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TFBC Combined With UCBT in the Treatment of High-risk Malignant Hematological Diseases

Primary Purpose

Hematopoietic Stem Cell Transplantation, Malignant Hematological Diseases

Status
Recruiting
Phase
Not Applicable
Locations
China
Study Type
Interventional
Intervention
Umbilical Cord Blood Transplantation
Sponsored by
The First Affiliated Hospital of Soochow University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hematopoietic Stem Cell Transplantation focused on measuring Umbilical Cord Blood Transplantation; Conditioning regimen

Eligibility Criteria

14 Years - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Gender is not limited, patients between 14 to 70 years old (including critical value); High-risk malignant hematological diseases (acute lymphoblastic leukemia, acute/chronic myeloid leukemia, multiple myeloma, etc.) diagnosed by bone marrow aspiration or biopsy according to the WHO diagnostic criteria; The indexes of cardiac function, liver and kidney function were within the following limits:(1) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3× Upper limit of normal (ULN); (2)Total bilirubin ≤ 3×ULN; (3) Serum creatinine ≤ 2×ULN or creatinine clearance ≥ 40mL/min; (4) Left ventricular ejection fraction (LVEF) as measured by echocardiography or multi-gated acquisition (MUGA) scan is within the normal range (> 50%); Umbilical cord blood with HLA match ≥ 4/6; Expected survival ≥3 months; Karnofsky (KPS) score ≥60%, Eastern Tumor Cooperative group (ECOG) status ≤ 2; Patient fully understood the nature of the study, and voluntarily participates and signs informed consent. Exclusion Criteria: Patients had serious adverse reactions to investigational drugs such as allergies; Patients with a history of immunodeficiency, or other acquired or congenital diseases, immunodeficiency diseases, and a history of organ transplantation; Patients with hypertension, ventricular arrhythmia requiring clinical intervention, acute coronary syndrome, congestive heart failure, stroke, or other grade III or higher cardiovascular events within 6 months; Two or more surgeries were performed within 4 weeks prior to enrollment; Patients with active viral infections, including HIV, HBV, HCV, TP; Pregnant or lactating patients; The patient is currently participating in another clinical studies; Patients deemed unsuitable for inclusion by other investigators.

Sites / Locations

  • The First Affiliated Hospital of Soochow universityRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

40 patients with malignant hematological diseases who underwent UCBT

Arm Description

Outcomes

Primary Outcome Measures

The cumulative incidence of neutrophil engraftment and platelet engraftment
Neutrophil and platelet engraftment is defined as the first occurrence of 3 consecutive days with an absolute neutrophil count of at least 0.5×109/L and a platelet count of over 20×109/L for 7 consecutive days without transfusion support.
The time to reconstitution of hematopoiesis
Recovery of hemopoietic function after treatment
The cumulative incidence of transplant-related mortality (TRM)
Transplant-related mortality was defined as mortality due to any cause other than disease progression within 100 days of transplantation.

Secondary Outcome Measures

The cumulative incidence and severity of pre-engraftment syndrome (PES)
Pre-engraftment syndrome (PES) is a condition occurring after umbilical cord blood transplantation (UCBT) characterized by fever and erythematous skin rash prior to neutrophil engraftment.
The cumulative incidence and grade of graft-versus-host disease (GVHD)
Graft-versus-host disease (GvHD) is a medical complication following the receipt of transplanted tissue from a genetically different person.
The cumulative incidence of relapse
We defined relapse as any clinical evidence of progression or recurrence of original diseases.
Overall survival rate
We estimated OS from the time of transplant until the date of death of any cause or last follow-up for patients still alive.
The cumulative incidence of adverse event
Following extraction of the tumor, a blood vessel burst causing increased blood loss during the procedure, an adverse event the surgeon did not expect.

Full Information

First Posted
June 24, 2023
Last Updated
July 3, 2023
Sponsor
The First Affiliated Hospital of Soochow University
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1. Study Identification

Unique Protocol Identification Number
NCT05929092
Brief Title
TFBC Combined With UCBT in the Treatment of High-risk Malignant Hematological Diseases
Official Title
Total Body Irradiation/ Fludarabine/ Busulfan/ Cyclophosphamide (TFBC) Combined With Umbilical Cord Blood Transplantation (UCBT) in the Treatment of High-risk Malignant Hematological Diseases
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 1, 2023 (Actual)
Primary Completion Date
December 31, 2024 (Anticipated)
Study Completion Date
May 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
The First Affiliated Hospital of Soochow University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
High-risk malignant hematological diseases refer to malignant hematological diseases, mainly include various types of leukemia, lymphoma, and multiple myeloma, with very poor prognoses, very short survival, and unsatisfactory outcomes. Chemotherapy, hypomethylating agents (HMA), radiotherapy, targeted therapy, immunotherapy, and hematopoietic stem cell transplantation (HSCT) are common treatments for high-risk malignant hematological diseases. Because of the multiple lines and long duration of exposure to chemotherapy drugs in patients with high-risk malignant hematological diseases, monotherapy is inefficient, and radiotherapy is used frequently as an adjunct treatment to HSCT. Conventional myeloablative conditioning regimens before HSCT are comprised of cyclophosphamide/total body irradiation (Cy/TBI) and busulfan/cyclophosphamide (Bu/Cy). The reduced-toxicity myeloablative conditioning regimen, FBC, is the combination of Bu, Cy, and fludarabine (Flu), which has a strong immunosuppressive effect to ensure the success of engraftment of donor cells. Compared to the conventional intensified chemotherapy regimens, HMA have certain advantages of efficacy and safety and are the first-line treatment options for patients with acute myeloid leukemia (AML). Although monotherapy improves survival rate, the response rate is low. What's more, it is difficult to achieve sustained remission and long-term benefits. The current research hotspots are HMA combined with chemotherapy, targeted drugs such as BCL-2 inhibitors, immunotherapy, and cell therapy. Targeted therapy and immunotherapy are effective, but show a high prevalence of relapse, heavy treatment burden, and the need for long-term maintenance. HSCT is an important therapy for the treatment of high-risk malignant hematological diseases, which could eliminate tumor cells through high-dose radiotherapy or chemotherapy, destroy the immune system of patients to prepare the engraftment of donor cells, and promote the reconstitution of hematopoiesis and immune recovery. HSCT has developed rapidly since the 1950s and has been performed in more than one million patients worldwide. HSCT is often the only definitive treatment available for patients with certain specific congenital or acquired diseases and is used in the treatment of many high-risk malignant hematological diseases. However, due to the strict criteria for HSCT, many patients do not have a matched donor. Since the first successful UCBT in a child with severe Fanconi anemia reported by Gluckman et al. in France in 1988, cord blood has been widely used as a graft source of hematopoietic stem cells for the treatment of hematological diseases. Cord blood is rich in hematopoietic stem cells, endothelial progenitor cells, mesenchymal stem cells, and other stem/progenitor cells, as well as natural killer cells, Treg cells, and other immune cells, which have strong self-renewal and proliferation ability and low immunogenicity. The hematologic growth factors produced by these cells could act on the formation of myeloid cells and granulocytes, which are beneficial to hematopoietic reconstruction and recovery. It contains a variety of cytokines such as thrombopoietin, erythropoietin, stem cell factor, and multi-class interleukins. Some cytokines such as stem cell factor, IL-6, and IL-11 are much higher in cord blood than in peripheral blood. The potential mechanism by which UCBT exerts its therapeutic effect in patients with hematological diseases is largely the result of the interaction of multiple growth factors and stem/progenitor cells with the organism. Compared with peripheral blood stem cell transplantation (PBST), UCBT has a higher transplantation rate, as cord blood stem cells are more primitive and purer than bone marrow stem cells. UCBT could be performed with four or more matches, and have a relatively lower rejection rate, lower relapse rate of malignant hematological diseases, and lower cumulative incidence of chronic graft-versus-host disease (GVHD), which greatly improves patient survival. Prof. Sun Zimin's team at Anhui Provincial Hospital was the first to use UCBT for the treatment of patients with AML and found that the cumulative incidence of chronic GVHD and relapse rate were significantly reduced. Based on the above, the TFBC regimen (TBI/Flu/Bu/Cy) combined with UCBT is safe and feasible for the treatment of patients with high-risk malignant hematological diseases, which has enormous potential to improve patient outcomes. Therefore, we designed this clinical study on the TFBC regimen combined with UCBT for the treatment of high-risk malignant hematological patients to observe the impact on the engraftment rate, relapse rate, the cumulative incidence of GVHD, and survival.
Detailed Description
High-risk malignant hematological diseases are commonly seen in patients with advanced age, complex karyotypes, genes related to poor prognosis, failure to achieve remission after remission-inducing chemotherapy, and relapsed or refractory diseases. The first sibling UCBT for leukemia was performed successfully by Professor Yongping Song in China, who played a pioneering role in the development of UCBT for leukemia in China. In a retrospective study done by Prof. Sun Zimin's team, the efficacy of intravenous Bu/Cy versus TBI/Cy was compared in 331 patients from 8 centers who underwent single-unit umbilical cord blood transplantation (UCBT). It was reported that the cumulative incidence of neutrophil engraftment was higher in the TBI/Cy group than in the Bu/Cy group (98.0% versus 91.6%, P < 0.001), but the time to neutrophil engraftment was shorter in the Bu/Cy group than in the TBI/Cy group (16 days versus 19 days, P < 0.001). There was no significant difference in the non-relapse mortality, relapse rate, or survival rate between the two groups. What's more, the GVHD-free and relapse-free survival rate of patients was significantly increased, greatly improving patient survival. UCBT has also been widely used in other malignant hematological diseases such as acute lymphoblastic leukemia (ALL), lymphoma, and multiple myeloma. In 2017, UCBT was performed for the treatment of an adult AML patient at the Central Hospital of Wuhan, and the patient was successfully discharged from hospital. In 2020, UCBT was performed for the treatment of a 14-year-old patient with myelodysplastic syndrome at the Tai'an Central Hospital, and the patient achieved a good recovery with very mild rejection after transplantation and was finally discharged safely. Since the first successful UCBT in the Seventh Hospital of Zhongshan University in April 2021, 10 cases have been successfully performed, including an obese patient weighing 85 kg, a patient with strong positive panel reactive antibodies (PRA), and a patient with AML who received a second transplant after the first PBST. The overall success rate was 100% and the longest disease-free survival was 2 years. No patients died due to transplant-related mortality (TRM), only 1 case of severe GVHD occurred, and none of them underwent relapse.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hematopoietic Stem Cell Transplantation, Malignant Hematological Diseases
Keywords
Umbilical Cord Blood Transplantation; Conditioning regimen

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
40 patients with malignant hematological diseases who underwent UCBT
Arm Type
Experimental
Intervention Type
Procedure
Intervention Name(s)
Umbilical Cord Blood Transplantation
Other Intervention Name(s)
Total Body Irradiation/Fludarabine/Busulfan/Cyclophosphamide
Intervention Description
Compared with peripheral blood stem cell transplantation (PBST), UCBT has a higher transplantation rate, as cord blood stem cells are more primitive. Since the first successful umbilical cord blood transplantation (UCBT) in a child with severe Fanconi anemia reported by Gluckman et al. in France in 1988, cord blood has been widely used as a graft source of hematopoietic stem cells for the treatment of hematological diseases. The first sibling UCBT for leukemia was performed successfully by Professor Yongping Song in China, who played a pioneering role in the development of UCBT for leukemia in China. On the basis of previous research, the TFBC regimen (TBI/Flu/Bu/Cy) combined with UCBT is safe and feasible for the treatment of patients with high-risk malignant hematological diseases, which has enormous potential to improve patient outcomes.
Primary Outcome Measure Information:
Title
The cumulative incidence of neutrophil engraftment and platelet engraftment
Description
Neutrophil and platelet engraftment is defined as the first occurrence of 3 consecutive days with an absolute neutrophil count of at least 0.5×109/L and a platelet count of over 20×109/L for 7 consecutive days without transfusion support.
Time Frame
on day 28±7 following UCBT
Title
The time to reconstitution of hematopoiesis
Description
Recovery of hemopoietic function after treatment
Time Frame
on day 28±7 following UCBT
Title
The cumulative incidence of transplant-related mortality (TRM)
Description
Transplant-related mortality was defined as mortality due to any cause other than disease progression within 100 days of transplantation.
Time Frame
within 100 days following UCBT
Secondary Outcome Measure Information:
Title
The cumulative incidence and severity of pre-engraftment syndrome (PES)
Description
Pre-engraftment syndrome (PES) is a condition occurring after umbilical cord blood transplantation (UCBT) characterized by fever and erythematous skin rash prior to neutrophil engraftment.
Time Frame
on day 28±7 following UCBT
Title
The cumulative incidence and grade of graft-versus-host disease (GVHD)
Description
Graft-versus-host disease (GvHD) is a medical complication following the receipt of transplanted tissue from a genetically different person.
Time Frame
within 1 year following UCBT
Title
The cumulative incidence of relapse
Description
We defined relapse as any clinical evidence of progression or recurrence of original diseases.
Time Frame
within 1 year following UCBT
Title
Overall survival rate
Description
We estimated OS from the time of transplant until the date of death of any cause or last follow-up for patients still alive.
Time Frame
within 1 year following UCBT
Title
The cumulative incidence of adverse event
Description
Following extraction of the tumor, a blood vessel burst causing increased blood loss during the procedure, an adverse event the surgeon did not expect.
Time Frame
within 1 year following UCBT

10. Eligibility

Sex
All
Minimum Age & Unit of Time
14 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Gender is not limited, patients between 14 to 70 years old (including critical value); High-risk malignant hematological diseases (acute lymphoblastic leukemia, acute/chronic myeloid leukemia, multiple myeloma, etc.) diagnosed by bone marrow aspiration or biopsy according to the WHO diagnostic criteria; The indexes of cardiac function, liver and kidney function were within the following limits:(1) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3× Upper limit of normal (ULN); (2)Total bilirubin ≤ 3×ULN; (3) Serum creatinine ≤ 2×ULN or creatinine clearance ≥ 40mL/min; (4) Left ventricular ejection fraction (LVEF) as measured by echocardiography or multi-gated acquisition (MUGA) scan is within the normal range (> 50%); Umbilical cord blood with HLA match ≥ 4/6; Expected survival ≥3 months; Karnofsky (KPS) score ≥60%, Eastern Tumor Cooperative group (ECOG) status ≤ 2; Patient fully understood the nature of the study, and voluntarily participates and signs informed consent. Exclusion Criteria: Patients had serious adverse reactions to investigational drugs such as allergies; Patients with a history of immunodeficiency, or other acquired or congenital diseases, immunodeficiency diseases, and a history of organ transplantation; Patients with hypertension, ventricular arrhythmia requiring clinical intervention, acute coronary syndrome, congestive heart failure, stroke, or other grade III or higher cardiovascular events within 6 months; Two or more surgeries were performed within 4 weeks prior to enrollment; Patients with active viral infections, including HIV, HBV, HCV, TP; Pregnant or lactating patients; The patient is currently participating in another clinical studies; Patients deemed unsuitable for inclusion by other investigators.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Xiaojin Wu
Phone
+8613057493105
Email
wuxiaojin@suda.edu.cn
Facility Information:
Facility Name
The First Affiliated Hospital of Soochow university
City
Suzhou
State/Province
Jiangsu
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Xiaojin Wu
Phone
+8613057493105
Email
wuxiaojin@suda.edu.cn

12. IPD Sharing Statement

Plan to Share IPD
Yes
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TFBC Combined With UCBT in the Treatment of High-risk Malignant Hematological Diseases

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