Severe Acute Hepatitis Following Administration of Rabbit Antithymocyte Globulin in Reduced Intensity Conditioning Regimen Before Allo-SCT. A Single Center Experience

Abstract 4135

Antithymocyte globulin (ATG) can be used in reduced intensity conditioning regimen before allogeneic stem cell transplantation (RIC allo) with the aim of reducing the incidence and severity of graft-versus-host disease (GVHD). The liver toxicity of ATG in this setting does exist, but its knowledge is limited by the scarcity of available data. Thus, in an effort to explore the incidence, the characteristics and the potential consequences of severe acute liver toxicity of ATG administered in RIC regimen, we undertook a retrospective analysis in our center between January 1, 2008 and April 30, 2012.

During this period, 186 RIC allo were performed with the same regimen of fludarabine (30 mg/m²/day from d-5 to d-1), IV busulfan (0.8 mg/kg × 4/day at d-4 and d-3) and rabbit ATG (Thymoglobulines,^® 2.5 mg/kg/day at d-2 and d-1). After reviewing all records, 27 patients (pts, 14%) developed a severe acute hepatitis (SAH) defined by aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 10 × ULN shortly after the administration of ATG. Their median age was 57 years (22–65). There were 15 females. Diagnoses were AML (n=7), ALL (n=2), T cell lymphoma (n=4), Hodgkin's disease (n=4), high-grade B cell lymphoma (n=1), multiple myeloma (n=5), myelodysplastic syndrome (n=3) and CLL (n=1). Status at transplant were CR1 (n=13), ≥ CR2 (n=6), PR1 (n=1), ≥ PR2 (n=5), SD (n=1) and untreated (n=1). The median number of lines of treatment before allo was 1 (0–5). Donors were matched related (n=15), matched unrelated (n=7) or mismatched unrelated (n=5, all C mismatch). The source of stem cells was peripheral blood in all cases with a median number of 7.5 × 10⁶ CD34+ cells/kg (2.8–21.6).

No patient had evidence of hepatic involvement by the hematological malignancy before allo. One patient had a chronic C hepatitis before allo while none had a history of B hepatitis. Twenty-six patients had transaminases < 2 × ULN before the administration of ATG, while 1 had ALT at 3 × ULN with normal AST. All pts had a normal renal function. All developed fever the 1^st day of ATG and received acetaminophen. Of note, they also received acetaminophen afterwards, during aplasia, without recurrence of hepatitis. No patient was receiving azoles at the time of hepatitis. No bacterium was isolated from blood cultures during fever except Enterococcus sp. in 1 patient. No virus was detected in blood by PCR (EBV, CMV, B and C hepatitis). The maximum median levels of AST and ALT were 22 × ULN (4–113) and 26 × ULN (9–109), respectively. The second day of ATG was cancelled in 8 patients when SAH was noted immediately after the 1^st day. No patient died of liver failure and the liver function tests improved in all cases with a median time to reach transaminases <5 × ULN and <2 × ULN of 7 days (4–19) and 14 days (4–22), respectively. The prothrombin test was below normal in 15 pts with a median of 40% (19%-68%) but rapidly went back to normal in less than 1 week. No patient developed VOD or acute GVHD of the liver. One patient developed chronic GVHD of the liver 11 months after transplant.

The median times to reach ANC > 500/mm³, platelets > 20,000/mm³ and > 50,000/mm³ were 18 days (13–31), 11 days (8–15) and 13 days (9–20), respectively. One patient transplanted for a CLL did not engraft, relapsed at 14 months and died of disease at 29 months. Prophylaxis of GVHD consisting of cyclosporine (CsA) in 14 pts and CsA+mycophenolate mofetil (MMF) in 2 pts were unchanged during SAH. Eleven pts were planned to receive CsA+methotrexate (at days +1, +3, +6). Methotrexate was replaced by MMF in 7 of them because of significant persistent hepatitis at day+1. With a median follow-up of 20 months (3–44), the 2-year OS, EFS, NRM, and relapse incidence were 75% ± 10%, 61% ± 11%, 6% ± 6%, and 32% ± 10%, respectively. The cumulative incidences of acute GVHD II-IV and extensive chronic GVHD were 15% ± 7% and 15% ± 8%, respectively. All these results (survival, NRM, relapse, GVHD) were similar in pts receiving 1 or 2 days of ATG.

We conclude that the incidence of SAH following ATG in RIC regimen is 14%. We also report that transaminases rapidly normalized in all patients, that no patient developed severe liver failure, VOD, or acute GVHD of the liver. Finally, our study does not provide any evidence that SAH following ATG might favor NRM and thus adversely affect the outcome of RIC allo. However, a comparative study is warranted to draw firm conclusions and delineate risk factors of SAH following ATG.