Antithymocyte globulin for graft versus host disease (GVHD) prophylaxis 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 in the peripheral circulation.

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.

*Previously known as ATG-fresenius^®. This product is only available via the SAS. 

**The incidence of serum sickness is low with shorter treatment periods of 7 days or less. Serum sickness has not been observed with single high-dose therapy of ATG-Grafalon^®.^r

Contraindications

• known hypersensitivity to the active substance (i.e. rabbit proteins (Thymoglobuline^®), equine gamma globulin preparations (ATGAM^®)) or to any product excipients 
• previous severe systemic reaction during therapy. The same ATG formulation should not be resumed
• active acute or chronic infections, which would contraindicate any additional immunosuppression.

Precautions

• risk of a immune mediated reaction e.g. anaphylaxis or cytokine release syndrome (CRS) 
• severe or unremitting thrombocytopenia
• severe or unremitting leukopenia
• increased susceptibility to Cytomegalovirus (CMV) and Epstein Barr Virus (EBV) infections 
• increased risk of post-transplant lymphoproliferative disease (PTLD) 
• early post-transplant use of granulocyte colony-stimulating factors (G-CSF) in ATG-containing protocols associated with increased nonrelapse mortality, risk of viral infection and decreased overall survival.^rr Consider G-CSF use on an individual patient basis only where benefits outweigh potential risks.

Storage 

• reconstituted solutions should be administered as soon as possible 
• storage after dilution should not exceed 24 hours from the time of preparation to the completion of administration
• store between 2-8 degrees, do not freeze or shake and rabbit source needs to be protected from light

Incompatibilities 

• blood and blood derivatives 
• lipid solutions 
• avoid administration with other drugs or fluids via Y-site 
• refer to the Australian Injectable Drugs Handbook (AIDH) opens in a new tab or window 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 high-flow vein to reduce the incidence of phlebitis and thrombosis. 

Infusion reactions:

Anaphylaxis has been reported with antithymocyte globulins. If anaphylaxis or other severe hypersensitivity reaction occurs, the ATG infusion should be discontinued immediately and appropriate medical interventions initiated. A reaction may occur immediately after commencement, during, or shortly after the infusion.

Observations and monitoring:

• baseline observations of temperature, blood pressure, respiratory rate and heart rate should be performed prior to infusion
• the patient should be monitored closely for adverse events during and for 3 to 4 hours after completion of the infusion; for both initial and subsequent infusions. Medical personal and emergency equipment should be readily available during and post each infusion

Premedication:

Administer premedication 30-60 minutes prior to each ATG infusion:

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

Alternative antihistamines or corticosteroids may be administered.

Dosing:

Note: The following doses and schedules are based on eviQ BMT Reference Committee consensus, however, alternative doses and schedules may be given - see individual protocols for more information.

* 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 for ATGAM^®

Intradermal skin testing may be considered prior to the administration of the initial dose of ATGAM^® due to its ability to guide initial infusion rates.^r However there is controversy regarding the role of skin testing for ATGAM^® as it has not been demonstrated to be predictive of severe allergic reactions. 

Skin testing procedure

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. In patients who have previously being exposed to ATG symptoms may develop within 1 to 7 days and the illness has a more severe and explosive onset^rrr.

The cardinal features of serum sickness are rash, fever and polyarthralgias or polyarthritis which begin one to two weeks after drug exposure^r.

Management

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

• high dose corticosteroids (i.e prednisone at 0.5 to 1mg/kg)^r may be prescribed as treatment for severe cases
• antihistamines and corticosteroid creams or ointments may relieve the discomfort of itching and rash.

Infection:

Local and systemic infections, reactivation of infections such as cytomegalovirus (CMV) and Epstein Barr Virus (EBV), sepsis or infectious complications 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.

EBV and CMV PCR monitoring post-transplant weekly until day 100^rr. 

Consider adenovirus, HHV6 and HHV8 PCR in persistently febrile patients^rr.

Haematological effects:

Thrombocytopenia and leukopenia are common and transient adverse effects. Anaemia is commonly observed after administration of ATG-Grafalon^® and fulminant haemolysis has been reported rarely with ATGAM^® administration for which red blood cell transfusion is required. Thrombocytopenia is usually transient and is managed with transfusions as required. Platelet and white cell count usually returns to normal levels. 

Management

Monitor blood counts pre, during and post ATG therapy. Blood product support as required. 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-Grafalon^®. These adverse events are 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 immune incompetent persons and 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 opens in a new tab or window .

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Bibliography

Admiraal, R., S. Nierkens, M. A. de Witte, et al. 2017. "Association between anti-thymocyte globulin exposure and survival outcomes in adult unrelated haemopoietic cell transplantation: a multicentre, retrospective, pharmacodynamic cohort analysis." Lancet Haematol 4(4):e183-e191.

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BACKGROUND: Anti-thymocyte globulin (ATG) is used to prevent graft-versus-host disease (GvHD) after allogeneic haemopoietic cell transplantation (HCT). However, ATG can also cause delayed immune reconstitution of T cells, negatively affecting survival. We studied the relation between exposure to ATG and clinical outcomes in adult patients with acute leukaemia and myelodysplastic syndrome. METHODS: We did a retrospective, pharmacokinetic-pharmacodynamic analysis of data from patients with acute lymphoid leukaemia, acute myeloid leukaemia, or myelodysplastic syndrome receiving their first T-cell repleted allogeneic peripheral blood stem cell HCT with ATG (thymoglobulin) as part of non-myeloablative conditioning from March 1, 2004, to June 1, 2015. Patients received a cumulative intravenous dose of 8 mg/kg divided over 4 days, starting on day -8 before HCT. Active ATG concentrations were measured using a validated bioassay and pharmacokinetic exposure measures (maximum concentration, concentration at time of infusion of the graft, time to reach a concentration of 1 arbitary unit [AU] per day/mL, area under the curve [AUC], and the AUC before and after HCT) were calculated with a validated population pharmacokinetic model. The main outcome of interest was 5-year overall survival, defined as days to death from any cause or last follow-up. Other outcomes were relapse-related mortality, non-relapse mortality, event-free survival, acute and chronic GvHD, and assessment of current and optimum dosing. We used Cox proportional hazard models and Fine-Gray competing risk models for the analyses. FINDINGS: 146 patients were included. ATG exposure after HCT was shown to be the best predictor for 5-year overall survival. Optimum exposure after transplantation was determined to be 60-95 AU per day/mL. Estimated 5-year overall survival in the group who had optimum exposure (69%, 95% CI 55-86) was significantly higher than in the group who had below optimum exposure (32%, 20-51, p=0.00037; hazard ratio [HR] 2.41, 95% CI 1.15-5.06, p=0.020) and above optimum exposure (48%, 37-62, p=0.030; HR 2.11, 95% CI 1.04-4.27, p=0.038). Patients in the optimum exposure group had a greater chance of event-free survival than those in the below optimum exposure group (HR 2.54, 95% CI 1.29-5.00, p=0.007; HR for the above optimum group: 1.83, 0.97-3.47, p=0.063). Above-optimum exposure led to higher relapse-related mortality compared with optimum exposure (HR 2.66, 95% CI 1.12-6.31; p=0.027). Below optimum exposure increased non-relapse mortality compared with optimum exposure (HR 4.36, 95% CI 1.60-11.88; p=0.0040), grade 3-4 acute GvHD (3.09, 1.12-8.53; p=0.029), but not chronic GvHD (2.38, 0.93-6.08; p=0.070). Modelled dosing based on absolute lymphocyte counts led to higher optimum target attainment than did weight-based dosing. INTERPRETATION: Exposure to ATG affects survival after HCT in adults, stressing the importance of optimum ATG dosing. Individualised dosing of ATG, based on lymphocyte counts rather than bodyweight, might improve survival chances after HCT.

Baron, F., M. Mohty, D. Blaise, et al. 2017. "Anti-thymocyte globulin as graft-versus-host disease prevention in the setting of allogeneic peripheral blood stem cell transplantation: a review from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation." Haematologica 102(2):224-234.

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Allogeneic hematopoietic stem cell transplantation is increasingly used as treatment for patients with life-threatening blood diseases. Its curative potential is largely based on immune-mediated graft-versus-leukemia effects caused by donor T cells contained in the graft. Unfortunately, donor T cells are also the cause of graft-versus-host disease. The vast majority of human leukocyte antigen-matched allogeneic hematopoietic stem cell transplants are nowadays carried out with peripheral blood stem cells as the stem cell source. In comparison with bone marrows, peripheral blood stem cells contain more hematopoietic stem/progenitor cells but also one log more T cells. Consequently, the use of peripheral blood stem cells instead of bone marrow has been associated with faster hematologic recovery and a lower risk of relapse in patients with advanced disease, but also with a higher incidence of chronic graft-versus-host disease. These observations have been the basis for several studies aimed at assessing the impact of immunoregulation with anti-thymocyte globulin on transplantation outcomes in patients given human leukocyte antigen-matched peripheral blood stem cells from related or unrelated donors. After a brief introduction on anti-thymocyte globulin, this article reviews recent studies assessing the impact of anti-thymocyte globulin on transplantation outcomes in patients given peripheral blood stem cells from human leukocyte antigen-matched related or unrelated donors as well as in recipients of grafts from human leukocyte antigen haploidentical donors.

Kekre, N., Y. Zhang, M. J. Zhang, et al. 2017. "Effect of antithymocyte globulin source on outcomes of bone marrow transplantation for severe aplastic anemia." Haematologica 102(7):1291-1298.

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For treatment of severe aplastic anemia, immunosuppressive therapy with horse antithymocyte globulin results in superior response and survival compared with rabbit antithymocyte globulin. This relative benefit may be different in the setting of transplantation as rabbit antithymocyte globulin results in more profound immunosuppression. We analyzed 833 severe aplastic anemia transplants between 2008 and 2013 using human leukocyte antigen (HLA)-matched siblings (n=546) or unrelated donors (n=287) who received antithymocyte globulin as part of their conditioning regimen and bone marrow graft. There were no differences in hematopoietic recovery by type of antithymocyte globulin. Among recipients of HLA-matched sibling transplants, day 100 incidence of acute (17% versus 6%, P<0.001) and chronic (20% versus 9%, P<0.001) graft-versus-host disease were higher with horse compared to rabbit antithymocyte globulin. There were no differences in 3-year overall survival, 87% and 92%, P=0.76, respectively. Among recipients of unrelated donor transplants, acute graft-versus-host disease was also higher with horse compared to rabbit antithymocyte globulin (42% versus 23%, P<0.001) but not chronic graft-versus-host disease (38% versus 32%, P=0.35). Survival was lower with horse antithymocyte globulin after unrelated donor transplantation, 75% versus 83%, P=0.02. These data support the use of rabbit antithymocyte globulin for bone marrow transplant conditioning for severe aplastic anemia.

Bacigalupo, A. 2017. "How I treat acquired aplastic anemia." Blood 129(11):1428-1436.

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Acquired severe aplastic anemia (SAA) is a rare hematologic disease associated with significant morbidity and mortality. Immune destruction of hemopoietic stem cells plays an important role in pathogenesis, as shown by successful treatment with immunosuppressive agents, leading to transfusion independence or complete recovery of peripheral blood counts in a proportion of patients. Growth factors can be combined with immunosuppressive therapy (IST) and may improve response rates, as recently shown with thrombopoietin analogs. Anabolic steroids may still play a role in combination with IST. The problem with IST is failure to respond and the development of late clonal disorders. Bone marrow transplantation (BMT) is the other therapeutic option: a matched sibling donor remains the best choice. For patients lacking a matched family donor, unrelated donors can be readily found, although mostly for patients of Caucasian origin. Other BMT options include unrelated cord blood or mismatched family donors. Acute and chronic graft-versus-host disease remain important complications of BMT. Patient age is a strong predictor of outcome for both IST and BMT, and must be considered when designing therapeutic strategies. Early diagnosis and treatment, as well as long-term monitoring, remain crucial steps for successful treatment of SAA.

Ruggeri, A., Y. Sun, M. Labopin, et al. 2017. "Post-transplant cyclophosphamide versus anti-thymocyte globulin as graft- versus-host disease prophylaxis in haploidentical transplant." Haematologica 102(2):401-410.

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Severe graft-versus-host disease is a major barrier for non-T-cell-depleted haploidentical stem cell transplantation. There is no consensus on the optimal graft-versus-host disease prophylaxis. This study compared the two most commonly used graft-versus-host disease prophylaxis regimens (post-transplant cyclophosphamide-based vs. the anti-thymocyte globulin-based) in adults with acute myeloid leukemia reported to the European Society for Blood and Bone Marrow Transplantation. A total of 308 patients were analyzed; 193 received post-transplant cyclophosphamide-based regimen and 115 anti-thymocyte globulin-based regimen as anti-graft-versus-host disease prophylaxis. The post-transplant cyclophosphamide-based regimen was more likely to be associated to bone marrow as graft source (60% vs. 40%; P=0.01). Patients in the post-transplant cyclophosphamide-based regimen group had significantly less grade 3-4 acute graft-versus-host disease than those in the anti-thymocyte globulin-based group (5% vs. 12%, respectively; P=0.01), comparable to chronic graft-versus-host disease. Multivariate analysis showed that non-relapse mortality was lower in the post-transplant cyclophosphamide-based regimen group [22% vs. 30%, Hazard ratio (HR) 1.77(95%CI: 1.09-2.86); P=0.02] with no difference in relapse incidence. Patients receiving post-transplant cyclophosphamide-based regimen had better graft-versus-host disease-free, relapse-free survival [HR 1.45 (95%CI: 1.04-2.02); P=0.03] and leukemia-free survival [HR 1.48 (95%CI: 1.03-2.12); P=0.03] than those in the anti-thymocyte globulin-based group. In the multivariate analysis, there was also a trend for a higher overall survival [HR 1.43 (95%CI: 0.98-2.09); P=0.06] for post-transplant cyclophosphamide-based regimen versus the anti-thymocyte globulin-based group. Notably, center experience was also associated with non-relapse mortality and graft-versus-host disease-free, relapse-free survival. Haplo-SCT using a post-transplant cyclophosphamide-based regimen can achieve better leukemia-free survival and graft-versus-host disease-free, relapse-free survival, lower incidence of graft-versus-host disease and non-relapse mortality as compared to anti-thymocyte globulin-based graft-versus-host disease prophylaxis in patients with acute myeloid leukemia.

Killick, S. B., N. Bown, J. Cavenagh, et al. 2016. "Guidelines for the diagnosis and management of adult aplastic anaemia." Br J Haematol 172(2):187-207.

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Atta, E. H., D. C. de Oliveira, L. F. Bouzas, et al. 2014. "Less graft-versus-host disease after rabbit antithymocyte globulin conditioning in unrelated bone marrow transplantation for leukemia and myelodysplasia: comparison with matched related bone marrow transplantation." PLoS One 9(9):e107155.

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One of the major drawbacks for unrelated donor (UD) bone marrow transplantation (BMT) is graft-versus-host disease (GVHD). Despite results from randomized trials, antithymocyte globulin (ATG) is not routinely included for GVHD prophylaxis in UD BMT by many centers. One of ways to demonstrate the usefulness of rabbit ATG in UD BMT is to evaluate how its results approximate to those observed in matched related (MRD) BMT. Therefore, we compared the outcomes between UD BMT with rabbit ATG (Thymoglobulin) for GVHD prophylaxis (n = 25) and MRD BMT (n = 91) for leukemia and myelodysplasia. All but one patient received a myeloablative conditioning regimen. Grades II-IV acute GVHD were similar (39.5% vs. 36%, p = 0.83); however, MRD BMT recipients developed more moderate-severe chronic GVHD (36.5% vs. 8.6%, p = 0.01) and GVHD-related deaths (32.5% vs. 5.6%, p = 0.04). UD BMT independently protected against chronic GVHD (hazard ratio 0.23, p = 0.04). The 6-month transplant-related mortality, 1-year relapse incidence, and 5-year survival rates were similar between patients with non-advanced disease in the MRD and UD BMT groups, 13.8% vs. 16.6% (p = 0.50), 20.8% vs. 16.6% (p = 0.37), and 57% vs. 50% (p = 0.67), respectively. Stable full donor chimerism was equally achieved (71.3% vs. 71.4%, p = 1). Incorporation of rabbit ATG in UD BMT promotes less GVHD, without jeopardizing chimerism evolution, and may attain similar survival outcomes as MRD BMT for leukemia and myelodysplasia especially in patients without advanced disease.

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