Risk of Severe GVHD Lower With Post-Transplant Cyclophosphamide Than ATG in Mismatched Unrelated Donor Transplant

Antithymocyte globulin (ATG) is considered standard graft-versus-host disease (GVHD) prophylaxis in patients with acute myeloid leukemia (AML) who undergo transplantation with a mismatched unrelated donor (MMUD). However, results from a retrospective analysis published in Blood suggest that post-transplant cyclophosphamide (PTCY) lowers the risk of severe GVHD, compared with ATG, and appeared to lead to longer leukemia-free survival (LFS).

“Despite this being a retrospective registry analysis, our findings provide first proof of evidence that PTCY may replace ATG in the near future in one antigen–MMUD transplant for AML, thus helping physicians when choosing GVHD prophylaxis in this setting,” lead study author Giorgia Battipaglia, MD, from the Hôpital Saint-Antoine in Paris, told ASH Clinical News.

In this study, Dr. Battipaglia and authors retrospectively analyzed data from patients who underwent a first allogeneic hematopoietic cell transplantation (alloHCT) from a 9/10 MMUD between 2011 and 2017 and were enrolled in the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party (EBMT-ALWP) registry. Only patients who received GVHD prophylaxis with either PTCY or ATG were included; patients who received GVHD prophylaxis with in vivo T-cell depletion other than ATG were excluded.

The researchers identified 272 eligible patients:

  • 93 patients who received PTCY (median age at transplant = 51 years [range = 20-73 years])
  • 179 patients who received ATG (median age at transplant = 53 years [range = 19-75 years])

The primary endpoint for the study was cumulative incidence (CI) of acute or chronic GVHD; secondary endpoints included engraftment rate, LFS, overall survival (OS), CI of relapse, and nonrelapse mortality (NRM).

The median follow-up was longer in the ATG group compared with the PTCY group (27 months vs. 14 months; p<0.01), largely because patients in the ATG group tended to be transplanted earlier during the study period.

“Post-transplant cyclophosphamide may replace antithymocyte globulin in the near future in one antigen-mismatched unrelated donor transplant for AML.”

—Giorgia Battipaglia, MD

Individuals in both groups had similar rates of engraftment during follow-up (96% vs. 95%, respectively; p=0.7). However, patients in the ATG group had a shorter median time to neutrophil engraftment compared with those in the PTCY group (17 days vs. 19 days; p<0.01). Graft failure was observed in 37 patients in the ATG group and four patients in the PTCY group.

At 100 days post-transplant, the cumulative incidence of grades II-IV acute GVHD was 30% in the PTCY group, compared with 32% in the ATG group (p=0.39). In addition, patients who received PTCY had a significantly lower incidence of grades III-IV acute GVHD compared with patients in the ATG group (9% vs. 19%; p<0.04).

However, at two years post-transplant, there were no differences in the CI of chronic GVHD of any grade between the PTCY and ATG groups. “The similar incidence of chronic GVHD with ATG and PTCY may be due to [the] mechanism of action of ATG, which acts not only with an extensive in vivo T-cell depletion and expansion of regulatory T cells, but by also targeting B cells,” the researchers explained. “Considering that donor T and B cells play an essential role in the development of chronic GVHD, the long-term inhibitory action of ATG on these cells may help in preventing this complication.”

The authors also reported that PTCY appeared to be associated with higher survival rates at two years, compared with ATG:

  • LFS: 55% vs. 34% (p<0.05)
  • OS: 56% vs. 38% (p<0.07)
  • relapse-free survival: 37% vs. 21% (p<0.03)

Similar proportions of patients in each group died due to disease recurrence: 37% in the PTCY-treated group and 40% in the ATG-treated group (p value not reported).

Next, the investigators performed subgroup analyses in three populations: patients receiving peripheral blood stem cells, patients in complete remission at the time of alloHCT, or patients receiving the same associated immunosuppressive agents. Each analysis confirmed the superiority of PTCY, particularly in PTCY-treated patients who underwent alloHCT in complete remission or received peripheral blood stem cells as a donor source (OS: 63% vs. 45% [p<0.05]). The patients who received PTCY also had lower NRM with the use of peripheral stem cell transplantation compared with patients who received ATG (14% vs. 28%; p=0.04).

“The differences in OS and NRM among the two groups may in part be explained by the higher mortality rate due to infections and GVHD in the ATG group and higher LFS in the PTCY group, both resulting in higher OS in the PTCY group,” the authors wrote, noting that patients receiving ATG were treated at an earlier time period than those in the PTCY group. “Unfortunately, we do not have data on the details of infectious complications in the two groups.” Other potential limitations include the study’s retrospective nature and the short median follow-up period of 14 months.

The authors report no conflicts of interest.

Reference

Battipaglia G, Labopin M, Kröger N, et al. Post-transplant cyclophosphamide versus antithymocyte globulin in HLA-mismatched unrelated donors transplantation. Blood. 2019 July 3. [Epub ahead of print]

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