Horse antithymocyte globulin (ATG) plus cyclosporine was found to be superior to rabbit ATG plus cyclosporine as a first-line treatment for severe aplastic anemia based on a randomized controlled trial. The hematologic response rate at 6 months was approximately half for rabbit ATG compared to horse ATG, resulting in about a 25% lower 3-year survival rate. Both regimens similarly depleted CD8+ T cells but rabbit ATG more profoundly depleted CD4+ T cells, including regulatory T cells, which may be detrimental to hematologic recovery. Horse ATG combined with cyclosporine remains the most effective first-line immunosuppressive treatment for severe aplastic
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Horse ATG Superior to Rabbit ATG for Aplastic Anemia
1. Horse versus Rabbit ATG
in Acquired Aplastic Anemia
Phillip Scheinberg, M.D., Olga Nunez, R.N., B.S.N., Barbara Weinstein, R.N.,
Priscila Scheinberg, M.S., Angélique Biancotto, Ph.D., Colin O. Wu, Ph.D.,
and Neal S. Young, M.D.
Dr.Govind Kendre
3rd yr Senior resident
6. Facts so far…
• Standard therapy- Horse ATG
• Rabbit ATG - More potent in depleting
peripheral blood lymphocytes
• Rabbit ATG induces the development of
regulatory T cells from normal T cells in tissue
culture, which should be beneficial in
suppressing a harmful immune response.
7. Study Patients and Oversight
• Older than 2 years of age
• December 2005 - July 2010
• Mark O. Hatfield Clinical Research Center of
the NIH, in Bethesda, Maryland
• The study was monitored by an external data
and safety monitoring board
• Government-sponsored study
• No commercial support
8. Inclusion criteria
• Severe aplastic anemia characterized by
– Bone marrow cellularity <30%
AND at least 2 of the following
– ANC < 500/ uL
– Platelet count < 20,000/ uL
– Absolute reticulocyte count < 60000
• ≥ 2 years old
• Weight ≥ 12 kg
9. Exclusion criteria
• Diagnosis of Fanconi’s anemia
• Evidence of a clonal disorder on cytogenetics
• Infection not adequately responding to appropriate
therapy
• Serologic evidence of HIV infection
• Moribund status or concurrent hepatic, renal, cardiac,
neurologic, pulmonary, infectious, or metabolic disease
severe enough to preclude tolerance to protocol
• History of carcinoma that is not considered cured
(except local cervical, basal cell, or squamous cell)
• Pregnancy
10. Immunosuppressive Regimens
1. Horse ATG(ATGAM, Pfizer) at 40 mg/kg/day for 4
days
2. Rabbit ATG at 3.5 mg/kg/day(Thymoglobulin,
Genzyme) for 5 days
3. Alemtuzumab 10 mg/day for 10 days
• Cyclosporine at a dose of 10 mg/kg/day BID
(15 mg/kg/day for children < 12 yr) from day 1 &
continued for at least 6 months in both the horse-
ATG and rabbit-ATG groups, with the dose
adjusted to maintain trough blood levels of 200
to 400 ng/ml
11. CRITERIA FOR RESPONSE
• 2 of the following values obtained on 2 serial
blood count measurement at least 1 week
apart at landmark time points (3, 6, and 12
months)
– ANC> 500/ uL
– Platelet count > 20,000/ uL
– Absolute reticulocyte count >60000
13. Study design
• After 16 patients were randomized to alemtuzumab,
accrual was discontinued (low response rate and early
deaths)
• The study continued as 1:1 randomization between
horse & rabbit ATG
• The primary endpoint was hematologic response
assessed at 6 months
• Responders in all groups were evaluated long-term for
secondary endpoints
• Non-responders in the horse ATG arm went off study
• Non-responders in rabbit ATG group & alemtuzumab
arm were allowed to cross-over with each other
18. Mean (±SE) Increase in Blood Counts in Patients with
Hematologic Improvement after Treatment
with Antithymocyte Globulin (ATG)
Among patients who had a response (41 patients in the horse-ATG group and 22 patients
in the rabbit-ATG group), there were similar increments in blood counts at 3 and 6 months.
26. Discussion
• Immunosuppression with ATG & CSA -often
the 1st therapy administered for severe
aplastic anemia
• Most published experience has involved the
horse formulation of the polyclonal antibody
27. Experience with Rabbit ATG
• In the past decade, rabbit ATG + CSA has gained in
popularity because of its activity in relapsed &
refractory SAA
• In some centers in the United States, rabbit ATG
has been used as the first therapy
• In Europe, Japan, and Latin America, rabbit ATG is
the only formulation currently available
• The reported experience with rabbit ATG plus CSA
as initial therapy for SAA is limited to
retrospective studies, with conflicting results
28. Other similar studies
• A phase 2 study in the US
– 13 patients with severe aplastic anemia
– A response to rabbit ATG was observed in 12 patients
(92%) at about 3 months after therapy
(Garg R, Faderl S, Garcia-Manero G, et al. Phase II study of rabbit anti-thymocyte
globulin, cyclosporine and granulocyte colony-stimulating factor in patients with
aplastic anemia and myelodysplastic syndrome. Leukemia 2009;23:1297-302.)
• A retrospective analysis in Brazil
– 71 patients showed a higher response rate at 6 months
among horse ATG (60%) than with rabbit ATG (35%), with a
survival benefit noted in the patients receiving horse ATG
(Atta EH, Dias DD, Marra VL, de Azevedo AM. Comparison between horse and
rabbit antithymocyte globulin as first-line treatment for patients with severe
aplastic anemia: a single-center retrospective study. Ann Hematol 2010;89:851-9.)
29. Other similar studies
• A retrospective study from Europe
– No significant difference was seen in the overall
response rate between horse ATG (49%) and rabbit
ATG (45%)
– The response rate of 49% with horse ATG was
markedly lower than reported response rates of 60 to
70% with this agent in large prospective studies in the
United States, Europe, and Japan
(Vallejo C, Montesinos P, Rosell A, et al. Comparison between
lymphoglobuline and thymoglobuline-based immunosuppressive
therapy as first-line treatment forpatients with aplastic anemia.
Blood 2009;114(22):3194. abstract)
30. Present study results
• In this randomized, prospective trial, rabbit ATG
plus cyclosporine was inferior to horse ATG plus
cyclosporine when administered as a first line
treatment
• The hematologic response rate with rabbit ATG
was about half that with horse ATG, which
translated into about a 25% lower survival rate at
3 years
• Despite a relatively short period of follow-up, the
rates of relapse and clonal evolution did not differ
significantly between the two groups
31. In vitro & in vivo differences
• Apparently similar manufacturing processes, but marked
differences in vitro and in vivo between the two preparations
• In human peripheral-blood mononuclear cells co-cultured
with different ATGs, an increase in the frequency of regulatory
T cells was observed with rabbit ATG but not with horse ATG
• Furthermore, a marked difference in gene-expression profile
was shown in human cells cultured with either horse or rabbit
ATG
• In humans, more prolonged lymphopenia follows rabbit ATG
administration, and patterns of viral reactivation have been
shown to differ between these two agents
33. Lot-to-lot variability
• Laboratory testing- No dissimilarity in cytotoxicity or antigen-
binding specificities among multiple lots of horse and rabbit
ATGs or among commercially available ATGs
• Over a period of several decades, the response rates with
horse ATG have been nearly identical, at an average of 62% &
with rabbit ATG to be stable, at about 33%
• Preparation of rabbit ATG involves many animals, less
variability would be expected in this formulation
• The kinetics of lymphocyte depletion with either agent were
consistent among the patients
• There were no significant differences in response rates among
patients treated with different lots of ATG in this study
34. Effect on T cells
• Horse and rabbit ATGs led to a similar
depletion of CD8+ cytotoxic T cells
• More profound depletion of CD4+ T cells after
the use of rabbit ATG
35. Inference
• The depletion of CD8+ T cells is linked to the
success of treatment with ATG (horse or
rabbit) but that the loss of CD4+ T cells after
the use of rabbit ATG may be detrimental
36. CD4 cells
• The CD4+ cell compartment is phenotypically
and functionally heterogeneous
• Contained within the large CD4+ cell
population are regulatory T cells, which
modulate immune responses
37. Effect on CD4 cells
• In the current study, the frequency of regulatory
T cells was higher after the use of rabbit ATG than
after the use of horse ATG (as predicted from
tissue-culture experiments),but this effect was
negated by the more potent depletion of CD4+ T
cells
• CD4+ cells have other positive effects on
hematopoiesis, and they may be important for
hematologic recovery as well as for the
promotion of tolerance in severe aplastic anemia
(as after stem-cell transplantation)
38. Profound immunosuppresion
• More prolonged lymphopenia after the use of
rabbit ATG might impair marrow recovery,
because stimulatory cytokines derived from T
cells are depleted
• The addition of MMF or sirolimus to horse
ATG + CSA has not achieved this goal, and the
use of more potent lymphocytotoxic agents
(rabbit ATG and alemtuzumab) in place of
horse ATG has had inferior results
39. Concluding remark
• Horse ATG combined with cyclosporine
appears to be the most effective first-line
immunosuppressive regimen for severe
aplastic anemia