Antithymocyte globulins for use in blood and marrow transplant (BMT)

Class and mode of action

Antithymocyte globulins (ATG) are polyclonal purified horse or rabbit antibodies against human lymphocytes that deplete the number of T lymphocytes.

Formulations

There are three commercially available formulations of antithymocyte globulin, as listed in the table below. The appropriate dosing of all three formulations is different, as protein compositions and concentrations vary depending on the source of the ATG used. Clinicians should therefore ensure that the dose prescribed is appropriate for the ATG product being administered.

Brand name	Source	Premedication	Serum sickness	Test dose	Filter required
ATGAM®	Horse	Yes	Yes	Yes	Yes
Thymoglobuline®	Rabbit	Yes	Yes	No	Yes
ATG-Fresenius S®	Rabbit	Yes	No*	No	No

*With shorter treatment periods of 7 days or less the incidence of serum sickness is low. With single high-dose therapy of ATG-Fresenius S^® serum sickness has not been observed.^r

Contraindications

• hypersensitivity to the active substance (i.e. rabbit proteins (Thymoglobuline^®), equine gamma globulin preparations (ATGAM^®)) or to any product excipients
• active acute or chronic infections, which would contraindicate any additional immunosuppression.

Precautions

• anaphylaxis
• severe or unremitting thrombocytopenia
• severe or unremitting leukopenia
• increased risk of CMV and EBV infection 
• increased risk of post-transplant lymphoproliferative disease (PTLD) 

Storage 

• Generally, reconstituted solutions should be stored between 2-8 degrees for no more than 24 hours. Local institution policies may differ. 

Incompatibilities 

• blood and blood derivatives 
• lipid solutions 
• avoid administering with other drugs or fluids via Y-site 
• refer to the Australian Injectable Drugs Handbook (AIDH) for further incompatibility information.

Venous access 

Where possible the preference is for ATG to be given via a central venous access device into a large vein to reduce the incidence of phlebitis and thrombosis. 

Premedication:

Administer suggested premedication (alternative antihistamines or corticosteroids may be administered):

• paracetamol 1000 mg PO
• promethazine 12.5 to 25 mg IV
• methylprednisolone 1 to 2 mg/kg IV.

If a patient has a hypersensitivity reaction - stop the infusion and have the patient reviewed immediately by a medical officer. A systemic reaction such as a generalised rash, tachycardia, dyspnoea, hypotension, or anaphylaxis precludes any additional administration of ATGAM^®.

Note: It is the consensus of the eviQ BMT Reference Committee that the following doses are utilised.

Formulation	Dose	Day to be administered	Administration (via IV infusion)
ATGAM ®	10 mg/kg (sibling) 20, 30 or 40 mg/kg (unrelated)	-5, -4, -3, -2 and -1*	over 4 to 6 hours IV giving set with 0.2 to 1.0 micron in-line filter must be used for ATGAM ® (to remove any precipitate) monitor blood pressure, pulse, temperature and respiratory rate every 30 minutes for the first hour, then hourly until 3 to 4 hours after the completion of the infusion flush with 100 mL of sodium chloride 0.9%
Thymoglobuline®	0.5 mg/kg	-3	over 6 hours initially 0.22 micron in-line filter recommended for administration (to remove any precipitate) baseline observations prior to infusion if well tolerated the rate may be increased for subsequent infusions but the total dose should not be infused over less than 4 hours infusions reactions are common monitor blood pressure, pulse, temperature and respiratory rate every 30 minutes for the first hour, then hourly until 3 to 4 hours after the completion of the infusion if hypotension or dyspnoea occurs, stop infusion and consult medical staff (rarely reported in the literature) when symptoms completely subside restart the infusion at a slower rate
	2 mg/kg	-2
	2 mg/kg	-1
ATG-Fresenius S ®	10 mg/kg (sibling) 20 mg/kg (unrelated)	-1	over ~ 2 to 4 hours first 30 minutes to be infused at a slower rate baseline observations prior to infusion monitor blood pressure, pulse, temperature and respiratory rate every 30 minutes for the first hour, then hourly until 3 to 4 hours after the completion of the infusion if hypotension or dyspnoea occurs, stop infusion and consult medical staff (rarely reported in the literature)

* The optimal dosing schedule of ATGAM^® varies widely in the literature. Variables such as age, stem cell source, donor type and the planned conditioning protocol make it difficult to delineate the optimal dose.

Skin testing

Although there is controversy regarding the role of skin testing for ATGAM^® and practise between units differs, we strongly advocate for skin testing due to its ability to guide initial infusion rates^r. As skin testing has not been demonstrated to be predictive of severe allergic reactions, many units do not perform skin testing prior to administration of ATGAM^®. Where skin testing is done the following practise is recommended:

No premedication to be administered prior to skin test.

Use an epicutaneous (prick) testing with undiluted ATG. If the patient does not show a wheal ten minutes after pricking, proceed to:

• Intradermal testing with 0.02 mL of a 1:1000 v/v (volume/volume) saline dilution of ATG on the inner aspect of one forearm, with a separate saline control injection of similar volume on the other arm
• Read the result at ten minutes
• A wheal at the ATG site greater than or equal to 3 mm larger in diameter than that at the saline control site (or a positive prick test) suggests clinical sensitivity and an increased possibility of a systemic allergic reaction should the drug be used intravenously
• A severe reaction or anaphylaxis is a contraindication to proceeding with treatment. However, the predictive nature of the skin test is not clinically proven. Allergic reactions such as anaphylaxis have occurred in patients whose skin test is negative. In the presence of a locally positive skin test to ATGAM^®, serious consideration to alternative forms of therapy should be given.

Immune-mediated reactions:

Anaphylaxis, infusion associated reactions (IAR), cytokine release syndrome and serum sickness (see below) are rare but potentially fatal reactions which have been reported. Reactions such as flushing, rash, erythema, oedema, dyspnoea with or without bronchospasm and cough are commonly observed during and after the administration.Cytokine release related symptoms include: fever, chills, headache, nausea, vomiting, tachycardia and circulatory changes. These reactions usually respond well to treatment.

Management

Prophylactic medication may be administered to alleviate these symptoms. Reduction in infusion rates may minimise the incidence of reactions. The occurrence of anaphylaxis/anaphylactic shock requires immediate termination of the infusion and medical treatment.

Serum sickness:

An immune-complex mediated reaction, may occur in patients after treatment with antithymocyte globulin (ATG). Serum sickness presents with significant morbidity but is usually self-limiting or resolves rapidly with corticosteroid treatment. Symptoms usually develop 7 to 21 days after the start of treatment with ATG. However, some patients may develop symptoms in 1 to 3 days if they have previously been exposed to ATG. 

Management

Prophylaxis with corticosteroids may reduce the frequency of this reaction. If serum sickness does develop:

• high dose corticosteroids may be prescribed as treatment for severe cases
• antihistamines and corticosteroid creams or ointments may relieve the discomfort of itching and rash.

Infection:

Infections, reactivation of infections such as cytomegalovirus (CMV) and sepsis have been reported after ATG administration. There is increased risk of infection especially when ATG is given in combination with immunosuppressive agents.

Management

Close monitoring of patient and appropriate anti-infective prophylaxis are recommended. Appropriate anti-infective therapy should be given if infection occurs.

Haematological effects:

Thrombocytopenia and leukopenia are common and transient adverse effects. Anaemia is commonly observed after administration of ATG-Fresenius S and fulminant haemolysis has been reported rarely with ATGAM administration for which transfusion of erythrocytes may be required. Platelet and white cell counts generally return to normal without interrupting therapy and with transfusions.

Management

Monitor blood counts prior to and throughout ATG therapy. Dose reductions may be required for concomitant immunosuppressive and/or ATG therapy.

Malignancy:

Malignancies including, but not limited to post-transplant lymphoproliferative disease (PTLD) and other lymphomas as well as solid tumours have been rarely reported with Thymoglobuline^® and ATG-Fresenius S^®. These adverse events were always associated with a combination of multiple immunosuppressive agents.

Management

Close monitoring of patient throughout and after the completion of treatment is recommended.

Vaccinations 

Live vaccinations should not be administered to patients being treated with ATGAM® for the duration of their therapy and for 6 months after treatment with ATGAM®. Patients should be advised that other vaccinations might be less efficacious. 

Live vaccines are contraindicated in immunocompetent persons and cancer patients receiving immunosuppressive therapy and/or those who have poorly controlled malignant disease. 

Management

Refer to the recommended schedule of vaccination for immunocompromised persons, as outlined in the Australian Immunisation Handbook 10th edition (updated 2017).