Co-transplantation of mesenchymal stem cells makes haploidentical HSCT a potential comparable therapy with matched sibling donor HSCT for patients with severe aplastic anemia

Abstract

The application of haploidentical hematopoietic stem cell transplantation (HSCT) with mesenchymal stem cell (MSC) infusion as a treatment regimen for severe aplastic anemia (SAA) has been reported to be efficacious in single-arm trials. However, it is difficult to assess without comparing the results with those from a first-line, matched-sibling HSCT. Herein, we retrospectively reviewed 91 patients with acquired SAA. They received HSCT from haploidentical donors combined with MSC transfer (HID group). We compared these patients with 103 others who received first-line matched-sibling HSCT (MSD group) to evaluate relative treatment efficacy. Compared with the patients in the MSD group, those in the HID group presented with higher incidences of grades II–IV and III–IV acute graft versus host disease (aGvHD) and chronic graft versus host disease (cGvHD) ( p < 0.05). However, the incidence of myeloid and platelet engraftment, graft failure, poor graft function, and extensive cGvHD were comparable for both groups. The median follow-up was 36.6 months and the 3-year overall survival rate was similar for both groups (83.5% versus 79.1%). Univariate and multivariate analyses revealed that time intervals greater than 4 months from diagnosis to transplantation, experienced graft failure, poor graft function, or grade III–IV aGvHD were significantly associated with adverse outcomes. All HID patients received MSC co-transplantation with hematopoietic stem cells. However, the infused MSCs were derived from umbilical cord (UC-MSC group; 43 patients) or bone marrow (BM-MSC group; 48 patients) and were administered at different medical centers. We first compared the outcomes between the two groups and detected that the BM-MSC group exhibited lower incidences of grade III–IV aGvHD and cGvHD ( p < 0.05). This study suggests that co-transplantation of hematopoietic and MSCs significantly reduces the risk and incidence of graft rejection and may effectively improve overall survival in patients with SAA even in the absence of closely related histocompatible donor material.

Comparison of Hematopoietic Stem Cell Transplantation Outcomes Using Matched Sibling Donors, Haploidentical Donors, and Immunosuppressive Therapy for Patients With Acquired Aplastic Anemia

“…Taking quality of life into consideration, cGvHD was the major concern of HID-HSCT compared to IST. However, in line with other studies in China (4,5,28), our work reported a culminative incidence of estimated 5-year moderate to severe cGvHD after HID-HSCT of 9% (95% CI, 0-18) vs. 3% (95% CI, 0-5) (p = 0.076) after MSD-HSCT, and no patients had severe cGvHD in the HID group. Cardiac toxicity related to high-dose CY is of great concern to patients with SAA who are elderly or have poor cardiac function due to anemia with lethal cardiotoxicity up to 2.3% (29).…”

The Incidence, Outcomes, and Risk Factors of Secondary Poor Graft Function in Haploidentical Hematopoietic Stem Cell Transplantation for Acquired Aplastic Anemia

“…In line with Liu et al. ( 24 ), our results reported an acceptable incidence of sPGF after haplo-HSCT for AA. In contrast, Japanese colleagues reported a higher incidence of sPGF of 15% in 49 pediatric AA patients, which included 3 transplantations from matched sibling donors (20.0%), 3 from unrelated donors (10.3%), and 1 from haploidentical donor (20%) ( 25 ).…”

Biological Characteristics of Umbilical Cord Mesenchymal Stem Cells and Its Therapeutic Potential for Hematological Disorders

“…However, the negative effects of bone marrow hematopoietic microenvironment damage and delayed immune reconstitution may lead to poor stem cell engraftment, and increase the rate of postoperative infection and recurrence ( Bair et al, 2020 ; Mallhi et al, 2020 ). A series of animal and clinical trials showed that HSCT or cord blood transplantation (CBT) combined with infusion of UC-MSCs is able to promote hematopoietic engraftment and reduce the occurrence GVHD ( Liu et al, 2020c ; Yang et al, 2020 ). It was reported that UC-MSCs promote myeloid-derived suppressor cell proliferation by secreting HLA-G to reduce acute GVHD after HSCT ( Yang et al, 2020 ).…”

“…UC-MSCs produce an immunosuppressive isoform of HLA-1, do not express HLA-DR and lack costimulatory signaling systems and immune response-related surface antigens such as CD40, CD40L, CD80, and CD86, which indicate that UC-MSCs can be tolerated in allogeneic transplantation ( Wang et al, 2014 ). There were no reports of any toxicity or side effects when UC-MSCs were injected into laboratory animals in pre-clinical trials ( Fan and Zhang, 2011 ), or were used to treat aplastic anemia ( Xu et al, 2018 ; Liu et al, 2020c ), leukemia ( Kang-Hsi et al, 2013 ; Wu Y. et al, 2013 ) in clinical studies. This indicates that it is safe enough to use allogeneic MSCs after the HLA molecule is detected.…”