Pediatric malignant solid tumors (including neuroblastoma, Wilms tumor, hepatoblastoma, rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, and germ cell tumors) account for approximately 60% of childhood malignancies. Despite multimodal therapy, children with relapsed or refractory disease have poor outcomes. Repeated lines of intensive salvage chemotherapy cause cumulative damage to the hematopoietic system, resulting in profound and prolonged myelosuppression (absolute neutrophil count \<0.5×10\^9/L or platelet count \<20×10\^9/L) that often fails to recover despite standard supportive care with short-acting recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human thrombopoietin (rhTPO). This leads to chemotherapy delays that compromise treatment continuity and intensity.
Umbilical cord blood (UCB) contains hematopoietic progenitor cells, NK cells, T lymphocytes, and various hematopoietic and immunomodulatory factors. UCB infusion has been shown to accelerate hematopoietic recovery after chemotherapy and may enhance anti-tumor immune function.
This is a single-center, single-arm, prospective exploratory study. Approximately 10 children (aged 1-18 years) with relapsed or refractory malignant solid tumors who develop severe post-chemotherapy myelosuppression with delayed hematopoietic recovery (persistent ANC \<1.0×10\^9/L and platelets \<50×10\^9/L despite ≥7 days of rhG-CSF/rhTPO support, resulting in chemotherapy delay) will receive UCB infusion in addition to continuing background anti-tumor therapy and standardized hematopoietic supportive care. Each patient may receive up to 3 UCB infusions. The follow-up period is 12 weeks from the first infusion.
The study aims to: (1) evaluate the effect of UCB infusion on promoting hematopoietic recovery and on-schedule chemotherapy completion (compared with institutional historical controls); (2) evaluate immune reconstitution after UCB infusion, including dynamics of T-lymphocyte subsets, NK cells, B cells, and serum cytokines; (3) assess the safety of UCB infusion; and (4) explore differences in hematopoietic recovery and immune reconstitution across tumor types and treatment backgrounds.
Age 1-18 years, any sex;
Histopathologically confirmed pediatric malignant solid tumor (including but not limited to neuroblastoma, Wilms tumor, hepatoblastoma, rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, and germ cell tumors), assessed by the investigator as high-risk, relapsed, or refractory;
In relapsed or refractory status requiring salvage chemotherapy;
Severe myelosuppression after the most recent chemotherapy cycle, meeting at least one of the following: ANC <0.5×10^9/L or platelet count <20×10^9/L; AND persistent ANC <1.0×10^9/L and platelets <50×10^9/L despite ≥7 days of standard supportive care (short-acting rhG-CSF 5 μg/kg/day and rhTPO 300 U/kg/day), resulting in a delay of ≥3 days of the next chemotherapy cycle;
Progressive disease (PD) with investigator judgment that the patient is not suitable for continued chemotherapy;
Concurrent second primary malignancy or prior history of other malignancies;
Any active autoimmune disease or history of autoimmune disease;
Current use of immunosuppressants, or systemic glucocorticoid therapy for immunosuppressive purposes (physiologic replacement therapy excepted), continued within 2 weeks before enrollment;
Single group
umbilical cord blood
Other interventionCryopreserved umbilical cord blood unit(s) selected by Tianjin Cord Blood Hematopoietic Stem Cell Bank (HLA-A, -B, -C, -DRB1, -DQB1 ≤5/10 match acceptable; ABO and Rh(D) compatible; TNC ≥1.5×10\^7/kg body weight). The unit is thawed in a 37-40°C water bath and infused intravenously over approximately 30 minutes with premedication (diphenhydramine and acetaminophen; dexamethasone if indicated) and continuous vital-sign monitoring. Each patient may receive up to 3 infusions, with an interval of ≥21 days between infusions.
Composite Primary Endpoint Achievement Rate
Proportion of UCB infusions for which all three of the following criteria are met: (1) on-schedule completion of the next chemotherapy cycle (delay ≤3 days); (2) ANC recovery to ≥1.0×10\^9/L sustained for ≥3 days within 21 days after infusion; (3) platelet recovery to ≥50×10\^9/L with platelet-transfusion independence for ≥7 days within 21 days after infusion. Each infusion is evaluated as an independent event, and the best response per patient is recorded. Results are described in comparison with institutional historical controls (on-schedule chemotherapy completion rate approximately 30%-40%).
On-schedule Chemotherapy Completion Rate
Proportion of UCB infusions after which the patient successfully receives the next chemotherapy cycle on the scheduled date (per the background regimen); the actual interval (days) from UCB infusion to the next chemotherapy cycle is recorded.
Time to ANC Recovery
Number of days from each UCB infusion to ANC ≥1.0×10\^9/L sustained for ≥3 days.
Time to Platelet Recovery
Number of days from each UCB infusion to platelet count ≥50×10\^9/L with platelet-transfusion independence for ≥7 days.
Number of participants with Grade ≥3 hematologic laboratory abnormalities, assessed by NCI-CTCAE v5.0
WBC, ANC, hemoglobin, and platelet results collected at baseline and on Days 1, 3, 5, 7, 10, and 14 after each infusion will be graded according to NCI-CTCAE v5.0. The number and percentage of participants with Grade ≥3 hematologic laboratory abnormalities will be reported.
Absolute counts and percentages of lymphocyte subsets (CD3+, CD4+, CD8+ T cells, CD16+CD56+ NK cells, CD19+ B cells, and CD4+CD25+FoxP3+ regulatory T cells), measured by multiparameter flow cytometry
Peripheral blood will be collected at baseline (before each cord blood infusion) and on Days 14 and 28 after each infusion. Lymphocyte subsets will be identified and quantified by multiparameter flow cytometry, including CD3+, CD4+, and CD8+ T cells (with the CD4+/CD8+ ratio), NK cells (CD16+CD56+), B cells (CD19+), and regulatory T cells (CD4+CD25+FoxP3+). Each subset will be reported separately: absolute counts (cells/µL) and percentages among lymphocytes (%) will be summarized at each time point using descriptive statistics (mean ± SD or median \[IQR\]), and changes from baseline will be compared by paired t-test or Wilcoxon signed-rank test.
Serum Cytokine Levels
Number of units of red blood cells transfused after cord blood infusion
Red blood cell transfusion records will be reviewed within 2 weeks after each cord blood infusion. The volume of red blood cell transfusion (in units) will be recorded for each infusion and summarized per participant using descriptive statistics (mean ± SD or median \[IQR\]). Post-infusion transfusion requirements will be compared with the participant's own pre-infusion/historical data using Wilcoxon signed-rank test.
Time to lymphocyte recovery (ALC ≥1.0×10⁹/L), NK cell recovery (≥100 cells/µL), and CD4+ T cell recovery (≥200 cells/µL), measured by automated hematology analyzer and multiparameter flow cytometry
Within 12 weeks from the first cord blood infusion, the time to recovery will be assessed for three parameters, each reported separately in days as median (range): (1) time to absolute lymphocyte count (ALC) recovery, defined as ALC ≥1.0×10⁹/L, measured by automated hematology analyzer; (2) time to NK cell recovery, defined as absolute NK cell count (CD16+CD56+) ≥100 cells/µL, measured by multiparameter flow cytometry; (3) time to CD4+ T cell recovery, defined as absolute CD4+ T cell count ≥200 cells/µL, measured by multiparameter flow cytometry. As an exploratory analysis, the correlation between each time-to-recovery endpoint and hematologic recovery time (ANC and platelet recovery time) will be evaluated by Spearman correlation analysis.
Time to ANC recovery, compared between neuroblastoma and other pediatric solid tumor subgroups
Participants will be stratified by tumor type (neuroblastoma versus other pediatric malignant solid tumors). Time from first cord blood infusion to ANC recovery (days) will be summarized within each stratum as median \[range\] and compared between strata by Mann-Whitney U test. This comparison is exploratory; no additional measurements are collected for this analysis.
Time to platelet recovery, compared between neuroblastoma and other pediatric solid tumor subgroups
Participants will be stratified by tumor type (neuroblastoma versus other pediatric malignant solid tumors). Time from first cord blood infusion to platelet recovery time (days) will be summarized within each stratum as median \[range\] and compared between strata by Mann-Whitney U test. This comparison is exploratory; no additional measurements are collected for this analysis.
Lymphocyte subset counts, compared between neuroblastoma and other pediatric solid tumor subgroups
Participants will be stratified by tumor type... Absolute counts of lymphocyte subsets (cells/μL) will be summarized within each stratum as mean ± SD or median \[IQR\] and compared between strata by Mann-Whitney U test. This comparison is exploratory; no additional measurements are collected for this analysis.
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Tianjin Medical University Cancer Institute and Hospital
Lead sponsor
Institute of Hematology & Blood Diseases Hospital, China
Collaborator
Union Stem Cell & Gene Engineering Co
Collaborator
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