Hepatitis B virus reactivation associated with ruxolitinib
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LETTER TO THE EDITOR Hepatitis B virus reactivation associated with ruxolitinib Chien-Heng Shen & Cih-En Hwang & Yi-Yang Chen & Chih-Cheng Chen Received: 4 October 2013 /Accepted: 8 October 2013 # Springer-Verlag Berlin Heidelberg 2013 Dear Editor, Ruxolitinib, a potent inhibitor of Janus kinases (JAKs) 1 and 2, is an effective therapy for patients with myelofibrosis (MF) by reducing spleen size, ameliorating debilitating symptoms, and improving overall survival [1, 2]. The reported incidence of treatment-associated hepatotoxicity was low [1, 2]. Herein, we describe a patient who experienced hepatitis B virus (HBV) reactivation during extended treatment with ruxolitinib. A 72-year-old man with a 7-year long history of essential thrombocythemia (ET) presented with progressive debilitating constitutional symptoms and painful splenomegaly. He has been a known carrier of HBV for decades. Post-ET MF was confirmed, and treatment with ruxolitinib commenced at the dose of 40 mg per day shortly afterwards. He had an excellent response with complete resolution of symptoms and significant reduction of spleen size while reporting minimal clinical side effects. About 8 months after start of therapy, his serum levels of transaminases rose [alanine aminotransferase (ALT), 179 U/ L; aspartate aminotransferase (AST), 136 U/L]. This was initially considered as drug-related hepatotoxicity, and an approach of step-wise reduction of ruxolitinib dosage was taken to avoid cytokine rebound phenomenon. However, with ruxolitinib at the maintenance dose of 10 mg twice a day, the levels of ALT and AST kept rising (291 and 185 U/ L, respectively), which prompted us to discontinue the medication gradually (Fig. 1). The serum levels of both enzymes remained high 1 month after cessation of ruxolitinib, and HBV reactivation was confirmed by detection of high titer of plasma HBV-DNA (1.23×10 7 viral copies/ml plasma). Results of serological testing showed anti-HBe antibody positivity but assay for HBeAg was nonreactive. Treatment with antiviral agent entecavir was initiated, and the levels of ALT and AST decreased gradually. Measurement of plasma HBV-DNA level is planned after normalization of both hepatic enzymes. Aside from its role in hematopoiesis, the JAK-STAT pathway also plays an essential role in a variety of cellular function, including hose defense and immunoregulation. Aberrancy of its signaling could lead to dysregulated immune function. Mutations in tyrosine kinase 2 (Tyk2), one of the JAKs family member, are associated with immunodeficiency, and STAT-1 deficiency increases the host’ s susceptibility to viral and bacterial infection [3]. Moreover, both JAK1-knockout mice and Tyk2-knockout mice exhibited immunodeficient phenotype in experimental model [4]. At nanomolar concentration, ruxolitinib potently inhibits the enzymatic activities of JAK1, JAK2, and Tyk2 [5]. Therefore, patients on prolonged use of ruxolitinib might be immunocompromised. However, no prominent adverse events related to drug-induced immuno- suppression have been reported across clinical trials of ruxolitinib. It was until very recently that consecutive case reports on opportunistic infection after use of ruxolitinib were published [6, 7]. About 350 million people are chronically infected by HBV worldwide. Hepatitis B virus reactivation and hepatitis flare induced by cytotoxic chemotherapy or immunosuppressive therapy is common and potentially life-threatening. The actual incidence of HBV reactivation following ruxolitinib therapy is unknown because most clinical trials excluded the enrollment of patients with chronic hepatitis B. Our case suggests that HBV reactivation may occur following long-standing exposure to ruxolitinib. This report highlights the importance of close monitoring of hepatic enzymes and plasma HBV- DNA level in HBV carrier patients receiving ruxolitinib therapy. Epidemiological studies to delineate the incidence of C.<H. Shen Division of Gastroenterology, Department of Medicine, Chang Gung Memorial Hospital-Chiayi, Chiayi, Taiwan, Republic of China C.<E. Hwang : Y.<Y. Chen : C.<C. Chen (*) Division of Hematology Oncology, Department of Medicine, Chang Gung Memorial Hospital-Chiayi, Chiayi, Taiwan, Republic of China e-mail: [email protected] C.<H. Shen : C.<C. Chen Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China Ann Hematol DOI 10.1007/s00277-013-1936-5
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Transcript of Hepatitis B virus reactivation associated with ruxolitinib
LETTER TO THE EDITOR
Hepatitis B virus reactivation associated with ruxolitinib
Chien-Heng Shen & Cih-En Hwang & Yi-Yang Chen &
Chih-Cheng Chen
Received: 4 October 2013 /Accepted: 8 October 2013# Springer-Verlag Berlin Heidelberg 2013
Dear Editor,Ruxolitinib, a potent inhibitor of Janus kinases (JAKs) 1 and2, is an effective therapy for patients with myelofibrosis(MF) by reducing spleen size, ameliorating debilitatingsymptoms, and improving overall survival [1, 2]. The reportedincidence of treatment-associated hepatotoxicity was low [1,2]. Herein, we describe a patient who experienced hepatitis Bvirus (HBV) reactivation during extended treatment withruxolitinib.
A 72-year-old man with a 7-year long history of essentialthrombocythemia (ET) presented with progressive debilitatingconstitutional symptoms and painful splenomegaly. He hasbeen a known carrier of HBV for decades. Post-ET MF wasconfirmed, and treatment with ruxolitinib commenced at thedose of 40 mg per day shortly afterwards. He had an excellentresponse with complete resolution of symptoms and significantreduction of spleen size while reporting minimal clinical sideeffects. About 8 months after start of therapy, his serum levelsof transaminases rose [alanine aminotransferase (ALT), 179 U/L; aspartate aminotransferase (AST), 136 U/L]. This wasinitially considered as drug-related hepatotoxicity, and anapproach of step-wise reduction of ruxolitinib dosage wastaken to avoid cytokine rebound phenomenon. However,with ruxolitinib at the maintenance dose of 10 mg twice aday, the levels of ALT and AST kept rising (291 and 185 U/L, respectively), which prompted us to discontinue themedication gradually (Fig. 1). The serum levels of both
enzymes remained high 1 month after cessation of ruxolitinib,and HBVreactivation was confirmed by detection of high titerof plasma HBV-DNA (1.23×107 viral copies/ml plasma).Results of serological testing showed anti-HBe antibodypositivity but assay for HBeAg was nonreactive. Treatmentwith antiviral agent entecavir was initiated, and the levels ofALT and AST decreased gradually. Measurement of plasmaHBV-DNA level is planned after normalization of bothhepatic enzymes.
Aside from its role in hematopoiesis, the JAK-STAT pathwayalso plays an essential role in a variety of cellular function,including hose defense and immunoregulation. Aberrancy ofits signaling could lead to dysregulated immune function.Mutations in tyrosine kinase 2 (Tyk2), one of the JAKs familymember, are associated with immunodeficiency, and STAT-1deficiency increases the host’s susceptibility to viral andbacterial infection [3]. Moreover, both JAK1-knockout miceand Tyk2-knockout mice exhibited immunodeficient phenotypein experimental model [4]. At nanomolar concentration,ruxolitinib potently inhibits the enzymatic activities of JAK1,JAK2, and Tyk2 [5]. Therefore, patients on prolonged use ofruxolitinib might be immunocompromised. However, noprominent adverse events related to drug-induced immuno-suppression have been reported across clinical trials ofruxolitinib. It was until very recently that consecutive casereports on opportunistic infection after use of ruxolitinib werepublished [6, 7].
About 350 million people are chronically infected by HBVworldwide. Hepatitis B virus reactivation and hepatitis flareinduced by cytotoxic chemotherapy or immunosuppressivetherapy is common and potentially life-threatening. The actualincidence of HBVreactivation following ruxolitinib therapy isunknown because most clinical trials excluded the enrollmentof patients with chronic hepatitis B. Our case suggests thatHBV reactivation may occur following long-standingexposure to ruxolitinib. This report highlights the importanceof close monitoring of hepatic enzymes and plasma HBV-DNA level in HBV carrier patients receiving ruxolitinibtherapy. Epidemiological studies to delineate the incidence of
C.<H. ShenDivision of Gastroenterology, Department of Medicine, Chang GungMemorial Hospital-Chiayi, Chiayi, Taiwan, Republic of China
C.<E. Hwang :Y.<Y. Chen :C.<C. Chen (*)Division of Hematology Oncology, Department of Medicine, ChangGungMemorial Hospital-Chiayi, Chiayi, Taiwan, Republic of Chinae-mail: [email protected]
C.<H. Shen : C.<C. ChenGraduate Institute of Clinical Medical Sciences, College ofMedicine, Chang Gung University, Tao-Yuan, Taiwan,Republic of China
Ann HematolDOI 10.1007/s00277-013-1936-5
HBVreactivation in patients receiving therapy with ruxolitinibare also warranted.
Conflict of interest The authors declare that they have no conflict ofinterest.
References
1. Harrison C, Kiladjian JJ, Al-Ali HK et al (2012) JAK inhibition withruxolitinib versus best available therapy for myelofibrosis. N Engl JMed366:787–798
2. Verstovsek S, Mesa RA, Gotlib J et al (2012) A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 366:799–807
3. O’Shea JJ, Holland SM, Staudt LM (2013) JAKs and STATs inimmunity, immunodeficiency, and cancer. N Engl J Med 368:161–170
4. Kontzias A, Kotlyar A, Laurence A et al (2012) Jakinibs: a new classof kinase inhibitors in cancer and autoimmune disease. Curr OpinPharmacol 12:464–470
5. Tefferi A (2012) JAK inhibitors for myeloproliferative neoplasms:clarifying facts from myths. Blood 119:2721–2730
6. Wathes R, Moule S, Milojkovic D (2013) Progressive multifocalleukoencephalopathy associated with ruxolitinib. N Engl J Med 369:197–198
7. Goldberg RA, Reichel E, Oshry LJ (2013) Bilateral toxoplasmosisretinitis associated with ruxolitinib. N Engl J Med 369:681–683
Fig. 1 Medication and serumlevels of transaminases during thecourse of HBVreactivation of thispatient
Ann Hematol
