Haplo-Cord HSCT for AML/MDS

Acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) are common and rapidly progressive malignant hematologic disorders associated with poor prognosis without effective intervention. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only first-line therapeutic strategy with curative potential for long-term remission or even definitive cure. However, the efficacy of conventional transplantation approaches is limited by multiple factors, particularly the management of graft-versus-host disease (GVHD) and disease recurrence. Balancing the graft-versus-leukemia (GVL) effect against residual leukemia while effectively mitigating GVHD represents an unresolved challenge in current transplantation strategies.

Although an HLA-matched donor is the optimal choice, access to such donors is restricted by time constraints and availability. In recent years, the widespread use of haploidentical donors has dramatically improved transplant accessibility, enabling nearly all patients to identify a suitable donor. China has emerged as a global leader in the development and application of haploidentical transplantation. Nevertheless, the established Beijing Protocol and the Baltimore post-transplantation cyclophosphamide (PTCY) regimen each have distinct limitations: the former is associated with high engraftment rates and low relapse incidence but a relatively high rate of chronic GVHD (approximately 20%), whereas the latter reduces GVHD risk but carries higher rates of engraftment failure and disease relapse.

Umbilical cord blood transplantation (UCBT) represents an alternative donor source, whose inherent immune properties offer the potential to reduce GVHD while preserving the GVL effect. However, the limited cell dose in single cord blood units results in delayed hematopoietic reconstitution, high infection rates, and elevated early mortality, restricting its broader application in adult patients.

Against this background, transplantation strategies combining the advantages of different donor sources have become a major research focus. The 'haplo-cord hematopoietic stem cell transplantation' strategy, which combines haploidentical peripheral blood stem cells with unrelated umbilical cord blood stem cells, has been proposed. This approach integrates the rapid hematopoietic engraftment of haploidentical stem cells with the immunomodulatory properties of cord blood, thereby accelerating hematopoietic recovery and reducing the risk of acute and chronic GVHD. Furthermore, the incorporation of immunomodulatory agents such as low-dose anti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCY) has led to simultaneous control of both transplantation-related mortality and relapse.

Domestic investigators reported that patients with relapsed/refractory acute leukemia (r/r-AL) who received combined haplo-HSCT and UCB-assisted transplantation exhibited superior leukemia-free survival and lower relapse rates compared with haploidentical transplantation alone, with 2-year overall survival, progression-free survival, cumulative incidence of relapse, and non-relapse mortality of 35.5%, 35.5%, 25.9%, and 38.0%, respectively. An international study comparing double UCBT (dUCBT) with haplo-cord transplantation for hematologic malignancies demonstrated that haplo-cord transplantation was associated with faster neutrophil and platelet engraftment, lower risks of grade II-IV acute GVHD and chronic GVHD, reduced relapse risk, and superior GVHD- and relapse-free survival compared with dUCBT.

In recent years, with the increasing incidence of AML and MDS, post-transplant relapse has become the primary obstacle to long-term therapeutic success. International multicenter data indicate that disease relapse remains the leading cause of transplant failure (59% for matched sibling donors vs. 51% for unrelated donors), followed by severe GVHD and infection. Although conventional strategies including re-induction chemotherapy, second transplantation, and donor lymphocyte infusion (DLI) have been explored, their efficacy is limited by high relapse rates, severe toxicities, and modest survival benefits, failing to meet current clinical needs.

Therefore, the development of novel transplantation models that enhance GVL while controlling GVHD has become an urgent bottleneck to address. Combined donor transplantation strategies represent one promising approach toward this goal. To date, several countries have conducted exploratory studies of the haplo-cord regimen, reporting faster hematopoietic recovery, lower rejection risk, and reduced relapse rates. Multiple centers in China have also initiated clinical validation with encouraging results.

The applicant's research team has developed and implemented a haplo-cord HSCT protocol based on low-dose ATG plus PTCY, with proven safety and efficacy in clinical practice. Compared with conventional haploidentical or single cord blood transplantation, this regimen achieved significantly higher relapse-free survival in patients with relapsed/refractory disease, effectively reduced the incidence of chronic GVHD, and improved quality of life and survival expectancy, with 2-year overall survival, disease-free survival, and GVHD- and relapse-free survival of 64.9%, 64.5%, and 60.8%, respectively. Notably, nearly half of the patients achieved dominant cord blood engraftment, challenging the traditional view that cord blood serves only an auxiliary role.

In the present prospective multicenter cohort study, we aim to further investigate the long-term efficacy of this combined transplantation strategy in patients with AML and high-risk MDS. By comparing immune reconstitution, relapse rates, GVHD, and other prognostic outcomes between cord blood-dominant and haploidentical-dominant engraftment, we intend to define its optimal indications and establish high-level evidence to optimize hematopoietic stem cell transplantation regimens.

This study aims to investigate the clinical efficacy of haploidentical-cord blood hematopoietic stem cell transplantation in patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS), and to analyze the impact of different engraftment patterns (haploidentical engraftment versus cord blood engraftment) on clinical outcomes. By comparing the efficacy of haploidentical-cord blood transplantation in different subtypes of AML and MDS, this research will explore its unique advantages and comparative effectiveness relative to conventional transplantation strategies, so as to provide new evidence for clinical practice.

Specific research objectives: 1. To evaluate the efficacy of haploidentical-cord blood hematopoietic stem cell transplantation for AML and high-risk MDS, including the speed of hematopoietic recovery, immune tolerance, and long-term survival rates. 2. To compare the effects of different engraftment patterns (haploidentical engraftment vs. cord blood engraftment) on quality of life, immune tolerance, early complications, and long-term prognosis. 3. To identify the clinical advantages and indications of haploidentical-cord blood transplantation through data analysis, and to provide a theoretical basis for clinical decision-making.