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Conditioning with rabbit versus horse ATG dramatically alters clinical outcomes in identical twins with severe aplastic anemia transplanted with the same allogeneic donor.

Vo PT, Pantin J, Ramos C, Cook L, Cho E, Kurlander R, Khuu H, Barrett J, Leitman S, Childs RW - J Hematol Oncol (2015)

Bottom Line: Conventional therapies with immunosuppressive therapy or allogeneic hematopoietic stem cell transplantation (HSCT) are highly effective.HSCT can offer a greater outcome in younger patients who have an available HLA match-related donor.These agents are pharmacologically distinct, having significant differences in their pharmacokinetics and in vivo immunosuppressive effects [N Engl J Med 365(5):430-438, 2011].

View Article: PubMed Central - PubMed

Affiliation: Hematology Branch, National Heart Lung and Blood Institute (NHLBI), National Institute of Health (NIH), Bethesda, MD, USA. uyenphuong18@yahoo.com.

ABSTRACT
Severe aplastic anemia (SAA) is a rare disorder leading to bone marrow failure, which if left untreated, is invariably fatal. Conventional therapies with immunosuppressive therapy or allogeneic hematopoietic stem cell transplantation (HSCT) are highly effective. HSCT can offer a greater outcome in younger patients who have an available HLA match-related donor. Recent studies showing the addition of antithymocyte globulin (ATG) to the conditioning regimen improves engraftment and reduces the risk of graft-versus-host disease (GVHD).There are currently two ATG preparations in the USA, equine (or horse) and rabbit ATG. These agents are pharmacologically distinct, having significant differences in their pharmacokinetics and in vivo immunosuppressive effects [N Engl J Med 365(5):430-438, 2011]. Here, we report a case of two monozygotic twins with constitutional SAA that evolved to myelodysplastic syndrome (MDS) who both underwent allogeneic peripheral blood stem cell transplantation (PBSC) from the same single HLA antigen mismatched sibling donor with the only difference in the transplant regimen being the type of ATG used in the preparative regimen; one twin received horse ATG and the other received rabbit ATG during conditioning. This report emphasizes that dramatic differences in donor T cell chimerism and clinical outcomes including GVHD can occur as a consequence of the type of ATG that is utilized in the transplant conditioning regimen. These differences highlight that these agents should not be considered interchangeable drugs when used in this setting.

No MeSH data available.


Related in: MedlinePlus

Comparison of T cell chimerism between twins
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Fig2: Comparison of T cell chimerism between twins

Mentions: Here, we report data where syngeneic twins with MDS who underwent allogeneic transplantation from the same donor had dramatically different donor T cell engraftment profiles and transplant outcome as a consequence of using rabbit versus horse ATG in the preparative regimen (Fig. 2). Twin #1, who received rabbit ATG with her conditioning, had a post-transplant course which was associated with exceedingly low degrees of donor T cell engraftment and a declining reticulocyte count necessitating a subsequent infusion of donor PBSCs and T cells to avoid graft rejection. Remarkably, this patient did not achieve full donor T cell chimerism until day +352, never developed acute GVHD, and only experienced mild chronic oral GVHD which occurred after the PBSC boost. In contrast, twin #2 who received from the same donor virtually the identical number of transplanted donor CD34+ cells and a slightly lower number of transplanted CD3+ T cells, received horse ATG with the conditioning regimen and experienced very rapid and complete donor T cell chimerism which was associated with both acute GVHD and extensive chronic GVHD (Fig. 3a–d). Of note, twin #1 but not twin #2 had received ATG previously before the transplant, and the donor and twin #2 were 2 years older when the transplant was performed on twin #2 relative to twin #1. Therefore, we are unable to conclude with complete certainty that the differences in clinical outcomes were solely related to the use of rabbit versus horse ATG in the conditioning regime. However, it is important to note that because twin #1 but not twin #2 had received ATG previously before the transplant as treatment for her aplastic anemia, she would have been expected to be the more immunosuppressed twin pre-transplant. This makes the chimerism differences more likely attributable to the type of ATG utilized during conditioning, as one would have expected to the more immunosuppressed twin to have faster donor T cell engraftment, which was not the case with twin #1. We theorize that the differences in the half-life of ATG likely accounted for the dramatic differences in the speed of donor T cell engraftment and the occurrence of and severity of GVHD observed between these patients. Rabbit ATG has a much longer half-life (29.8 days) compared to horse ATG (5.7 days) [15, 16]. As a consequence, rabbit ATG likely depleted transplanted donor T cells in vivo much more efficiently in twin #1 compared to twin #2 (who received horse ATG), which prevented acute GVHD but also dramatically delayed donor T cell engraftment, placing the patient at increased risk for graft rejection. Given its shorter half-life, horse ATG given to twin #2 was less effective in inducing in vivo T cell depletion of transplanted donor cells, which resulted in very rapid donor T cell engraftment with subsequent acute and chronic GVHD. A recent retrospective, non-randomized study comparing horse to rabbit ATG in addition to cyclophosphamide as conditioning for allogeneic HSCT patients with SAA reported similar observations, namely conditioning with rabbit ATG was more protective against acute and chronic GVHD than conditioning with horse ATG, with rabbit ATG being associated with a higher incidence of mixed chimerism. Recipients of rabbit ATG were also observed to have a higher incidence of viral and fungal infections [17].Fig. 2


Conditioning with rabbit versus horse ATG dramatically alters clinical outcomes in identical twins with severe aplastic anemia transplanted with the same allogeneic donor.

Vo PT, Pantin J, Ramos C, Cook L, Cho E, Kurlander R, Khuu H, Barrett J, Leitman S, Childs RW - J Hematol Oncol (2015)

Comparison of T cell chimerism between twins
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4487559&req=5

Fig2: Comparison of T cell chimerism between twins
Mentions: Here, we report data where syngeneic twins with MDS who underwent allogeneic transplantation from the same donor had dramatically different donor T cell engraftment profiles and transplant outcome as a consequence of using rabbit versus horse ATG in the preparative regimen (Fig. 2). Twin #1, who received rabbit ATG with her conditioning, had a post-transplant course which was associated with exceedingly low degrees of donor T cell engraftment and a declining reticulocyte count necessitating a subsequent infusion of donor PBSCs and T cells to avoid graft rejection. Remarkably, this patient did not achieve full donor T cell chimerism until day +352, never developed acute GVHD, and only experienced mild chronic oral GVHD which occurred after the PBSC boost. In contrast, twin #2 who received from the same donor virtually the identical number of transplanted donor CD34+ cells and a slightly lower number of transplanted CD3+ T cells, received horse ATG with the conditioning regimen and experienced very rapid and complete donor T cell chimerism which was associated with both acute GVHD and extensive chronic GVHD (Fig. 3a–d). Of note, twin #1 but not twin #2 had received ATG previously before the transplant, and the donor and twin #2 were 2 years older when the transplant was performed on twin #2 relative to twin #1. Therefore, we are unable to conclude with complete certainty that the differences in clinical outcomes were solely related to the use of rabbit versus horse ATG in the conditioning regime. However, it is important to note that because twin #1 but not twin #2 had received ATG previously before the transplant as treatment for her aplastic anemia, she would have been expected to be the more immunosuppressed twin pre-transplant. This makes the chimerism differences more likely attributable to the type of ATG utilized during conditioning, as one would have expected to the more immunosuppressed twin to have faster donor T cell engraftment, which was not the case with twin #1. We theorize that the differences in the half-life of ATG likely accounted for the dramatic differences in the speed of donor T cell engraftment and the occurrence of and severity of GVHD observed between these patients. Rabbit ATG has a much longer half-life (29.8 days) compared to horse ATG (5.7 days) [15, 16]. As a consequence, rabbit ATG likely depleted transplanted donor T cells in vivo much more efficiently in twin #1 compared to twin #2 (who received horse ATG), which prevented acute GVHD but also dramatically delayed donor T cell engraftment, placing the patient at increased risk for graft rejection. Given its shorter half-life, horse ATG given to twin #2 was less effective in inducing in vivo T cell depletion of transplanted donor cells, which resulted in very rapid donor T cell engraftment with subsequent acute and chronic GVHD. A recent retrospective, non-randomized study comparing horse to rabbit ATG in addition to cyclophosphamide as conditioning for allogeneic HSCT patients with SAA reported similar observations, namely conditioning with rabbit ATG was more protective against acute and chronic GVHD than conditioning with horse ATG, with rabbit ATG being associated with a higher incidence of mixed chimerism. Recipients of rabbit ATG were also observed to have a higher incidence of viral and fungal infections [17].Fig. 2

Bottom Line: Conventional therapies with immunosuppressive therapy or allogeneic hematopoietic stem cell transplantation (HSCT) are highly effective.HSCT can offer a greater outcome in younger patients who have an available HLA match-related donor.These agents are pharmacologically distinct, having significant differences in their pharmacokinetics and in vivo immunosuppressive effects [N Engl J Med 365(5):430-438, 2011].

View Article: PubMed Central - PubMed

Affiliation: Hematology Branch, National Heart Lung and Blood Institute (NHLBI), National Institute of Health (NIH), Bethesda, MD, USA. uyenphuong18@yahoo.com.

ABSTRACT
Severe aplastic anemia (SAA) is a rare disorder leading to bone marrow failure, which if left untreated, is invariably fatal. Conventional therapies with immunosuppressive therapy or allogeneic hematopoietic stem cell transplantation (HSCT) are highly effective. HSCT can offer a greater outcome in younger patients who have an available HLA match-related donor. Recent studies showing the addition of antithymocyte globulin (ATG) to the conditioning regimen improves engraftment and reduces the risk of graft-versus-host disease (GVHD).There are currently two ATG preparations in the USA, equine (or horse) and rabbit ATG. These agents are pharmacologically distinct, having significant differences in their pharmacokinetics and in vivo immunosuppressive effects [N Engl J Med 365(5):430-438, 2011]. Here, we report a case of two monozygotic twins with constitutional SAA that evolved to myelodysplastic syndrome (MDS) who both underwent allogeneic peripheral blood stem cell transplantation (PBSC) from the same single HLA antigen mismatched sibling donor with the only difference in the transplant regimen being the type of ATG used in the preparative regimen; one twin received horse ATG and the other received rabbit ATG during conditioning. This report emphasizes that dramatic differences in donor T cell chimerism and clinical outcomes including GVHD can occur as a consequence of the type of ATG that is utilized in the transplant conditioning regimen. These differences highlight that these agents should not be considered interchangeable drugs when used in this setting.

No MeSH data available.


Related in: MedlinePlus