REVIEW ARTICLE
Krzysztof Warzocha1, Wojciech Homenda2, Andrzej Pluta3, Tomasz Sacha3, Maria Cioch4,
Marek Dudziński5, Dorota Krochmalczyk6, Joanna Góra-Tybor1, Ilona Seferyńska1,
Monika Joks7, Marta Sobas8
1Department of Haematology, Institute of Haematology and Transfusion Medicine, Warszawa, Poland
2Department of Physiotherapy and Emergency Medicine, Pomeranian University, Słupsk, Poland
3Department of Haematology, Collegium Medicum of Jagiellonian University, Kraków, Poland
4Department of Haemato-oncology and Bone Marrow Transplantation, Medical University of Lublin, Poland
5Department of Haematology, Clinical Voivodeship Hospital no. 1, Rzeszów, Poland
6Clinical Ward of Haematology, University Hospital, Kraków, Poland
7Department of Haematology and Steam Cell Transplantation, University of Medical Sciences, Poznań, Poland
8Department of Haematology, Blood Neoplasm and Bone Marrows Transplantation, Medical University, Wrocław, Poland
Ruxolitinib in the treatment of patients with
myelofibrosis — questions and answers
This is a translation of an article published in Polish in the journal „Hematologia” 2018, vol. 9, no. 4, 269–284.
DOI: 10.5603/Hem.2018.0035
Introduction the presence of the described “driver” mutations, seve-
ral types of mutations in genes regulating epigenetic
Myelofibrosis (MF) is a clonal disease, arising changes can be found (including ASXL1, EZH2, TET2,
as a result of somatic mutations in pluripotent stem DNMT3A, IDH1/2, SRFS2, SRF3B1, TP53). Detection
cells. This leads to proliferation of atypical megakaryo- of at least one mutation in ASXL1, EZH2, SRSF2, and
cytes and disfunction of the bone marrow microenvi- IDH1/2 genes determines high molecular risk (HMR),
ronment. Deregulation of JAK-STAT (Janus kinase associated with shorter overall survival (OS) and higher
— signal transducers and activators of transcription) risk of blastic transformation.
pathway plays a key role in MF pathogenesis. Most Described clinical and molecular features were
patients carry mutation of the tyrosine kinase gene incorporated in the newest prognostic scales, which
JAK2 V617F in exon 14. In patients with wild-type supports optimal clinical management of patients
JAK2 gene, about 10% have mutation in the MPL with MF. In 2009, the International Working Group
W515L/K gene coding receptor for thrombopoietin, — Myeloproliferative Neoplasms Research and Treat-
and in 80% of the remaining patients a mutation in the ment (IWG-MRT) collaboration developed the Interna-
calreticulin gene (CALR) can be detected. All three tional Prognostic Scoring System (IPSS) scale, based on
described mutations lead to constitutive activation of five independent progression risk factors assessed at the
JAK-STAT pathway, which results in increased secre- time of MF diagnosis. This included: age over 65 years;
tion of proinflammatory cytokines, including interleukin presence of systematic symptoms; haemoglobin (Hb)
8, 10, 15, and tumour necrosis factor alpha (TNFa), as concentration lower than 10 g/dl; hyperleukocytosis over
well as increased secretion of growth factors: vascular 25 G/l; and the presence of at least 1% of blasts in pe-
endothelial growth factor (VEGF), basic fibroblast ripheral blood smear. The IPSS scale was subsequently
growth factor (bFGF), platelet-derived growth factor expanded into Dynamic IPSS (DIPSS), which included
(PDGF), and transforming growth factor beta (TGFß). the possibility of acquisition of the aforementioned risk
Excess of enumerated particles increases fibrosis, factors during the course of the disease, and provides
induces extra-medullary haematopoiesis, stimulates prognostic stratification at any point of MF duration.
angiogenesis, and raises constitutional catabolism. Lack In the DIPSS Plus scale, three additional independ-
of either of these three mutations, found in about 10% ent prognostic factors were included: dependency on
of patients, is correlated with poor prognosis. Besides blood transfusions; unfavourable karyotype (trisomy 8;
Address for correspondence: prof. dr hab. n. med. Krzysztof Warzocha, Klinika Hematologii, Instytut Hematologii i Transfuzjologii, ul. Indiry Gandhi 14, 167
02–776 Warszawa, e-mail: warzocha@ihit.waw.pl
Translation: lek. Maciej Kawecki
Oncology in Clinical Practice, 2019, Vol. 15, No. 3, 167–179, DOI: 10.5603/OCP.2019.0021, Copyright © 2019 Via Medica, ISSN 2450–1654
, OncOlOgy in clinical practice 2019, Vol. 15, No. 3
monosomy 7/7q–; i(17q); inv(3); monosomy 5/5q– or of ruxolitinib treatment in patients with MF, including
12p–; rearrangement of 11q23); and thrombocytopaenia groups with different clinical, laboratory, and pathologi-
(platelet count lower than 100 G/l). cal features. Expert opinions are supported with litera-
Until recently, there was no drug to slow MF progres- ture data and provide valuable advice for haematologists
sion or to control systemic symptoms. Ruxolitinib — an in their daily practice.
inhibitor of JAK1/JAK2 kinase — is the first and, at
present, only registered drug for MF that has changed
this calamitous situation. It was approved by the Food Ruxolitinib in patients with liver injury
and Drug Administration (FDA) in the USA in 2011 to
treat patients with intermediate- or high-risk accord- The mean age of patients with MF is 65.9 years
ing to IPSS. In 2012, the European Medicines Agency and with polycythaemia vera (PV) — 60.8 years [1].
(EMA) registered ruxolitinib in the EU to treat pa- This population is characterised by numerous co-
tients with MF, who had splenomegaly and/or systemic morbidities, including the presence of liver injury
symptoms. Both decisions were based on the results of detected in physical examination, laboratory results,
two phase III trials: COMFORT-I and COMFORT-II. or in radiological imaging. With rising age, the rate
The trials proved effectiveness of ruxolitinib in reducing of patients with hepatopathy increases, mostly due
splenic volume and in decreasing constitutive symptoms to toxic (alcohol, drugs) or metabolic (diabetes,
in MF patients with and without V617F mutation. hyperlipidaemias) factors. A significant proportion
Combined analysis of OS after three years of follow-up of hepatopathies arise from common infections with
showed over 30% reduction in death risk in patients hepatitis B virus (HBV) or hepatitis C virus (HVC).
receiving ruxolitinib when compared to best available Another significant factor responsible for hepatopa-
therapy or placebo. The described results and further thy in patients with myeloproliferative diseases is
statistical analyses led to the reimbursing ruxolitinib in extra-medullar haematopoiesis, usually in the liver.
Poland on 1st January 2017. Now the drug is available As a result, hepatomegaly might be present in more
as a part of the Polish National Health Fund Drug than half of all patients with MF. One of the most
Program, which includes patients with both primary common non-haematological adverse events observed
and secondary MF, intermediate (2) or high IPSS risk, with ruxolitinib in registration trials was an increase
splenomegaly (spleen palpable ≥ 5 cm under ribs and/or in aminotransferases activity. This might be observed
splenomegaly present in ultrasound examination), and in about 20–30% of treated patients. Additionally,
systemic symptoms. ruxolitinib elimination might be prolonged in patients
Of utmost importance, ruxolitinib can be used in MF with liver insufficiency [2].
patients scheduled to receive allogenic haematopoietic Evaluation of liver function is required before
stem cell transplantation (allo-HSCT). A decrease in ruxolitinib treatment initiation. Laboratory studies
concentration of proinflammatory cytokines, reduction should include aminotransferase activity and bilirubin
of systematic symptom burden, shrinkage of spleen, and concentration. Patients qualified for ruxolitinib treat-
improvement of physical performance achieved before ment should have bilirubin concentration not higher
transplantation can lead to lower mortality and better than two-fold of the upper limit of normal (ULN) and
outcomes associated with bone marrow transplant. Ac- alanine and aspartate aminotransferase activity lower
cording to European Leukaemia Net (ELN) and Eu- than 2.5-fold of ULN. In patients with aminotransferases
ropean Society for Blood and Marrow Transplantation and/or bilirubin elevated below mentioned thresholds,
(EBMT) guidelines, treatment with ruxolitinib should be detailed diagnostics should be undertaken. This is cru-
initiated at least two months before a planned transplan- cial because ruxolitinib treatment might lead to further
tation. The ruxolitinib dose should be gradually reduced increases in aminotransferase activity due to its hepato-
5–7 days before conditioning and withdrawn one day toxic potential. Patients with elevated liver exams should
prior to the procedure. Retrospective analyses suggest be evaluated for the presence of active HBV or HCV
that the presence of HMR mutations significantly reduce hepatitis (HBsAg, anti-HBc, anti-HCV). Positive results
duration of response to ruxolitinib. Therefore, in pa- should mitigate quantitative assessment for HBV-DNA
tients with HMR mutations, who are qualified for bone and HCV-RNA. Infectious diseases specialist consulta-
marrow transplant, treatment with ruxolitinib should be tion might be required. Another possible cause of liver
restrained to the period before transplantation, without injury might be abuse of non-steroidal anti-inflammatory
postponement of this potentially curative procedure. drugs. The most important task should be withdrawal of
However, ruxolitinib can lead to numerous adverse the over-used drugs. Liver regeneration may be support-
events, both haematological and non-haematological. ed with phospholipids (Esseliv forte, Essentiale forte,
Knowledge of the toxicity profile and proper adverse Essentialne Vital) or silymarin preparations (Sylimarol
event management is required for effective and safe Vita). In patients with primary bone marrow fibrosis,
treatment. The article below presents the clinical aspects who require numerous blood transfusions, secondary
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