Management ATG (SIRS)

Currently horse and rabbit anti-lymphoglobulins (ATLG) or antithymocyte globulin (ATG) is available; the main, although not exclusive, use is for the treatment of aplastic anemia (horse) and for GVHD prophylaxis (rabbit).


ATLG/ATG Infusion Protocol (See
.1) ATLG/ATG infusion should be performed in trained centers. Standard hygienic handling of the injection site, careful evaluation of the infusion speed, and appropriate choice of the venous access are crucial. Medical personnel should carefully watch over patients for adverse events not only during but also after infusion.
During administration, the patient needs to be monitored for symptoms related to infusion reactions or anaphylaxis. The first dose should be administered at a reduced speed for the first 30 min. If no symptoms of intolerance occur, infusion rate may be increased. In case of anaphylactic or anaphylactoid reactions, physicians must be prepared to promptly manage this event, and appropriate medical treatment has to be implemented.
A central venous catheter is preferred, although a peripheral large high-flow access may be acceptable, if a central line is not available. Thrombophlebitis is the major risk when a peripheral vein is used. The availability of a highflow access is important in case of treatment of infusion reactions.
Premedication is mandatory in order to improve systemic and local tolerance (see later). Stability, compatibility, and dilution are different for each product, and specific manufacturer recommendations should be followed carefully.
Preinfusion intraepidermal tests are not yet validated for rabbit ATG but, according to manufacturer indications, are recommended for horse ATLG.
-Although standard infusion time is between 4 and 12 h, a longer administration time correlates with milder side effects, thus making infusions of 12 h highly advised.
The currently used doses of ATLG/ATG are calculated and validated in clinical trials, according to body weight. A strong rationale and some preliminary data (Admiraal et al. 2017) suggest that calculating the ATG/ATLG dose according to the cellular target, i.e., the number of total lymphocyte before infusion of the first dose, can provide the optimal drug exposure and therefore maximize the benefit (GVHD decrease) over the potential risks (increase of relapses and infections). Since ATLG and ATG are different preparations arising from different manufacturing processes and different pulsed antigens, no dose equivalence can be established.
Even if the NCI Terminology Criteria for Adverse Events (CTCAE) use different scales for grading reactions to infusion of chemotherapy and allergic/anaphylaxis reactions, there are no specific symptoms enabling to distinguish "standard" infusion reaction from an allergic one that can evolve to anaphylaxis.
Anaphylaxis and acute allergic reactions are based on IgE effect and histamine release by mastocytes, but the vast majority of symptoms can be Anaphylaxis: severe anaphylaxis, always. De-sensitization protocols: not validated SIRS: depending on grading and clinical evaluation of pros and cons. In case of rechallenge, more stringent monitoring is required attributed to the cytokine release syndrome (CRS) and are generally reversible. CRS is a form of systemic inflammatory response syndrome (SIRS) (Matsuda and Hattori 2006;Balk 2014). CRS can follow not only ATG/ATLG infusion but also chemotherapy, MoAb (Remberger et al. 1999;Feng et al. 2014), bispecific antibodies, or CAR-T cell therapies (Lee et al. 2014). All these (both allergic and nonallergic, such as CRS) are infusion reactions. Serum sickness is a hypersensitivity phenomenon that can develop after 5-15 days after the infusion, and it is well responsive to steroid treatment.

SIRS
SIRS is a clinical syndrome due to dysregulated inflammation. SIRS may occur in several conditions, such as infection, autoimmune disorders, vasculitis, thromboembolism, chemotherapy infusion, surgery, and burns. The denomination originates from changes of some parameters (temperature, heart and respiratory rates, and white blood cell count) occurring after infection/ sepsis according to Bone (Bone et al. 1992). A pediatric version tailored on patient age is also available (Goldstein 2005). More recently, some authors (Lee et al. 2014) revised the classification of the cytokine release syndrome according to the treatment required (oxygen, vasopressors, organ toxicity).

Risk Factors for SIRS
SIRS after ATLG/ATG infusion cannot be predicted and the risk factors are not well known.
The binding of ATLG/ATG to the surface of target cells (lymphocytes, monocytes, dendritic cells) elicits cytokine production and systemic inflammation (Bone et al. 1992).
Thus, that the higher the number of lymphocytes at the moment of the (first) infusion, the more likely is the risk of systemic activation of inflammation and then SIRS.
Accordingly, RIC regimens are reported to be associated with greater cytokine release syndrome (Remberger and Sundberg 2004) because of the likely higher number of residual lymphocytes in RIC in comparison with MAC regimens.

Prophylaxis
ATLG/ATG infusion reactions can be reduced in frequency and severity by two factors: premedication and speed of infusion. Premedication is performed with steroids, antihistamine, and acetaminophen. The optimal schedule of premedication is not yet well established. Doses of prednisolone of 250 mg (higher than 1 mg/kg), given before the first infusion and followed by an additional dose in the same day, reduce the incidence of infusion reactions and cytokine release as reported (Pihusch et al. 2002).
The rate of infusion is one of the most important factors to reduce the incidence and severity of infusion reactions since lower infusion rates are associated with a lower incidence and the severity of reactions. Administration time ≥12 h is the preferred schedule to yield high compliance to ATLG/ATG infusion.

Treatment
If symptoms of SIRS appear, the drug should be discontinued, at least temporarily.
Treatment is symptomatic and depends upon the clinical manifestations. Intensive care for respiratory and hemodynamic support should be given according to international guidelines for critical patients, and the intervention of an intensive specialist may be requested. SIRS after ATLG/ATG is different from sepsis-induced SIRS where steroids failed to achieve a significant benefit (Cronin et al. 1995). Symptoms due to ATLG/ATG-related SIRS are more pronounced on day +1 and then tend to decrease. Steroids, widely used preemptively, provide high response rates also as a treatment measure.

Permanent Discontinuation/Rechallenge
Rechallenge after anaphylaxis and after standard infusion reactions >3 is strongly discouraged.
Non-controlled life-threatening infections are contraindications to transplant and should not modify ATLG/ATG administration per se.
Desensitization protocols are not yet clearly validated.
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