Ruxolitinib and Decitabine-Enhanced Conditioning Versus Modified Bu/Cy or BuF Conditioning for the Impact on Relapse of Acute Myeloid Leukemia in First Complete Remission (CR1)After Allogeneic Hematopoietic Stem Cell Transplantation: A Multicenter, Prospective Randomized Controlled Trial
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 200
- 试验地点
- 1
- 主要终点
- GRFS
研究概览
简要总结
This study aims to determine whether the recurrence rate of high-risk acute myeloid leukemia CR1 patients who received allogeneic hematopoietic stem cell transplantation with the Ruxolitinib, Decitabine combined with Bu/Cy or BuF intensive pretreatment regimen is reduced compared with the traditional Bu/Cy or BuFpretreatment regimen.
详细描述
Allogeneic hematopoietic stem cell transplantation is the only radical treatment for high-risk acute myeloid leukemia (AML), but the traditional Bu/Cy pretreatment regimen is highly toxic and has a high recurrence rate after transplantation (the long-term survival rate is only 10-30%). Although the existing improved regimens such as sequential chemotherapy can reduce the leukemia burden, they lead to prolonged myelosuppression time (17-39 days) and a non-relapse mortality rate as high as 17.2%. There is an urgent need to develop new pretreatment regimens that have both strong anti-leukemia effects and low toxicity.
Studies have found that the JAK-STAT signaling pathway is generally abnormally activated in hematological tumors such as AML. The objective response rate of Ruxolitinib (a JAK1/2 inhibitor) as a monotherapy for relapsed/refractory leukemia reached 45%. When combined with the demethylated drug decitabine, it can synergistically inhibit leukemia cells. Clinical data show that decitabine reduces the recurrence rate after transplantation by 20% (15.0% vs 38.3%), and the combination of the two has good safety. The main adverse reaction is grade 1-2 hematological toxicity.
Our center innovatively proposed the Rux-Dec-mBu/Cy or BuF combined regimen: integrating Ruxolitinib (step-based dose reduction) and decitabine (20mg/m²/d) on the basis of the classic Bu/Cy or BuF. Previous single-arm studies have shown that the one-year recurrence rate of CR1 patients is 0%, and the incidence of toxicity above grade 3 is less than 11%. This study intends to conduct a multicenter randomized controlled trial to verify the superiority of this regimen in reducing recurrence after transplantation in patients with high-risk AML CR1. Its core advantage lies in simultaneously achieving anti-leukemia enhancement (through JAK-STAT targeting and epigenetic regulation) and controllable toxicity (The median grain deficiency time was shortened to 14 days).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 14 Years 至 75 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1) Acute myeloid leukemia with indications for allogeneic hematopoietic stem cell transplantation, CR1 2) Have HLA-matched sibling donors or haploidentical donors or ≥8/10 HLA-matched unrelated donors 3) The patients' ages range from 12 to 64 years old 4) Liver function: ALT and AST≤2.5 times the upper limit of normal values, bilirubin ≤2 times the upper limit of normal values 5) Renal function: Creatinine ≤ the upper limit of the normal value 6) There are no uncontrollable infections or serious mental and psychological disorders 7) Sign the informed consent form.
排除标准
- •1. Patients with acute promyelocytic leukemia (M3)
- •One of the donor and recipient is pregnant
- •Suffering from mental illness or other conditions that prevent one from following the plan.
研究组 & 干预措施
Assigned Interventions
- Decitabine: 20 mg/m²/day, administered from Day -15 to Day -10.
- Ruxolitinib(with Voriconazole):
- 10 mg twice daily (bid), Day -15 to Day -5
- 5 mg twice daily (bid), Day -4 to Day -3
- 5 mg once daily (Qd), Day -2
- Busulfan (Bu): 0.8 mg/kg every 6 hours (Q6h), Day -8 to Day -6.
- Carmustine (BCNU): 250 mg every 8 hours (Q8h), Day -3.
- Cytarabine (Ara-C):
- 4 g/m²/day, Day -10 to Day -9 (for unrelated or haploidentical donors)
- 4 g/m²/day, Day -9 only (for matched sibling donors)
- Cyclophosphamide (CTX): 50 mg/kg/day, Day -5 to Day -4. or Fludarabine 30mg/m2/day, iv, Day -6 to Day -2;
- Antithymocyte Globulin (ATG):
- 10 mg/kg/day, Day -5 to Day -2 (for unrelated or haploidentical donors)
- 5 mg/kg/day, Day -5 to Day -2 (for matched sibling donors)
干预措施: Ruxolitinib, Decitabine (Combination Product)
The control group
- Busulfan (Bu): 0.8 mg/kg every 6 hours (Q6h), Day -8 to Day -6.
- Carmustine (BCNU): 250 mg every 8 hours (Q8h), Day -3.
- Cytarabine (Ara-C):
- 4 g/m²/day, Day -10 to Day -9 (for unrelated or haploidentical donors)
- 4 g/m²/day, Day -9 only (for matched sibling donors)
- Cyclophosphamide (CTX): 50 mg/kg/day, Day -5 to Day -4. or Fludarabine 30mg/m2/day, iv, Day -6 to Day -2;
- Antithymocyte Globulin (ATG):
- 10 mg/kg/day, Day -5 to Day -2 (for unrelated or haploidentical donors)
- 5 mg/kg/day, Day -5 to Day -2 (for matched sibling donors)
结局指标
主要结局
GRFS
时间窗: 1 year
GVHD-free, relapse-free survival (GRFS) was defined as a composite endpoint of death from any cause, disease relapse, grade Ⅲ-Ⅳ acute GVHD, or chronic GVHD requiring systemic immunosuppression therapy.
次要结局
- The incidence of aGVHD(100 days after transplantation)
- The incidence of cGVHD(1 years after transplantation)
- Neutrophil engraftment(+28 days after transplantation)
- CR rate(30 days after transplantation)
- Disease-free survival rate (DFS)(1 years after transplantation)
- Cumulative recurrence rate (CIR)(1 years after transplantation)
- Treatment-related safety indicators(1 years after transplantation)
- Non-relapse mortality(1 year)
- The cumulative incidence of virus reactivation(Day +180 days post-transplantation)
- Graft failure(+28 days after transplantation)
- Progression-Free Survival（PFS）(1 years after transplantation)
- Platelet engraftment(+28 days after transplantation)
- CD4+T cell reconstitution(the first 100 days post-transplantation)
研究者
Daihong Liu
Dr.
Chinese PLA General Hospital