Breakthrough Clinical Results
Ascentage Pharma announced positive clinical data for lisaftoclax, a Bcl-2 inhibitor, and alrizomadlin, an MDM2-p53 inhibitor. Data from a Phase 1b/2 study of lisaftoclax combined with azacitidine in patients with treatment-naïve or venetoclax-exposed myeloid malignancies will be presented orally at ASCO 2025. The study showed promising therapeutic potential in venetoclax-refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), with an overall response rate ranging from 17% to 64% depending on the patient group. Alrizomadlin data, from a Phase 2 study in solid tumors, will also be presented as a poster. Both drugs demonstrated antitumor activity, supporting further clinical development. Ascentage Pharma also highlighted the recent new drug application submission for lisaftoclax in China.
Key Highlights
- Positive clinical data for lisaftoclax (Bcl-2 inhibitor) and alrizomadlin (MDM2-p53 inhibitor) to be presented at ASCO 2025.
- Lisaftoclax demonstrated promising therapeutic potential in venetoclax-refractory AML and MDS patients.
- Lisaftoclax combination therapy with azacitidine showed an overall response rate ranging from 17% to 64%.
- New drug application for lisaftoclax submitted in China.
Incidence and Prevalence
Global Incidence and Prevalence of Myeloid Malignancies
Recent PubMed data provides important insights into the incidence and prevalence of myeloid malignancies globally, with significant regional variations:
Brazil
- Overall age-standardized incidence rate (ASR) for myeloid malignancies: 14.57 per million
- Mortality rate: 8.83 per million
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Specific subtypes:
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Acute myeloid leukemia (AML): 8.18 per million
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Other myeloid malignancy subtypes: 2.62 per million
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Not otherwise specified (NOS): 3.70 per million
Hong Kong
- AML incidence: 2.23 cases per 100,000
- Myeloproliferative neoplasms (MPNs): 2.10 cases per 100,000
- All other subtypes: <1 case per 100,000 person-years
- Overall rates of AML, myelodysplastic syndrome (MDS), and MDS/MPN were lower in Hong Kong compared to white and Asian individuals in the U.S.
United States
- AML accounts for 1.0% of all new cancer cases
- 5-year relative survival rate for AML: 30.5%
- For myeloid malignancies, rates in U.S. Asians were intermediate to those in Hong Kong and white individuals in the U.S.
Europe
- Age-standardized incidence rates: 7.55 per 100,000 for myeloid malignancies
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Most common myeloid malignancies:
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Acute myeloid leukemia: 2.96 per 100,000
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Other myeloproliferative neoplasms: 1.76 per 100,000
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Myelodysplastic syndrome: 1.24 per 100,000
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Regional variations:
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Lowest incidence of hematologic malignancies in Eastern Europe
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Lower incidence in women than in men
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Highest incidence of myeloid malignancies in the United Kingdom and Ireland
Eastern Morocco
- Hematological malignancies account for approximately 10.9% (660/6075) of all cancers recorded between 2008-2012
The data demonstrates significant regional variations in incidence rates of myeloid malignancies, highlighting the importance of region-specific approaches to diagnosis, treatment, and prevention strategies.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Myeloid Malignancies
Recent PubMed publications highlight several key mechanisms of action emerging for the treatment of myeloid malignancies.
Immune Checkpoint Inhibitors
Immune checkpoint inhibitors are emerging as a promising therapeutic approach for myeloid malignancies. Specifically: - PD-1 inhibitors and targeting PD-L1 expression have demonstrated potential in treating myelodysplastic syndromes (MDS) - In MDS, immune checkpoints (PD-1 and CTLA4 molecules) enable tumor cells to evade immune surveillance - Clinical evidence shows that a patient treated with an anti-PD-1 inhibitor developed normal trilineage hematopoiesis after therapy, with PD-L1 expression decreasing significantly from 15% to 5% after 26 months of treatment
Hypomethylating Agents (HMAs)
Hypomethylating agents continue to be a cornerstone treatment for MDS: - HMA therapy induces sustained hematological responses and delays progression to leukemia - Despite effectiveness, most patients experience treatment failure within 2 years - Research is focusing on novel approaches for patients who become refractory to HMA treatment
Mesenchymal Stromal Cells (MSCs)
The role of mesenchymal stromal cells is an active area of investigation: - MSCs exert immunosuppressive functions by inhibiting both innate and adaptive immune systems - They regulate myeloid leukemia cell proliferation, apoptosis, and chemotherapy resistance - Better understanding of MSCs could lead to new immunotherapy approaches for myeloid malignancies
Myeloid-Derived Suppressor Cells (MDSCs)
Myeloid-derived suppressor cells are emerging as important players: - MDSCs display immunoregulatory properties that may create a tolerant microenvironment conducive to neoplasm development - The number of MDSCs is elevated in myeloid malignancies with high immunosuppressive capacities - There appears to be a relationship between MSCs and MDSCs, as MSCs may promote MDSC expansion, with both cell types mutually contributing to an immuno-tolerant neoplasm microenvironment
These emerging mechanisms highlight the increasing focus on understanding and targeting the immune microenvironment in myeloid malignancies, suggesting potential new therapeutic avenues beyond conventional approaches.
Study Design Parameters
Study Design Parameters and Endpoints in Key Trials for Myeloid Malignancies
Study Design Parameters
K-RAS Mutations in AML
- Randomized trial of 71 de novo AML patients
- Male:Female ratio of 1.4:1, ages 21-59 years (median 37 years)
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Randomization into two groups based on cytarabine (ara-C) dose in consolidation treatment:
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HDAC group (400 mg)
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LDAC group (100 mg)
- Follow-up period of 5 years (median 43 months, range 11-57 months)
CMML Molecular Characterization Study
- Molecular genetic characterization of 81 patients with CMML
- Patient groups: CMML type 1 (n=45) and CMML type 2 (n=36)
- Used Next-generation sequencing (NGS) to investigate CBL, JAK2, MPL, NRAS, and KRAS at known mutational hotspot regions, plus complete coding regions for RUNX1 and TET2
Tumor Microenvironment in AML Study
- Division of AML samples into high and low-score groups
- Used ESTIMATE and CIBERSORT algorithms to evaluate stromal, immune, and ESTIMATE scores
Functional Precision Medicine Study
- Prospective series of 252 samples from 186 AML patients
- Employed ex vivo drug-response and multiomics profiling
- Implementation through a Functional Precision Medicine Tumor Board (FPMTB)
ceRNA Network Study in AML
- Data sources: Transcriptome data from TCGA, GTEx, and GEO databases
- Risk stratification: Division of AML samples into high and low risk groups based on risk score
Endpoints
K-RAS Mutations in AML
- Overall survival (OS)
- Disease-free survival (DFS)
CMML Molecular Characterization Study
- Molecular mutation profiles
- Survival outcomes
Tumor Microenvironment in AML Study
- Association between clinicopathological characteristics, survival rate, and scores
- Identification of differentially expressed genes (DEGs)
- Pathway enrichment analysis
- Protein-protein interaction network
- Cox regression analysis
- Kaplan-Meier survival analysis
- Identification of biomarkers associated with AML microenvironment
Functional Precision Medicine Study
- Identification of actionable drugs (found in 97% of patients)
- Objective response rate (59%)
- Complete responses (13)
- Bridging to transplantation (5 patients)
- Identification of drug response biomarkers
ceRNA Network Study in AML
- Survival analysis
- Establishment of prognostic ceRNA regulatory network
Drug used in other indications
Based on the provided context, there is no information available about Lisaftoclax and azacitidine being trialled for indications other than myeloid malignancies. The context does not mention Lisaftoclax at all, and azacitidine is only referenced in relation to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), which are myeloid malignancies.
Additionally, there is no information provided about intervention models for any trials involving Lisaftoclax and azacitidine.