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Pulmonary tuberculosis reactivation following ruxolitinib treatment in a patient with primary myelofibrosis a

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Yen-Hao Chen , Chen-Hsiang Lee & Sung-Nan Pei

a

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Division of Hema-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan b

Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan Published online: 29 May 2015.

Click for updates To cite this article: Yen-Hao Chen, Chen-Hsiang Lee & Sung-Nan Pei (2015) Pulmonary tuberculosis reactivation following ruxolitinib treatment in a patient with primary myelofibrosis, Leukemia & Lymphoma, 56:5, 1528-1529, DOI: 10.3109/10428194.2014.963082 To link to this article: http://dx.doi.org/10.3109/10428194.2014.963082

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Leukemia & Lymphoma, May 2015; 56(5): 1528–1529 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.963082

LETTER TO THE EDITOR

Pulmonary tuberculosis reactivation following ruxolitinib treatment in a patient with primary myelofibrosis Yen-Hao Chen1, Chen-Hsiang Lee2 & Sung-Nan Pei1 1Division of Hema-Oncology and 2Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung

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Memorial Hospital, and Chang Gung University College of Medicine, Kaohsiung, Taiwan

⬍ 40 IU/mL); therefore, danazol was stopped (prednisolone had been continued). He then received ruxolitinib 20 mg twice a day beginning in July 2013. In 2 months, his body weight had increased by 2 kg and computed tomography (CT) imaging revealed a mild reduction in spleen volume. However, the patient developed a high fever in September 2013, 2 months after the initiation of ruxolitinib therapy. A source of infection could not be identified, and the fever did not respond to antibiotic (ceftriaxone) therapy. Blood and urine cultures and cryptococcal antigen tests were negative. Cytomegalovirus and Epstein–Barr virus DNA were not detected in serum. Due to the fever of unknown origin, positron emission tomography (PET)-CT was performed in October 2013, and revealed hypermetabolic pulmonary nodules in the bilateral upper lobes and mediastinal lymph nodes. The patient had mild respiratory symptoms at that time; sputum samples yielded Mycobacterium tuberculosis colonies after 1 month of culture. Based on these findings, a diagnosis of pulmonary TB reactivation was confirmed. Ruxolitinib therapy was discontinued abruptly, with no cytokine rebound phenomenon. Prednisolone had been tapered since the TB diagnosis. The patient’s fever persisted until microbiological test results led to a definitive diagnosis. The patient then received anti-TB treatment, including rifampicin/isoniazid/ pyrazinamide and ethambutol. He reported no past TB infection, and no family members had a history of TB infection. His concurrent medications included allopurinol, dipyridamole, clonazepam, colchicine, aspirin and folic acid. The patient had been taking these medications for more than 3 years prior to the ruxolitinib treatment. The Naranjo adverse drug reaction probability scale was 8 in this case, and indicated a probable association between ruxolitinib and reactivation of pulmonary TB. The JAK–signal transducer and activator of transcription (STAT) pathway influences not only hematopoiesis but also plays an essential role in a variety of cellular functions, including host defense and autoimmunity [9]. Ruxolitinib inhibits JAK1 and JAK2, resulting in depressed T helper cell type 1

The classic BCR–ABL-negative myeloproliferative neoplasms (MPNs) include polycythemia vera, essential thrombocythemia and primary myelofibrosis. Primary myelofibrosis is characterized by bone marrow fibrosis, anemia, splenomegaly and constitutional symptoms (such as fatigue, night sweats, weight loss, pruritus and bone pain) and has the worst prognosis among MPNs [1]. The Janus kinase-2 (JAK2) V617F genetic mutation was identified as the most common somatic mutation in patients with MPNs; this mutation is present in 50–60% of patients with primary myelofibrosis. Ruxolitinib (INCB018424) is the first drug approved for the treatment of myelofibrosis in North America and Europe. It is an orally bioavailable, potent and selective inhibitor of JAK1 and JAK2, and has remarkable effects on constitutional symptoms, especially splenomegaly [1,2]. The major adverse effect of ruxolitinib is hematologic suppression; no significant increase in infectious complications was noted during clinical trials [1,2]. However, several case reports on the development of opportunistic infections after ruxolitinib therapy have recently been published [3–8], and the potential for immunosuppression associated with this novel agent has attracted a great deal of attention [9,10]. We report here a case of reactivated pulmonary tuberculosis (TB) after ruxolitinib treatment. An 82-year-old man was diagnosed with primary myelofibrosis in 2005. His initial presentations included anemia, leukocytosis and mild splenomegaly. Analysis of peripheral blood neutrophils showed heterozygous positivity for the JAK2 V617F genetic mutation. The patient was monitored regularly and did not require active treatment until 2007. Then, hydroxyurea was administered for 18 months to treat progressive leukocytosis and thrombocytosis. In 2009, hydroxyurea was discontinued owing to anemia, but the patient did not require regular transfusions. In early 2013, he experienced weight loss (6 kg in 6 months). Danazol (200 mg twice daily) and prednisolone (10 mg per day) were administered to treat this constitutional symptom of myelofibrosis from early May. However, 2 weeks later, alanine transaminase levels had increased from 38 to 92 IU/mL (reference range,

Correspondence: Sung-Nan Pei, MD, Division of Hema-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, No. 123, Dapi Rd., Niaosong Dist., Kaohsiung City 833, Taiwan (R.O.C.). Tel: ⫹ 886-7-7317123, ext. 8303. Fax: ⫹ 886-7-7322402. E-mail: [email protected] Received 7 July 2014; revised 25 August 2014; accepted 30 August 2014

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Letter to the Editor 1529 (Th1) response and down-regulation of multiple cytokines responsible for the constitutional symptoms of myelofibrosis, including interleukin-1 (IL-1), IL-6, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) [11,12]. Among these cytokines, TNF-α has been shown to play a critical role of immune mediator in protection against M. tuberculosis, and other intracellular pathogens [13]. TNF-α is associated with T cell function, macrophage activation and granuloma formation. Ruxolitinib has a potent suppressive effect on TNF-α [14], and may increase the risk of growth and spread of TB. Four cases of opportunistic infection after ruxolitinib use have recently been reported. Colomba et al. reported that a man with primary myelofibrosis received ruxolitinib and developed fever and inguinal lymphadenopathy [4]. M. tuberculosis was cultured from sputum samples, and a biopsied lymph node sample was positive for TB by polymerase chain reaction (PCR). The authors did not describe the duration of ruxolitinib treatment before this complication developed. Other reported opportunistic infections after ruxolitinib treatment included bilateral toxoplasmosis retinitis, simian virus 40 (SV40)-associated progressive multifocal leukoencephalopathy and pulmonary Cryptococcus neoformans infection [5,7,8]. Only 5% of individuals develop primary TB after contact with individuals with active TB infections. The immune system in the remaining 95% responds to M. tuberculosis by encasing the bacteria in granulomas, and the infection enters a latent phase. The prevalence of latent TB infection is about 15% in Taiwan [15,16], and many elderly people have unknowingly been exposed to TB. When these patients receive biologics such TNF blockers, interleukin antagonists or JAK inhibitors, latent TB may be reactivated [15]. Our patient denied previous TB infection and exposure history. However, due to the close chronological relationship between the administration of ruxolitinib therapy and development of TB-related fever, TB reactivation was favored over a diagnosis of primary infection. This patient was not screened for latent TB prior to ruxolitinib therapy. However, according to our experience and a provisional recommendation published recently [10], routine TB screening may be considered before the use of ruxolitinib, especially in TB endemic areas. In conclusion, our case demonstrates that ruxolitinib may trigger reactivation of latent TB. As ruxolitinib therapy becomes more common, clinicians should be aware of the

potential for unusual infectious causes and presentations as described in this case. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

References [1] Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012;366:787–798. [2] Verstovsek S, Mesa RA , Gotlib J, et al. A double-blind, placebocontrolled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366:799–807. [3] Caocci G, Murgia F, Podda L , et al. Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis. Leukemia 2014;28:225–227. [4] Colomba C, Rubino R, Siracusa L, et al. Disseminated tuberculosis in a patient treated with a JAK2 selective inhibitor: a case report. BMC Res Notes 2012;5:552. [5] Goldberg RA , Reichel E, Oshry LJ. Bilateral toxoplasmosis retinitis associated with ruxolitinib. N Engl J Med 2013;369:681–683. [6] Shen CH, Hwang CE, Chen YY, et al. Hepatitis B virus reactivation associated with ruxolitinib. Ann Hematol 2014;93:1075–1076. [7] Wathes R, Moule S, Milojkovic D. Progressive multifocal leukoencephalopathy associated with ruxolitinib. N Engl J Med 2013;369:197–198. [8] Wysham NG, Sullivan DR, Allada G. An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor. Chest 2013;143:1478–1479. [9] O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 2013;368:161–170. [10] Heine A , Brossart P, Wolf D. Ruxolitinib is a potent immunosuppressive compound: is it time for anti-infective prophylaxis? Blood 2013;122:3843–3844. [11] Ostojic A , Vrhovac R, Verstovsek S. Ruxolitinib for the treatment of myelofibrosis: its clinical potential. Ther Clin Risk Manag 2012;8: 95–103. [12] Tefferi A . Challenges facing JAK inhibitor therapy for myeloproliferative neoplasms. N Engl J Med 2012;366:844–846. [13] Miller EA , Ernst JD. Anti-TNF immunotherapy and tuberculosis reactivation: another mechanism revealed. J Clin Invest 2009;119: 1079–1082. [14] Verstovsek S, Kantarjian H, Mesa RA , et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 2010;363:1117–1127. [15] Chiu HY, Hsueh PR, Tsai TF. Clinical experience of QuantiFERON(®) -TB Gold testing in patients with psoriasis treated with tumour necrosis factor blockers in Taiwan. Br J Dermatol 2011; 164:553–559. [16] Hung WT, Lee SS, Sy CL, et al. Prevalence of latent tuberculosis infection in BCG-vaccinated healthcare workers by using an interferongamma release assay and the tuberculin skin test in an intermediate tuberculosis burden country. J Microbiol Immunol Infect 2013 Sep 23. [Epub ahead of print]

Pulmonary tuberculosis reactivation following ruxolitinib treatment in a patient with primary myelofibrosis.

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