TBI/Flu/Bu/Mel Combined With Secondary UCBT in Patients With Hematological Malignancies Who Relapsed After Allo-HSCT

April 21, 2025 updated by: The First Affiliated Hospital of Soochow University

A Clinical Study of Low-dose Total Body Irradiation and Fludarabine/Busulfan/Melphalan as a Conditioning Regimen for Secondary Umbilical Cord Blood Transplantation in Patients With Hematological Malignancies Who Relapsed After Allo-HSCT

About 33% of patients with myeloid or lymphoid malignancies experience relapse with HLA loss after haplo-HSCT. Due to the specificity of HLA-loss relapse, the 2019 European Society for Blood and Marrow Transplantation (EBMT) pointed out that for diagnosed HLA-loss patients, it is recommended to use different HLA-haploidentical donors, and lymphocyte infusions from the original donor cannot improve the prognosis. Clinical studies have found that second transplantation can achieve prolonged disease-free survival than chemotherapy for patients with HLA loss, and it may be an effective treatment strategy for these patients.

However, due to the high standard of second hematopoietic stem cell transplantation (HSCT), not all patients can find suitable donors. Since the first successful application of umbilical cord blood transplantation (UCBT) by Gluckman et al. in France in 1988 for the treatment of Fanconi anemia, umbilical cord blood (UCB) has been widely used as a reliable source for HSCT in the treatment of hematological diseases. In 1998, Professor Yongping Song led the first successful UCBT in the treatment of leukemia, opening up the path of it in China. Compared with peripheral blood stem cell transplantation (PBST), UCBT has a higher engraftment rate. UCB contains more primitive and purer stem cells than bone marrow hematopoietic stem cells. UCBT can be performed with only 4 HLA matches, and the degree of rejection, the risk of disease relapse, and the incidence of chronic graft-versus-host disease (cGVHD) are all relatively low, greatly improving the survival of patients.

Although UCBT has been a potential treatment for second transplantation, the effective conditioning regimen is still under discussion. Improving the incidence of engraftment , the tolerance of conditioning, and reducing transplant-related mortality (TRM) are issues of great concern in second transplantation. A standard RIC regimen composed of fludarabine (200mg/m2) combined with cyclophosphamide (50mg/kg) and 2Gy or 3Gy total body irradiation (TBI) is the most common conditioning regimen used in UCBT. Although the tolerance of this RIC is acceptable, the relapse rate after transplantation is relatively high, and the implantation failure rate is also high in high-risk populations. The inclusion of thiotepa (10mg/kg) combined with fludarabine, cyclophosphamide, and 4Gy TBI in an intensified version of the RIC regimen has improved the engraftment rate without increasing TRM. In addition, studies have also confirmed that increasing the dose of TBI can improve engraftment in transplant recipients at high risk of UCBT failure. The fludarabine/busulfan/melphalan (Flu/Bu/Mel) conditioning regimen was first used for salvaging UCBT in unresponsive hematological malignancies in 2016 and achieved good clinical outcomes. Subsequently, several transplant centers in Japan adopted the Flu/Bu/Mel conditioning regimen for UCBT and confirmed that, compared with the Flu/Bu4 regimen, it not only improved overall survival (OS) but also reduced disease relapse rate without increasing TRM. A recent multicenter retrospective study of UCBT in patients with acute myeloid leukemia in remission found that compared with the TBI/Cy conditioning regimen, the Flu/Bu/Mel conditioning regimen improved the engraftment rate and exerted the GVL effect, reducing NRM and improving OS.

Based on the above, TBI/Flu/Bu/Mel as a conditioning regimen for secondary UCBT in patients with hematological malignancies who relapsed after allo-HSCT is safe and feasible, and is expected to improve the prognosis of these patients. Therefore, based on existing clinical experience with research evidence, our center plans to conduct a clinical study of low-dose TBI and FBM as a conditioning regimen for secondary UCBT in patients with hematological malignancies who relapsed after allo-HSCT, observing the improvement in the cumulative incidence of engraftment, disease relapse, GVHD, and survival rate in patients who received this regimen.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for hematological malignancies, and post-transplant relapse is the primary cause of death. The optimal treatment strategy for leukemia relapse after allo-HSCT is still unclear, and the treatment options for these relapsed patients are limited. They mainly include chemotherapy, targeted therapy, donor lymphocyte infusion, immune checkpoint inhibitors, chimeric antigen receptor T-cell therapy (CAR-T), bispecific antibodies, and secondary hematopoietic stem cell transplantation. Although many factors may contribute to post-transplant relapse, such as insensitivity of leukemia cells to the conditioning regimen, in most cases, the leukemia cells escape immune surveillance by donor T cells, leading to 'immune escape'. The source of T cells is one of the main driving factors for the graft-versus-leukemia (GVL) effect after allo-HSCT. Therefore, all the typical mechanisms of immune escape and tumor immunity in relapse after allo-HSCT will ultimately eliminate the interaction between T cells and tumors. This may be due to the mechanisms of patient-specific HLA loss in dual relapse: cytotoxic T lymphocytes (CTL) reduce the GVL effect of allogeneic immunity through non-MHC-restricted HLA; important HLA locus loss reduces leukemia antigen presentation and cannot induce CTL production, directly leading to immune escape.

In traditional relapsed patients, only 10-32% of acute myeloid leukemia (AML) patients can achieve remission again through treatment, and the prognosis is worse in acute lymphocytic leukemia (ALL) patients, with a median survival of about 10 months. Yaara Yerushalmi et al. conducted a retrospective analysis of 407 patients with post-transplant relapse, among which 62 patients underwent secondary HSCT. The 5-year overall survival (OS) rate in the secondary transplantation group reached 25%, while it was only 7% in the non-secondary transplantation group of 345 patients. Secondary HSCT improves the prognosis of these patients.

UCB contains abundant hematopoietic stem cells, endothelial progenitor cells, mesenchymal stem cells, and other types of stem/progenitor cells, as well as immune cells such as natural killer cells and Treg cells. These stem/progenitor cells have strong self-renewal and proliferation ability, low immunogenicity, and could secrete various hematopoietic growth factors that act on myeloid cells, granulocytes, etc., facilitating hematopoietic reconstruction and recovery. They include platelet growth factor, erythropoietin, stem cell factor, and various interleukins. The content of various cytokines such as stem cell factor, IL-6, and IL-11 in UCB is much higher than that in peripheral blood. The potential mechanism of UCB in hematological disease treatment is largely the result of the interaction between various growth factors and stem/progenitor cells and the body.

The team led by Professor Sun Zimin at the Anhui Provincial Hospital was the first to use UCBT to treat patients with AML. They found that the incidence of cGVHD and relapse in patients significantly decreased, while the survival rate of patients without GVHD or relapse significantly improved, greatly improving the OS of patients. UCBT has also been widely applied in other malignant diseases such as ALL, malignant lymphoma, and multiple myeloma (MM). In 2017, an adult AML patient was successfully treated with UCBT at Wuhan Central Hospital and discharged to resume normal life. In 2020, a 14-year-old patient with myeloproliferative neoplasms was treated with UCBT at Tai'an Central Hospital. The patient had a mild rejection reaction after transplantation but achieved good recovery and was eventually safely discharged. Since April 2021, the Seventh Hospital of Zhongshan has successfully completed 10 cases of UCBT, including patients with high body weight (85kg), highly positive panel reactive antibodies (PRA), or second transplantation. The overall response rate is 100%, with the longest disease-free survival time being 2 years, only 1 case of severe GVHD, no TRM, or relapse. Therefore, UCBT has tremendous potential in the second HSCT.

The conditioning regimen is a key link in transplantation, and a reduced-intensity conditioning (RIC) regimen has improved the second transplantation tolerance in patients due to its relatively low toxicity. Whether after autologous transplantation or allo-HSCT, a reduced-intensity conditioning regimen has been proven in multiple studies to reduce non-relapse mortality and relapse rate in second transplantation (RIC2 HSCT). A retrospective study which conducted by EBMT included 234 patients who underwent a RIC regimen for second transplantation, with a 2-year non-relapse mortality rate of 22.4% and a relapse rate of 63.9%.

Study Type

Interventional

Enrollment (Estimated)

38

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • China
    • Jiangsu
      • Suzhou, Jiangsu, China
        • Recruiting
        • The First Affiliated Hospital of Soochow University
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Gender is not limited, patients between 10 to 65 years old (including critical value);
  2. According to the WHO diagnostic criteria, the diagnosis of hematological malignancies ( acute lymphoblastic leukemia, acute / chronic myeloid leukemia, etc. ) was confirmed by bone marrow puncture or biopsy after allogeneic hematopoietic stem cell transplantation. The definition of relapse includes the proportion of bone marrow blast cells > 5 %, blast cells in peripheral blood ( excluding the use of G-CSF and GM-CSF ), or extramedullary leukemia infiltration;
  3. Planned to received umbilical cord blood transplantation;
  4. 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%);
  5. Umbilical cord blood with HLA match ≥ 6/10;
  6. Expected survival ≥3 months;
  7. Karnofsky (KPS) score ≥60%, Eastern Tumor Cooperative group (ECOG) status ≤ 2;
  8. Patient fully understood the nature of the study, and voluntarily participates and signs informed consent.

Exclusion Criteria:

  1. Patients had serious adverse reactions to investigational drugs such as allergies;
  2. Patient was complicated with pulmonary infection, which was confirmed by imaging to be progressive;
  3. 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;
  4. Patients with active viral infections, including HIV, HBV, HCV, TP;
  5. Pregnant or lactating patients;
  6. The patient is currently participating in another clinical studies;
  7. Patients deemed unsuitable for inclusion by other investigators.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 38 patients with hematological malignancies who received TBI/Flu/Bu/Mel combined with secondary UCBT
Treatment stage : ( 1 ) conditioning : -7d, total body irradiation (TBI), 4Gy, 2 times ; -7d, semustine ( MECCNU ) 250mg / m2 ; -6d ~ -3d ; fludarabine ( Flu ) 30mg / m2 / d, ivgtt ; -6d ~ -5d, busulfan ( Bu ) 2.4mg / kg / d, 3 times a day, ivgtt ; -4d ~ -3d, melphalan ( Mel ) 40mg / m2 / d, ivgtt. ( 2 ) Transplantation : On day 0, unrelated umbilical cord blood ( TNC ≥ 2.3 × 107 / kg or CD34 + ≥ 1 × 105 / kg ) was transplanted, and the donor-recipient HLA matching degree was ≥ 6 / 10.
Procedure: Umbilical Cord Blood Transplantation
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, TBI/Flu/Bu/Mel combined with UCBT is safe and feasible for the treatment of patients with malignant hematological diseases who experienced post-transplant relapse, which has enormous potential to improve patient outcomes.
Other Names:
  • Total Body Irradiation/Fludarabine/Busulfan/Melphalan

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival rate
Time Frame: within 1 year following UCBT
We estimated OS from the time of transplant until the date of death of any cause or last follow-up for patients still alive.
within 1 year following UCBT

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The cumulative incidence of relapse
Time Frame: within 1 year following UCBT
We defined relapse as any clinical evidence of progression or recurrence of original diseases.
within 1 year following UCBT
The cumulative incidence of adverse event
Time Frame: within 1 year following UCBT
Following extraction of the tumor, a blood vessel burst causing increased blood loss during the procedure, an adverse event the surgeon did not expect.
within 1 year following UCBT
The cumulative incidence and severity of pre-engraftment syndrome (PES)
Time Frame: on day 28±7 following UCBT
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.
on day 28±7 following UCBT
The cumulative incidence of engraftment
Time Frame: Neutrophil engraftment: on day 28±7 following UCBT; Platelet engraftment: on day 100±7 following UCBT
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.
Neutrophil engraftment: on day 28±7 following UCBT; Platelet engraftment: on day 100±7 following UCBT
The cumulative incidence and grade of graft-versus-host disease (GVHD)
Time Frame: within 100 days following UCBT (acute GVHD); within 1 year following UCBT (chronic GVHD)
Graft-versus-host disease (GVHD) is a medical complication following the receipt of transplanted tissue from a genetically different person.
within 100 days following UCBT (acute GVHD); within 1 year following UCBT (chronic GVHD)
The cumulative incidence of non-relapsed mortality (NRM)
Time Frame: within 1 year following UCBT
Non-relapsed mortality was defined as mortality due to any cause other than disease progression or relapse.
within 1 year following UCBT
The time of disease-free survival
Time Frame: within 1 year following UCBT
Disease-free survival (DFS) is defined as the time from randomization to recurrence of tumor or death.
within 1 year following UCBT

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The First Affiliated Hospital of Soochow University

Investigators

  • Principal Investigator: Xiaojin Wu, Prof., The First Affiliated Hospital of Soochow University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 1, 2023

Primary Completion (Estimated)

April 30, 2025

Study Completion (Estimated)

October 31, 2026

Study Registration Dates

First Submitted

November 6, 2023

First Submitted That Met QC Criteria

November 6, 2023

First Posted (Actual)

November 9, 2023

Study Record Updates

Last Update Posted (Actual)

April 24, 2025

Last Update Submitted That Met QC Criteria

April 21, 2025

Last Verified

September 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SOOCHOW-WXJ-2023-300

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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