Complete Reversion of Imatinib-Induced Hepatotoxicity in Chronic Myeloid Leukemia Patients by Low-Intermediate Dose Corticosteroid.

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.

Rechallenge of ponatinib in chronic myeloid leukaemia after hepatotoxicity

“…4 Successful reversion of imatinib-induced hepatotoxicity in CML patients has been previously reported. 5 We observed rapid improvement in our patient's liver function following corticosteroid therapy, and thus managed to avoid permanent discontinuation of ponatinib in the treatment of T315I mutation CML. The commencement of ponatinib at lower dose is recommended, with gradual escalation of dosage as tolerated by the patient.…”

Сase Report of Acute Toxic Imatinib-induced Hepatitis in a Patient with Chronic Myeloid Leukemia, Sulfa Allergy, and Rheumatoid Arthritis

“…Elevation of the serum transaminases to more than 5 upper limit of normal (ULN) requires a dose reduction or temporary discontinuation of imatinib therapy. In some cases, therapy was resumed, especially with simultaneous prednisolone administration (from 10 mg to 20 mg per day) [ 10 ].…”

Imatinib and liver toxicity

“…Steroids are the main stay of treatment for established hepatotoxicity and generally result in normalisation of LFTs within 2–4 weeks 20. Sunitinib malate, another multitargeted TKI, has been approved as a second-line option for patients with GIST who are intolerant or resistant to imatinib 19.…”

“…Imatinib rechallenge has also been reported in a few cases but has resulted in further episodes of hepatotoxicity (table 1). Ferrero et al reported a series of five cases where prednisone or methylprednisolone at 25–40 mg/day resolved the hepatotoxicity in 3–8 weeks and allowed imatinib to be resumed at full doses 20. Steroids were then tapered off over 3–5 months without recurrence of hepatotoxicity.…”