Hematopoietic MalignancyNCT06125483
TBI/Flu/Bu/Mel Combined With Secondary UCBT in Patients With Hematological Malignancies Who Relapsed After Allo-HSCT
A study testing Umbilical Cord Blood Transplantation in people with Hematopoietic Malignancy and Relapse/Recurrence, run by The First Affiliated Hospital of Soochow University at 1 site in China.
Trial 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… Read more about this study
- Who is it for?
- Ages 10 to 65 years
- Conditions the study is for
- Hematopoietic Malignancy, Relapse/Recurrence, Hematopoietic Stem Cell Transplantation
- What is being tested?
- Umbilical Cord Blood Transplantation
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 38 participants
- Where
- 1 siteChina
- Study dates
- 1 Nov 2023to 31 Oct 2026
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 10 to 65 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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;
- Patients deemed unsuitable for inclusion by other investigators.
Trial locations and contacts
1 site in 1 country.
China1 site, 1 recruiting
- Recruiting
The First Affiliated Hospital of Soochow university
Suzhou, Jiangsu
Xiaojin Wu, +8613057493105, wuxiaojin@suda.edu.cn
About this study
Official title: 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.
Read more
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.
Read the 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%.
- Being tested
- Umbilical Cord Blood Transplantation
- Keywords
- Umbilical Cord Blood Transplantation, Conditioning Regimen, Secondary transplantation, Post-transplant Relapse
- Medical subject headings
- Hematologic Neoplasms, Recurrence
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Umbilical Cord Blood TransplantationProcedure or surgery
Also called Total Body Irradiation/Fludarabine/Busulfan/Melphalan
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Procedure: Umbilical Cord Blood Transplantation |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: within 1 year following UCBT
Secondary outcomes (7)
The cumulative incidence of 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.
Measured: 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)
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.
Measured: on day 28±7 following UCBT
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.
Measured: within 100 days following UCBT (acute GVHD); within 1 year following UCBT (chronic GVHD)
The cumulative incidence of relapse
We defined relapse as any clinical evidence of progression or recurrence of original diseases.
Measured: within 1 year following UCBT
The cumulative incidence of non-relapsed mortality (NRM)
Non-relapsed mortality was defined as mortality due to any cause other than disease progression or relapse.
Measured: within 1 year following UCBT
The time of disease-free survival
Disease-free survival (DFS) is defined as the time from randomization to recurrence of tumor or death.
Measured: within 1 year following UCBT
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.
Measured: within 1 year following UCBT
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Nov 2023
- Study start1 Nov 2023
- Primary completion30 Apr 2025 (estimated)
- Study completion31 Oct 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (24)Papers the sponsor has linked to this study.
- Other trials for Hematopoietic MalignancyStudies of the same condition, open and under way.
- More trials run by The First Affiliated Hospital of Soochow UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 38 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Xiaojin Wu, Prof., Principal investigator, The First Affiliated Hospital of Soochow University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06125483
- Sponsor's protocol ID
- SOOCHOW-WXJ-2023-300
- Status last verified
- Sep 2024
- First submitted
- 6 Nov 2023
- Last updated
- 24 Apr 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes
Publications
Cao XY, Zhang JP, Zhao YL, Xiong M, Zhou JR, Lu Y, Sun RJ, Wei ZJ, Liu DY, Zhang X, Yang JF, Lu P. Analysis benefits of a second Allo-HSCT after CAR-T cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia who relapsed after transplant. Front Immunol. 2023 Jul 4;14:1191382. doi: 10.3389/fimmu.2023.1191382. eCollection 2023.
PubMed 37469510de Lima M, Porter DL, Battiwalla M, Bishop MR, Giralt SA, Hardy NM, Kroger N, Wayne AS, Schmid C. Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse After Hematopoietic Stem Cell Transplantation: part III. Prevention and treatment of relapse after allogeneic transplantation. Biol Blood Marrow Transplant. 2014 Jan;20(1):4-13. doi: 10.1016/j.bbmt.2013.08.012. Epub 2013 Sep 7.
PubMed 24018392Christopeit M. When is second allogeneic HSCT for relapse of acute leukaemia an option? Bone Marrow Transplant. 2016 Feb;51(2):184-5. doi: 10.1038/bmt.2015.285. Epub 2015 Dec 7. No abstract available.
PubMed 26642335Rovatti PE, Gambacorta V, Lorentino F, Ciceri F, Vago L. Mechanisms of Leukemia Immune Evasion and Their Role in Relapse After Haploidentical Hematopoietic Cell Transplantation. Front Immunol. 2020 Feb 25;11:147. doi: 10.3389/fimmu.2020.00147. eCollection 2020.
PubMed 32158444Crucitti L, Crocchiolo R, Toffalori C, Mazzi B, Greco R, Signori A, Sizzano F, Chiesa L, Zino E, Lupo Stanghellini MT, Assanelli A, Carrabba MG, Marktel S, Marcatti M, Bordignon C, Corti C, Bernardi M, Peccatori J, Bonini C, Fleischhauer K, Ciceri F, Vago L. Incidence, risk factors and clinical outcome of leukemia relapses with loss of the mismatched HLA after partially incompatible hematopoietic stem cell transplantation. Leukemia. 2015 May;29(5):1143-52. doi: 10.1038/leu.2014.314. Epub 2014 Nov 5.
PubMed 25371177Arnold PY. Review: HLA loss and detection in the setting of relapse from HLA-mismatched hematopoietic cell transplant. Hum Immunol. 2022 Oct;83(10):712-720. doi: 10.1016/j.humimm.2022.03.001. Epub 2022 Mar 11.
PubMed 35287976Wu H, Shi J, Luo Y, Yu J, Lai X, Liu L, Fu H, Ouyang G, Xu X, Xiao H, Huang H, Zhao Y. Assessment of Patient-Specific Human Leukocyte Antigen Genomic Loss at Relapse After Antithymocyte Globulin-Based T-Cell-Replete Haploidentical Hematopoietic Stem Cell Transplant. JAMA Netw Open. 2022 Apr 1;5(4):e226114. doi: 10.1001/jamanetworkopen.2022.6114.
PubMed 35385089Mielcarek M, Storer BE, Flowers ME, Storb R, Sandmaier BM, Martin PJ. Outcomes among patients with recurrent high-risk hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2007 Oct;13(10):1160-8. doi: 10.1016/j.bbmt.2007.06.007. Epub 2007 Aug 3.
PubMed 17889352Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R, Stadler M, Kuball J, Cornelissen J, Vorlicek J, Socie G, Falda M, Vindelov L, Ljungman P, Jackson G, Kroger N, Rank A, Polge E, Rocha V, Mohty M; Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood. 2012 Feb 9;119(6):1599-606. doi: 10.1182/blood-2011-08-375840. Epub 2011 Dec 13.
PubMed 22167752Yerushalmi Y, Shem-Tov N, Danylesko I, Canaani J, Avigdor A, Yerushalmi R, Nagler A, Shimoni A. Second hematopoietic stem cell transplantation as salvage therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after a first transplantation. Haematologica. 2023 Jul 1;108(7):1782-1792. doi: 10.3324/haematol.2022.281877.
PubMed 36475520Gluckman E, Broxmeyer HA, Auerbach AD, Friedman HS, Douglas GW, Devergie A, Esperou H, Thierry D, Socie G, Lehn P, et al. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med. 1989 Oct 26;321(17):1174-8. doi: 10.1056/NEJM198910263211707. No abstract available.
PubMed 2571931Ehrhart J, Sanberg PR, Garbuzova-Davis S. Plasma derived from human umbilical cord blood: Potential cell-additive or cell-substitute therapeutic for neurodegenerative diseases. J Cell Mol Med. 2018 Dec;22(12):6157-6166. doi: 10.1111/jcmm.13898. Epub 2018 Oct 18.
PubMed 30334335Sun HP, Zhang X, Chen XH, Zhang C, Gao L, Feng YM, Peng XG, Gao L. Human umbilical cord blood-derived stromal cells are superior to human umbilical cord blood-derived mesenchymal stem cells in inducing myeloid lineage differentiation in vitro. Stem Cells Dev. 2012 Jun 10;21(9):1429-40. doi: 10.1089/scd.2011.0348. Epub 2011 Dec 5.
PubMed 22023173Sanchez-Petitto G, Rezvani K, Daher M, Rafei H, Kebriaei P, Shpall EJ, Olson A. Umbilical Cord Blood Transplantation: Connecting Its Origin to Its Future. Stem Cells Transl Med. 2023 Mar 3;12(2):55-71. doi: 10.1093/stcltm/szac086.
PubMed 36779789Zheng CC, Zhu XY, Tang BL, Zhang XH, Zhang L, Geng LQ, Liu HL, Sun ZM. Clinical separation of cGvHD and GvL and better GvHD-free/relapse-free survival (GRFS) after unrelated cord blood transplantation for AML. Bone Marrow Transplant. 2017 Jan;52(1):88-94. doi: 10.1038/bmt.2016.182. Epub 2016 Jul 4.
PubMed 27376453
Study at a glance
From the registry record, last updated by the sponsor on 24 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT06125483
- Acronym / sponsor ID
- SOOCHOW-WXJ-2023-300
- Keywords
- Umbilical Cord Blood Transplantation, Conditioning Regimen, Secondary transplantation, Post-transplant Relapse
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 38 participants (estimated)
- Lead sponsor
- The First Affiliated Hospital of Soochow UniversityUniversity, hospital or other
- Study start
- 1 Nov 2023 (actual)
- Primary completion
- 30 Apr 2025 (estimated)
- Study completion
- 31 Oct 2026 (estimated)
- First posted
- 9 Nov 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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%.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 38 patients with hematological malignancies who received TBI/Flu/Bu/Mel combined with secondary UCBT | Experimental | Procedure: Umbilical Cord Blood TransplantationTreatment 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. |
Who may qualify
- Ages
- 10 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (8 listed)
- 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;
Key exclusion criteria (7 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Umbilical Cord Blood TransplantationAlso: Total Body Irradiation/Fludarabine/Busulfan/MelphalanCompared 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. | Procedure or surgery | 38 patients with hematological malignancies who received TBI/Flu/Bu/Mel combined with secondary UCBT |
Primary outcome
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.
7 secondary outcomes
The cumulative incidence of engraftment
Time frame: 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)
Time frame: on day 28±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)
The cumulative incidence of relapse
Time frame: within 1 year following UCBT
The cumulative incidence of non-relapsed mortality (NRM)
Time frame: within 1 year following UCBT
The time of disease-free survival
Time frame: within 1 year following UCBT
The cumulative incidence of adverse event
Time frame: within 1 year following UCBT
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Apr 2025.
- Background: PubMed 37469510Cao XY, Zhang JP, Zhao YL, Xiong M, Zhou JR, Lu Y, Sun RJ, Wei ZJ, Liu DY, Zhang X, Yang JF, Lu P. Analysis benefits of a second Allo-HSCT after CAR-T cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia who relapsed after transplant. Front Immunol. 2023 Jul 4;14:1191382. doi: 10.3389/fimmu.2023.1191382. eCollection 2023.
- Background: PubMed 24018392de Lima M, Porter DL, Battiwalla M, Bishop MR, Giralt SA, Hardy NM, Kroger N, Wayne AS, Schmid C. Proceedings from the National Cancer Institute's Second International Workshop on the Biology, Prevention, and Treatment of Relapse After Hematopoietic Stem Cell Transplantation: part III. Prevention and treatment of relapse after allogeneic transplantation. Biol Blood Marrow Transplant. 2014 Jan;20(1):4-13. doi: 10.1016/j.bbmt.2013.08.012. Epub 2013 Sep 7.
- Background: PubMed 26642335Christopeit M. When is second allogeneic HSCT for relapse of acute leukaemia an option? Bone Marrow Transplant. 2016 Feb;51(2):184-5. doi: 10.1038/bmt.2015.285. Epub 2015 Dec 7. No abstract available.
- Background: PubMed 32158444Rovatti PE, Gambacorta V, Lorentino F, Ciceri F, Vago L. Mechanisms of Leukemia Immune Evasion and Their Role in Relapse After Haploidentical Hematopoietic Cell Transplantation. Front Immunol. 2020 Feb 25;11:147. doi: 10.3389/fimmu.2020.00147. eCollection 2020.
- Background: PubMed 25371177Crucitti L, Crocchiolo R, Toffalori C, Mazzi B, Greco R, Signori A, Sizzano F, Chiesa L, Zino E, Lupo Stanghellini MT, Assanelli A, Carrabba MG, Marktel S, Marcatti M, Bordignon C, Corti C, Bernardi M, Peccatori J, Bonini C, Fleischhauer K, Ciceri F, Vago L. Incidence, risk factors and clinical outcome of leukemia relapses with loss of the mismatched HLA after partially incompatible hematopoietic stem cell transplantation. Leukemia. 2015 May;29(5):1143-52. doi: 10.1038/leu.2014.314. Epub 2014 Nov 5.
- Background: PubMed 35287976Arnold PY. Review: HLA loss and detection in the setting of relapse from HLA-mismatched hematopoietic cell transplant. Hum Immunol. 2022 Oct;83(10):712-720. doi: 10.1016/j.humimm.2022.03.001. Epub 2022 Mar 11.
- Background: PubMed 35385089Wu H, Shi J, Luo Y, Yu J, Lai X, Liu L, Fu H, Ouyang G, Xu X, Xiao H, Huang H, Zhao Y. Assessment of Patient-Specific Human Leukocyte Antigen Genomic Loss at Relapse After Antithymocyte Globulin-Based T-Cell-Replete Haploidentical Hematopoietic Stem Cell Transplant. JAMA Netw Open. 2022 Apr 1;5(4):e226114. doi: 10.1001/jamanetworkopen.2022.6114.
- Background: PubMed 17889352Mielcarek M, Storer BE, Flowers ME, Storb R, Sandmaier BM, Martin PJ. Outcomes among patients with recurrent high-risk hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2007 Oct;13(10):1160-8. doi: 10.1016/j.bbmt.2007.06.007. Epub 2007 Aug 3.
- Background: PubMed 22167752Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R, Stadler M, Kuball J, Cornelissen J, Vorlicek J, Socie G, Falda M, Vindelov L, Ljungman P, Jackson G, Kroger N, Rank A, Polge E, Rocha V, Mohty M; Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood. 2012 Feb 9;119(6):1599-606. doi: 10.1182/blood-2011-08-375840. Epub 2011 Dec 13.
- Background: PubMed 36475520Yerushalmi Y, Shem-Tov N, Danylesko I, Canaani J, Avigdor A, Yerushalmi R, Nagler A, Shimoni A. Second hematopoietic stem cell transplantation as salvage therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after a first transplantation. Haematologica. 2023 Jul 1;108(7):1782-1792. doi: 10.3324/haematol.2022.281877.
- Background: PubMed 2571931Gluckman E, Broxmeyer HA, Auerbach AD, Friedman HS, Douglas GW, Devergie A, Esperou H, Thierry D, Socie G, Lehn P, et al. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med. 1989 Oct 26;321(17):1174-8. doi: 10.1056/NEJM198910263211707. No abstract available.
- Background: PubMed 30334335Ehrhart J, Sanberg PR, Garbuzova-Davis S. Plasma derived from human umbilical cord blood: Potential cell-additive or cell-substitute therapeutic for neurodegenerative diseases. J Cell Mol Med. 2018 Dec;22(12):6157-6166. doi: 10.1111/jcmm.13898. Epub 2018 Oct 18.
- Individual participant dataSharing planned: Yes
Related trials for Hematopoietic Malignancy
Not yet recruitingPhase 4
MACE and BTK Inhibitors
Hematologic Cancer, MACE
RecruitingEarly Phase 1
HMCT/CT2401: Abatacept GVHD Prophylaxis Following Omidubicel HCT
Hematologic Malignancy
Recruiting
Tele-HOPE: A Telehealth Pharmacist Opioid Patient Education Pilot Study
Hematopoietic and Lymphatic System Neoplasm, Malignant Solid Neoplasm
Active, not recruitingPhase 2
Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia
Adult Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
Recruiting
An Exploratory Study to Evaluate Immune Determinants of the Response to Adoptive Cell Therapy (ACT) in Solid and Hematologic Tumors
Solid Tumor, Adult, Solid Tumor, Childhood
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Xiaojin Wu, Prof. principal investigator
The First Affiliated Hospital of Soochow University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Umbilical Cord Blood Transplantation in people with Hematopoietic Malignancy and Relapse/Recurrence, run by The First Affiliated Hospital of Soochow University at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 24 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Xiaojin Wu, Prof. (+8613057493105, wuxiaojin@suda.edu.cn), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall survival rate (time frame: within 1 year following UCBT). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06125483, which also lists 24 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Apr 2025.