Boccadoro, Mario

Campa, E

Dellacasa, C

Fava, Carmen

Ferrero, Dario

Fumagalli, M

Mattioli, G

Perfetti, P

Pogliani, Em

Rege Cambrin, G

English

Institutional Research Information System University of Turin

haematologica online 2006 haematologica/the hematology journal | 2006; 91(1) | 35 |Corticosteroids can reverse severe imatinib-induced hepatotoxicityBackground. Imatinib can induce severe hepato-toxicity,in 1-5% of CML patients, many of whomneed permanent imatinib discontinuation. Designand Results: We report 5 CML patients who devel-oped grade 3-4 hepatotoxicity after 2-8 months inimatinib. Different aetiologies of liver damage wereruled out and toxicity recurred in 2 patients withfurther attempts at low dose imatinib. In allpatients prednisone or methylprednisolone at 25-40 mg/day resolved hepatotoxicity in 3-8 weeksand allowed imatinib to be resumed at full doses.Corticosteroid were tapered off in 3-5 monthswithout hepatotoxicity recurrence. Conclusions.Corticosteroid may avoid discontinuation for hepa-totoxicity of the most effective anti-CML therapy. Tyrosine- kinase inhibitor imatinib (STI571) hasbecome the first line therapy for most patients withchronic myelogenous leukemia (CML)1,2 gastro-intestinalstromal tumors (GIST)3 and other rare neoplasms (der-matofibrosarcoma protuberans, myeloproliferative disor-ders with 5;12 chromosomal translocation, hypere-osinophilic syndromes) with genetic abnormalitiesinvolving PDGF receptors.4,5 In combination with cyto-toxic drugs it has acquired an important role in the treat-ment of BCR/ABL positive acute lymphoblastic leukemia6, 7 and evidenced some activity in relapsed malignantgliomas.8 In spite of a generally good tolerance, imatinibcan induce severe hepatotoxicity in 2-5% of treatedpatients.1, 9, 10 While generally reversible after imatinib dis-continuation, this adverse effect often recurs with drugreintroduction and many patients are prevented from theuse of a very effective drug.1, 9-11, 13Here we describe 5 CML patients displaying imatinib-induced hepatotoxicity that completely resolved after theintroduction of corticosteroids for a few months, thusallowing imatinib resumption and achievement of com-plete hematological and cytogenetic responses (CCR).Patients and resultsAll patients displayed normal values of liver enzymesand functions at the beginning of imatinib therapy. Thefirst patient evidenced markers of previous hepatitis B(HbsAg negative, HBV-DNA negative, anti-HbsAg posi-tive, anti-HBc positive); no liver disease was found in theothers. All markers of active viral hepatitis were negativeat the time of aminotransferase increment.Case 1. Fifty year old male with chronic phase CML.He began imatinib therapy in October 2000 for cytoge-netic resistance to interferon + cytarabine. Two monthslater AST and ALT values increased, in spite of promptdrug discontinuation, up to 10 × (350 U/l) and 30 × (1080U/l), respectively, the upper normal limits (UNL).Bilirubin, ALP, albumin, PT, fibrinogen remainedunchanged, whereas anti-thrombin III dropped to 42% ofthe normal level. No HBV reactivation was detected.Anti-mitochondria and anti-smooth muscle antibodieswere absent. Liver biopsy documented areas of necrosis,fibrous scars and peri-portal inflammatory infiltrate.Aminotransferases and anti-thrombin III normalised in 2months after drug withdrawal; however, 2 furtherattempts at low dose imatinib were again followed byaminotransferase increments. Meanwhile, CML hemato-logical relapse occurred. In July 2001 imatinib therapywas further attempted, starting from 300 mg/day, in asso-ciation to prednisone 25 mg/day for 5 months: hepato-toxicity did not recur and imatinib dose could be escalat-ed to 400 mg/day. A CCR was achieved, while pred-nisone was tapered and discontinued after 5 moremonths. The patient is still on imatinib therapy, in CCR,without hepatotoxicity recurrence. Case 2. Sixty-six old woman with chronic phase CML.She began imatinib treatment (400 mg daily) inNovember 2000 for cytogenetic resistance to interferon.After 8 months of therapy aminotransferase valuesincreased up to 406 (AST) and 421 (ALT) U/l (13 x UNL),without evidence of cholostasis or liver failure. Anti-mitochondria and anti-smooth muscle antibodies wereabsent. Imatinib was discontinued, without aminotrans-ferase improvement for 2 months. Prednisone was thengiven at 50 mg/day for 4 weeks (September 2001) withresolution of hepatotoxicity, then tapered off in 2 moreweeks. A further attempt at lower dose imatinib (200 mgdaily) was again followed by hepatotoxicity, thatregressed after prednisone resumption at 25 mg/ day.Prednisone at 25 and then 12.5 mg daily for 6 monthsallowed imatinib to be reintroduced at 300 mg dailywithout hepatotoxicity. CCR was obtained but thepatient died of undifferentiated thyroid cancer in June2004.Case 3. Seventy-nine old woman. She started imatinib(300 mg/day) in April 2002 for CML in chronic phase,after 6 months in hydroxyurea treatment. In September2002 imatinib was increased to 400 mg daily but, 4weeks later, while partial cytogenetic response had beenachieved, AST and ALT levels progressively increased inspite of drug discontinuation up to 946 and 2243 U/l (31and 60 × UNL, respectively). Cholostasis markers andhepatic synthesis were not affected. Anti-mitochondriaand anti-smooth muscle antibodies were absent.Methylprednisolone was given (40 mg daily) and amino-transferase values completely subsided in 3 months,while CML hematological relapse occurred. Imatinibtherapy was then resumed (200 and then 300 mg daily),together with prednisone 25 mg/ day, without hepato-toxicity recurrence. Prednisone was tapered (5-10 mgdaily) and then discontinued after 8 months, while ima-tinib dose was increased to 400 mg daily, with optimaltolerance and CCR achievement. The patient is still tak-ing imatinib in continuous CCR.Case 4. Seventy-eight old male with accelerated phaseCML. He started imatinib treatment at 300-600 mg dailyin May 2001. Six months later, while in hematologicalremission, AST and ALT levels increased up to 117 and183 U/l (4 × and 6 ×, respectively, UNL) and GGT to 150U/l. Imatinib was temporary stopped and prednisonegiven (25 mg daily), to achieve hepatotoxicity resolution.Imatinib could be resumed 3 weeks later at 300 and then600 mg daily, while prednisone was reduced to 12.5 mgdaily and maintained at that level because of concomitantchronic bronchopneumopathy. Cytogenetic responsewas not obtained and the patient died of blastic phase inMay 2003.Case 5. Sixty old woman. Chronic phase CML wasdiagnosed in June 2004 and imatinib started at 400 mgdaily. In January 2005, while in CCR, AST and ALT val-ues increased up to 190 and 360 U/l, (6 × and 10 × UNL,respectively), without other liver abnormalities. Imatinibwas stopped but one week later aminotransferase valueswere unchanged. Prednisone (25 and then 37 mg/day)was given and hepatotoxicity resolved in 4 weeks. CMLrelapse occurred and imatinib has been resumed in March2005 (300 and then 400 mg/day), while maintainingprednisone 25 and then 12.5 mg/day until May 2005.From June 2005 imatinib dose was increased up to 800mg/day because of acquired CML resistance.Hepatotoxicicity did not recur but only a partial hemato-logical response was achieved, due to an acquiredBCR/ABL mutation. A complete hematological andminor cytogenetic response has been then achieved byDecember 2005, after addition of continuous low doseARA-C (10 mg/day) to imatinib 800 mg /day withoutsigns of liver toxicity.Table1 summarises main clinical data of the 5 patients. DiscussionLiver toxicity developed in our patients after 2-8 (medi-an 6) months of imatinib therapy. Aminotransferaseincrease was very pronounced (grade 4 toxicity accordingto W.H.O.) in 2 patients, moderate (grade 3) in 3,although, differently from other reports (11-13), bilirubinremained in the normal range. Patient 1 probably had themost severe liver damage, with reduction of AT III andistological findings of hepatic necrosis, fibrosis andinflammatory infiltrate. However, re-activation of previ-ous hepatitis B could be ruled out. The role of imatinib in liver damage was evidenced inpatients 1 and 2 by the recurrence of aminotransferaseincrement every time the drug was resumed before corti-costeroid addition and, in all patients, by the absence ofdifferent liver damage aetiologies.Pathogenic mechanisms of imatinib-induced hepato-toxicity are unknown; however, istopathology findingsfrom patient 1 and the response to corticosteroids sug-gested an inflammatory reaction. Some recent reports ofimatinib-induced toxicity also pointed out similar- hepa-titis features: aminotransferase increment11-13 and istolog-ical evidence of focal necrosis and inflammatory infil-trate. While liver damage seems to be reversible after ima-tinib discontinuation, 2 cases of fatal hepatic failure werereported: the first was a CML patient taking imatinib andparacetamol, this suggesting a synergism in drug toxici-ty14; the last was a patient treated for polycythemia vera.15In that case, pathological examination revealed differentfeatures: massive necrosis and diffuse microthrombi inliver, spleen and lung vessels. Four of our 5 and 3 of the 5 described patients11, 12, 15were > 60 year old when hepatotoxicity developed; how-ever, imatinib hepatotoxicity was not found to be morefrequent in large casistics of old patients.16,17 In our patients hepatotoxicity promptly regressed afterthe addition of prednisone or methyl-prednisolone. Thisallowed imatinib prosecution and CCR achievement in 3chronic phase patients. Moreover, corticosteroids werediscontinued after a few months without hepatotoxicityrecurrence in spite of increased imatinib dosage in 2patients up to 600 and 800 mg/day, respectively.Therefore, corticosteroids look as a promisingapproach in imatinib- induced hepatotoxicity to avoid thepermanent discontinuation of a very effective anti- neo-plastic drug.Authors’ contribution to the study: EMP and his co-workersPP and MF first started prednisone therapy in patient 1 inMonza and collected part of his clinical data. DF, CD and ECcontinued patient 1 follow up in Torino, started corticosteroidtherapy in patients 3 and 5 and collected their data. DF alsowrote the manuscript. MB supervised clinical care and reviewedthe manuscript. GRC and her co-workers CF and GM inde-pendently started prednisone therapy in patients 2 and 4 inOrbassano and collected their clinical data. GRC also reviewedthe manuscript. References1. Guilhot F. Indications for imatinib mesylate therapy and clini-cal management. Oncologist 2004; 9: 271-81. 2. Peggs K, Mackinnon S. Imatinib mesylate: the new gold stan-dard for treatment of chronic myeloid leukemia. N Engl J Med2003; 348: 1048-50.3. Blanke CD, Corless CL. State-of-the art therapy for gastroin-testinal stromal tumors. Cancer Invest 2005; 23: 274-80.4. McArthur G. Molecularly targeted treatment for dermatofi-brosarcoma protuberans. Semin Oncol 2004; 2 Suppl 6: 30-6. 5. Pardanani A, Tefferi A. Imatinib targets other than bcr/abl andtheir clinical relevance in myeloid disorders. Blood 2004; 104:1931-9.6. Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, KornblauSM et al. Treatment of Philadelphia chromosome-positiveacute lymphocytic leukemia with hyper-CVAD and imatinibmesylate. Blood 2004; 103: 4396-407. 7. Towatari M, Yanada M, Usui N, Takeuchi J, Sugiura I,Takeuchi M et al. Combination of intensive chemotherapyand imatinib can rapidly induce high-quality complete remis-sion for a majority of patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia. Blood 2004; 104:3507-12. 8. Dresemann G. Imatinib and hydroxyurea in pretreated pro-gressive glioblastoma multiforme: a patient series. Ann Oncol2005; 16: 1702-8. 9. Deininger MW, O'Brien SG, Ford JM, Druker BJ. Pratical man-agement of patients with chronic myeloid leukemia receivingimatinib. J Clin Oncol 2003; 21: 1637-47. Dario Ferrero et al.| 36 | haematologica/the hematology journal | 2006; 91(1)Table 1. Patients' main clinical features.CASE 1 CASE 2 CASE 3 CASE 4 CASE 5Age 50 66 79 78 60previous hepatic disease Hepatitis B No No No Nodiagnosis ° CML CP CML CP CML CP CML AP CML CP daily imatinib dose (mg) 400 400 400 600/400* 400-800weeks from imatinib star t7 32 25 25 28peak AST value (U/l) 350 406 946 117 190peak ALT value (U/l) 1080 412 2243 183 360other liver abnormalities AT III 42% No No GGT 150 U/l Noweeks to normal AST/ALT 7 12 12 3 6liver toxicity recurrence without steroid ** Yes Yes ND ND NDliver toxicity recurrence No No No No Nowith steroid*Dose reduced for hematological toxicity before the occurrence of liver toxicity.; °CP: chronic phase; AP: accelerated phase.; ** Hepatotoxicity recurrence at 2nd –3rdattempt to imatinib therapy before corticosteroid addition.10. Hensley ML, Ford JM. Imatinib treatment: specific issues relat-ed to safety, fertility, and pregnancy. Semin Hematol 2003; 40:21-5. 11. James C, Trouette H, Marit G, Cony-Makhoul P, Mahon FX.Histological features of acute hepatitis after imatinib mesylatetreatment. Leukemia 2003; 17: 978-9.12. Ohyashiki K, Kuriyama Y, Nakajima A, Tauchi T, Ito Y,Miyazawa H et al. Imatinib mesylate-induced hepato-toxicityin chronic myeloid leukemia demonstrated focal necrosisresembling acute viral hepatitis. Leukemia 2002; 16: 2160-1.13. Ayoub WS, Geller SA, Tran T, Martin P, Vierling JM, PoordadFF. Imatinib (Gleevec)-induced hepatotoxicity. J ClinGastroenterol 2005; 39: 75-7.14. Cohen MH, Williams G, Johnson JR, Duan J, Gobburu J,Rahman A et al. Approval summary for imatinib mesylatecapsules in the treatment of chronic myelogenous leukemia.Clin Cancer Res 2002; 8: 935-42. 15. Lin NU, Sarantopoulos S, Stone JR, Galinsky I, Stone RM,Deangelo DJ et al. Fatal hepatic necrosis following imatinibmesylate therapy. Blood 2003; 102: 3455-6.16. Cortes J, Talpaz M, O'Brien S, Giles F, Beth Rios M, Shan J etal. Effects of age on prognosis with imatinib mesylate therapyfor patients with Philadelphia chromosome-positive chronicmyelogenous leukemia. Cancer 2003; 98: 1105-13. 17. Latagliata R, Breccia M, Carmosino I, Sarlo C, Montefusco E,Mancini M et al. Elderly patients with Ph+ chronic myeloge-nous leukemia (CML): results of imatinib mesylate treatment.Leuk Res 2005; 29: 287-91. Dario Ferrero*, Enrico Maria Pogliani°, Giovanna Rege-Cambrin**, Carmen Fava**, Giovanna Mattioli**, ChiaraDellacasa*, Elisabetta Campa*§, Paola Perfetti°, MonicaFumagalli°, Mario Boccadoro**Divisione di Ematologia dell’Università degli Studi di Torino;Molinette Hospital, Turin; ° Divisione di Ematologia, Università diMilano Bicocca, S. Gerardo Hospita, Monza; **Divisione diMedicina Interna 2 ed Ematologia, S. Luigi Gonzaga Hospital;Orbassano; §Divisione di Medicina, Asti Hospital; Asti, Italy.Key words: imatinib, liver toxicity, chronic myeloid leukemia, corticosteroidsSupported by: Università degli Studi di Torino (funds from MIUR)Correspondence: Dr. Dario FerreroDivisione di Ematologia dell' Università di Torino; OspedaleMolinette ia Genova 3; 10126 Torino; ItalyPhone: (011) 39 0116336728/ 4554; Fax: (011) 39 0116963737E-mail: daferrero@yahoo.comhaematologica online 2006 haematologica/the hematology journal | 2006; 91(1) | 37 |

Corticosteroids can reverse severe imatinib-induced hepatotoxicity

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Corticosteroids can reverse severe imatinib-induced hepatotoxicity

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