Allogeneic Hematopoietic Stem Cell Transplantation for 4/M Neuroblastoma

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:

• 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.];
• 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.

• Evaluation criteria for disease before and after transplantation:

• Complete response (CR): all primary and metastatic lesions disappear, and neuron specific enolase (NSE), catecholamines and metabolites return to normal.
• Very good partial response (VGPR): the primary tumor volume is reduced by 90% to 99%, all measurable metastases disappear, and NSE, catecholamines and metabolites return to normal; radionuclide bone scanned lesions can be positive (because bone metastases have not healed), but if an metaiodobenzylguanidine (MIBG) scan is performed, all lesions are negative.
• Partial response (PR): The volume of all primary tumors and measurable metastases is reduced by more than 50%, the number of bone-positive lesions is reduced by more than 50%, and there is no more than one bone-positive site.
• Mixed response (MR): no new lesions, the volume of any one or more measurable lesions decreases more than 50%, and the volume of any other one or more lesions decreases less than 50%, and volume of any existing lesions increases less than 25%.
• No response (NR): There are no new lesions, and the volume of any existing lesions decreases less than 50% or increases less than 25%.
• Progressive disease (PD): new lesions appear, the volume of existing measurable lesions increases more than 25%, and the bone marrow changes from negative to positive.

• Inclusion Criteria: 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;
• 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;
• 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;
• 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;
• Whole brain and whole spinal cord radiotherapy have completed before HSCT in patients with central invasion at onset;
• The blood routine has generally returned to normal and there is no dysfunction of major organs such as the heart, liver, lung, and kidney;
• The guardian/patient accept the treatment of this research, sign the informed consent, and complete the follow-up.

• Exclusion Criteria: 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.