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

NCT06125483 | Recruiting DMC

• 1 other identifier: SOOCHOW-WXJ-2023-300
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hematopoietic Malignancy; Relapse/Recurrence; Hematopoietic Stem Cell Transplantation

Keywords

Umbilical Cord Blood Transplantation; Conditioning Regimen; Secondary transplantation; Post-transplant Relapse

Outcome Measures

Primary Outcomes (1)

• 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.

  within 1 year following UCBT

Secondary Outcomes (7)

• The cumulative incidence of engraftment

  Neutrophil engraftment: on day 28±7 following UCBT; Platelet engraftment: on day 100±7 following UCBT

• The cumulative incidence and severity of pre-engraftment syndrome (PES)

  on day 28±7 following UCBT

• The cumulative incidence and grade of graft-versus-host disease (GVHD)

  within 100 days following UCBT (acute GVHD); within 1 year following UCBT (chronic GVHD)

• The cumulative incidence of relapse

  within 1 year following UCBT

• The cumulative incidence of non-relapsed mortality (NRM)

  within 1 year following UCBT

Study Arms (1)

38 patients with hematological malignancies who received TBI/Flu/Bu/Mel combined with secondary UCBT

EXPERIMENTAL

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

Interventions

Umbilical Cord Blood Transplantation PROCEDURE

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.

Also known as: Total Body Irradiation/Fludarabine/Busulfan/Melphalan

38 patients with hematological malignancies who received TBI/Flu/Bu/Mel combined with secondary UCBT

Eligibility Criteria

• Age: 10 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Gender is not limited, patients between 10 to 65 years old (including critical value);
• 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;
• Planned to received umbilical cord blood transplantation;
• 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 ≥ 6/10;
• 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.

You may not qualify if:

• Patients had serious adverse reactions to investigational drugs such as allergies;
• Patient was complicated with pulmonary infection, which was confirmed by imaging to be progressive;
• 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;
• Patients with active viral infections, including HIV, HBV, HCV, TP;
• Pregnant or lactating patients;
• The patient is currently participating in another clinical studies;

Sponsors & Collaborators

• The First Affiliated Hospital of Soochow University: lead

Study Sites (1)

The First Affiliated Hospital of Soochow university

Suzhou, Jiangsu, China

RECRUITING

Related Publications (24)

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MeSH Terms

Conditions

Hematologic Neoplasms; Recurrence

Interventions

Cord Blood Stem Cell Transplantation; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Radiotherapy; Investigative Techniques

Study Officials

• Xiaojin Wu, Prof.

  The First Affiliated Hospital of Soochow University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Xiaojin Wu, Prof.

CONTACT

+8613057493105; wuxiaojin@suda.edu.cn

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 6, 2023
• First Posted: November 9, 2023
• Study Start: November 1, 2023
• Primary Completion: April 30, 2025
• Study Completion (Estimated): October 31, 2026
• Last Updated: April 24, 2025

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will share

Locations

CN (1)