Ruxolitinib, an oral JAK1 and JAK2 inhibitor, in myelofibrosis
Introduction: Myelofibrosis (MF) is a debilitating hematologic malignancy characterized by progressive splenomegaly, burdensome symptoms, cytope- nias and shortened survival. Chronic alterations in Janus-associated kinase- signal transducer and activator of transcription (JAK-STAT) signaling have been identified in the pathogenesis of MF, making this pathway a target for drug development. Ruxolitinib is the first JAK1 and JAK2 inhibitor to be approved by the US Food and Drug Administration.
Areas covered: This review describes the characteristics of MF, the current therapeutic options and need for effective therapies, the contribution of aberrant JAK-STAT signaling to various disease-specific manifestations and the pharmacodynamics, pharmacokinetics, efficacy and tolerability of ruxo- litinib. Articles describing MF disease burden and results of ruxolitinib pre-clinical and clinical trials were identified and summarized.
Expert opinion: Conventional MF treatments alleviate some MF symptoms but have limited efficacy, do not modify the natural history of the disease and are not approved for MF. The JAK1 and JAK2 inhibitor ruxolitinib has shown promising results in pre-clinical and clinical trials. In Phase III trials, ruxolitinib was shown to reduce splenomegaly and improve MF-related symptoms. Recent evidence also suggests that ruxolitinib may improve survival. The most common adverse events were anemia and thrombocytopenia, which were managed with dose adjustments (or red blood cell transfusions for anemia).
Keywords: immunomodulatory, JAK2 inhibitor, Janus-associated kinase, myelofibrosis, ruxolitinib
1. Introduction
Myelofibrosis (MF) is a rare hematologic malignancy in which progressive fibrosis interferes with normal blood cell formation [1]. In addition to cytopenias, patients often suffer from splenomegaly and debilitating symptoms, such as fatigue, night sweats, fever, itching (pruritus), abdominal pain, left subcostal pain and discomfort, early satiety, weight loss and bone/muscle pain [2]. Primary myelofibrosis (PMF) is one of the classic Philadelphia chromosome (BCR-ABL1)-negative myeloprolifera- tive neoplasms (MPNs), a classification that includes polycythemia vera (PV) and essential thrombocythemia (ET) [1]. Secondary forms of MF result from PV and ET progression and are also known as post-polycythemia vera myelofibrosis (PPV-MF) and post-essential thrombocythemia myelofibrosis (PET-MF) [3]. Crite- ria for the diagnosis of PMF have been developed by the World Health Organiza- tion [4] and criteria for PPV-MF and PET-MF by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) [5].
MF affects primarily older individuals, with a median age at diagnosis of 64 years [6]. MF is also a very heterogenous disease. Its natural history varies from an indolent course that persists for almost a decade in some to a rapidly progressive disease in others [6-9]. International Prognostic Scoring System (IPSS) risk categories (low, intermediate-1, intermediate-2 and high) are based on the presence at diagnosis of the following five adverse prognostic factors for overall survival: age > 65 years, presence of constitutional symptoms, hemoglobin level < 10 g/dl, leukocyte count
> 25 × 109/l and circulating blast cells > 1%. Table 1 shows the proportions of patients at each risk level and the associated median survival in the population used to establish these categories [6].
Until recently, specific therapies for MF have been largely palliative and limited in efficacy [2]. Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative option; however, it is applicable in only a minority of MF patients [2]. This article reviews the mechanism of action (MOA), pharmacodynamics, pharmacokinetics (PK), efficacy and tolerability of ruxolitinib, a new, first-in-class oral agent approved by the US Food and Drug Administration (FDA) in November 2011 for patients with intermediate- or high-risk MF, including PMF, PPV-MF and PET-MF (Box 1). Canadian market approval was obtained in July 2012 [10], and European market approval was obtained in August 2012 [11].
2. Body of review
2.1 Overview of market
Prior to the approval of ruxolitinib (formerly known as INCB018424), available treatments focused on MF symptoms rather than molecular targets. The symptoms of MF relate predominantly to splenomegaly, cytopenias (mainly anemia) and debilitating constitutional symptoms, which contribute to a considerable disease burden. Progressive splenomegaly and hepatomegaly are believed to result from extramedullary hema- topoiesis. The etiology of debilitating symptoms is thought to be related to high circulating levels of inflammatory and proangiogenic cytokines [12]. This constellation of clinico- laboratory changes is associated with an increased risk of thrombohemorrhagic events, which along with an increased propensity of leukemic transformation, lead to shortened sur- vival [2]. The conventional pharmacologic treatment options, for example, hydroxyurea, corticosteroids, thalidomide, lenali- domide and danazol, are not approved by the FDA for MF and have not been shown to improve survival, or for that matter, offer consistent and durable relief from debilitating symptoms or progressive extramedullary hematopoiesis (such as hepatosplenomegaly) [2].
Medical/surgical procedures for MF include splenic irradi- ation and splenectomy, which aim to relieve splenomegaly- related symptoms. Allogeneic HCT, although potentially curative, is associated with high morbidity and mortality that precludes its use in the vast majority of MF patients [2,13]. Several other compounds are under investigation for the treatment of MF. Those in late clinical development include the Janus-associated kinase (JAK) 2 inhibitors SAR302503 (formerly known as TG101348) [14] and pacritinib (formerly known as SB1518) [15], the JAK1/JAK2 inhibitor CYT387 [16], pomalidomide (a ‘third-generation’ immunomodulatory drug) [17] and histone deacetylase inhibitors (panobinostat and givinostat) [2,13].
2.2 Introduction to the compound
Aberrant signaling of JAK and signal transducer and activator of transcription (STAT) has been identified in patients with BCR-ABL1-negative chronic MPNs. Notably, the JAK2 V617F gain-of-function mutation, which leads to constitutively active JAK2, is often present. Its frequency varies among PMF (~ 60%), PV (> 95%) and ET (~ 60%). Other JAK2 mutations, and mutations in other genes, such as that for myeloproliferative leukemia virus proto-oncogene (thrombopoietin receptor) have also been found [1]. The discovery of JAK mutations and the role of aberrant JAK-STAT signaling in MPNs led investigators to design and study the effects of potential treatments that inhibit both JAK1 and JAK2. Ruxolitinib is a potent small-molecule JAK1 and JAK2 inhibitor.
2.3 Chemistry
The chemical name of ruxolitinib phosphate is (R)-3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentyl- propanenitrile phosphate. It has a molecular weight of 404.36 and is soluble in aqueous buffers of pH 1 — 8. Tablets are stable at 20 — 25◦C with excursions permitted between 15 and 30◦C [18].
2.4 Pharmacodynamics
2.4.1 JAK-STAT activity in MF
JAKs are intracellular non-receptor tyrosine kinases that are required for signaling of a number of cytokines and growth factors and include four family members: JAK1, JAK2, JAK3 and TYK2 [13]. In most cases, two JAK family members are required for signaling with the exception of some growth factors, such as erythropoietin and thrombopoietin, which require only JAK2. Indeed, when activated by ligand–receptor dimers translocate to the nucleus to regulate the transcription of genes involved in cell growth, differentiation, proliferation and survival (Figure 1) [13]. In MF, the activity of both JAK1 and JAK2 are increased resulting in an overall persistent dysregulation of the JAK-STAT pathway [19]. Although the JAK2 V617F mutation is present in about half of MF cases, evidence indicates that dysregulated JAK-STAT activity is present in a majority of MF patients, regardless of JAK2 mutation status [13]. Consequently, JAK1 and JAK2 have become the focus of study for pharmacologic intervention in MF.
2.4.2 Ruxolitinib pharmacodynamic correlates Ruxolitinib is a potent inhibitor of JAK1 and JAK2, the molecular effect of which can be measured by examining the inhibition of STAT phosphorylation. In whole blood samples from ruxolitinib-treated healthy subjects, in vitro cytokine- stimulated STAT3 phosphorylation was inhibited in a dose- and time-dependent manner [20]. In blood samples from ruxolitinib-treated MF patients in a Phase II clinical trial, dose-dependent inhibition of STAT3 phosphorylation was evident 2 h after dosing (Figure 2A), and in patients who received ruxolitinib 25 mg twice daily (b.i.d.), phosphorylated STAT3 was reduced to levels similar to those of healthy vol- unteers following 28 days of therapy (Figure 2B). In addition, ruxolitinib treatment reduced levels of circulating pro- inflammatory cytokines in patients with MF; changes in selected cytokines correlated with symptomatic improvement. Ruxolitinib inhibition of proinflammatory cytokines does not depend on JAK2 mutation status, as these effects were seen in patients both with and without the JAK2 V617F mutation [21].
2.5 Pharmacokinetics and metabolism
The single-dose PK parameters of ruxolitinib in fasted, healthy subjects are summarized in Table 2. Single oral doses were rapidly and almost completely (96%) absorbed, and maximum serum concentrations (Cmax) were reached 1 — 2 h after dosing [20,22]. Cmax and area under the concentration-versus- time curve (AUC) were dose-proportional from 5 to 200 mg. Although consumption of a high-fat, high-calorie meal at the time of administration of a single dose of ruxolitinib 25 mg slowed its absorption and tmax, the AUC did not change signifi- cantly from that obtained in the fasted state, indicating that ruxolitinib can be given with or without food [20].
The elimination half-life of ruxolitinib was approximately 3 h in healthy subjects. Ruxolitinib has a low, dose-independent oral dose clearance of approximately 20 l/h, a moderate apparent volume of distribution (range, 75 — 91 l for doses from 5 to 100 mg) and a high rate of plasma protein binding (97%). Results of multiple-dose PK studies in healthy subjects indicated no appreciable accumulation of ruxolitinib [20].
Ruxolitinib is metabolized by CYP3A4 [23] and has two active metabolites, which have one-fifth and one-half of its activity [18]. Elimination is mainly via metabolism and excre- tion is mainly via the kidney, with 74% excreted in urine and 22% excreted in feces [22]. PK parameters are similar in healthy subjects and subjects with renal impairment; how- ever, the plasma AUC of ruxolitinib metabolites increases with increasing severity of renal impairment. Dose reduction is recommended for patients with moderate or severe renal impairment with a platelet count 100 × 109 to 150 × 109/l. Hepatic impairment is associated with increases in ruxolitinib exposure (AUC) proportional to the severity of impairment; therefore, dose reduction is required for patients with hepatic impairment and a platelet count 100 × 109 to 150 × 109/l [18]. Strong CYP3A4 inhibitors (ketoconazole) and inducers (rifampin) also alter the PK of ruxolitinib [23]. The ruxolitinib US prescribing information advises the use of a lower starting dose (10 mg b.i.d.) with strong CYP3A4 inhibitors, provided the platelet count is ‡ 100 × 109/l; concurrent administration of strong CYP3A4 inhibitors is not recommended if the platelet count is < 100 × 109/l [18].
2.6 Clinical efficacy
The clinical efficacy of ruxolitinib was established in a Phase I/II study [21] and two pivotal Phase III trials, the COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Therapy (COMFORT)-I and COMFORT-II [24,25]. The Phase I/II, open-label study, which was conducted at MD Anderson Cancer Center (MDACC) and the Mayo Clinic-Rochester, enrolled 153 patients with PMF, PPV-MF and PET-MF and Eastern Cooperative Oncology Group score £ 2; 65% had high-risk disease (by the Lille system: hemoglobin < 10 g/dl and leukocytes < 4 × 109 or > 30 × 109/l) and 82% had the JAK2 V617F mutation [21]. Within the first 3 months of treatment, an objective response (‡ 50% reduction in a ‡ 50% reduction in palpable spleen length (IWG-MRT) with median response duration of 166 weeks. Ruxolitinib treatment was associated with median symptom reductions of about 60% over more than 2 years [28].
COMFORT-I was a randomized (1:1) double-blind study of ruxolitinib versus placebo in 309 patients in the USA, Australia and Canada [24]; COMFORT-II was a randomized (2:1) open-label study of ruxolitinib versus best available therapy (BAT) in 219 patients in Europe [25]. Key eligibility criteria were similar in both studies and included patients with intermediate-2 or high-risk PMF, PPV-MF or PET-MF [24,25]. The primary end point of each trial was a ‡ 35% reduction in spleen volume (SV) from baseline by magnetic resonance imaging (MRI) or computed tomogra- phy, evaluated at week 24 in COMFORT-I and week 48 in COMFORT-II [24,25].
Significantly greater proportions of patients achieved the primary end point with ruxolitinib versus comparators: COMFORT-I, 41.9% with ruxolitinib versus 0.7% with placebo (p < 0.001) [24]; COMFORT-II, 28% with ruxoliti- nib versus 0% with BAT (p < 0.001) [25]. Nearly all ruxolitinib-treated patients experienced reductions in SV; by contrast, almost all placebo-treated patients had increased or unchanged SV, and almost half of BAT-treated patients had increased SV (Figure 3) [24,25]. Ruxolitinib responses were durable (‡ 48 weeks) [24,25] and rapid, with a median time to response of 12.3 weeks in COMFORT-II (MRI palpable splenomegaly) was achieved by 44% of patients with an enlarged spleen at study entry. Post hoc analyses indi- cated similar response rates among patients with and without the JAK2 V617F mutation and among patients with PMF, PPV-MF and PET-MF [21]. An independent analysis conducted at the Mayo Clinic-Rochester showed long-term response rates of 29, 21 and 63% for spleen size, anemia and consti- tutional symptoms, respectively, using criteria from the IWG-MRT [26,27]. Long-term data obtained at MADCC showed that 61 of 97 patients with splenomegaly achieved
IPSS risk category or baseline spleen size [29,30].
Ruxolitinib treatment also improved patient-reported outcomes as indicated on symptom and quality of life (QoL) assessments. In COMFORT-I, the modified Myelofi- brosis Symptom Assessment Form version 2.0, a validated instrument created specifically to evaluate QoL and symp- toms in MF, showed that significantly (p < 0.001) more ruxolitinib-treated patients (45.9%) achieved a ‡ 50% reduction in the total symptom score (TSS; combined score for abdominal discomfort, pain under ribs on left side, early satiety, itching, night sweats and bone/muscle pain) versus placebo-treated patients (5.3%) [24]. Improvements in TSS, European Organisation for the Research and Treat- ment of Cancer (EORTC) QoL Questionnaire-Core 30 (QLQ-C30)-Global Health, Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue and Patient Global Impression of Change (PGIC) were apparent with even small reductions in SV (i.e., 10%) [31]. The COMFORT-II study incorporated use of the EORTC QLQ-C30 and Functional Assessment of Cancer Therapy- Lymphoma; ruxolitinib-treated patients on average experi- enced greater improvement in Global Health Status/QoL than BAT-treated patients, including significant improve- ment in role functioning. Ruxolitinib treatment also improved MF-related symptoms (appetite loss, dyspnea, fatigue, insomnia and pain), whereas BAT treatment was associated with no improvement or worsening of these symp- toms [25]. Differences between treatment groups in physical and role functioning, fatigue and appetite loss were observed at week 8 and maintained through week 48 [32].
In COMFORT-I at a median follow-up of 51 weeks, there were 13 (8.4%) deaths in the ruxolitinib group and 24 (15.6%) in the placebo group. A survival analysis at this time suggested a benefit for ruxolitinib over placebo (hazard ratio [HR] = 0.50; p = 0.04) [24]. In COMFORT-II, at a median follow-up of 61 weeks, ruxolitinib was not associated with a significant increase in survival probability versus BAT (HR = 1.01; 95% confidence interval [CI], 0.32 -- 3.24). How- ever, the interpretation of the survival data is confounded by insufficient statistical power, lack of survival information on patients who discontinued study participation early and were lost to follow-up before enactment of a protocol amendment, as well as the small number of patients randomized to BAT. As the COMFORT-II clinical database matures and more events (deaths) accumulate over time, it remains to be seen whether survival differences between the two trial arms might emerge at the time of future analyses [25]. Retrospective survival analyses based on long-term data from the ruxolitinib Phase I/II study yielded inconsistent results between the two study sites. In an analysis at MDACC that compared
107 patients treated with ruxolitinib with 310 matched historical controls who met study enrollment criteria, ruxoliti- nib was associated with a significant survival advantage (HR = 0.58, p = 0.005) [28]. By contrast, investigators at Mayo Clinic-Rochester observed no significant differences in survival rates between 51 study participants and 410 controls (p = 0.58) [26]. As described below, there was a greater discontinuation rate at the Mayo Clinic-Rochester study site that may in part explain these differences [28]. To date, there have been no differences in leukemic transformation rates between ruxolitinib (COMFORT-I, two cases; COMFORT-II, no cases) and placebo (no cases) or BAT (two cases) [24,25].
2.7 Safety and tolerability
In the Phase I/II study, non-hematologic toxicities were of low grade and frequency (< 10%), and the main hematologic toxi- cities were anemia and dose-limiting grade 3 or 4 thrombo- cytopenia [21]. However, although long-term data showed that only 4 of 158 patients discontinued due to unacceptable toxicity in the Phase I/II trial [28], discontinuation rates (for any reason) were substantially higher at Mayo Clinic-Rochester than at MDACC (89 vs 46% at 3 years) [26,28].
In COMFORT-I, the most common non-hematologic adverse events (AEs) (almost all grade 1 or 2) that were more frequent with ruxolitinib treatment than placebo were ecchymosis, dizziness and headache (Table 3). The most common hematologic AEs (overall and grade 3 or 4) were thrombocytopenia and anemia. Both types of events were manageable with dose modifications or treatment interrup- tions or, in the case of anemia, with red blood cell transfu- sions. Approximately 50% of grade ‡ 3 thrombocythemia and anemia events occurred during the first 8 weeks of the study. During this period, mean hemoglobin levels fell to 95 g/l before stable concentrations of approximately 101 g/l were reached at week 24 [24]. Overall similar results were obtained in COMFORT-II [25].
The dosing protocol used in COMFORT-I and -II speci- fied starting dose for ruxolitinib based on baseline platelet count (15 and 20 mg b.i.d. for platelet counts 100 × 109 to 200 × 109/l and > 200 × 109/l, respectively) and mandated maximum restarting doses after treatment interruptions (Table 4). Corresponding dose adjustment recommendations have been incorporated in the ruxolitinib US prescribing information [18]. During treatment, blood counts should be monitored every 2 — 4 weeks until a stable dose of ruxolitinib is reached, and subsequently as clinically indicated. If treat- ment is resumed after treatment interruptions, a starting dose of 5 mg b.i.d. is recommended for patients with a plate- let count of 50 to <75 × 109/l or absolute neutrophil count (ANC) of 0.5 to <0.75 × 109/l. For patients with baseline platelet counts of 50 × 109 to 100 × 109/l, preliminary data from a Phase II trial support a starting dose of 5 mg b.i.d., with subsequent dose titration to optimize safety and efficacy [33]. At the time of that analysis, most patients had reached stable final (eventually attained) doses of 10 mg b.i.d. or higher, and mean hemoglobin levels remained consis- tent over time. Although the number of patients was relatively small (N = 41), improvements in spleen size and symptoms were overall consistent with the results from COMFORT-I,suggesting that 10 mg b.i.d. may be an effective dose with a low risk of worsening anemia.
Patients should be evaluated and monitored for risk of serious bacterial, mycobacterial, fungal and viral infections [18]. At one Phase II study site (51 of 153 total study patients), serious AEs were reported following discontinuation in five patients who required hospitalization [26]; however, these events were not observed in patients who discontinued at the other Phase II site. In addition, there was no evidence of any specific pattern of adverse withdrawal effects on stopping treatment in the COMFORT trials. Nonetheless, MF-related symptoms returned to baseline levels over approximately 1 week after treatment interruption. According to the ruxoli- tinib US prescribing information, gradual tapering of the dose may be considered when discontinuing treatment for reasons other than thrombocytopenia [18].
2.8 Regulatory affairs
Ruxolitinib is approved by the FDA for the treatment of patients with intermediate- or high-risk MF, including PMF, PPV-MF and PET-MF [18]. The safety and efficacy of ruxolitinib in pediatric patients have not been established [18]. Health Canada and the European Commission approved ruxolitinib for the treatment of disease-related splenomegaly or symptoms in adult patients with MF [10,11].
3. Conclusions
The JAK1 and JAK2 inhibitor ruxolitinib is a new targeted treatment for patients with MF. With the exception of alloge- neic HCT, traditional treatments for this progressive malig- nancy were palliative and of limited benefit. Ruxolitinib inhibited the dysregulated JAK-STAT signaling present in JAK2 V617F-positive and -negative MF patients and resulted in clinically meaningful and durable reductions in spleno- megaly, as well as marked improvements in measures of MF-related symptoms and health-related QoL. Data from COMFORT-I also suggested that ruxolitinib may improve survival. Side effects were manageable with treatment inter- ruption and dose reduction. This new agent has the potential to offer meaningful short-term and long-term benefits to patients with MF, and based on its MOA, may also prove beneficial in other malignancies.
4. Expert opinion
MF is a chronic, progressive hematologic malignancy mainly involving older individuals. Until November 2011, there were no approved medications for MF. Allogeneic HCT is a potentially curative treatment option; however, it has limited applicability. A large proportion of patients are too old at the time of diagnosis to be considered for HCT. For those in the transplant age group, donors are identified only in a small proportion of patients, and some are further excluded because of a high burden of comorbidities and poor performance status. In the authors’ experience, only 5 -- 10% of patients in the transplant age group are able to undergo HCT (VG, unpublished data from Princess Margaret Hospital).
Conventional treatments for MF are mainly directed at alleviating symptoms of the disease and are not FDA- approved. None of the conventional treatments has been shown to modify the natural history of MF. The efficacy of these agents is limited and well-conducted prospective studies on these agents are scarce in MF; thus, use is mainly physi- cian-dependent. Therefore, novel efficacious treatments that have the potential to alter the natural history of the disease are needed.
Discovery of the JAK2 V617 mutation has paved the way for drug development in patients with MF. Dysregulated JAK-STAT signaling due to loss or gain of function mutations is central to the pathophysiology of MF. Ruxolitinib is the first-in-class JAK1/JAK2 inhibitor approved by the FDA. At present, at least 11 JAK inhibitors are in human clinical trials. The clinical benefits of ruxolitinib are related to reducing the burden of troublesome symptoms of MF by reduction of splenomegaly and inflammatory cytokines, and to improv- ing QoL and overall well-being. Ruxolitinib is efficacious irrespective of JAK2 mutation status. Anti-JAK1-mediated downregulation of proinflammatory and proangiogenic cytokines is an important effect of ruxolitinib that may have disease-modifying properties. While a trend toward improve- ment in survival that is statistically significant over placebo (HR = 0.5; nominal p = 0.04) was seen in the COMFORT- I study, because of the cross-over design of the COMFORT studies (in particular, additional confounding factors in COMFORT-II), longer follow-up data are needed to better define the degree of benefit on survival with the use of ruxolitinib in MF.
Ruxolitinib is generally well tolerated. Its main toxicities are hematologic (anemia and thrombocytopenia) and their inci- dence can be reduced by individualizing the dose according to baseline platelet count and clinicolaboratory monitoring during the patients’ follow-up. In the COMFORT-I study,
patients with baseline platelet counts ‡ 100 × 109/l receiving initial doses of 15 or 20 mg b.i.d. experienced an initial drop in mean hemoglobin (with a nadir of 95 g/l at 8 -- 12 weeks) that subsequently recovered to near baseline levels; platelet counts declined in the first 8 -- 12 weeks and then remained somewhat stable over time. Therefore, patients should be monitored frequently and managed appropriately with dose adjustments for decreases in platelet counts and/or with RBC transfusions for decrements in hemoglobin. In COMFORT- I, the median final (eventually attained) doses were 10 and 20 mg b.i.d. in patients starting at 15 and 20 mg b.i.d., respec- tively (Incyte Corp., data on file). It is interesting that in a separate ongoing Phase II study in patients with baseline platelet counts between 50 × 109 and 100 × 109/l, a starting dose of 5 mg b.i.d. with careful titration to 10 mg b.i.d. (or higher) did not result in an appreciable decrease in mean hemoglobin values.
It is important to educate patients that MF-related symp- toms may return to baseline levels within 7 days of interrup- tion. If discontinuation of ruxolitinib is required for reasons other than thrombocytopenia, gradual tapering of dosing may be considered. Long-term data on the use of ruxolitinib are desirable but limited at present.
A key question is the positioning of JAK1/JAK2 inhi- bitor therapy in the clinical management of MF. In clinical practice, one should ideally first determine whether a patient is a suitable candidate for HCT. If a patient is not suitable, then the clinician should carefully evaluate the associated symptom burden, particularly the symptoms related to splenomegaly, but also the cytokine-related symptoms, which include the classic constitutional symp- toms of night sweats, fever and weight loss. For patients who demonstrate significant symptoms in either category (splenomegaly- or cytokine-related), JAK1/JAK2 inhibitor therapy is recommended. For potential HCT-eligible patients, the decision should be made about choice of primary therapy (HCT vs JAK1/2 inhibitor therapy) after careful review of a given patient’s comorbidities,STAT5-IN-1 perfor- mance status, donor–recipient matching and personal risk tolerance [34].