Neoplasms

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Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

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Neoplasms, Nerve Tissue

Neuroepithelioma

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Cyclophosphamide

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Fludarabine phosphate

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Topotecan

Melphalan

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Busulfan

Thiotepa

Antilymphocyte Serum

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Alkylating Agents

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Folinic Acid

Folate

Vitamin B9

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).

2.5 mg/kg/day；2 doses on day -3 and day -2 for matched sibling donor transplantation；3 doses on day -4，-3 and day -2 for unrelated donor transplantation；4 doses on day -5，-4，-3 and day -2 for haploidentical donor transplantation

Anti Thymocyte Globulin

60 mg/kg/day for 2 days in cord blood stem cell transplantation

Cyclophosphamide injection

2mg/m2/day for 3 days in cord blood stem cell transplantation

70mg/m2/day，for peripheral stem cell transplantation or haploidentical bone marrow combined with peripheral stem cell transplantation；2 doses on day -3 and day -2 when conditioning regimen containing thiotepa；3 doses on day -4，-3 and day -2 when conditioning regimen not containing thiotepa；

5 mg/kg/day for 2 days in peripheral stem cell transplantation or haploidentical bone marrow combined with peripheral stem cell transplantation

0.8mg/kg/dose；8 doses in cord blood stem cell transplantation；12 doses in peripheral stem cell transplantation or haploidentical bone marrow combined with peripheral stem cell transplantation when conditioning regimen containing thiotepa；16 doses in peripheral stem cell transplantation or haploidentical bone marrow combined with peripheral stem cell transplantation when conditioning regimen not containing thiotepa；

2.5\~4 mg/kg/dose every 12 hours orally；1.5\~2 mg /kg/dose every 12 hours intravenously; trough concentration maintained at 150\~250ng/ml

0.02\~0.03 mg/kg/day as continuous infusion or 12 hour divided doses

Mycophenolate Mofetil

15 mg/m2/dose on d+1 and 10 mg/m2/dose on d+3，d+6 in peripheral stem cell transplantation

Ke Huang, MD

Su Liu, MD

Yang Li, MD

Jianpei Fang, MD

Yang Li

Jianpei Fang

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.

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.

Allogeneic Hematopoietic Stem Cell Transplantation for 4/M Neuroblastoma

Clinical Research of Allogeneic Hematopoietic Stem Cell Transplantation for Treatment of Children With Stage 4/M Neuroblastoma: A Prospective, Single-arm, Phase II, Multi-center Trial

From the date of day 0 of transplantation until the date of death from any cause

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

Conditioning toxicity is graded according to the Common Terminology Criteria for Adverse Events(CTCAE Version 5.0)

Donor engraftment represents donor cells replace at least 95% of recipient hematopoietic stem cells.

Death due to transplantation, excluding other causes such as disease progression or relapse.

Sinusoidal obstruction syndrome is diagnosed according to classification from the European society for blood and marrow transplantation.

TA-TMA is diagnosed according to the Jodele standard.

Acute graft versus host disease is diagnosed according to the modified Glucksberg grading standard.

e.g. EBV/CMV viremia or related disease, bacteria/fungi /tuberculosis infection

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)".

Spots Global Cancer Trial Database for anti thymocyte globulin