Complete Reversion of Imatinib-Induced Hepatotoxicity in Chronic Myeloid Leukemia Patients by Low-Intermediate Dose Corticosteroid.
Authors: Ferrero Dario , Pogliani Enrico M. , Rege-Cambrin Giovanna , Fava Carmen , Mattioli Giovanna , Dellacasa Chiara , Giai Valentina , Genuardi Mariella , Perfetti Paola , Fumagalli Monica , Boccadoro Mario 
Published: April 2020

Abstract
Tyrosine- kinase inhibitor imatinib (STI571) has become the first line therapy for most patients with chronic myelogenous leukemia (CML), due to its high efficacy and generally good tolerance. However, severe hepatotoxicity has been observed in 1–5 % of patients. While generally reversible after imatinib discontinuation, this complication often recurs with drug reintroduction and many patients are prevented from the use of a very effective drug (Deininger MW et al.: J Clin Oncol2003; 21: 1637–1647). Here we describe 5 CML patients displaying imatinib- induced hepatotoxicity that completely resolved after the introduction of corticosteroid for a few months, thus allowing imatinib resumption.
Five patients (age 50 – 79, median 66), received imatinib treatment at 400 – 600 mg/day for CML in chronic (4 patients) or accelerated phase (1 patient). At the beginning of imatinib treatment one patient had serological evidence of previous hepatitis B (HBsAg negative, HBV-DNA negative, anti-HBcAg and anti-HBsAg positive); however, all patients evidenced normal values of liver enzymes and functions. After a median 6 months of therapy (range 2–8), a sharp increment of serum aminotransferase values was detected, featuring grade III (3 patients) or grade IV (2 patients) liver toxicity according to WHO grading. No cholostatic changes were detected, whereas a reduction of serum anti-thrombin III level (to 48% of normal activity) was observed in the first patient. This patient underwent a liver biopsy that documented areas of necrosis, fibrous scars and peri-portal inflammatory infiltrate. In all patients, markers of active viral or autoimmune hepatitis were negative at the time of aminotransferase increment and no other drug, except imatinib, might have been implicated in hepatotoxicity. In 2 patients signs of liver toxicities gradually disappeared after imatinib withdrawal but promptly reappeared with imatinib resumption at lower dosage. In the other 3 patients aminotransferase values remained stable or slightly increased for 1–3 weeks after imatinib withdrawal, until corticosteroid addition.
In all patients the start of corticosteroid therapy with prednisone (25–37 mg/day) or methylprednisolone (40 mg/day) resulted in the normalisation of aminotransferase values in 2–4 weeks. Imatinib therapy was then resumed at increasing dosage from 200–300 mg/day to full therapeutical dosage of 400–800 mg /day, while corticosteroids were gradually tapered off in 2– 4 months, without recurrence of liver toxicity. All patients obtained a complete hematological response and 3 patients a durable complete cytogenetic remission.
While the mechanism of imatinib- induced hepatotoxicity is not fully understood, istological evidences from others’ (James C et al. Leukemia2003;17:978–9; Ohyashiki K et al. Leukemia2002;16:2160–1) and our reports suggest an inflammatory reaction with lymphocyte infiltration playing a role in liver damage. Corticosteroids at low-intermediate dosage look as a very promising treatment in order to reverse imatinib-induced hepatotoxicity and to avoid the permanent discontinuation of the most effective anti- CML drug.