ATG in Cord Blood Transplantation: Is Timing Everything?

The practice of using antithymocyte globulin (ATG) to overcome the risks of graft rejection in patients who require allogeneic hematopoietic stem cell transplantation with umbilical cord blood but lack a suitable HLA-matched donor is unwarranted, and may even be detrimental to recovery, according to a recent study published in Blood.

Unrelated cord blood transplantation (UCBT) is an alternative source of stem cells for these patients, but cord blood contains significantly fewer CD34+ cells and mature lymphocytes than other sources of stem cells, which can lead to delayed post-transplant immune reconstitution and an increased risk of graft failure.

“The use of ATG, incorporated within the conditioning regimen prior to UCBT is still controversial, especially for adults receiving a reduced-intensity conditioning, single-unit allogeneic cord blood transplant,” the authors, led by Laurent Pascal, MD, from Hôpital Saint Vincent de Paul, GHICL, Hematologie in Lille, France, wrote.

Dr. Pascal and colleagues conducted a multicenter, retrospective study to examine the impact of ATG on the outcomes of patients undergoing single- or double-unit UCBT following a reduced-intensity conditioning.

A total of 661 adult patients from 79 European Society for Blood and Marrow Transplantation centers were included: 226 patients underwent single-unit UCBT, while 435 underwent double-unit UCBT. The reduced-intensity conditioning regimen consisted of cyclophosphamide (50 mg/kg), fludarabine (200 mg/m2), and a single fraction of total body irradiation (200 cGy in 86%, 400 cGy in 12%, and 600 cGy in 2% of patients).

The median age of study participants was 54 years and diagnoses included acute leukemias (51%), lymphoproliferative diseases (30%), and myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN; 19%). Forty-four percent of patients who were transplanted had advanced disease, all patients received UCBT grafts with at least four out of six HLA compatibilities, and the median number of infused total nucleated cells was 3.5 x 107/kg.

The 82 patients in the ATG group were older compared with the 579 patients in the non-ATG group (54 years vs. 52 years, respectively; p=0.068), patients in the ATG group presented with a higher proportion of MDS/MPN (31% vs. 17%; p=0.009), and patients in the ATG group had more advanced disease (p=0.063).

With a median follow-up of 36 months (range, 2-99 months), the cumulative incidence of 60-day neutrophil engraftment (defined as neutrophil recovery, excluding patients with autologous recovery) was 83 percent, with no significant difference according to ATG use (84% for non-ATG and 82% for ATG; p=0.17). Graft failure occurred in 103 patients (15.6%), including 88 patients in the non-ATG cohort and 15 in the ATG group. Of those patients, 30 were alive at a median of 33 months post-transplantation.

Dr. Pascal and authors concluded, “in adults undergoing UCBT following a reduced-intensity conditioning regimen for hematological malignancies, this study shows that adding rabbit ATG to the conditioning leads to less satisfactory outcomes.” In multivariate analyses, the use of ATG was associated with a significantly decreased risk of acute graft-versus-host disease (GVHD), but also a significantly higher risk of non-relapse mortality and a decrease in overall survival (TABLE).

In terms of mortality, 24 percent of patients (n=20/82) in the ATG group died of relapse or progression, compared with 27 percent of patients (n=158/579) in the non-ATG group (p=.58). Deaths in the ATG group were more likely due to infection (28% vs. 13%; p=0.0013) and post-transplant lymphoproliferative disorders (6% vs. 0.5%; p=0.001), compared with the non-ATG group.

Although the absence of ATG in the conditioning regimen was associated with higher rates of GVHD, there was no clear improvement on survival when ATG was used, the authors noted. “This could be explained by an overlapping impact of several complex variables on the final outcome,” they wrote. “Indeed, the higher non-relapse mortality observed in the ATG group might outweigh the lower incidence of GVHD in the same group and could explain the detrimental impact of ATG on overall survival.”

Data on timing of ATG infusion were available for 64 patients in the study; the median number of treatment days for these patients was three (range, 1-5), and the drug was stopped at a median of two days before the graft infusion (range, 1-7). Patients were divided into three categories according to time of ATG discontinuation:

  • 27 patients stopped ATG at 1 day before or on day of UCBT
  • 20 patients stopped ATG at 2 days before UCBT
  • 17 patients stopped ATG between 3 and 7 days before UCBT

The interval from the last dose of ATG and graft infusion did seem to have an impact on overall survival, with better survival with the greater gap between ATG discontinuation and infusion: Overall survival was 18±7 percent, 31±11 percent, and 59±12 percent in these three groups, respectively (p=0.07).

“Although we acknowledge that it is difficult to draw definitive conclusions of timing of ATG due to the low number of patients and missing information, we do believe in the adverse effect of ATG and its timing,” Dr. Pascal and colleagues wrote. While recognizing that the retrospective nature of the study is a limitation, the authors argued that “our findings are important and potentially practice-changing for transplanters.”


Reference

Pascal L, Tucunduva L, Ruggeri A, et al. Impact of ATG-containing reduced-intensity conditioning after single or double-unit allogeneic cord blood transplantation. Blood. 2015 July 9. [Epub ahead of print]

TABLE. Hazard Ratios for Outcomes after UCBT According to the Use of ATG
ATG in Conditioning
No Yes 95% CI (p Value)
3-Year overall survival 1.0 1.69 1.19-2.41 (p=0.003)
3-Year non-relapse mortality 1.0 1.68 1.16-2.43 (p=0.0009)
Acute III-IV graft-versus-host disease 1.0 0.31 0.17-0.55 (p<0.0001)

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