tfbc combined with ucbt in the treatment of high-risk malignant hematological diseases

Conditions: Hematopoietic Stem Cell Transplantation; Malignant Hematological Diseases

Summary: 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.

high-risk malignant hematological diseases are commonly seen in patients with advanced age, complex karyotypes, genes related to poor prognosis, failure to achieve remission after remission-inducing chemotherapy, and relapsed or refractory 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. in a retrospective study done by prof. sun zimin's team, the efficacy of intravenous bu/cy versus tbi/cy was compared in 331 patients from 8 centers who underwent single-unit umbilical cord blood transplantation (ucbt). it was reported that the cumulative incidence of neutrophil engraftment was higher in the tbi/cy group than in the bu/cy group (98.0% versus 91.6%, p \< 0.001), but the time to neutrophil engraftment was shorter in the bu/cy group than in the tbi/cy group (16 days versus 19 days, p \< 0.001). there was no significant difference in the non-relapse mortality, relapse rate, or survival rate between the two groups. what's more, the gvhd-free and relapse-free survival rate of patients was significantly increased, greatly improving patient survival. ucbt has also been widely used in other malignant hematological diseases such as acute lymphoblastic leukemia (all), lymphoma, and multiple myeloma. in 2017, ucbt was performed for the treatment of an adult aml patient at the central hospital of wuhan, and the patient was successfully discharged from hospital. in 2020, ucbt was performed for the treatment of a 14-year-old patient with myelodysplastic syndrome at the tai'an central hospital, and the patient achieved a good recovery with very mild rejection after transplantation and was finally discharged safely. since the first successful ucbt in the seventh hospital of zhongshan university in april 2021, 10 cases have been successfully performed, including an obese patient weighing 85 kg, a patient with strong positive panel reactive antibodies (pra), and a patient with aml who received a second transplant after the first pbst. the overall success rate was 100% and the longest disease-free survival was 2 years. no patients died due to transplant-related mortality (trm), only 1 case of severe gvhd occurred, and none of them underwent relapse.

Eligibility criteria:
inclusion criteria: 1. gender is not limited, patients between 14 to 70 years old (including critical value); 2. high-risk malignant hematological diseases (acute lymphoblastic leukemia, acute/chronic myeloid leukemia, multiple myeloma, etc.) diagnosed by bone marrow aspiration or biopsy according to the who diagnostic criteria; 3. 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%); 4. umbilical cord blood with hla match ≥ 4/6; 5. expected survival ≥3 months; 6. karnofsky (kps) score ≥60%, eastern tumor cooperative group (ecog) status ≤ 2; 7. 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. patients with a history of immunodeficiency, or other acquired or congenital diseases, immunodeficiency diseases, and a history of organ transplantation; 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. two or more surgeries were performed within 4 weeks prior to enrollment; 5. patients with active viral infections, including hiv, hbv, hcv, tp; 6. pregnant or lactating patients; 7. the patient is currently participating in another clinical studies; 8. patients deemed unsuitable for inclusion by other investigators.

Keywords: umbilical cord blood transplantation; conditioning regimen