Trial Title:
TBI/Flu/Bu/Mel Combined With Secondary UCBT in Patients With Hematological Malignancies Who Relapsed After Allo-HSCT
NCT ID:
NCT06125483
Condition:
Hematopoietic Malignancy
Relapse/Recurrence
Hematopoietic Stem Cell Transplantation
Conditions: Official terms:
Neoplasms
Hematologic Neoplasms
Recurrence
Fludarabine
Melphalan
Busulfan
Conditions: Keywords:
Umbilical Cord Blood Transplantation
Conditioning Regimen
Secondary transplantation
Post-transplant Relapse
Study type:
Interventional
Study phase:
N/A
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Umbilical Cord Blood Transplantation
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, 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.
Arm group label:
38 patients with hematological malignancies who received TBI/Flu/Bu/Mel combined with secondary UCBT
Other name:
Total Body Irradiation/Fludarabine/Busulfan/Melphalan
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.
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%.
Criteria for eligibility:
Criteria:
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.
Gender:
All
Minimum age:
10 Years
Maximum age:
65 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
The First Affiliated Hospital of Soochow university
Address:
City:
Suzhou
Country:
China
Status:
Recruiting
Contact:
Last name:
Xiaojin Wu
Phone:
+8613057493105
Email:
wuxiaojin@suda.edu.cn
Start date:
November 1, 2023
Completion date:
October 31, 2026
Lead sponsor:
Agency:
The First Affiliated Hospital of Soochow University
Agency class:
Other
Source:
The First Affiliated Hospital of Soochow University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06125483
