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This is a multicenter, open-label, randomized, controlled phase III clinical trial designed to evaluate the efficacy and safety of the combination of Venetoclax, Azacitidine, and Homoharringtonine (VAH) compared to Venetoclax and Azacitidine (VA) alone in newly diagnosed elderly patients with Acute Myeloid Leukemia (AML).
A total of 308 treatment-naïve patients aged 60-75 years with AML (non-APL) will be enrolled and randomly assigned in a 1:1 ratio to either the control arm (VA) or the experimental arm (VAH). The study aims to determine if the addition of Homoharringtonine to the standard VA regimen can improve response rates. To mitigate bias in this open-label study, the primary and key secondary efficacy endpoints will be assessed by an Independent Review Committee or central laboratory blinded to treatment allocation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental: VAH | Experimental | Patients receive Venetoclax, Azacitidine, and Homoharringtonine |
|
| Active Comparator: VA | Active Comparator | Patients receive Venetoclax and Azacitidine |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Venetoclax | Drug | Venetoclax: 100 mg orally on Day 1, 200 mg on Day 2, then 400 mg orally on Days 3-28 of a 28-day cycle (dose ramp-up recommended for newly diagnosed patients). |
|
| Measure | Description | Time Frame |
|---|---|---|
| Composite Complete Remission Rate (CRc) | The proportion of randomized participants who achieve complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), according to the 2022 ELN criteria, from randomization up to the initiation of Cycle 3. | Up to approximately 8 weeks (from randomization to initiation of Cycle 3; each cycle is planned as 28 days). |
| Measure | Description | Time Frame |
|---|---|---|
| Event-Free Survival (EFS) | Time from randomization to morphological relapse, initiation of subsequent therapy (while in CR/CRi), or death | up to 36 months |
| Overall Survival (OS) | Time from randomization to death from any cause |
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Inclusion Criteria:
Serum creatinine ≤ 1.5 × upper limit of normal (ULN). Oxygen saturation > 92% on room air. Total bilirubin ≤ 3.0 × ULN. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN.
If laboratory abnormalities are considered due to leukemic organ involvement, total bilirubin ≤ 5.0 × ULN and ALT/AST ≤ 5.0 × ULN are permitted.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Xianmin Song | Contact | （+86）18918029692 | shongxm@sjtu.edu.cn |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Shanghai General Hospital | Shanghai | Shanghai Municipality | 200080 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22846839 | Background | Peyrade F, Gastaud L, Re D, Pacquelet-Cheli S, Thyss A. Treatment decisions for elderly patients with haematological malignancies: a dilemma. Lancet Oncol. 2012 Aug;13(8):e344-52. doi: 10.1016/S1470-2045(12)70234-6. | |
| 35767897 | Background | Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, Wang SA, Bagg A, Barbui T, Branford S, Bueso-Ramos CE, Cortes JE, Dal Cin P, DiNardo CD, Dombret H, Duncavage EJ, Ebert BL, Estey EH, Facchetti F, Foucar K, Gangat N, Gianelli U, Godley LA, Gokbuget N, Gotlib J, Hellstrom-Lindberg E, Hobbs GS, Hoffman R, Jabbour EJ, Kiladjian JJ, Larson RA, Le Beau MM, Loh ML, Lowenberg B, Macintyre E, Malcovati L, Mullighan CG, Niemeyer C, Odenike OM, Ogawa S, Orfao A, Papaemmanuil E, Passamonti F, Porkka K, Pui CH, Radich JP, Reiter A, Rozman M, Rudelius M, Savona MR, Schiffer CA, Schmitt-Graeff A, Shimamura A, Sierra J, Stock WA, Stone RM, Tallman MS, Thiele J, Tien HF, Tzankov A, Vannucchi AM, Vyas P, Wei AH, Weinberg OK, Wierzbowska A, Cazzola M, Dohner H, Tefferi A. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022 Sep 15;140(11):1200-1228. doi: 10.1182/blood.2022015850. |
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| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| C579720 | venetoclax |
| D001374 | Azacitidine |
| D000077863 | Homoharringtonine |
| ID | Term |
|---|---|
| D001372 | Aza Compounds |
| D009930 | Organic Chemicals |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
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| Azacitidine | Drug | Azacitidine: 75 mg/m² subcutaneously or intravenously on Days 1-7. |
|
| Homoharringtonine | Drug | Homoharringtonine (HHT): 1 mg/m² intravenously on Days 1-7. |
|
| up to 36 months |
| CR/CRi Rate by Cycle 1 and Cycle 2 | Proportion of patients achieving CR/CRi prior to the start of Cycle 2 and Cycle 3 | End of Cycle 1 and end of Cycle 2 (each cycle is planned as 28 days; assessments performed prior to initiation of Cycle 2 and Cycle 3) |
| Complete Remission (CR) Rate | The proportion of randomized participants who achieve complete remission (CR) according to the 2022 European LeukemiaNet (ELN) criteria. CR is defined as bone marrow blasts <5%, absence of circulating blasts and extramedullary disease, absolute neutrophil count ≥1.0 ×10⁹/L, and platelet count ≥100 ×10⁹/L. Participants will be evaluated for CR from randomization through the end of Cycle 3. Participants who do not undergo disease assessment within this period will be considered non-responders for this endpoint. | From randomization through the end of Cycle 3 (approximately 12 weeks). |
| Minimal Residual Disease (MRD) Negativity Rate | The proportion of randomized participants who achieve measurable residual disease (MRD) negativity (<0.1%), assessed according to protocol-defined methodology. MRD assessments will be performed on Day 14 (±1 day) of Cycle 1, at the end of Cycle 1 (±3 days), at the end of each subsequent treatment cycle (±7 days), and every 3 months during follow-up after achieving CR/CRi, for up to 2 years after completion of treatment. Participants who are randomized but do not undergo MRD assessment will be considered non-responders. MRD negativity rates will be compared between treatment groups using the Cochran-Mantel-Haenszel (CMH) test, stratified by age (60-64, 65-69, 70-75 years) and study center. Two-sided 95% confidence intervals will be calculated. | Up to 2 years after completion of treatment. |
| Time to First Composite Complete Remission (CR or CRi) | Time to first composite complete remission is defined as the number of days from the date of randomization to the earliest date on which a participant achieves complete remission (CR) or complete remission with incomplete hematologic recovery (CRi). | From randomization until the first documented CR or CRi during study treatment (up to approximately 12 months). |
| D006402 |
| Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D011743 |
| Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D012263 | Ribonucleosides |
| D006248 | Harringtonines |
| D000470 | Alkaloids |
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |