Hematopoietic Stem Cell Transplantation, TP53
Conditions
Keywords
hematopoietic stem cell transplantation, TP53, relapse, decitabine
Brief summary
This study aims to evaluate the effectiveness and safety of Venetoclax and Decitabin based conditioning regimen followed with post-HSCT Decitabin maintenance therapy in TP53 mutant AML/MDS Patients.
Detailed description
In acute myeloid leukemia and myelodysplastic syndromes, TP53 gene mutation is a poor prognostic factor and a strong indication for hematopoietic stem cell transplantation. However, because of the high relapse rate of myeloid tumors with TP53 mutation, new comprehensive treatment is urgently needed to improve the efficacy of transplantation. Decitabin(DEC) has shown certain efficacy in primary patients with TP53 mutation, and Venetoclax (VEN) and DEC have synergistic effect. Based on this, we hypothesized that DEC and VEN should be added to the conditioning regimen in TP53 mutant AML/MDS patients in order to eliminate malignant clones with P53 mutation as much as possible, and intermittent DEC maintenance therapy should be used to prevent relapse after post-HSCT hematopoietic reconstruction. We intend to conduct a multicenter, single-arm clinical study to evaluate the efficacy and safety of this protocol.
Interventions
DRUGDEC
In the time window of 60-120 days after transplantation: DEC 5mg/m2/d for 5 consecutive days every 6 to 8 weeks with a total of 4 to 6 courses if there is no severe aGVHD (grade 3 or higher) and the donor chimerism rate of bone marrow blood (STR)\>95%. If the MRD turns positive, DLI can be performed.
DRUGVEN and DEC based conditioning regimen
Patients with age\<50 years and HCT-CI\<3: Haploidentical transplantation: AraC 2g/m2 d-10\ d-9, BU 0.8mg/kg q6h d-8\ -6, CTX 1.8g/m2 d-5\ d-4, Meccnu 250mg/m2 d-3, ATG 1.5mg/kg/d d-5\ -2, VEN 400mg/d d-15\ -9, DEC 20mg/m2 d-15\ -11; HLA-matched transplantation: BU 0.8mg/kg q6h d-7\ -4, CTX 60mg/kg d-3\ d-2, Meccnu 250mg/m2 d-1, VEN d-12\ -8, DEC 20mg/m2 d-12\ -6, and ATG for the unrelated donor type. Patients with age\>50 years or HCT-CI≥3: Flu 30mg/m2 d-10\ -5, BU 0.8mg/kg q6h d-7\ -5, Meccnu 250mg/m2 d-4, ATG 7.5mg/kg divided into d-4\ -1, VEN d-15\ -9, DEC 20mg/m2 d-15\ -11. Note: if Voriconazole or Posaconazole is used to prevent or treat fungal infections, VEN should be 200mg/d for 7 consecutive days.
Sponsors
Zhejiang University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. AML or MDS diagnosed according to 2016 WHO criteria with TP53 mutation before enrollment; 2. Aged from 12 to 70 years; 3. The Eastern Cooperative Oncology Group (ECOG) performance score of 0-2; 4. Creatinine clearance rate ≥ 60 mL/min (according to Cockcroft-Gault formula); 5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥ 3× upper limit of normal range (ULN), total bilirubin ≤ 2×ULN; 6. Left ventricular ejection fraction (LVEF) assessed by echocardiography (ECHO) ≥ 45%; 7. Life expectancy \> 8 weeks; 8. Sign the informed consent voluntarily, understand and comply with all trial requirements.
Exclusion criteria
1. Active autoimmune diseases, such as SLE, rheumatoid arthritis, etc. 2. Current active cardiovascular disease with clinically significance, such as uncontrolled arrhythmias, uncontrolled hypertension, congestive heart failure, any grade 3 or 4 heart disease determined by the New York Heart Association (NYHA) functional classification, or a history of myocardial infarction within the 6 months prior to screening; 3. Other serious medical conditions (e.g., advanced infection) that may limit the patient's participation in the trial; 4. Known human immunodeficiency virus (HIV) infection, or drug-uncontrolled chronic infection of hepatitis B virus (HBV-DNA \> 1000IU/ml) or hepatitis C virus (anti-HCV positive); 5. Pregnant or lactating women; 6. Fail to understand, comply with the study protocol or sign the informed consent form.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | At Year 1 | The time from transplantation to the occurrence of any of the following: 1. Death from any cause 2. Disease recurrence, defined as one of the following: Leukemia blasts reappeared in peripheral blood, or blasts ≥ 5%, naive monocytes ≥ 5% in bone marrow, or extramedullary lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative relapse rate | At Year 1 | Assessment of cumulative relapse rate at Year 1 |
| Non-relapse mortality (NRM) | At Year 1 | Assessment of NRM at Year 1 |
| Overall survival (OS) | At Year 1 | Assessment of OS at Year 1 |
| Chronic graft-versus-host disease (GVHD) | through study completion, an average of 1 year | Chronic GVHD incidence |
| Adverse effects | through study completion, an average of 1 year | Drug related adverse effects |
| Acute graft-versus-host disease (GVHD) | At Day 100 | Acute GVHD incidence |
Countries
China
Contacts
Primary ContactYanmin Zhao, PhD
Outcome results
None listed