Cerchione, Claudio

Martinelli, Vincenzo

Nappi, Davide

Pane, Fabrizio

Pareto, Anna Emanuele

Peluso, Ilaria

Picardi, Marco

PubMed

Claudio Cerchione

Ilaria Peluso

Davide Nappi

Anna Emanuele Pareto

Marco Picardi

Vincenzo Martinelli

Fabrizio Pane

Crossref

Annals of Hematology

Ruxolitinib rechallenge in combination with hydroxyurea is effective in reverting cachexia and reducing blood transfusion demand and splenomegaly symptoms in a patient with primary myelofibrosis

CERCHIONE, CLAUDIO

PELUSO, ILARIA

NAPPI, DAVIDE

PARETO, ANNA EMANUELE

PICARDI, MARCO

MARTINELLI, VINCENZO

PANE, FABRIZIO

Archivio della ricerca - Università degli studi di Napoli Federico II

LETTER TO THE EDITORRuxolitinib rechallenge in combination with hydroxyureais effective in reverting cachexia and reducing blood transfusiondemand and splenomegaly symptoms in a patient with primarymyelofibrosisClaudio Cerchione1 & Ilaria Peluso1 & Davide Nappi1 & Anna Emanuele Pareto1 &Marco Picardi1 & Vincenzo Martinelli1 & Fabrizio Pane1Received: 17 December 2016 /Accepted: 28 January 2017 /Published online: 14 February 2017# The Author(s) 2017. This article is published with open access at Springerlink.comKeywords Primarymyelofibrosis . Cachexia . Ruxolitinib .Hydroxyurea . SplenomegalyDear Editor,Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN)whose pathogenesis mainly involves JAK/STAT signaling;approximately 65% of patients carry V617F-JAK2 mutationwith a gain-of-function mechanism [1, 2]. Hydroxyurea isrecommended as the first-line therapy for MF in low andintermediate-1 patients, whereas ruxolitinib, an orally avail-able and selective JAK2-inhibitor, is recommended inInternat ional Prognost ic Scor ing System (IPSS)intermediate-2 and high-risk patients as front-line treatmentof symptoms and splenomegaly in non-transplant candidates[3].We describe the case of a 57-year-old Caucasian man withprimary MF (PMF). The patient was 166 cm in height andweighed 60 kg; before diagnosis, he had been in fair physicalcondition. At diagnosis (November 2012), his main symp-toms were early satiety and a sense of fullness in the left upperabdomen that rapidly deteriorated into cachexia. His bloodcount showed anemia and leukocytosis, and a physical exam-ination revealed splenomegaly (10 cm from costal margin);size measured by ultrasound scan [4] was 22 cm (longitudinaldiameter) × 14 cm (transverse diameter) with a spleen volumeof 2700 mL. Bone marrow biopsy demonstrated grade 3 fi-brosis (MF = 3) and the presence of JAK2-V617Fmutation. InDecember 2012, cytoreductive therapy with hydroxyurea (1and 2 capsules daily on alternate days) was started, obtaining astable disease for fewmonths. After 3months, systemic symp-toms and splenomegaly worsened. The patient was cachectic,his weight had fallen to 47 kg, and his spleen was of hardconsistency and had enlarged, extending to the iliac fossa.He had lack of appetite, he was having difficulty eating, andhis quality of life had deteriorated badly. The severity of thepatient’s condition led to the consideration of other treatmentoptions.The patient refused allogeneic stem cell transplantation af-ter becoming aware of transplant-related risks and peri-transplant mortality. Therefore, treatment with ruxolitinibwas initiated, initially at 10 mg twice daily (bid), and reducedto 5 mg bid in response to grade 3 thrombocytopenia. Thepatient experienced only partial relief from symptoms and,in September 2014, ruxolitinib was discontinued due to severeleukocytosis and very poor compliance. After hydroxyureawas reintroduced to control leukocytosis, there was a consid-erable increase in the need for blood transfusions over subse-quent months (up to 8 units/month; Fig. 1) and spleen sizeincreased, reaching 27.8 cm longitudinal diameter. Followingpoor compliance with gastroprotective drugs, the patient re-quired hospitalization in April 2015 for gastric bleeding, andhydroxyurea therapy was stopped due to severe anemia andthrombocytopenia (30,000/mm3).Hydroxyurea was reintroduced with palliative intent after1 month and, in June 2015, low-dose ruxolitinib (5 mg bid)rechallenge was undertaken, in combination with hydroxy-urea (1 and 2 capsules daily on alternate days for 5 days/week). The ruxolitinib dose was increased to 10 mg bid after1 month, and after 2 months (September 2015), the patient* Claudio Cerchioneclaudiocerc@hotmail.com1 Hematology Azienda Ospedaliera Universitaria Federico II, ViaPansini 5, 80131 Naples, ItalyAnn Hematol (2017) 96:697–699DOI 10.1007/s00277-017-2938-5experienced a dramatic reduction in spleen size with substan-tial relief from symptomatic splenomegaly (longitudinal diam-eter 15.6 cm), control of anemia and leukocytosis, and im-proved nutritional status, with an increase in appetite and anincrease in weight to 55 kg. He regained a decent quality oflife and was able to resume routine activities, such asshopping.Resolution of cachexia and substantial improvement inclinical status continued and, as of May 2016, the patientwas continuing combination treatment with ruxolitinib(10 mg bid) and hydroxyurea.Single-agent ruxolitinib is effective in improving spleno-megaly, systemic symptoms, and overall survival, comparedwith placebo and standard treatment, in patients withintermediate-2 or high-risk MF [5, 6]. As with hydroxyurea,significant anemia and thrombocytopenia are the most com-mon side effects, often requiring discontinuation [7].However, despite the combination of ruxolitinib with acytoreductive agent, we obtained control of leukocytosis andanemia with concurrent increase in platelet count to stable nor-mal values, without the expected synergic cytotoxic effects. Ofinterest, the safe and effective use of combination of ruxolitinibplus hydroxyurea in reducing platelet count and splenomegalyin a patient with uncontrolled thrombocytosis on ruxolitinibmonotherapy has been described [8]. Furthermore, in additionto its primary anti-myeloproliferative action via JAK2 inhibi-tion, ruxolitinib appears to exert a remarkable improvement incachexia status [9], as observed in our case.In conclusion, combined ruxolitinib plus hydroxyurea ef-fectively controlled myeloproliferation without worseninganemia, instead leading to a remarkable decrease in the needfor blood transfusions. Our patient’s cachectic status wasreverted, and overall quality of life dramatically improved.Acknowledgments The authors thank Ray Hill, an independent medi-cal writer, who provided English-language editing and journal styling onbehalf of Health Publishing & Services Srl and Novartis.Compliance with ethical standards Written informed consent wasobtained from the patient for publication.Conflict of interest The authors declare that they have no conflict ofinterest.Open Access This article is distributed under the terms of the CreativeCommons Att r ibut ion 4.0 In ternat ional License (h t t p : / /creativecommons.org/licenses/by/4.0/), which permits unrestricteduse, distribution, and reproduction in any medium, provided you giveappropriate credit to the original author(s) and the source, provide a linkto the Creative Commons license, and indicate if changes were made.References1. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR,Tichelli A, Cazzola M, Skoda RC (2005) A gain-of-function muta-tion of JAK2 in myeloproliferative disorders. N Engl J Med 352(17):1779–1790. doi:10.1056/NEJMoa0511132. Tefferi A, Pardanani A (2015) Myeloproliferative neoplasms: a con-temporary review. JAMA Oncol 1(1):97–105. doi:10.1001/jamaoncol.2015.893. Tefferi A (2014) Primary myelofibrosis: 2014 update on diagnosis,risk-stratification, and management. Am J Hematol 89(9):915–925.doi:10.1002/ajh.23703Fig. 1 Patient clinical history showing platelet (PLT) count (dashed line), white blood cell (WBC) count (solid line), blood units per month (BU/M;broad arrows), spleen longitudinal diameter (black rectangles), and timeline of hydroxyurea (HU) and ruxolitinib administrations698 Ann Hematol (2017) 96:697–6994. Picardi M, Martinelli V, Ciancia R, Soscia E, Morante R, Sodano A,Fortunato G, Rotoli B (2002) Measurement of spleen volume byultrasound scanning in patients with thrombocytosis: a prospectivestudy. Blood 99(11):4228–42305. Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF,Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M,Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO, Lyons RM,Raza A, Vaddi K, Sun W, Peng W, Sandor V, Kantarjian H, investi-gators C-I (2015) Efficacy, safety, and survival with ruxolitinib inpatients with myelofibrosis: results of a median 3-year follow-up ofCOMFORT-I. Haematologica 100(4):479–488. doi:10.3324/haematol.2014.1158406. Vannucchi AM, Kantarjian HM, Kiladjian JJ, Gotlib J, Cervantes F,Mesa RA, Sarlis NJ, PengW, Sandor V, Gopalakrishna P, Hmissi A,Stalbovskaya V, Gupta V, Harrison C, Verstovsek S, Investigators C(2015) A pooled analysis of overall survival in COMFORT-I andCOMFORT-II, 2 randomized phase III trials of ruxolitinib for thetreatment of myelofibrosis. Haematologica 100(9):1139–1145. doi:10.3324/haematol.2014.1195457. Al-Ali HK, Griesshammer M, le Coutre P, Waller CF, Liberati AM,Schafhausen P, Tavares R, Giraldo P, Foltz L, Raanani P, Gupta V,Tannir B, Ronco JP, Ghosh J, Martino B, Vannucchi AM (2016)Safety and efficacy of ruxolitinib in an open-label, multicenter,single-arm phase 3b expanded-access study in patients with myelo-fibrosis: a snapshot of 1144 patients in the JUMP trial.Haematologica 101(9):1065–1073. doi:10.3324/haematol.2016.1436778. Polverelli N, Catani L, Vianelli N, Baccarani M, Cavo M, Palandri F(2015) Ruxolitinib—but not fedratinib—induced extremethrombocytosis: the combination therapy with hydroxyurea andruxolitinib is effective in reducing platelet count and splenomegaly/constitutional symptoms. Ann Hematol 94(9):1585–1587. doi:10.1007/s00277-015-2397-99. Mesa RA, Verstovsek S, Gupta V, Mascarenhas JO, Atallah E, BurnT, Sun W, Sandor V, Gotlib J (2015) Effects of ruxolitinib treatmenton metabolic and nutritional parameters in patients with myelofibro-sis from COMFORT-I. Clin Lymphoma Myeloma Leuk 15(4):214–221 e211. doi:10.1016/j.clml.2014.12.008Ann Hematol (2017) 96:697–699 699

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Ruxolitinib rechallenge in combination with hydroxyurea is effective in reverting cachexia and reducing blood transfusion demand and splenomegaly symptoms in a patient with primary myelofibrosis

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