among 51 evaluable patients (median age 77 years), 19.6% received best supportive care, 45.1% received hypomethylating agents (HMA), and 25.5% received HMA combined with venetoclax. The study found that CRP > 10 mg/L and albumin < 35 g/L were associated with significantly shorter overall survival (OS). The GPS stratified patients into three groups with distinct survival outcomes, and within the adverse risk group, the GPS further delineated survival differences.

Relevance: This study highlights the additional prognostic value of CRP and albumin in elderly AML patients, particularly those classified as adverse risk by ELN2022. These easily accessible and low-cost biomarkers can provide important prognostic information, potentially guiding more personalized treatment approaches. Further evaluation in larger patient cohorts is warranted to validate these findings.

Link to Abstract: Abstract PB2516

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Abstract #S141

A Post Hoc Analysis of Outcomes of Patients with Acute Myeloid Leukemia with Myelodysplasia-Related Changes Who Received Oral Azacitidine Maintenance Therapy in the QUAZAR AML-001 Study

Authors: Maria Teresa Voso, Stéphane De Botton, Michael Pfeilstöcker, et al

Background: Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) accounts for 25%-34% of all AML cases and is associated with poor outcomes. The QUAZAR AML-001 study evaluated the efficacy of oral azacitidine (Oral-AZA) as maintenance therapy in AML patients post-remission who were ineligible for hematopoietic stem cell transplantation (HSCT).

Study Overview and Results: This post hoc analysis of the phase 3 QUAZAR AML-001 study aimed to report the outcomes of AML-MRC patients who received Oral-AZA versus placebo (PBO). Patients aged 55 years and older with AML in first remission and intermediate- or poor-risk cytogenetics were randomized to receive either Oral-AZA 300 mg or PBO daily for 14 days of a 28-day cycle. AML-MRC was identified using the 2008 World Health Organization criteria. In this analysis, 101 out of 472 patients had AML-MRC. The Oral-AZA arm included 56 AML-MRC patients, and the PBO arm included 45. Poor-risk cytogenetics were more common in AML-MRC patients compared to non-AML-MRC patients.

Median overall survival (OS) did not significantly differ between AML-MRC and non-AML-MRC patients in either treatment arm. However, median relapse-free survival (RFS) was significantly inferior for AML-MRC patients compared to non-AML-MRC patients in both treatment arms. Importantly, Oral-AZA significantly improved median OS (19.9 months vs 14.8 months) and RFS (7.5 months vs 3.7 months) compared to PBO for AML-MRC patients. The duration of measurable residual disease (MRD) negativity was also longer in the Oral-AZA group.

Relevance: This analysis indicates that Oral-AZA maintenance therapy significantly improves survival outcomes in AML-MRC patients, a group with a particularly poor prognosis. These findings suggest that Oral-AZA is an effective maintenance treatment option for this high-risk patient population.

Link to Abstract: Abstract S141

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Abstract #P621

Prognostic Factors in TP53-Mutated AML/MDS Patients Undergoing Allo-HSCT: Insights from a Multi-Center Study

Authors: Yeqian Zhao, Weihao Chen, Ji-Min Shi, Yi Luo, Jian Yu, et al 

Background: TP53 mutations, present in approximately 8-13% of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cases, are associated with poor outcomes and limited response to conventional therapies. While allogeneic hematopoietic stem cell transplantation (allo-HSCT) can improve outcomes for TP53-mutated patients, their prognosis remains inferior compared to those with wild-type TP53.

Study Overview and Results: This multi-center retrospective study analyzed 84 patients with TP53-mutated AML/MDS who underwent allo-HSCT between January 2017 and September 2023. The median age at diagnosis was 46 years, with 87% diagnosed with de novo AML/MDS and 13% with secondary AML. Most patients (79%) received haploidentical HSCT. The three-year overall survival (OS) was 68.4%, relapse-free survival (RFS) was 55.7%, and cumulative incidence of relapse (CIR) was 32.8%. Patients with secondary AML had poorer prognosis (OS: HR 2.4, p = 0.08; RFS: HR 2.9, p = 0.02). A complex karyotype (CK) negatively impacted OS (HR 2.5, p = 0.05) and RFS (HR 2.5, p = 0.02), and was significantly associated with multi-hit TP53 status (p = 0.004). Instances of clonal evolution were noted, indicating potential malignant progression.

Relevance: This study highlights the prognostic factors affecting outcomes in TP53-mutated AML/MDS patients undergoing allo-HSCT. The findings underscore the importance of genetic profiling, particularly for TP53 and complex karyotypes, in predicting patient prognosis and guiding treatment strategies. The study suggests that while allo-HSCT offers survival benefits, patients with secondary AML and complex karyotypes require closer monitoring and potentially novel therapeutic approaches to improve outcomes.

Link to Abstract: Abstract P621

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Abstract #PB2465

The Efficacy and Safety of Selinexor Combined with Venetoclax for Untreated Elderly Unfit Acute Myeloid Leukemia (AML)

Authors: Dexiang Ji, Fancong Kong, Yulan Zhou, Jieyu Wang, et al

Background: Acute myeloid leukemia (AML) incidence increases with age, with a median diagnosis age around 68. Elderly patients often cannot tolerate intensive chemotherapy due to age and comorbidities. Combining venetoclax with azacitidine shows a 64% response rate and 14.7 months median overall survival, though resistance is a challenge. Selinexor, approved for refractory/relapsed multiple myeloma, shows potential in overcoming venetoclax resistance and has demonstrated efficacy and tolerability in phase I/II AML trials.

Study Overview and Results: This study evaluated the efficacy and safety of selinexor combined with venetoclax in newly diagnosed elderly unfit AML patients. Eligible patients were aged 60 or older, unfit for intensive chemotherapy, with an ECOG score ≥2. The primary endpoints were complete response (CR)/complete response with incomplete count recovery (CRi) rate and overall response rate (ORR) after two cycles. Patients received selinexor 40mg on specified days and venetoclax 100mg on day 1, 200mg on day 2, and 400mg on days 3 to 28 in 28-day cycles.

From April 2023 to February 2024, nine patients were enrolled, with a median age of 67 years; 78% were adverse-risk. The ORR was 66.7%, with all responders achieving CR/CRi. Four patients achieved MRD-negative status after two cycles, and one turned negative after three cycles. Grade 3 or higher adverse events included neutropenia (100%), thrombocytopenia (66.7%), febrile neutropenia (33.3%), and infections (22.2%). Grade 1-2 adverse events included nausea, anorexia, diarrhea, fatigue, anemia, edema, and hyponatremia.

Relevance: Selinexor and venetoclax show promising efficacy and manageable safety in elderly unfit AML patients, especially those with adverse-risk profiles. This regimen offers community oncologists a potential alternative for patients who cannot undergo intensive chemotherapy, demonstrating high response rates and manageable toxicity. Further multicenter trials are needed to confirm these findings.

Link to Abstract: Abstract PB2465

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Abstract #P557

Safety and Efficacy of Tuspetinib as Monotherapy and Combined with Venetoclax in a Phase 1/2 Trial of Patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML)

Authors: Naval Daver, Kyoo-Hyung Lee, Yunsuk Choi, et al

Background: Tuspetinib is a novel oral kinase inhibitor targeting key pathways involved in AML pathogenesis. Combining tuspetinib with venetoclax, a BCL-2 inhibitor, may enhance anti-leukemic activity, particularly in patients with relapsed or refractory (R/R) AML.

Study Overview and Results: This phase 1/2 study evaluated tuspetinib, an oral kinase inhibitor, alone and with venetoclax (VEN) in R/R AML patients. Tuspetinib showed good tolerability and achieved a 26.3% complete response (CR) rate at the recommended phase 2 dose (RP2D). When combined with VEN, the overall response rate was 16.9%, with higher responses observed in FLT3-mutated AML patients.

Relevance: These results suggest that tuspetinib, particularly when combined with venetoclax, offers a promising treatment option for R/R AML patients, especially those with FLT3 mutations. Oncologists may consider this combination for patients who have failed previous therapies.

Link to Abstract: Abstract P557

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Abstract #P1806

Treatment Patterns and Molecular Testing Across the Patient Journey: A Real-World Analysis in a U.S.-Based Cohort of Newly Diagnosed and Relapsed/Refractory AML Patients

Authors: Amer M. Zeidan, Gloria Graf, Hsien-Yen Chang, Alex Z. Fu, et al

Background: The treatment landscape for acute myeloid leukemia (AML) has expanded significantly with seven new therapies approved in the United States since 2017. This has broadened treatment options, especially for patients with unfavorable risk profiles and those unfit for traditional chemotherapy. Clinical guidelines increasingly recommend appropriate molecular testing for treatment and ongoing disease management of AML patients.

Study Overview and Results: This study used Optum's Informatics® Extended Data Mart to analyze treatment patterns and molecular testing practices in a U.S.-based cohort of newly diagnosed (ND) and relapsed/refractory (RR) AML patients from 2016-2022. The study included 5,135 ND AML patients and 987 RR AML patients. Findings revealed that molecular testing within 12 months of diagnosis was nearly universal among ND patients receiving HSCT in the first line (98%), but lower among those receiving non-HSCT treatment (83%) and no active treatment (49%). For ND patients receiving first-line treatment, 63% had molecular testing prior to treatment, and 53% had testing afterward. Among RR patients, 77% had molecular testing after disease recurrence. Despite the introduction of novel therapies, the proportion of patients who did not receive any treatment remained high over the study period.

Relevance: These findings highlight the importance of molecular testing in the management of AML and reveal gaps in testing before treatment initiation. For practicing oncologists, the study emphasizes the need to ensure comprehensive molecular testing to guide treatment decisions, particularly as new therapies become available. It also underscores the persistent challenge of providing effective treatment options for older and more frail AML patients.

Link to Abstract: Abstract P1806

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Abstract #PB2390

Stability Assessment of Fresh or Cryopreserved Whole Blood and Bone Marrow Samples from AML Patients to Monitor CD123 Receptor and Immune Cells Subsets

Authors: Jacqueline Courta, Marielle Balzano, Wilfried Passe-Coutrin, Margaux Lagier, et al 

Background: Compounds targeting CD123 are under clinical development for the treatment of acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Monitoring CD123 expression and immune cell subsets through quantitative flow cytometry (qFC) is crucial in clinical trials involving bone marrow (BM) aspirates and whole blood (WB) samples. One significant challenge is the stability of these biological samples, which impacts the accuracy of biomarker analysis. A reliable cryopreservation method could simplify sample preparation and improve centralized analysis in multicenter and worldwide clinical studies.

Study Overview and Results: This study aimed to evaluate the pre-analytical stability of fresh and cryopreserved samples for monitoring CD123 expression and immune cell subsets in AML/MDS patients. Fresh BM and WB samples were collected from five patients and stored at room temperature for varying durations before immunostaining and analysis by qFC. Additionally, samples were cryopreserved using a new method and stored at -80°C for extended periods. Results showed that CD123 density in blast and normal cells in BM and WB remained stable at room temperature for up to 48 hours post-collection. T-cell distribution and activation markers also exhibited stability within this timeframe. Furthermore, the immunoprofiles of blast subsets and T cells from fresh samples were comparable to those from cryopreserved samples, demonstrating stability for at least six months. This indicates that the new cryopreservation method effectively maintains the integrity of these biomarkers.

Relevance: This study highlights a reliable cryopreservation method that ensures the stability of CD123 density and immune cell subsets in WB and BM samples from AML patients. This method enables easier sample preparation, standardizes clinical sample analysis, and facilitates centralized qFC in multicenter clinical trials. Practicing oncologists can benefit from these findings by adopting this method to enhance the accuracy and consistency of biomarker monitoring in AML clinical studies.

Link to Abstract: Abstract PB2390

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Abstract #PB2394

Study of the Molecular Genetic Profile of High-Risk AML Patients Using Next Generation Sequencing

Authors: Ekaterina Motyko, Anna Kirienko, Daria Kustova, Tatiyana Gert, et al

Background: Acute myeloid leukemia (AML) is characterized by significant genetic heterogeneity. The identification of recurrent mutations has enhanced our understanding of the disease, allowing for more precise risk stratification and targeted therapies. Despite these advancements, only a few mutations have been integrated into clinical risk models. The European LeukemiaNet (ELN) 2022 recommendations have expanded the unfavorable prognosis group to include new molecular and cytogenetic markers. However, outcomes within this group vary significantly, necessitating further molecular-genetic profiling to develop personalized treatment approaches.

Study Overview and Results: This study aimed to analyze the molecular-genetic profile of high-risk AML patients using next-generation sequencing (NGS) and evaluate the prognostic impact of common genetic aberrations. The study included 30 high-risk AML patients according to ELN 2022 criteria, with a median age of 60 years. Patients underwent NGS to identify mutations in a targeted panel of 118 genes. A total of 137 mutations were identified across 58 genes, with frequent mutations in genes such as ASXL1, DNMT3A, PTPN11, SRSF2, and TP53. The presence of more than six mutations and mutations in ASXL1 and SRSF2 were associated with poorer overall survival. Specifically, patients with more than six mutations had a median survival of 10 months compared to 29 months for those with fewer mutations.

Relevance: The findings highlight the complexity of the molecular landscape in high-risk AML and underscore the importance of comprehensive genetic profiling for prognostication and treatment planning. The identification of specific mutations associated with poor outcomes, such as ASXL1 and SRSF2, can guide therapeutic decisions and inform the development of targeted therapies. For practicing oncologists, incorporating NGS into routine clinical practice may enhance risk stratification and enable more personalized treatment approaches, ultimately improving patient outcomes.

Link to Abstract: Abstract PB2394

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Abstract #PB2457

Genetic Abnormalities Associated with Outcomes in Patients with NPM1-Mutated Acute Myeloid Leukemia

Authors: Shunjie Yu, Sen Yang, Lijuan Hu, Yijing Zhao, Zongru Li, et al

Background: Nucleophosmin1 (NPM1)-mutated acute myeloid leukemia (AML) patients exhibit considerable genomic heterogeneity, especially when considering the presence or absence of FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations. Understanding the integration of genomic abnormalities with clinical variables is essential, particularly in the era of FLT3 inhibitors.

Study Overview and Results: This study aimed to explore the genomic abnormalities associated with outcomes in NPM1-mutated AML patients with or without FLT3-ITD mutations. The data of 262 consecutive NPM1-mutated AML patients, including clinical variables and genomic information, were reviewed. The cohort consisted of 164 patients without FLT3-ITD mutations (NPM1mut/FLT3-ITDwt) and 98 with FLT3-ITD mutations (NPM1mut/FLT3-ITDmut). Patients with FLT3-ITD mutations were treated with chemotherapy plus FLT3 inhibitors (sorafenib or gilteritinib), and eligible patients received hematopoietic stem cell transplantation in CR1. The 2-year EFS, RFS, and OS rates for the NPM1mut/FLT3-ITDwt cohort were 45%, 68%, and 81%, respectively. Multivariate analyses identified SRSF2 and DNMT3A mutations as significantly associated with inferior EFS, and TET2 mutation with poor RFS and OS, while IDH2 and NRAS mutations were linked to favorable EFS. For the NPM1mut/FLT3-ITDmut cohort, the 2-year EFS, RFS, and OS rates were 42%, 52%, and 73%, respectively. WT1 mutation was significantly associated with inferior OS. Higher LDH levels and CD34+HLA-DR- blast phenotype were also linked to poor outcomes in both cohorts.

Relevance: The study identifies specific genetic mutations that predict poor outcomes in NPM1-mutated AML patients, with or without FLT3-ITD mutations. For community oncologists, this information is crucial for risk stratification and personalized treatment planning. Recognizing the impact of mutations such as SRSF2, DNMT3A, TET2, and WT1 on patient prognosis can guide therapeutic decisions and improve management strategies for patients with AML.

Link to Abstract: Abstract PB2457

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Abstract #P454

Biomarker Results of the Phase 1 Dose Escalation Trial of the HLA-A2-WT1 CD3 T-Cell Bispecific (TCB) Antibody RO7283420 (RG6007) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)

Authors: Anne Catherine Bretz, Min Sun,  Jan Attig, Tobias Rutishauser, Marion Subklewe, et al.

Background: RO7283420 (RG6007) is a T-cell bispecific (TCB) antibody designed to target WT1 in HLA-A2-positive AML patients, aiming to enhance T-cell-mediated cytotoxicity against leukemia cells. Given the challenging nature of treating R/R AML, innovative therapies like TCB antibodies are crucial.

Study Overview and Results: This phase 1 trial involved 51 patients and investigated the pharmacokinetics, pharmacodynamics, and mechanisms of action of RO7283420. The study found that RO7283420 induced T-cell activation and expansion, with significant cytokine release following infusion. Baseline biomarkers associated with blast reduction included higher levels of naive CD8+ T cells and lower levels of TIGIT+ regulatory T cells. Despite promising biomarker data, the study was discontinued due to limited clinical efficacy.

Relevance: These findings provide insights into the immunological effects of RO7283420 and highlight the importance of biomarker analysis in understanding T-cell bispecific therapies in AML. However, the limited clinical efficacy underscores the need for further research to optimize treatment strategies.

Link to Abstract: Abstract P454

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Last modified: July 17, 2024

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