Severe Hepatic Injury Caused by Imatinib Mesylate Administered for the Treatment of Chronic Myeloid Leukemia and the Efficacy of Prednisolone for its Management

Abstract

Imatinib mesylate is a specific inhibitor of BCR-ABL tyrosine kinase, which is now widely used for the treatment of chronic myeloid leukemia (CML) with a high efficacy. Although severe hepatic injury caused by imatinib mesylate is rare, such a side effect may force patients to discontinue taking imatinib mesylate. In the present paper, we report on the case of a 51-year-old woman with CML who experienced hepatic injury with severe hyperbilirubinemia caused by imatinib mesylate. The findings from a liver biopsy specimen and her clinical course suggested the hepatic injury to presumably have been caused by an allergic mechanism. The co-administration of prednisolone was thus tried, and she has been able to continue imatinib mesylate administration without any liver dysfunction and finally was able to obtain a complete cytogenetic response.We therefore recommend that prednisolone should be tried when severe hepatic injury caused by imatinib mesylate is observed, since it might enable such patients to continue imatinib mesylate treatment and thereby improve the prognosis in such cases.

Formation of reactive metabolites and management of tyrosine kinase inhibitor-induced hepatotoxicity: a literature review

“…Additionally, in the context of a clear danger signal, such as underlying inflammation, infection or trauma, all of which may constitute the danger signal, the risk of IDRs increases [52]. The usefulness of corticosteroids may be based on their ability to suppress the inflammatory response in the liver as a part of drug hypersensitivity or an immuno-allergic reaction, and this supports the speculation that an allergic mechanism may be involved in the TKIassociated liver injury seen in these patients [48,49]. Therefore, cautiously re-challenging after complete resolution of the liver injury under steroid administration and with very gradual dose increment may allow patients who have developed severe liver toxicity to continue taking the drug [51].…”

“…Harbaum et al [41] and Ferrero et al [45] demonstrated that when corticosteroids are applied early after the onset of imatinib-induced hepatotoxicity, it may result in rapid and complete hepatic recovery. The concurrent use of corticosteroids with imatinib has also allowed the continuance of imatinib therapy without hepatotoxicity recurrence in many cases ( Table 2) [45][46][47][48][49][50][51].…”

“…A previous study conducted by our group demonstrated an increase in risk of hepatotoxicity with the concomitant use of lapatinib and dexamethasone [53], which [59] IMA Treatment Prednisolone 100 mg/day 3 days [44] IMA Treatment Prednisolone 0.8 mg/kg/day 2 months [56] IMA Prevention Prednisolone 25 mg/day 5 months [45] IMA Prevention Prednisolone 25 mg/day 2 months [48] IMA Prevention Prednisolone 20 mg/day N.A. [49] IMA Prevention Prednisolone 50 mg/day N.A [50] IMA Treatment and prevention Prednisolone 1 mg/kg/day 6 months [46] IMA Treatment and prevention Prednisolone (T) 1 mg/kg/day (P) 30 mg/day* N.A. [47] IMA Treatment and prevention Prednisolone (T) 50 mg/day (P) 25 mg and then 12.5 mg/day (T) 6 weeks (P) 6 months [45] IMA Treatment and prevention (T) Methylprednisolone (P) Prednisolone is contrasting with the case reports mentioned earlier.…”

Recurrent imatinib-induced hepatotoxicity in a chronic myeloid leukaemia patient successfully managed with prednisone

“…The introduction of corticosteroids into the patient's regimen has been previously shown in a few case reports to enable use of imatinib in patients who develop recurrent hepatotoxicity, even at reduced doses 6 9 13 14. Steroids used in these case reports included oral prednisone 25 mg daily tapered over 5–8 months,6 prednisone 30 mg daily tapered over 5 months,9 prednisone 20 mg daily (duration not mentioned)13 and prednisone 25 mg twice daily (duration not mentioned) 14. The usefulness of corticosteroids may be based on their ability to suppress the inflammatory response in the liver as a part of drug-hypersensitivity or an immuno-allergic reaction.…”

Imatinib metabolite profiling in parallel to imatinib quantification in plasma of treated patients using liquid chromatography–mass spectrometry

“…However, it has been shown that patients with an increased drug exposure had a better survival prognosis 23. In addition, rare but sometimes severe side effects have been reported with imatinib therapy 24–30. Taken together with the large interindividual pharmacokinetic variability,31 there is a rationale for monitoring plasma levels of imatinib and its metabolites, at least for research purposes.…”