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Efficacy of early repeated infusion of MSCs in GvHD prophylaxis after haplo-HSCT

Jul 28, 2022
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Learning objective: After reading this article, learners will be able to cite a new clinical development in GvHD.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a major therapeutic advance as it exhibits multiple advantages, such as widespread availability of stem cell sources and favorable clinical outcomes improved by post-transplant cyclophosphamide, granulocyte colony stimulating factor allografts, and antithymocyte globulin. The outcomes of haplo‑HSCT are currently not inferior to other transplantation modalities.1 However, complications such as graft failure, relapse, and particularly graft-versus-host disease (GvHD), are the main barriers to further improving outcomes in patients undergoing haplo-HSCT. The use of immunosuppressive agents in the prevention of GvHD may lead to severe side effects; therefore, there is a need for effective and safer GvHD prophylaxis.2

Mesenchymal stromal cells (MSCs) are multipotent progenitor cells with immune regulatory ability that may have a potential role in the prevention of GvHD.2 However, there is conflicting evidence that suggests the application of MSCs in haplo-HSCT can decrease the incidence and severity of chronic GvHD (cGvHD) and improve survival but it may not reduce the risk of GvHD, which warrants further investigation.3

During the European Hematology Association (EHA) 2022 Congress, Huang presented results of their trial (ChiCTR-IOR-15006330), which assessed the efficacy of early repeated infusion of umbilical cord-derived MSCs (UC-MSCs) 45 days after haplo‑HSCT.3 This trial followed on from their previous study, which demonstrated the efficacy of early infusion of UC-MSCs in GvHD prophylaxis 100 days post-haplo-HSCT.2 The key findings presented during the EHA presentation are summarized here.

Study design

This was a multicenter, open label, randomized controlled trial in patients aged 18−60 years, who were diagnosed with acute leukemia between May 2015 and January 2020, and who had a human leukocyte antigen-matched donor for HSCT. Patients were randomly assigned to receive UC-MSCs or saline infusion, as shown in Figure 1.

Figure 1. Study design*

GvHD, graft-versus-host disease; UC-MSC, umbilical cord-derived mesenchymal stromal cell.

*Adapted from Huang.2 

The primary endpoint was 1-year GvHD relapse-free survival (GRFS) defined as survival without Grade III/IV acute GvHD (aGvHD), systemic treatment for cGvHD, relapse, or death. Secondary endpoints included incidence and severity of aGvHD and cGvHD, relapse, progression-free survival, overall survival, and changes in lymphocyte subsets. The 2014 National Institute for Health (NIH) consensus criteria was used for organ scoring and global GvHD assessment.

Results

Baseline characteristics

A total of 128 patients were included and the baseline characteristics are as shown in Table 1. Patient characteristics were not significantly different between the two arms.

Table 1. Baseline characteristics*

Characteristic, % (unless otherwise stated)

UC-MSC arm
(n = 64)

Control arm
(n = 64)

Median age (range), years

31.3 (18–60)

30.3 (18–55)

Female/male

26/38

25/39

HLA compatibility

 

 

              1 loci-mismatched

20.3

26.6

              2 loci-mismatched

37.5

29.7

              3 loci-mismatched

42.2

43.7

Disease type

 

 

              AML

60.9

59.4

              ALL

36.0

34.4

              MAL

3.1

6.2

Donor-recipient sex match

 

 

              Female-female

4.7

4.7

              Female-male

20.3

15.6

              Male-male

39.1

48.4

              Male-female

35.9

31.3

Donor-recipient relationship

 

 

              Father-child

54.7

51.6

              Mother-child

9.4

10.9

              Siblings

35.9

37.5

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; HLA, human leucocyte antigen; MAL, megakaryoblastic acute leukemia; UC-MSC, umbilical cord-derived mesenchymal stromal cell.
*Adapted from Huang.2

Primary endpoint

GRFS at 1-year was significantly higher in the UC-MSC arm compared with the control arm (65.6% vs 43.7%, respectively; p = 0.0129).

Secondary endpoints

In the UC-MSC and control arms, aGvHD developed in 17.2% and 35.9%, respectively (p = 0.0163), and cGvHD occurred in 28.1% and 45.3%, respectively (p = 0.0437). Specifically, there was a significantly lower incidence of Grade III–IV aGvHD (3.1% vs 25.6%) and severe cGvHD (6.3% vs 18.8%) in the UC-MSC arm compared with the control arm (Figure 2).

Figure 2. aGvHD and cGvHD incidence and severity*

aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease; GI, gastrointestinal; UC‑MSC, umbilical cord-derived mesenchymal stromal cell.
*Adapted from Huang.2
p < 0.05.

The relapse rate and cumulative survival were not significantly different between the two arms. However, patients in the UC-MSC arm demonstrated an improved 2-year overall survival and progression-free survival compared with patients in the control arm, although these improvements were not statistically significant.

With regards to lymphocyte subsets, the frequencies of natural killer cells after infusion and CD19+ B lymphocytes 6 months after infusion were lower in UC-MSC arm compared with the control arm. The number of regulatory T cells was higher in the UC-MSC arm at 3, 4-, 5-, 6-, and 8-months post-infusion compared with the control arm.

During the complication analysis it was shown that

  • the cytomegalovirus rate was significantly lower in the UC-MSC arm compared with the control arm (21.9% vs 39%; p = 0.0347);
  • the incidence of Grade III–IV hemorrhagic cystitis was significantly lower in the UC-MSC arm compared with the control arm (14.1% vs 29.7%; p = 0.0325); and
  • the Epstein-Barr virus activation rate was lower in the MSC arm compared with the control arm (40.6% vs 53.1%), although this was not significant (p = 0.1565).

Conclusion

The trial summarized here demonstrated that early and repeated infusion of UC-MSCs in patients from 45 days post-haplo-HSCT significantly improved the GRFS rate. The incidence and severity of GvHD were reduced, whilst the incidence of relapse was not increased. The findings suggest that repeated UC-MSC infusion from 45 days is safe and effective at managing not only aGvHD but also cGvHD.
However, the results of this trial should be interpreted in the context of several limiting factors. For example, the underlying mechanism of UC-MSC infusion in GvHD prophylaxis, the combination mode of MSCs with other immunosuppressive agents, and the best infusion point for MSCs require further research in a larger population.

  1. Cytryn S, Abdul-Hay M. Haploidentical Hematopoietic Stem Cell Transplantation Followed by 'Post-Cyclophosphamide': The Future of Allogeneic Stem Cell Transplant. Clin Hematol Int. 2020;2(2):49-58. DOI: 2991/chi.d.200405.001.
  2. Huang R. Early infusion of MSCs in the prophylaxis of GvHD after haplo-hematopoietic stem-cell transplantation. Oral abstract #S242. European Hematology Association 2022 Congress; Jun 12, 2022; Vienna, AT.
  3. Li R, Tu J, Zhao J, et al. Mesenchymal stromal cells as prophylaxis for graft-versus-host disease in haplo-identical hematopoietic stem cell transplantation recipients with severe aplastic anemia?—a systematic review and meta-analysis. Stem Cell Res Ther. 2021;12(1):106. DOI: 1186/s13287-021-02170-7
  4. Wang R, Wang X, Yang S, et al. Umbilical cord-derived mesenchymal stem cells promote myeloid-derived suppressor cell enrichment by secreting CXCL1 to prevent graft-versus-host disease after hematopoietic stem cell transplantation. Cytotherapy. 2021;23(11):996-1006. DOI: 1016/j.jcyt.2021.07.009