Bone Marrow Transplantation (2000) 26, 1243–1245  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Case report Lamivudine therapy for a hepatitis B surface antigen (HBsAg)-positive leukemia patient receiving myeloablative chemotherapy and autologous stem cell transplantation

N Uchida1, H Gondo1, D Himeji1, Y Kaji1, M Sata2 and Y Niho1

1First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka; and 2Second Department of Internal Medicine, Faculty of Medicine, Kurume University, Fukuoka, Japan

Summary: Case report

Hepatitis B virus (HBV) can be a cause of fatal liver failure after chemotherapy for viral carrier patients and A 33-year-old Japanese man was diagnosed with acute limits the indication of myeloablative therapy for them. myelogenous leukemia (FAB classification, M2) and found We describe an HBsAg-positive leukemia patient who to be an asymptomatic carrier of HBV. After achieving successfully underwent autologous PBSC transplant. complete remission with induction chemotherapy, he After chemotherapeutic treatment his serum HBV DNA received consolidation chemotherapy twice (Figure 1).6 His level rose in association with hepatitis. To prevent pro- clinical course was uneventful until following his second gression to fulminant hepatitis, we administered lamivu- consolidation chemotherapy when HBV DNA and ALT dine, a viral reverse transcriptase inhibitor, during the levels increased to 3800 meq/ml (measured by branched transplantation procedure. The patient did not show DNA probe method7) and 217 U/l, respectively. With bed any increase of HBV DNA or a worsening of his hepa- rest only these levels decreased to normal by 3 months. titis. Thus, lamivudine may be a promising treatment Since his leukemic cells had poor prognostic karyotypes for HBsAg-positive patients receiving myeloablative (trisomy 8 and 21), the patient decided to receive an auto- chemotherapy and autologous stem cell transplantation. logous peripheral blood stem cell transplantation as further Bone Marrow Transplantation (2000) 26, 1243–1245. treatment. The pretransplant conditioning regimen con- Keywords: lamivudine; hepatitis type B; stem cell trans- sisted of busulfan, cytosine arabinoside and etoposide plantation (BEA regimen).6 Granulocyte colony-stimulating factor (G- CSF) was administered concurrently with the BEA regimen during conditioning. Lamivudine (Glaxo Wellcome Reactivation of the hepatitis B virus (HBV) and subsequent Research and Development, Greenford, UK) 100 mg/day fulminant hepatitis have been reported following myeloabl- was administered orally starting on day −1. Peripheral + ative chemotherapy and stem cell transplantation for leuke- blood stem cells (3.7 × 106 CD34 cells/kg) which had been mia patients with HBV infection.1 Interferon is effective collected during recovery after consolidation chemotherapy in approximately 30% of such patients with chronic HBV were infused on day 0. infection.2 However, adverse effects including fever, mal- Post transplantation, granulocytes exceeded 500 × 106/l aise, anorexia and depression are major concerns with inter- and platelets exceeded 20 × 109/l on days 14 and 18, feron treatment. Lamivudine is a nucleoside analogue respectively. HBV DNA or ALT levels were not elevated which specifically inhibits viral reverse transcriptase while during the therapy (Figure 1), and lamivudine adminis- suppressing HBV replication.3 A trial of lamivudine for tration was discontinued 3 months after transplantation. The chronic HBV infection has demonstrated that it signifi- patient subsequently experienced HBV DNA elevation 4 cantly reduces HBV DNA and alanine aminotransferase months later, but this was successfully treated with read- (ALT) levels.4,5 In the present study, lamivudine was ministration of lamivudine. There were no adverse effects administered to an HBsAg-positive leukemia patient to during lamivudine therapy. Lamivudine therapy was prevent progression to fulminant hepatitis following stopped when the patient suffered a relapse of his leukemia. autologous PBSC transplantation. Despite re-induction chemotherapy, the patient did not ach- ieve complete remission and died of pneumonia 3 months after relapse. HBV DNA did not become elevated and he did not develop hepatitis, even after the discontinuation Correspondence: Dr N Uchida, The Terry Fox Laboratory, 601 West 10th of lamivudine. Avenue, Vancouver, British Columbia, V5Z 1L3, Canada Received 8 May 2000; accepted 20 June 2000 Lamivudine therapy for HBV carrier in PBSC transplant N Uchida et al 1244 IDR/ MIT/ VP16/ IDR/ Ara-C Ara-C Ara-C G-CSF Ara-C 400 BU/VP16/Ara-C

300 Lamivudine 100 mg 100 mg

PBSCH PBSCT relapse 200

100 Alanine aminotransferase (U/l) 0 4000 3000 2000 1000 0 HBV DNA (meq/ml) HBV DNA 1997 1998 1999

Oct Jan Oct Jan Aug Sept Nov Dec Feb April May June July Aug Sept Nov Dec March

Figure 1 Chart showing serum levels of alanine aminotransferase (upper panel) and HBV DNA (lower panel) before and after lamivudine therapy. It shows clear correlation between HBV load and hepatitis which means hepatitis was caused by HBV. Lamivudine therapy kept viral load at a low level and successfully prevented acute exacerbation of hepatitis. IDR, idarubicin; MIT, mitoxantrone; VP16, etoposide; Ara-C, cytosine arabinoside; BU, busulfan; PBSCH, peripheral blood stem cell harvest; PBSCT, peripheral blood stem cell transplantation.

Discussion loablative therapy and stem cell transplantation, and that a prospective study of lamivudine for stem cell transplan- Patients with HBV infection are at risk of an exacerbation tation in HBsAg-positive patients is warranted. of viral hepatitis after cytotoxic treatment.1 There are no specific markers to anticipate viral reactivation, and every patient with HBV needs to be carefully monitored during Acknowledgements chemotherapy. Lamivudine, an oral nucleoside analogue, has shown The authors wish to thank the Glaxo Wellcome Research and promise in patients with chronic hepatitis B.3 It inhibits Development (Greenford, UK) for kindly providing lamivudine. viral reverse transcriptase and suppresses viral replication. It has also recently been reported that this drug is also use- ful for the treatment of viral hepatitis after cytotoxic ther- References apy.8,9 In the present patient lamivudine appeared to work to not only avoid HBV exacerbation during transplantation, 1 Lau GKK, Liang R, Chiu EKW et al. Hepatic events after but also to treat reactivation of HBV later. bone marrow transplantation in patients with hepatitis B infec- Lamivudine can be administered without significant tion: a case controlled study. Bone Marrow Transplant 1997; adverse effects, but one of the concerns with this treatment 19: 795–799. is the emergence of viral mutants. A trial of lamivudine 2 Perrillo RP. Treatment of chronic hepatitis B with interferon: for chronic HBV infection has demonstrated that long-term experience in Western countries. Semin Liver Dis 1989; 9: usage of this drug is associated with HBV tyrosine-meth- 240–248. 3 Doong SL, Tsai CH, Schinazi RF et al. Inhibition of the repli- ionine-aspartate-aspartate (YMDD) motif mutation, and the cation of hepatitis B virus in vitro by 2′,3′-dideoxy-3′-thiacyti- incidence of exacerbation is much higher in patients with dine and related analogues. Proc Natl Acad Sci USA 1991; 10 this mutation. As a result it is not recommended that this 88: 8495–8499. drug be administered for long periods of time. We therefore 4 Lai CL, Chien RN, Leung NWY et al. A one-year trial of stopped lamivudine 3 months after transplantation and then lamivudine for chronic hepatitis B. New Engl J Med 1998; carefully followed the serum viral DNA levels. The patient 339: 61–68. experienced viral DNA elevation 4 months later, but was 5 Dienstag JL, Schiff ER, Wright TL et al. Lamivudine as initial again successfully treated with readministration of lamivu- treatment for chronic hepatitis B in the United States. New dine, indicating the virus was still sensitive to this drug. Engl J Med 1999; 341: 1256–1263. Thus, it would appear that lamivudine should be adminis- 6 Gondo H, Harada M, Miyamoto T et al. Autologous peripheral blood stem cell transplantation for acute myelogenous leuke- tered for as short a time as possible, and the HBV DNA mia. Bone Marrow Transplant 1997; 20: 821–826. level carefully monitored, so that the drug can be readmin- 7 Urdea MS, Horn T, Fultz TJ et al. Branched DNA amplifi- istered without delay if necessary. cation multimers for the sensitive, direct detection of human These results suggest that lamivudine may be useful in hepatitis viruses. Nucleic Acids Symp Ser 1991; 24: 197–200. the prophylaxis of HBV fulminant hepatitis following mye- 8 Picardi M, Selleri C, De Rosa G et al. Lamivudine treatment

Bone Marrow Transplantation Lamivudine therapy for HBV carrier in PBSC transplant N Uchida et al 1245 for chronic replicative hepatitis B virus infection after allo- 10 Liaw YF, Chien RN, Yeh CT et al. Acute exacerbation and geneic bone marrow transplantation. Bone Marrow Transplant hepatitis B virus clearance after emergence of YMDD motif 1998; 21: 1267–1269. mutation during lamivudine therapy. Hepatology 1999; 30: 9 Clark FL, Drummond MW, Chambers S et al. Successful 567–572. treatment with lamivudine for fulminant reactivated hepatitis B infection following intensive therapy for high-grade non- Hodgkin’s lymphoma. Ann Oncol 1998; 9: 385–387.

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