Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Conditions
Keywords
HSCT
Brief summary
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.
Detailed description
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).
Interventions
COMBINATION_PRODUCTRuxolitinib, Decitabine
1. Decitabine: 20 mg/m²/day, administered from Day -15 to Day -10. 2. Ruxolitinib: * 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
Sponsors
Chinese PLA General Hospital
The First Affiliated Hospital of Zhengzhou University, Zhengzhou
Peking University People's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Random Group Assignment
Eligibility
Sex/Gender
ALL
Age
14 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* 1\. Patients with acute promyelocytic leukemia (M3) 2. One of the donor and recipient is pregnant 3. Suffering from mental illness or other conditions that prevent one from following the plan.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| GRFS | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative recurrence rate (CIR) | 1 years after transplantation | Calculated from the first day after stem cell infusion to the last follow-up, the number of patients with hematological or MRD recurrence/the total number of cases ×100%. The definition of hematological recurrence: After remission, patients present with one of the following three conditions: (1) ≥5% of primary lymphocytes and immature lymphocytes in the bone marrow; (2) Extramedullary leukemia occurs; (3) Leukemia cells were found in peripheral blood smears. The definition of MRD recurrence: Leukemia cells are detected by flow cytometry or molecular biology. |
| Progression-Free Survival（PFS） | 1 years after transplantation | The time from the date of transplantation to the recurrence of leukemia or death for any reason. |
| CR rate | 30 days after transplantation | The proportion of bone marrow in complete remission from the first day after stem cell infusion to +30 days. |
| The incidence of aGVHD | 100 days after transplantation | Calculated from the first day after stem cell infusion, the time from the occurrence of aGVHD, the time of recurrence or death. The actual incidence rate is the number of patients who occur/the total number of cases ×100%. |
| The incidence of cGVHD | 1 years after transplantation | Calculated from the first day after stem cell infusion, the time from the occurrence of cGVHD, the time of recurrence or death. The actual incidence rate is the number of patients who occur/the total number of cases ×100%. |
| Disease-free survival rate (DFS) | 1 years after transplantation | Disease-free survival rate (DFS) refers to the survival period without evidence of recurrence or progression. |
| Treatment-related safety indicators | 1 years after transplantation | Mainly include bacterial infection, viral infection, fungal infection, and PTLD from the time calculated after transplantation to the last follow-up. |
| Non-relapse mortality | 1 year | Non-relapse mortality (NRM) was defined as death from any cause other than disease relapse. |
| The cumulative incidence of virus reactivation | Day +180 days post-transplantation | The cumulative incidence of virus reactivation by Day +180 days post-transplantation was defined as the proportion of virus reactivation occurring at any monitoring point during days 180 post-transplant. |
| Graft failure | +28 days after transplantation | Graft failure was defined as non-engraftment (ie, autologous reconstitution) or graft rejection (ie, secondary loss of donor chimerism) at +28 days |
| Neutrophil engraftment | +28 days after transplantation | Neutrophil engraftment was defined as the first of three consecutive days with a neutrophil count \>0.5 ×109/L. |
| Platelet engraftment | +28 days after transplantation | Platelet engraftment was defined as the first of seven consecutive days with a platelet count \>20×109/L without transfusion support. |
| CD4+T cell reconstitution | the first 100 days post-transplantation | CD4+T cell reconstitution was defined as CD4+ T cell count ≥ 50/μL in two consecutive measurements within the first 100 days post-transplantation. |
Countries
China
Contacts
CONTACTLi-ping Dou, Dr.
CONTACTDai-hong Liu, Dr.
Outcome results
None listed