Clinical Research Directory

A Single-Arm, Prospective Study of TBI+BUMEL as Conditioning for SCT2 in Patients With Malignant Hematologic Diseases

Each year, over 20,000 patients in China undergo hematopoietic stem cell transplantation (HSCT). Unfortunately, the prognosis in patients with disease relapse or graft failure is often inferior. A second allogeneic hematopoietic stem cell transplantation (SCT2) has emerged as a vital salvage therapy option. Despite varying prognoses, most patients undergoing SCT2 have a five-year overall survival (OS) rate of less than 30%. The primary challenges of SCT2 include treatment strategy, immune regulation, complication management, and transplantation technique improvements. By optimizing these key aspects, SCT2 can effectively address issues that arose after the first transplant, reduce complications, and provide more effective treatment for patients. Clinical practice indicates that SCT2 is crucial in treating various hematologic diseases. For patients who failed the first transplant (SCT1), SCT2 can more effectively treat the primary disease, provide timely hematopoietic engraftment, extend survival time, and improve the quality of life. Additionally, the successful application of SCT2 provides clinicians with more treatment options and hope. Currently, the modified BU/CY conditioning regimen, which consists of busulfan (BU) and cyclophosphamide (CY), is commonly used in SCT1 in China. However, for patients who relapse after SCT1, these drugs may become ineffective, and the physical condition often worsens, with a higher likelihood of infections and organ dysfunction. Therefore, finding new conditioning regimens is crucial. Studies have shown that a melphalan (MEL)-based conditioning regimen may have better outcomes for patients with acute myeloid leukemia (AML) compared to a Cy-based regimen. The Conditioning regimen that includes total body irradiation (TBI) has also been considered effective for patients with acute leukemia. Thus, low-dose TBI combined with a BU + MEL regimen could be a promising conditioning regimen for SCT2. In the investigators' preliminary studies, three patients who underwent SCT2 with this regimen successfully achieved engraftment and were discharged. Based on this, the investigators plan to conduct a clinical study to observe the effects of the TBI+BUMEL regimen combined with SCT2 on the engraftment rate, disease relapse rate, GVHD incidence, and survival rate in patients with malignant hematologic diseases who relapsed after SCT1.

TFBC Combined With UCBT in the Treatment of High-risk Malignant Hematological Diseases

High-risk malignant hematological diseases refer to malignant hematological diseases, mainly include various types of leukemia, lymphoma, and multiple myeloma, with very poor prognoses, very short survival, and unsatisfactory outcomes. Chemotherapy, hypomethylating agents (HMA), radiotherapy, targeted therapy, immunotherapy, and hematopoietic stem cell transplantation (HSCT) are common treatments for high-risk malignant hematological diseases. Because of the multiple lines and long duration of exposure to chemotherapy drugs in patients with high-risk malignant hematological diseases, monotherapy is inefficient, and radiotherapy is used frequently as an adjunct treatment to HSCT. Conventional myeloablative conditioning regimens before HSCT are comprised of cyclophosphamide/total body irradiation (Cy/TBI) and busulfan/cyclophosphamide (Bu/Cy). The reduced-toxicity myeloablative conditioning regimen, FBC, is the combination of Bu, Cy, and fludarabine (Flu), which has a strong immunosuppressive effect to ensure the success of engraftment of donor cells. Compared to the conventional intensified chemotherapy regimens, HMA have certain advantages of efficacy and safety and are the first-line treatment options for patients with acute myeloid leukemia (AML). Although monotherapy improves survival rate, the response rate is low. What's more, it is difficult to achieve sustained remission and long-term benefits. The current research hotspots are HMA combined with chemotherapy, targeted drugs such as BCL-2 inhibitors, immunotherapy, and cell therapy. Targeted therapy and immunotherapy are effective, but show a high prevalence of relapse, heavy treatment burden, and the need for long-term maintenance. HSCT is an important therapy for the treatment of high-risk malignant hematological diseases, which could eliminate tumor cells through high-dose radiotherapy or chemotherapy, destroy the immune system of patients to prepare the engraftment of donor cells, and promote the reconstitution of hematopoiesis and immune recovery. HSCT has developed rapidly since the 1950s and has been performed in more than one million patients worldwide. HSCT is often the only definitive treatment available for patients with certain specific congenital or acquired diseases and is used in the treatment of many high-risk malignant hematological diseases. However, due to the strict criteria for HSCT, many patients do not have a matched donor. Since the first successful 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. Cord blood is rich in hematopoietic stem cells, endothelial progenitor cells, mesenchymal stem cells, and other stem/progenitor cells, as well as natural killer cells, Treg cells, and other immune cells, which have strong self-renewal and proliferation ability and low immunogenicity. The hematologic growth factors produced by these cells could act on the formation of myeloid cells and granulocytes, which are beneficial to hematopoietic reconstruction and recovery. It contains a variety of cytokines such as thrombopoietin, erythropoietin, stem cell factor, and multi-class interleukins. Some cytokines such as stem cell factor, IL-6, and IL-11 are much higher in cord blood than in peripheral blood. The potential mechanism by which UCBT exerts its therapeutic effect in patients with hematological diseases is largely the result of the interaction of multiple growth factors and stem/progenitor cells with the organism. Compared with peripheral blood stem cell transplantation (PBST), UCBT has a higher transplantation rate, as cord blood stem cells are more primitive and purer than bone marrow stem cells. UCBT could be performed with four or more matches, and have a relatively lower rejection rate, lower relapse rate of malignant hematological diseases, and lower cumulative incidence of chronic graft-versus-host disease (GVHD), which greatly improves patient survival. Prof. Sun Zimin's team at Anhui Provincial Hospital was the first to use UCBT for the treatment of patients with AML and found that the cumulative incidence of chronic GVHD and relapse rate were significantly reduced. Based on the above, the TFBC regimen (TBI/Flu/Bu/Cy) combined with UCBT is safe and feasible for the treatment of patients with high-risk malignant hematological diseases, which has enormous potential to improve patient outcomes. Therefore, we designed this clinical study on the TFBC regimen combined with UCBT for the treatment of high-risk malignant hematological patients to observe the impact on the engraftment rate, relapse rate, the cumulative incidence of GVHD, and survival.