Allogeneic Hematopoietic Stem Cell Transplantation for 4/M Neuroblastoma
- Conditions
- Neuroblastoma
- Interventions
- Registration Number
- NCT05303727
- Brief Summary
Neuroblastoma (NB) is the most common extracranial solid tumor of embryonal origin in children. According to the International Neuroblastoma Risk Group (INRG) staging criteria and the International Neuroblastoma Staging System (INSS) ，NB preoperative staging is divided into L1, L2, M and Ms stages, the postoperative staging is divided into 1 to 4 stages and 4s stage. Among them, 4/M stage is of the highest degree of malignancy and the worst prognosis. Despite the aggressive combination therapy, the 5-year survival rate (OS) is still less than 15%, and the 2-year relapse rate is 80%. Currently, no effective treatment is accessible for refractory/relapsed stage 4/M NB after completing conventional therapy.
In hematopoietic stem cell transplantation (HSCT) , conditioning regimen with high-dose radiotherapy and chemotherapy is implemented to eradicate tumor cells and abnormal clonal cells in the patient, block the pathogenesis, and restore the patient's hematopoietic and immune systems by transplanting normal hematopoietic stem cells. According to the source of hematopoietic stem cells, HSCT can be divided into two types: autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). It has been confirmed that benefiting from the graft versus tumor(GVT) effect, allo-HSCT can clear residual lesions in refractory/relapsed NB patients post-auto-HSCT，and prolong the survival time of patients. Our center has explored the conditioning regimen, treatment of residual tumor lesions before transplantation, and strategies to reduce transplantation-related death (TRM) and enhance the GVT effect. However, the sample size is small, and multicenter and larger sample size research are needed. This study will further observe the clinical efficacy and safety of allo-HSCT in the treatment of 4/M stage NB, and provide a new treatment method and option for 4/M stage NB.
- Detailed Description
Purposes: To evaluate the efficacy and safety of allo-HSCT in children with stage 4/M high-risk NB through a multi-center prospective single-arm clinical research grouped according to different types of donors, graft sources, and stratified conditioning regimen.
Primary objectives: To evaluate the efficacy (3-year OS, EFS) of allo-HSCT in the treatment of children with stage 4/M NB through a multicenter prospective single-arm clinical study.
Secondary objectives:
1. To evaluate the safety of allo-HSCT in the treatment of children with stage 4/M NB \[toxicity of conditioning regimen, engraftment rate, early transplantation-related mortality (\<100d TRM), transplantation-related complications (VOD, thrombotic microangiopathy(TMA), acute/chronic graft-versus-host disease (GVHD), Epstein-Barr virus(EBV)/cytomegalovirus(CMV) viremia and EBV/CMV related diseases or other pathogenic infections, etc.\];
2. Improvement and optimization of allo-HSCT conditioning regimen. Outline: This is a multicenter study. Conditioning regimen: There are 3 protocols according to different sources of donor: (1) Cord blood HSCT: Flu+Bu+cyclophosphamide (CTX)+Topotecan (without ATG); (2) Peripheral blood HSCT or haploid bone marrow combined with peripheral stem cell transplantation: Flu+Bu+Melphalan+Antithymocyte globulin (ATG)+ Thiotepa (TT) or (3) Flu+Bu+Melphalan+ATG (applicable to peripheral stem cells or haploid bone marrow combined with peripheral stem cell transplantation for which TT cannot be used).
Transplantation: Patients undergo cord blood stem cell or bone marrow or granulocyte colony stimulating factor (G-CSF) mobilized peripheral blood stem cell transplantation on day 0.
GVHD prophylaxis: Cyclosporine or tacrolimus combined with methotrexate is used for related matched transplantation, cyclosporine combined with mycophenolate mofetil for umbilical cord blood transplantation, and cyclosporine combined with mycophenolate mofetil and methotrexate for haploidentical transplantation to prevent GVHD.
After completion of transplantation, patients are followed periodically at least 3 years.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 64
one of the following criteria (2), (3) or (4) must be met and all other criterions must be met at the same time:
-
Age≤18 years old;
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After at least 7 courses of induction chemotherapy (surgical resection of the primary tumor or metastatic disease has been completed during the period), evaluation of disease is CR, tumor markers (blood NSE and urine VMA) and minimal residual disease by flow cytometry of bone marrow and peripheral blood are negative; the primary tumor has completed radiotherapy before HSCT;
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For patients with PR or VGPR, tumor markers (blood NSE and urine VMA) and minimal residual disease by flow cytometry of bone marrow and peripheral blood are negative; the primary tumor and metastatic lesions have completed radiotherapy before HSCT;
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Relapsed patients achieve CR/VGPR/PR after re-induction or salvage chemotherapy, tumor markers (blood NSE and urine VMA) and minimal residual disease by flow cytometry of bone marrow and peripheral blood are negative; the primary tumor and metastatic lesions have completed radiotherapy before HSCT;
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Whole brain and whole spinal cord radiotherapy have completed before HSCT in patients with central invasion at onset;
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The blood routine has generally returned to normal and there is no dysfunction of major organs such as the heart, liver, lung, and kidney;
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The guardian/patient accept the treatment of this research, sign the informed consent, and complete the follow-up.
meeting one of the following criterions:
- With severe cardiac insufficiency, cardiac ejection fraction (EF) is less than 50%; or severe cardiac disease, the patient can not tolerate the conditioning regimen according to the investigators' evaluation;
- With severe pulmonary insufficiency (severe obstructive and/or restrictive ventilation disorders), the patient can not tolerate the conditioning regimen according to the investigators' evaluation;
- With severe liver function impairment, ALT>5 times upper limit of normal, or total bilirubin>3 times upper limit of normal; the patient can not tolerate the conditioning regimen according to the investigators' evaluation;
- With severe renal insufficiency, creatinine>2 times upper limit of normal; or corrected creatinine clearance rate Ccr<50ml/min; the patient can not tolerate the conditioning regimen according to the investigators' evaluation;
- With severe active bleeding or severe active infection; the patient can not tolerate the conditioning regimen according to the investigators' evaluation;
- Allergic reactions or serious adverse reactions occurred in the previous use of conditioning regimen-related drugs, the patient can not tolerate the conditioning regimen according to the investigators' evaluation;
- The guardian/patient cannot understand or comply with the treatment plan;
- Other reasons for not being selected due to the investigator's evaluation.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Conditioning regimen for different sources of donors Cyclophosphamide injection There are 3 groups according to different sources of donor: (1) Cord blood HSCT: Flu+Bu+CTX+Topotecan (without ATG); (2) Peripheral blood HSCT or haploid bone marrow combined with peripheral stem cell transplantation: Flu+Bu+Melphalan+Antithymocyte globulin (ATG)+ Thiotepa (TT) or (3) Flu+Bu+Melphalan+ATG (applicable to peripheral stem cells or haploid bone marrow combined with peripheral stem cell transplantation for which TT cannot be used). Conditioning regimen for different sources of donors Anti Thymocyte Globulin There are 3 groups according to different sources of donor: (1) Cord blood HSCT: Flu+Bu+CTX+Topotecan (without ATG); (2) Peripheral blood HSCT or haploid bone marrow combined with peripheral stem cell transplantation: Flu+Bu+Melphalan+Antithymocyte globulin (ATG)+ Thiotepa (TT) or (3) Flu+Bu+Melphalan+ATG (applicable to peripheral stem cells or haploid bone marrow combined with peripheral stem cell transplantation for which TT cannot be used). Conditioning regimen for different sources of donors Mycophenolate Mofetil There are 3 groups according to different sources of donor: (1) Cord blood HSCT: Flu+Bu+CTX+Topotecan (without ATG); (2) Peripheral blood HSCT or haploid bone marrow combined with peripheral stem cell transplantation: Flu+Bu+Melphalan+Antithymocyte globulin (ATG)+ Thiotepa (TT) or (3) Flu+Bu+Melphalan+ATG (applicable to peripheral stem cells or haploid bone marrow combined with peripheral stem cell transplantation for which TT cannot be used). Conditioning regimen for different sources of donors Fludarabine There are 3 groups according to different sources of donor: (1) Cord blood HSCT: Flu+Bu+CTX+Topotecan (without ATG); (2) Peripheral blood HSCT or haploid bone marrow combined with peripheral stem cell transplantation: Flu+Bu+Melphalan+Antithymocyte globulin (ATG)+ Thiotepa (TT) or (3) Flu+Bu+Melphalan+ATG (applicable to peripheral stem cells or haploid bone marrow combined with peripheral stem cell transplantation for which TT cannot be used). Conditioning regimen for different sources of donors Busulfan There are 3 groups according to different sources of donor: (1) Cord blood HSCT: Flu+Bu+CTX+Topotecan (without ATG); (2) Peripheral blood HSCT or haploid bone marrow combined with peripheral stem cell transplantation: Flu+Bu+Melphalan+Antithymocyte globulin (ATG)+ Thiotepa (TT) or (3) Flu+Bu+Melphalan+ATG (applicable to peripheral stem cells or haploid bone marrow combined with peripheral stem cell transplantation for which TT cannot be used). Conditioning regimen for different sources of donors Melphalan There are 3 groups according to different sources of donor: (1) Cord blood HSCT: Flu+Bu+CTX+Topotecan (without ATG); (2) Peripheral blood HSCT or haploid bone marrow combined with peripheral stem cell transplantation: Flu+Bu+Melphalan+Antithymocyte globulin (ATG)+ Thiotepa (TT) or (3) Flu+Bu+Melphalan+ATG (applicable to peripheral stem cells or haploid bone marrow combined with peripheral stem cell transplantation for which TT cannot be used). Conditioning regimen for different sources of donors Topotecan There are 3 groups according to different sources of donor: (1) Cord blood HSCT: Flu+Bu+CTX+Topotecan (without ATG); (2) Peripheral blood HSCT or haploid bone marrow combined with peripheral stem cell transplantation: Flu+Bu+Melphalan+Antithymocyte globulin (ATG)+ Thiotepa (TT) or (3) Flu+Bu+Melphalan+ATG (applicable to peripheral stem cells or haploid bone marrow combined with peripheral stem cell transplantation for which TT cannot be used). Conditioning regimen for different sources of donors Cyclosporine There are 3 groups according to different sources of donor: (1) Cord blood HSCT: Flu+Bu+CTX+Topotecan (without ATG); (2) Peripheral blood HSCT or haploid bone marrow combined with peripheral stem cell transplantation: Flu+Bu+Melphalan+Antithymocyte globulin (ATG)+ Thiotepa (TT) or (3) Flu+Bu+Melphalan+ATG (applicable to peripheral stem cells or haploid bone marrow combined with peripheral stem cell transplantation for which TT cannot be used). Conditioning regimen for different sources of donors Thiotepa There are 3 groups according to different sources of donor: (1) Cord blood HSCT: Flu+Bu+CTX+Topotecan (without ATG); (2) Peripheral blood HSCT or haploid bone marrow combined with peripheral stem cell transplantation: Flu+Bu+Melphalan+Antithymocyte globulin (ATG)+ Thiotepa (TT) or (3) Flu+Bu+Melphalan+ATG (applicable to peripheral stem cells or haploid bone marrow combined with peripheral stem cell transplantation for which TT cannot be used). Conditioning regimen for different sources of donors Tacrolimus There are 3 groups according to different sources of donor: (1) Cord blood HSCT: Flu+Bu+CTX+Topotecan (without ATG); (2) Peripheral blood HSCT or haploid bone marrow combined with peripheral stem cell transplantation: Flu+Bu+Melphalan+Antithymocyte globulin (ATG)+ Thiotepa (TT) or (3) Flu+Bu+Melphalan+ATG (applicable to peripheral stem cells or haploid bone marrow combined with peripheral stem cell transplantation for which TT cannot be used). Conditioning regimen for different sources of donors Methotrexate There are 3 groups according to different sources of donor: (1) Cord blood HSCT: Flu+Bu+CTX+Topotecan (without ATG); (2) Peripheral blood HSCT or haploid bone marrow combined with peripheral stem cell transplantation: Flu+Bu+Melphalan+Antithymocyte globulin (ATG)+ Thiotepa (TT) or (3) Flu+Bu+Melphalan+ATG (applicable to peripheral stem cells or haploid bone marrow combined with peripheral stem cell transplantation for which TT cannot be used).
- Primary Outcome Measures
Name Time Method overall survival(OS) at 3 year 3 years post-HSCT From the date of day 0 of transplantation until the date of death from any cause
event free survival(EFS) at 3 year 3 years post-HSCT Survival time from day 0 of transplantation to the occurrence of the first adverse event. Disease or treatment-related adverse events, such as tumor recurrence, implant failure, and death, are counted in this study; accidental deaths that assessed unrelated to the above factors are not included
- Secondary Outcome Measures
Name Time Method incidence of transplant associated thrombotic microangiopathy(TA-TMA) 3 years post-HSCT TA-TMA is diagnosed according to the Jodele standard.
incidence of donor engraftment 100 days post-HSCT Donor engraftment represents donor cells replace at least 95% of recipient hematopoietic stem cells.
early transplant-related mortality 100 days post-HSCT Death due to transplantation, excluding other causes such as disease progression or relapse.
incidence of infection 3 years post-HSCT e.g. EBV/CMV viremia or related disease, bacteria/fungi /tuberculosis infection
incidence of conditioning toxicity 100 days post-HSCT Conditioning toxicity is graded according to the Common Terminology Criteria for Adverse Events(CTCAE Version 5.0)
incidence of sinusoidal obstruction syndrome 3 years post-HSCT Sinusoidal obstruction syndrome is diagnosed according to classification from the European society for blood and marrow transplantation.
incidence of acute graft versus host disease 100 days post-HSCT Acute graft versus host disease is diagnosed according to the modified Glucksberg grading standard.
incidence of chronic graft versus host disease 3 years post-HSCT Chronic graft versus host disease is diagnosed according to the grading and scoring system recommended by the "Chinese Consensus on the Diagnosis and management of Chronic Graft-versus-Host Disease(2021)".
Trial Locations
- Locations (1)
Sun Yat-sen Memorial Hospital, Sun Yat-sen University
🇨🇳Guangzhou, Guangdong, China