SOLVING CLINICAL PROBLEMS IN BLOOD DISEASES A physician or group of physicians considers presentation and evolution of a real clinical case, reacting to clinical information and data (boldface type). This is followed by a discussion/commentary A life-threatening ruxolitinib discontinuation syndrome Giacomo Coltro 1,2,3 | Francesco Mannelli 1 | Paola Guglielmelli 1,2 | Annalisa Pacilli 1,2 | Alberto Bosi 3 | Alessandro Maria Vannucchi 1,2,3 1 CRIMM, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; 2 Department of Experimental and Clinical Medicine, University of Florence, DenoThe Excellence Center, Florence, Italy; 3 Hematology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy Correspondence Alessandro M. Vannucchi, MD, CRIMM, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, AOU Careggi, Dipartimento di Medicina Sperimentale e Clinica, 50134 Firenze, Italy. Email: amvannucchi@unifi.it Funding information Supported by a grant from AIRC Investigator Grant 2014 (AIRC; Milan, Italy) project #15967, Special Program Molecular Clinical Oncology 5x1000 to AIRC- Gruppo Italiano Malattie Mieloproliferative (AGIMM) project #1005, Bando Ricerca Finalizzata e Giovani Ricercatori Anno 2011–2012 (Ministero della Salute, Italy) project GR-2011-02352109. 1 | CASE PRESENTATION A 56-year-old woman with a history of essential thrombocythemia currently treated with ruxolitinib presented to the clinic for a routine visit in October 2016. She referred unintentional weight loss of about 5 kg in the last 3 months, asthenia, and osteoarticular pain. She denied fever, cough, diarrhea, shortness of breath, constitutional symptoms, or hemorrhage. Essential thrombocythemia (ET), one of the classic chronic myelo- proliferative neoplasms together with polycythemia vera (PV) and pri- mary myelofibrosis (MF), 1 is an overall indolent disease characterized by persistent thrombocytosis because of abnormal megakaryocytes’ proliferation; the latter is sustained by autonomous activation of the Janus kinase/signal transducers and activators of transcription (JAK/ STAT) pathway induced by mutations in JAK2 (V617F), myeloprolifera- tive leukemia virus oncogene (MPL) and calreticulin (CALR). Increased risk of arterial and venous thrombosis and hemorrhage are the main causes of morbidity and mortality in ET; treatment is thereby mainly addressed to reduce the risk of cardiovascular events, and is delivered based on risk stratification criteria. 2,3 Although overall survival in ET is similar to reference population, transformation to post-ET MF (PET- MF) and acute myeloid leukemia (AML) occur in 5-8% and 1-3% of cases, respectively, and are associated with shortening of survival. 4 Ruxolitinib, an oral adenosine triphosphate (ATP) mimetic inhibitor of JAK1 and 2 that has received approval for the treatment of patients with MF and PV, 5–8 is under investigation in ET in a phase I/II trial. The trial also included patients with PV, that have been already reported. 9 The symptomatology referred by the patient was rather unspecific but raised concerns since she had been very well doing in the last years after beginning treatment with ruxolitinib. Her asthenia could be ascribed to ruxolitinib-related anemia, one of the most frequent adverse events of ruxolitinib. Conversely, the remarkable weight loss could be hardly referred to the experimental drug, which eventually causes weight gain; rather, it might be more consistent with progres- sion to PET-MF or, less commonly, to post-ET AML. Of course, other nonhematologic causes had to be taken into an account, including endocrine disorders, infectious and inflammatory states, solid tumors, to name a few. The patient had been diagnosed with ET in another institution 8 years before, following the discovery of extensive thrombocytosis (in excess of 2 millions) and referral of microvascular symptoms. She was initially treated with low-dose aspirin and hydroxycarbamide, which was stopped soon because of hydroxyurea-related fever even at low drug dosage (500 mg daily). She was therefore enrolled in a phase II trial of ruxolitinib in advanced PV and ET in December 2008. At study entry, her white blood cell (WBC) count was 13.8 3 10 9 /L, hemoglo- bin 138 g/L, platelet count was 2012 3 10 9 /L. Bone marrow (BM) biopsy documented normal cellularity with unilineage hyperplasia of megakaryocytes and absent reticulin fibrosis. A JAK2V617F mutation was documented, variant allele frequency (VAF) was 39%. Physical examination and an abdominal scan excluded splenomegaly. She referred debilitating symptoms including erythromelalgia, paresthesia, scotomas, headache, osteoarticular pain, and occasionally aquagenic pruritus, all refractory to aspirin. Treatment with ruxolitinib was started at 25 mg twice daily, then it was increased to 75 mg daily, the maximum dosage allowed per protocol, because of persistent throm- bocytosis. Following dosage increase, the patient referred rapid relief of constitutional symptoms and the platelet count stabilized at 800- 900 3 10 9 /L. In April 2014, 65 months while on treatment, the JAK2V617F mutation resulted undetectable despite persistent mild Am J Hematol. 2017;92:833–838. wileyonlinelibrary.com/journal/ajh V C 2017 Wiley Periodicals, Inc. | 833 Received: 20 April 2017 | Accepted: 22 April 2017 DOI: 10.1002/ajh.24775 AJH AJH