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This study was designed as a prospective, multicenter, open-label, randomized controlled trial. Eligible participants were patients aged 15-65 years with high risk or relapsed/refractory acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic neoplasms (MDS), diagnosed based on bone marrow morphology, immunophenotyping, genetic testing, and treatment response assessment. The experimental group received SHR2554 combined with azacitidine as an overlapped sequential combination with the mBuCy conditioning regimen, whereas the control group received the mBuCy conditioning regimen, both followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). The primary endpoint is 1-year event-free survival (EFS). Secondary endpoints include 2-year overall survival, 2-year cumulative incidence of relapse, transplant-related mortality, incidence of acute/chronic GVHD, and safety profiles.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental: SHR2554/AZA + Overlapped mBUCY | Experimental |
| |
| Active Comparator: mBUCY conditioning Regimen Group | Active Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| SHR2554/AZA + Overlapped mBUCY | Drug | SHR2554 350 mg BID and azacitidine 75 mg/m² daily on days -9 to -3, overlapping with mBUCY conditioning:semustine 250 mg/m² on day -8; cytarabine 2 g/m² q12h on day -7; busulfan 0.8 mg/kg q6h on days -6,-5, -4 (total 3.2 mg/kg/day); cyclophosphamide 1.8 g/ m²/day on days -3 and -2. |
| Measure | Description | Time Frame |
|---|---|---|
| Event-Free Survival (EFS) | It is measured from the time of entry into this trial to the date of first event (relapse, death from any cause); patients not known to have experienced any event at last follow-up are censored on the date they were last known to be event-free. | 1 years |
| Measure | Description | Time Frame |
|---|---|---|
| Overall survival（OS） | It is measured from the date of entry into this trial to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive. | 2 years |
| Cumulative incidence of relapse（CIR） |
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Inclusion Criteria:
Age 15-60 years, of either sex.
Diagnosis of AML or ALL according to the WHO 2022 criteria, with an indication for allogeneic hematopoietic stem cell transplantation:
AML with high-risk genetics at diagnosis (risk stratification per ELN 2022) or relapsed/refractory AML (meeting any of the following: refractory-failure to achieve complete remission (CR) after two cycles of induction chemotherapy; relapse-reappearance of blasts in peripheral blood or bone marrow (≥5%) after first CR, or extramedullary relapse (EMR)).
High-risk B-ALL at diagnosis (risk stratification per ELN 2022) or pre-transplant MRD-positive B-ALL.
Confirmed T-ALL. History of central nervous system leukemia (CNSL) or pathologically confirmed extramedullary disease (EMD) during AML or ALL.
Myelodysplastic neoplasms (MDS): IPSS score intermediate-2 or high; IPSS-R score high or very high; IPSS-M score high or very high.
Availability of an appropriate HLA-matched donor.4: ECOG performance status 0-2.5: Adequate major organ function, defined as: Left ventricular ejection fraction ≥50%. Pulmonary function: DLCO ≥50% of predicted value. Liver function: ALT/AST ≤3×ULN, total bilirubin ≤2×ULN. Renal function: estimated creatinine clearance (CrCl) ≥60 mL/min.6: Ability to understand the study and voluntary signed informed consent.
Exclusion Criteria:
1: Acute promyelocytic leukemia (APL);2: Active central nervous system leukemia;3: Prior allogeneic hematopoietic stem cell transplantation;4: Prior treatment with any EZH2 inhibitor;5: Uncontrolled active infection as assessed by the investigator;6: Myocardial infarction or unstable angina within the previous 6 months;7: Known hypersensitivity to SHR2554, azacitidine, or any excipient of the mBuCy regimen;8: Pregnant or breastfeeding women;9: Any other medical condition that, in the investigator's judgment, would preclude study enrollment.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| LIMIN LIU, MD | Contact | +86-512-6778183 | Liminliu1006@163.com |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The First Affiliated Hospital of Soochow University | Suzhou | Jiangsu | 215006 | China |
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|
| mBUCY conditioning Regimen Group | Drug | semustine 250 mg/m² on day -8; cytarabine 2 g/m² q12h on day -7; busulfan 0.8 mg/kg q6h on days -6,-5, -4 (total 3.2 mg/kg/day); cyclophosphamide 1.8 g/ m²/day on days -3 and -2 |
|
It is measured the date from complete remission after transplantation to hematological relapse was recorded. Patients who had no relapse at the last follow-up were considered as censored data, and non-relapse death was regarded as a competing risk event. |
| 2 years |
| event-free survival (EFS) | It is measured from the time of entry into this trial to the date of first event (relapse, death from any cause, or grade III-IV acute GVHD); patients not known to have experienced any event at last follow-up are censored on the date they were last known to be event-free. | 2 years |
| transplant related mortality (TRM) | cumulative incidence of transplant related mortality | 2 years |
| graft-versus-host disease (GvHD) | incidence and severity of acute (aGvHD) and chronic graft-versus-host disease (cGvHD) (aGvHD refer to Glucksberg Criteria and cGvHD refer to the National Institutes of Health Consensus) | 2 years |
| Time period for hematopoietic reconstruction | Granulogenetic hematopoietic reconstitution: The absolute neutrophil count in peripheral blood needs to reach or exceed 0.5×10^9 cells/L for 3 consecutive days. Megakaryotic hematopoietic reconstitution: platelet count needs to be more than 20×10^9/L and does not rely on platelet transfusion for 7 consecutive days. | 24 weeks |
| Regimen related toxicity | Number of participants with regimen related toxicity as assessed by CTCAE v5.0 | 2 years |
| veno-occlusive disease (VOD) | incidence of veno-occlusive disease (VOD) events (refer to modified Seattle Criteria of VOD) | 2 years |
| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| D054198 | Precursor Cell Lymphoblastic Leukemia-Lymphoma |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D007945 | Leukemia, Lymphoid |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
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