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%.