ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION, Acute Myeloid Leukemia
Conditions
Keywords
FLT3-mutated AML, Myeloablative Conditioning, Reduced-intensity conditioning, Ultra-high-sensitivity next-generation sequencing（UHS-NGS）
Brief summary
This is a multicenter, open-label, 1:1 randomized non-inferiority trial with stratification. The study will enroll patients aged 18-60 years with FLT3-ITD-mutated acute myeloid leukemia (AML) who are in first complete remission (CR1) and have no detectable FLT3-ITD measurable residual disease (MRD) by polymerase chain reaction-next-generation sequencing (PCR-NGS) before allogeneic hematopoietic stem cell transplantation (allo-HSCT). Eligible patients will be randomly assigned to receive either reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) before allo-HSCT. All patients will receive FLT3 inhibitor maintenance therapy after transplantation. The primary objective is to determine whether RIC is non-inferior to MAC in terms of 2-year relapse-free survival (RFS), defined as the time from transplantation to relapse or death from any cause. Secondary objectives include comparisons of overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse, and graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) between the two conditioning groups.
Detailed description
FLT3 internal tandem duplication (FLT3-ITD) is an adverse prognostic factor in acute myeloid leukemia (AML). Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) and post-transplant FLT3 inhibitor maintenance have improved outcomes, relapse remains a major cause of treatment failure. Conditioning intensity is an important determinant of both relapse and non-relapse mortality (NRM), and the optimal conditioning strategy for patients with FLT3-ITD-mutated AML remains uncertain. Previous studies have shown that myeloablative conditioning (MAC) can reduce relapse compared with reduced-intensity conditioning (RIC), particularly in patients with detectable measurable residual disease (MRD) before transplantation. However, the benefits of MAC must be balanced against its greater treatment-related toxicity. These findings suggest that pre-transplant MRD status may help identify patients who can achieve adequate disease control with less intensive conditioning. In addition, post-transplant FLT3 inhibitor maintenance provides an additional strategy for reducing relapse risk in patients with FLT3-ITD-mutated AML. A retrospective study conducted by the Chinese TROPHY collaborative group evaluated 219 patients with FLT3-ITD-mutated AML undergoing allo-HSCT, most of whom received post-transplant FLT3 inhibitor maintenance. Among patients with detectable pre-transplant FLT3-ITD MRD by an ultrasensitive next-generation sequencing assay, RIC was associated with higher relapse incidence and inferior relapse-free survival (RFS) and overall survival (OS) than MAC. In contrast, outcomes were comparable between conditioning groups among patients with undetectable pre-transplant molecular MRD. These findings support further prospective evaluation of an MRD-guided conditioning strategy. This multicenter, open-label, randomized non-inferiority trial will compare RIC with MAC in patients with FLT3-ITD-mutated AML who are in first complete remission and have no detectable pre-transplant FLT3-ITD MRD by polymerase chain reaction-next-generation sequencing (PCR-NGS). Participants will be randomly assigned to one of the two conditioning strategies, and all participants will receive FLT3 inhibitor maintenance after allo-HSCT. The study is designed to determine whether RIC provides comparable relapse-free survival to MAC in this molecularly defined population while potentially reducing conditioning-related toxicity and NRM. The results may help establish a prospective evidence base for integrating pre-transplant molecular MRD status and post-transplant maintenance therapy into individualized conditioning-intensity selection.
Interventions
PROCEDURERIC
1. Flu/Bu2 or Flu/Bu3: The total dose of fludarabine is 120-180 mg/m², and the total intravenous dose of busulfan is 6.4-9.6 mg/kg. 2. Flu/Mel: The total dose of fludarabine is 120-180 mg/m², and the total dose of melphalan is 120-150 mg/m². For the purposes of this study, Flu/Bu3 is included in the RIC group as a protocol-specified reduced-toxicity conditioning regimen.
PROCEDUREMAC
1. Bu4/Cy2: The total intravenous dose of busulfan is 12.8 mg/kg, and the total dose of cyclophosphamide is 120 mg/kg. 2. Bu4/Flu: The total intravenous dose of busulfan is 12.8 mg/kg, and the total dose of fludarabine is 120-180 mg/m². 3. Modified Bu/Cy regimen: For patients undergoing haploidentical transplantation, a modified Bu/Cy-based regimen incorporating cytarabine (Ara-C) could be used according to institutional protocols. The regimen consisted of Ara-C at a total dose of 4-8 g/m², intravenous busulfan at a total dose of 9.6 mg/kg, and cyclophosphamide at a total dose of 3.6 g/m².
Sponsors
First Affiliated Hospital of Zhejiang University
Ruijin Hospital
The First Affiliated Hospital of Zhengzhou University
Union Hospital, Tongji Medical College, Huazhong University of Science and Technolog
Peking University People's Hospital
Tongji Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
1. Age between 18 to 60 years, any gender 2. Diagnosis of AML according to WHO criteria 3. Presence of FLT3-ITD mutation at diagnosis 4. In first complete remission 5. Planned first allogeneic hematopoietic stem cell transplantation using peripheral blood stem cells 6. Planned post-transplant maintenance therapy with a FLT3 inhibitor (including sorafenib or gilteritinib) 7. FLT3-ITD UHS-NGS MRD \< 0.001% at 14 to 28 days prior to transplantation 8. Completion of routine pre-transplant assessments; in the investigator's judgment, the patient is able to complete the conditioning regimen, stem cell infusion, and study follow-up as planned; 9. HCT-CI score of 0 to 2; in the investigator's judgment, the patient is eligible for either MAC or RIC conditioning intensity 10. ECOG performance status at 0 to 2 11. Estimated survival time ≥ 6 months 12. Major organ function meets the following requirements: ALT and AST ≤2.5 × ULN; Total bilirubin ≤1.5 × ULN; subjects with Gilbert syndrome or elevated indirect bilirubin due to documented inactive hemolysis may be enrolled at the investigator's discretion; eGFR ≥30 mL/min/1.73 m², and not receiving maintenance dialysis; LVEF ≥50%, or cardiac function status determined by the investigator to be adequate to tolerate the study treatment; No requirement for high-flow oxygen therapy or mechanical ventilation support at rest 13. Blood pressure is well-controlled; systolic blood pressure \<160 mmHg and diastolic blood pressure \<100 mmHg at rest during the screening period; if receiving antihypertensive therapy, the dosage should be essentially stable prior to randomization 14. Able to undergo assessments (including complete blood count, reticulocyte count, iron metabolism markers, adverse event monitoring, and transfusion records) as required by the protocol, and demonstrates good compliance 15. Women of childbearing potential have a negative serum or urine pregnancy test; subjects of childbearing potential and their partners are willing to use effective contraceptive measures during the study and for the specified period following the last dose 16. The subject or their legally authorized representative has signed a written informed consent form approved by the ethics committee prior to the implementation of any study-specific procedures
Exclusion criteria
1. Prior allogeneic hematopoietic stem cell transplantation 2. Achieved complete remission (CR) only after more than two cycles of induction therapy, or met the criteria for primary refractory AML 3. Clear evidence of disease progression, relapse, or a need to immediately initiate new anti-tumor therapy prior to randomization, which could significantly impact the assessment of study endpoints 4. Active central nervous system (CNS) leukemia 5. Uncontrolled severe infection prior to randomization, including but not limited to: Sepsis or septic shock; Active invasive fungal infection; Bacterial or viral infection requiring escalation of broad-spectrum anti-infective therapy where the clinical condition remains unstable; Other severe infections deemed by the investigator to make the patient unsuitable for enrollment 6. Concomitant high-risk cardiovascular or cerebrovascular conditions, including: Myocardial infarction, acute coronary syndrome, stroke, or transient ischemic attack within 6 months prior to randomization; Deep vein thrombosis, pulmonary embolism, or other clinically significant thromboembolic events within 6 months prior to randomization; New York Heart Association (NYHA) Class III-IV heart failure; Uncontrolled severe cardiac arrhythmia; Unacceptable thrombotic risk as determined by the investigator 7. Uncontrolled hypertension, defined as resting systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg despite optimized antihypertensive therapy 8. Gastrointestinal disorders significantly affecting oral drug absorption or adherence (e.g., persistent vomiting, short bowel syndrome, active severe diarrhea, or other conditions judged by the investigator to significantly affect drug exposure), or inability to tolerate post-transplant FLT3 inhibitor maintenance therapy as determined by the investigator 9. Pregnant or lactating women, or individuals unwilling to use effective contraceptive measures 10. Participation in another interventional clinical trial involving treatment with an investigational drug or device within the 4 weeks prior to randomization, where the investigator determines that such participation might interfere with the results of this study 11. Presence of uncontrolled psychiatric disorders, cognitive impairment, substance abuse, or other conditions that could affect informed consent, adherence, or safety follow-up 12. Any other medical, laboratory, or social factors that, in the investigator's opinion, could increase the risk to the subject, affect study adherence, or interfere with the assessment of efficacy or safety 13. Concurrent active malignancy; exceptions include: Malignancies that have been curatively treated with no evidence of recurrence within 5 years; Adequately treated basal cell carcinoma or squamous cell carcinoma of the skin; Treated carcinoma in situ determined by the investigator to have no impact on the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 2-year relapse-free survival (RFS) | 2 years after randomization | Relapse-free survival is defined as the time from randomization until disease relapse or death from any cause, whichever occurs first. Patients who are alive without relapse will be censored at the date of last follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) | 2 years after randomization | Overall survival is defined as the time from randomization to death from any cause. Patients alive at last follow-up will be censored. |
| Non-relapse mortality (NRM) | 2 years after randomization | Non-relapse mortality is defined as death without prior disease relapse. Cumulative incidence of non-relapse mortality will be estimated, with relapse treated as a competing risk. |
| Cumulative incidence of relapse | 2 years after randomization | Disease relapse defined as hematologic recurrence of FLT3-ITD mutated acute myeloid leukemia. Cumulative incidence of relapse will be estimated, with death without relapse treated as a competing risk. |
| GVHD-free and relapse-free survival (GRFS) | 2 years after randomization | GVHD-free, relapse-free survival is defined as time from randomization until grade III-IV acute GVHD, chronic GVHD requiring systemic immunosuppression, leukemia relapse, or death from any cause, whichever occurs first. |
Countries
China
Contacts
CONTACTYanmin Zhao, PhD
CONTACTYI YU, PhD
Outcome results
None listed