Profound lymphopenia is associated with a lower risk of hepatic cytolysis during antithymocyte globulin administration
Authors: Bashar Al Dweik, Rabah Redjoul, Sylvie Bastuji‐Garin, Florence Beckerich, Christine Robin, Cécile Pautas, Andréa Toma, Ludovic Cabanne, Sébastien Maury, Catherine Cordonnier
Journal: American Journal of Hematology (2016)

To the Editor: Antithymocyte globulins (ATG) are widely used for the treatment of aplastic anemia (AA) and in allogeneic hematopoietic cell transplantation (HCT) both for conditioning regimen, and for treatment of acute graft-versus-host disease (aGVHD). ATG induces a deep T-lymphocyte depletion but may affect other cell lineages 1. Adverse events induced by ATG mainly include early chills and fever, rarely anaphylactic shock, and later on, serum sickness. Acute hepatic cytolysis (AHC) has been rarely reported in large series, and its mechanism and risk factors are unknown. We assess here the incidence of, and risk factors for, early, acute, AHC in 85 consecutive patients receiving ATG in our department between 2005 and 2012. Patients who had received 2 ATG courses were included only for the first course. ATG was administered over ≥8 hr under hyperhydratation, dexchlorpheniramine, and methylprednisolone (1 mg/kg/d from day-1 until the last day of ATG, then progressively tapered over 7 days). Thymoglobulins® were used for HCT conditioning. ATGAM® replaced other ATG forms from 2011 for AA treatment 2. Total doses varied between 5 and 18 mg/kg over 2–4 consecutive days for rabbit ATG Thymoglobulins®, and between 75 and 160 mg/kg over 4–5 days for horse ATGs (ATGAM® and Lymphoglobulins®). Data were collected from the medical charts. Liver function tests were assessed 2–3 times a week for three weeks after ATG. AHC was defined according to the CTCAE v4 as moderate [ALT or AST > 2.5 and ≤5 times the upper normal limit (UNL); grade 1–2] or severe (ALT or AST > 5 UNL; grade 3–4). Characteristics of the patients developing AHC within 10 days of ATG administration were compared with those of patients who did not, using X2 or exact Fisher test. Odd ratios and 95% confidence intervals were estimated using exact logistic regression models when the association was significant (P ≤ 0.05) or when a trend was observed (P ≤ 0.10). All tests were 2-tailed. The analysis was performed using the Strata software, V12. The patients received ATG for AA (n = 17, 20%), HCT conditioning (n = 56, 66%), or aGVHD (n = 12, 14%). AHC was observed in 24 (28%) patients [grade 1–2: n = 9 (10.7%), grade 3–4: n = 15 (17.6%)]. Maximal ALT/AST levels reached 3–28 UNL, always within the first 4 days. Due to AHC, ATG was stopped in 3 patients, delayed in 2, and pursued without change in others. None patient developed hepatic failure. AHC was rarely concomitant to elevation of bilirubin or alkaline phosphatases (15%) and evolved favorably in 79% within 10 days. HC did not affect 3-month survival (77 vs. 75%). Two HCT patients with AHC developed sinusoidal obstruction syndrome. Both died, one from leukemia relapse, one from multiorgan failure. Age, underlying disease and its status, type of ATG (horse vs. rabbit), baseline creatinine levels, TBI, side effects during ATG (chills, fever, hypotension), transplant characteristics (Table 1), and concomitant administration of hepatotoxic drugs were not associated with the risk of AHC (Supporting Information Table II). There was a non-significant trend for an association between AHC and baseline elevated transaminases (≥2.5 UNL). Although 58.3% of the patients receiving ATG for HCT conditioning developed AHC versus 16.7 and 25% in the AA and aGVHD groups, respectively, this difference was not statistically significant. Two factors were associated with a decreased risk of AHC: baseline lymphopenia <500/mm3 [6/53 (11.3%) vs. 18/32 (56%), P < 0.001], and conditioning with amsacrine and/or cytarabine [0/11 vs. 24/74 (32%), P = 0.029]. Among the patients who developed AHC, none had received one of these 2 drugs. In our experience, AHC was frequent (28%) and often severe (18%). In a previous study, 26% of allogeneic HCT recipients receiving conditioning with ATG developed AHC, without impact on 3-month survival 3. The authors identified two risk factors for AHC: two previous autologous HCT—suggesting previous liver toxicity of chemotherapy—and severe hypotension during ATG, evocative of shock liver. We were unable to show any relationship between AHC and other early side effects of ATG. However, severe lymphopenia, and amsacrine and/or cytarabine administration were associated with a decreased risk of AHC. Indeed, 25% of lymphopenic versus 75% of nonlymphopenic patients developed AHC. Amsacrine and/or cytarabine were administered within a FLAMSA reduced intensity conditioning combining 4-days of chemotherapy followed, 7 days later, by ATG, cyclophosphamide and TBI, so that the patients were deeply immunodepressed before ATG. Although we could not run a multivariate analysis due to the limited number of patients, our findings suggest that the more immunodepressed patients could be protected from ATG-related HC. Therefore, ATG-related cytolysis could be more an immuno-allergic reaction, rather than a direct toxicity supported by the wide diversity of ATG target antigens, including some expressed by hepatocytes (HLA class I and II, CD95, CD11a, or CD80 antigens), or sinusoidal endothelial cells (CD86) 4-6. We recognize the limitations of our study: (1) This is a retrospective, but consecutive single-center study. (2) We analyzed together 3 different indications of ATG, one in AA, and two in allogeneic HCT, but in patients having in common to be immunodepressed, and to receive many concomitant medications. (3) 90.6% of our patients received rabbit ATG, and with various doses. However, the onset of AHC was not associated with the type of ATG, and the dose-effect could not be assessed, as most of the patients except three received the planned doses. Despite these limitations, we were able to identify the patients with a lymphocyte counts ≥500/mm3 as at a higher risk of developing AHC than the lymphopenic patients. Although AHC did not impact on survival, the onset of AHC should be avoided as much as possible as it may impair the metabolism of concomitant liver-dependent drugs, notably around transplant, and compromise the expected drug-efficacy when the dose or timing of ATG is modified. Nonlymphopenic patients should be closely monitored for this complication. The fact that lymphopenia is associated with a decreased risk of ATG-induced AHC mainly suggests an immuno-allergic reaction. This encourages us to reinforce the administration of steroids in case of AHC during ATG administration. Whether a reinforced prophylactic steroid regimen may decrease the incidence of this complication needs further investigations. BAD, RR: study concept and design, data collection. SBG: statistical analysis and interpretation of the data. FB, CR, CP, AT: interpretation of data. LC: data collection, CCJ: data collection, SM: critical revision of the manuscript, CC: study concept and design, analysis and interpretation of data, drafting the manuscript. The authors are grateful to Philippe Mavier, Hepatology Department, Henri Mondor Hospital, for his useful comments on the manuscript. They also thank the pharmacy staff, for providing the list of hematology patients who received ATG during the study period. Bashar Al Dweik,1 Rabah Redjoul,1 Sylvie Bastuji-Garin,2,3 Florence Beckerich,1,4 Christine Robin,1,4 Cécile Pautas,1 Andréa Toma,1 Ludovic Cabanne,1Sébastien Maury,1,4 Catherine Cordonnier1,4* 1Department of Hematology, Henri Mondor Teaching Hospital, Assistance Publique-Hôpitaux De Paris (AP-HP), Creteil, France; 2Department of Public Health, AP-HP, Henri Mondor Teaching Hospital, Créteil, France; 3CEpiA (Clinical Epidemiology and Ageing) Unit EA 7376, UPEC, DHU A-TVB, IMRB, Créteil, France; 4Paris-Est Créteil University (UPEC), Créteil, France Additional Supporting Information may be found in the online version of this article. Supporting Table II Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.