Literature review on Antithymocyte globulin associated hypersensitivity reaction -Adverse Drug Reaction

1. Anti-Thymocyte globulin [Equine] associated hypersensitivity
reaction
8/5/2021 Department of Clinical Pharmacology 1
Dr. Miteshkumar Maurya
Assistant Professor
Department of Clinical Pharmacology
Seth GSMC & KEMH

2. Polyclonal IgG component prepared & collected from serum
of rabbit/horse/ goat/pig that have been immunized against
human thymocytes or other lymphocytes.
In past, produced as anti-lymphocyte serum [ALS] that was a
cytotoxic heterologous antibody directed against lymphoid
cells.
Russian immunologist Élie Metchnikoff first produced it by
injecting rabbit lymph node cells into guinea pigs in 1899.
Levey and Medawar showed ALS produced in rabbit against
mouse thymus cells had immunosuppressive effects.
Anti-thymocyte globulin (ATG)- History
Russian immunologist
Élie Metchnikoff [1845-1916]
Nobel Prize in Physiology or
Medicine[1908] in recognition of
work on immunity with Paul
Ehlrich
8/5/2021 Department of Clinical Pharmacology 2

3. 8/5/2021 Department of Clinical Pharmacology 3
Mechanisms of T-cell depletion by anti-thymocyte globulin [ATG]
Complement-dependent lysis
Selective elimination of in vivo activated T-cells in organ transplantation
Opsonization & phagocytosis by lymphocytes in liver, spleen & lung
macrophages
Apoptotic cell death with subsequent phagocytosis by macrophages
[lymphoid tissues of spleen & in lymph nodes] - main mechanism of
depletion
Peripheral T-cell counts restores graduallyafter cessation of Rabbit anti-thymocyte globulin,
with a partial increase at 3 months.

4. 8/5/2021 Department of Clinical Pharmacology 4
Types
of
Anti-thymocyte
globulin
–
rabbit
&
equine

5. 8/5/2021 Department of Clinical Pharmacology 5
US FDA approved Dosage & administration for anti-thymocyte globulin [IgG]
Indication -acute rejection in patients receiving a
kidney transplant/ in conjunction with concomitant
immunosuppression
Dose Regimen [i.v infusion]
Prophylaxis 1.5 mg/kg of body weight administered
daily for 4 to 7 days
Treatment 1.5 mg/kg of body weight administered
daily for 7 to 14 days
Indication –renal transplant recipients and aplastic
anemia
Dose Regimen [i.v infusion]
Renal allograft recipients to prevent first graft
rejection episode [concomitant with Azathioprine &
corticosteroids]
10-30 mg/kg body weight in adults daily while 5-25
mg/kg body weight daily in pediatric population.
[Rx- 10-15 mg/kg daily / delay-15mg/kg daily-for 14 days
Aplastic Anemia [concomitant with cyclosporine &
corticosteroids]
10-20 mg/kg daily for 8 to 14 days. Additional alternate
day therapy up to total 21 doses can be administered.
Rabbit ATG, r-ATG, Thymoglobulin
Equine ATG, h-ATG, Thymogam, Atgam

6. 8/5/2021 Department of Clinical Pharmacology 6
Diagnostic criteria for aplastic anemia [Camitta criteria]
Incidence of aplastic anemia varied from 10- 52.7% among patients with pancytopenia.

7. 8/5/2021 Department of Clinical Pharmacology 7
Treatment modalities for aplastic anemia
Allogenic
Hemopoietic
Stem cell
transplantation
[HSCT]- Young
patients with HLA
matched donor
Bone marrow
transplantation
[superior over
PBPC]
Peripheral blood
progenitor cells
[PBPC] with
granulocyte-
colony
stimulating factor
(G-CSF)
Anti-thymocyte
globulin with
cyclosporin –
decrease
cGVHD[chronic
graft versus host
disease]
Severe acquired aplastic anemia, hematopoietic failure is the result of immune-mediated
destruction of bone marrow stem and progenitor cells.

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ClinicalTrials.gov number, NCT00260689.

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Inclusion Criteria
Exclusion Criteria
1. Severe aplastic anemia characterized by bone marrow cellularity less than 30% (excluding lymphocytes) and
at least two of the following:
• Absolute neutrophil count less than 500/microliter
• Platelet count less than 20,000/microliter
• Absolute reticulocyte count less than 60,000/microliter
2. Age greater than or equal to 2 years old & weight greater than 12 kg
1. Diagnosis of Fanconi's anemia or evidence of a clonal disorder on cytogenetics.
2. Prior immunosuppressive therapy with ATG, ALG, alemtuzumab, or high dose cyclophosphamide.
3. Infection not responding to Rx or Serologic evidence of HIV infection.
4. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease
[death within 7-10 days is likely]
5. Potential subjects with cancer who are on active chemotherapeutic treatment / take drugs with
hematological effects
6. Current pregnancy or unwillingness to take OCP or refrain from pregnancy if of childbearing potential.
7. Not able to understand the investigational nature of the study or give informed consent

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• Absolute neutrophil count > 500/ μL
• Platelet count > 20,000/ μL
• Reticulocyte count > 60,000/ μL
• Improvement in counts that are dependent upon exogenously administered growth
factors or transfusion will not be considered as fulfilling response criteria.
Primary outcome measures
Hematologic response at 3 month, 6 month and 12 month time duration
Hematologic response is defined as subjects having blood counts in Severe Aplastic Anemia,
equivalent to two of following values obtained on two serial blood count measurements at
least one week apart at landmark time points (3, 6 and 12 months)

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RCTs on Severe Aplastic anemia patients at single facility
Study duration: Dec 2005-july 2010
60 patients Rx with
rabbit ATG
60 patients Rx with
horse ATG
Outcome- Hematologic
response[HR] at 6 months
[blood counts]
Outcome- Hematologic response
[HR] at 6 months [blood counts]
HR6- 37% [95% CI-24 to 49]
OS3-76% (95% CI, 61 to 95)
HR6- 68% [95% CI-56 to 80]
OS3- 96% (95% CI, 90 to 100)
HR, P<0.001
OS3, P<0.04

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ATG + Cyclosporin protocol for severe aplastic anemia
After giving test dose, start ATG [equine] 40 mg/kg/day for 4 days OD [d1-d4]
Tab. Prednisolone 1 mg/kg/day [d5-d13], taper dose [d14-d18], stop by d19
Tab. Cyclosporine 5mg/kg/day on d18 onwards [TDM from d32]
To monitor Blood Pressue, Complete Blood Counts, Serum Creatinine daily during
ATG therapy
Prophylaxis -Tab. Valciclovir 500 mg OD, Tab. Septran DS OD [Mon./Wed./Fri.],Tab.
Fluconazole 4mg/kg OD for 3 months.
Absolute Lymphocyte Count monitoring at regular intervals

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Parameters Horse [equine] Anti-thymocyte globulin
[standard therapy]
Rabbit Anti-thymocyte globulin [RATG]-
preferred
Potent with respect to
depleting peripheral blood
lymphocytes [CD3 T-cell
lympopenia]
less potent more potent
Reversing acute rejection
episodes & preventing
recurrent rejection
episodes in renal transplant
recipients.
76% 88%
Hematological response &
overall survival [RCTs]
Better [68%] Poor [37%]
KIM J.M et al study-
delayed graft function &
graft survival
lower higher
Choice between equine [h-ATG] & rabbit [r-ATG]anti-thymocyte globulin

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Summary
Anti-Thymocyte globulin is commonly used immunosuppressing agent from equine or
rabbit origin.
Equine Anti-thymocyte globulin has shown superiorty over the rabbit ATG in hematology
clinical trials for aplastic anemia [hematologic response] while rabbit ATG proved
superior over equine ATG in renal Tx recipients [renal graft outcomes].
Adverse drug reactions such as chronic Graft versus host disease [cGVHD] are result of
therapeutic [ATG] failure while other infusion/hematologic related complications could
be either due to ATG or apalstic disease that need adequate evaluation.

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Thank You