Using Janus kinase inhibitors in myeloproliferative neoplasms

Introduction

Myeloproliferative neoplasms (MPNs) are chronic clonal blood disorders (i.e. conditions arising from a single abnormal stem cell that expands), which are characterised by the overproduction of mature myeloid cells^​1​. Blood cells are normally produced in the bone marrow through haematopoiesis (i.e. the process of blood cell formation from stem cells). MPNs therefore represent disorders of dysregulated stem cell signalling rather than simply abnormalities of circulating blood counts.  

The three main subtypes of classical Philadelphia chromosome-negative MPNs are:

• Polycythaemia vera (PV) — increased red blood cell production; 
• Essential thrombocythaemia (ET) — increased platelet production; 
• Myelofibrosis (MF) — bone marrow fibrosis (i.e. scarring), cytopenias (i.e. reduced blood counts) and extramedullary haematopoiesis (i.e. blood production outside the bone marrow).

These conditions originate at the level of the haematopoietic stem cell (i.e. a primitive cell capable of forming all blood cell types), and are driven by acquired mutations that confer a proliferative and survival advantage.

The most common driver mutation is JAK2V617F, which is present in over 95% of PV cases and approximately 50–60% of MF and ET cases^​1​. Additional mutations, including CALR and MPL, activate overlapping signalling pathways and contribute to disease heterogeneity.

Importantly, MPNs are increasingly recognised as inflammatory diseases. Patients experience a substantial symptom burden, including fatigue, pruritus (i.e. itching), night sweats, bone pain, fever and weight loss. These symptoms are largely driven by dysregulated cytokine signalling (i.e. chemical communication between cells), rather than blood counts alone.

It is recommended that you read this in conjunction with ‘JAK inhibitors: risks and safety principles’. 

Janus kinases and their relevance

The Janus kinase (JAK) family of proteins are intracellular enzymes that act as signalling switches, transmitting signals from cell surface receptors to the nucleus. Recognition of the central role of JAK2 in MPNs directly led to the development of targeted therapies known as JAK inhibitors (JAKi)^​2–4​. This link between mutation and signalling pathway activation remains fundamental to understanding both the disease and its treatment.

Normal function of the JAK–STAT pathway

The JAK–STAT pathway — a signalling system that transmits messages from the cell surface to the nucleus to control gene activity — plays a central role in:

• Haematopoiesis (i.e. blood cell production);
• Immune regulation (i.e. control of immune responses);
• Cytokine signalling (i.e. communication between cells using signaling proteins).

JAK proteins are intracellular enzymes associated with receptors on the cell surface. While the JAK family includes JAK1, JAK2, JAK3 and Tyrosine kinase 2 (TYK2), JAK1 and JAK2 are most relevant to MPNs and their treatment. Figure 1 illustrates the JAK2 signalling pathway, where a stepwise signalling cascade linking extracellular signals to gene expression within the nucleus ensures controlled blood cell production and immune homeostasis. 

Figure 1: The JAK2 signalling pathway

Aberrant JAK signalling in MPNs

Under normal conditions, activation of the JAK–STAT pathway is dependent on ligand — either cytokine or growth factor — binding^​5​. Dysregulation of the JAK–STAT pathway in MPNs results in persistent and uncontrolled signalling activity, even in the absence of external stimuli^​5​. For example, mutations of the MPL gene cause the MPL receptor to signal continuously without needing thrombopoetin, while the JAK2V617F mutation enables receptor-associated signalling in the absence of ligand binding (see Figure 2)^​1​. Mutant CALR proteins also lead to constitutive activation of the JAK2-STAT signalling pathway^​1​. 

Figure 2: Dysregulation of the JAK–STAT signalling

The strength of aberrant signalling is influenced by the configuration of JAK2 activation. Heterodimeric signalling — involving one mutated and one wild-type JAK2 molecule — typically produces lower-level pathway activation, whereas homodimeric signalling — involving two mutated JAK2V617F molecules — is associated with more sustained and amplified downstream signalling (see Figure 2). This difference in signalling intensity contributes to variation in disease phenotype and progression, including increased proliferative drive and symptom burden in patients with higher mutant allele burden. Together, these processes reinforce one another, driving both disease progression and the characteristic symptom burden seen in MPNs. Clinically, this explains why patients experience fatigue, night sweats, pruritus and weight loss, as these symptoms correlate more closely with cytokine levels than with blood counts alone^​1​.

Clonal haematopoiesis and disease evolution

Many patients develop clonal haematopoiesis of indeterminate potential (CHIP) prior to overt disease. CHIP refers to the expansion of mutated blood cell clones without clinical symptoms^​6​.

It is also associated with increased risk of haematological malignancy and cardiovascular disease.

Using phylogenetic trees, which are genetic lineage maps showing how cell populations evolve over time, MPNs develop through sequential mutation acquisition, clonal selection and eventual dominance of malignant clones^​6​.

Mechanism of action of JAKis

The human body is a complex organism, and as such, it takes energy to maintain its functioning. Adenosine triphosphate (ATP) is the primary energy source for cellular energy use and storage^​7​. JAKis block ATP binding to JAKs, thereby preventing downstream signalling through the JAK–STAT pathway. This interrupts the transmission of signals from cytokine receptors at the cell surface to the nucleus, reducing activation of genes involved in cell growth, survival and inflammation^​8​.

It is important to recognise that these drugs do not simply “turn off” a single mutation. Instead, they act at the level of the signalling pathway itself, meaning their effects extend across both mutated and non-mutated signalling processes — you do not need a JAK2 mutation for these agents to work in PV and MF.

In MPNs, where JAK signalling is persistently activated owing to mutations, such as JAK2V617F, and reinforced by cytokine-driven feedback loops (see Figure 2), JAKis exert several interconnected effects. 

First, inhibition of JAK activity reduces the continuous downstream activation of STAT proteins that drives uncontrolled cell proliferation. This dampens the proliferative signal originating from mutated haematopoietic stem cells. Second, JAK inhibition leads to suppression of cytokine production. Cytokine overproduction is central to both disease biology and symptom burden. By reducing circulating levels of pro-inflammatory cytokines, JAKis disrupt the self-perpetuating inflammatory loop that sustains disease activity. Third, this reduction in cytokine signalling translates into meaningful clinical benefit. Improvements in fatigue, pruritus, night sweats and weight loss correlate closely with reductions in inflammatory cytokine levels, reinforcing the concept that MPN symptoms are largely cytokine-driven rather than purely owing to abnormal blood counts. Finally, JAKis reduce splenomegaly by suppressing extramedullary haematopoiesis (i.e. blood cell production occurring outside the bone marrow), particularly within the spleen^​9​.

Importantly, clinical benefits occur regardless of JAK2 mutation status^​2–4​. This reflects the fact that JAKis target pathway activation rather than a single genetic lesion, suppressing both mutant-driven and cytokine-mediated signalling.

From a mechanistic perspective, JAKis are therefore best understood as pathway modulators that reduce both proliferative signalling and cytokine-driven inflammation, rather than purely mutation-specific therapies. However, this also explains an important limitation. While JAKis improve symptoms and disease control, they do not fully eradicate the malignant clone. The underlying clonal architecture persists, including differences in signalling strength driven by JAK2V617F configuration. These differences may contribute to variability in disease phenotype, progression and response to therapy.

Additional mechanisms of select JAKis

While all JAKis share a common core mechanism, several agents have additional targets that influence their clinical profile and therapeutic niche.

Momelotinib inhibits JAK1 and JAK2 but also targets activin A receptor type I (ACVR1), which is a key regulator of hepcidin, a hormone that restricts iron availability. Inhibition of ACVR1 reduces hepcidin levels, improves iron mobilisation and enhances erythropoiesis (i.e. red blood cell production), thereby addressing anaemia — a major limitation of other JAKis^​10​.

Fedratinib is a more selective JAK2 inhibitor and also inhibits FLT3, which is a receptor involved in cell survival and proliferation. This may contribute to its anti-proliferative effects, particularly in patients with more aggressive disease biology^​11​.

Pacritinib inhibits JAK2 while sparing JAK1, which may help preserve aspects of immune function. In addition, it inhibits interleukin-1 receptor-associated kinase 1 and colony-stimulating factor 1 receptor, both of which are involved in inflammatory signalling and macrophage activity. These additional effects may contribute to its anti-inflammatory and anti-fibrotic properties, as well as help explain its utility in patients with severe thrombocytopenia^​12​. 

Clinical application

Management of MPNs is guided by clinical phenotype, prognostic risk stratification, patient age, performance status and comorbidities. Shared decision-making is central to optimising outcomes, and all patients should be considered for clinical trial enrolment following multidisciplinary discussion, where appropriate.

JAKis are most extensively used in MF but also play a key role in PV, particularly in patients with hydroxycarbamide-resistant or intolerant disease. Their role in essential thrombocythaemia (ET) remains investigational.

Ruxolitinib 

Ruxolitinib is an oral JAK1/JAK2 inhibitor recommended for adults with intermediate-2 or high-risk MF and disease-related splenomegaly or constitutional symptoms^​13​. It is also recommended for adults with polycythaemia vera who are resistant to or intolerant of hydroxycarbamide^​14​.

In MF, ruxolitinib was established through the pivotal COMFORT-I and COMFORT-II trials — the results of which demonstrated significant reductions in spleen volume (≥35% reduction in spleen volume in a substantial proportion of patients) and improvements in symptom burden compared with placebo and best available therapy^​2​.

Long-term follow-up from these studies suggests a modest survival advantage in responding patients, although precise quantification is limited by cross-over design. Retrospective analyses of pooled COMFORT data indicate that earlier initiation of ruxolitinib may be associated with improved outcomes, including more durable spleen responses, reduced rates of cytopenia and prolonged overall survival^​2​.

In PV, ruxolitinib has been evaluated in the 2015 RESPONSE trial — the results of which demonstrated superiority over best available therapy in achieving combined haematocrit control and spleen volume reduction, alongside significant improvements in symptom burden^​15​. The results of the RESPONSE-2 trial, published in 2017 and conducted in patients without splenomegaly, confirmed improved haematocrit control and reduced requirement for phlebotomy^​16​.

Mechanistically, these effects reflect suppression of JAK2-driven erythropoiesis (i.e. red blood cell production) and attenuation of inflammatory signalling. Improved haematocrit control reduces blood viscosity and is associated with a lower risk of thrombotic complications, which is a major driver of morbidity and mortality in PV.

Fedratinib

Fedratinib is a selective JAK2 inhibitor, which is recommended for adults with myelofibrosis and disease-related splenomegaly or symptoms following prior ruxolitinib, where momelotinib is not suitable^​11​.

Clinical efficacy was demonstrated in the findings of the JAKARTA and JAKARTA2 trials, published in 2015 and 2017 respectively, and showed clinically meaningful reductions in spleen volume and improvements in symptom burden in both JAKi-naïve and previously treated populations^​3​. Fedratinib also inhibits FLT3 — a receptor involved in cellular survival signalling — which may contribute to its anti-proliferative effects.

Transition from ruxolitinib requires careful management owing to the risk of withdrawal phenomena associated with abrupt discontinuation.

Momelotinib

Momelotinib is an oral JAK1/JAK2 inhibitor, which is recommended for adults with intermediate-2 or high-risk MF and moderate-to-severe anaemia, either as first-line therapy or following prior ruxolitinib^​10​. 

Efficacy has been demonstrated across multiple phase III trials:

• SIMPLIFY-1 — JAKi-naïve patients^​17​; 
• SIMPLIFY-2 — patients previously treated with ruxolitinib^​18​; 
• MOMENTUM — patients with prior JAKi exposure and symptomatic anaemia^​19​. 

These studies demonstrated improvements in anaemia-related outcomes, symptom burden and splenomegaly, with increased rates of transfusion independence.

Momelotinib is administered at a fixed dose — irrespective of platelet count — with generally stable dose intensity. Gastrointestinal adverse effects and peripheral neuropathy should be discussed during patient counselling.

Pacritinib

Pacritinib is a selective JAK2 inhibitor approved by the US Food and Drug Administration for adults with myelofibrosis and severe thrombocytopenia (platelet count <50 × 10⁹/L)^​20​. It is not currently approved or routinely commissioned by the National Institute for Health and Care Excellence in the UK.

The results of the PERSIST-1 and PERSIST-2 trials, published in 2017 and 2018, respectively, showed that pacritinib demonstrated clinically meaningful spleen volume reduction (≥35%) and improvements in symptom burden compared with best available therapy^​4​. The PACIFICA trial is ongoing in patients with severe thrombocytopenia. Pacritinib should be avoided in patients with active bleeding and withheld prior to planned surgical procedures.

Clinical positioning of JAKis

Despite a shared mechanism of JAK–STAT pathway inhibition, differences in kinase selectivity and additional molecular targets result in distinct clinical profiles and therapeutic positioning (see Table 1^{​10–13​}).

Table 1: Mechanistic profiles and clinical positioning of JAKis in myelofibrosis

Safety considerations

JAKis are associated with a broad and clinically significant spectrum of adverse effects that reflect their central role in immune signalling, haematopoiesis and metabolic regulation. 

While many toxicities represent class effects related to JAK1 and JAK2 inhibition, others are agent-specific and influenced by kinase selectivity and off-target activity. Careful patient selection, baseline risk stratification, and longitudinal monitoring are essential to optimise safety and therapeutic outcomes.

Infectious risk

JAKis impair cytokine-mediated immune responses, particularly pathways involving interferons and interleukins that are critical for antiviral and intracellular pathogen defense. An increased risk of herpes zoster reactivation is consistently observed and may justify vaccination prior to therapy initiation. Opportunistic infections, including tuberculosis, Pneumocystis jirovecii pneumonia (PJP), cytomegalovirus (CMV) reactivation and invasive fungal infections, have been reported^​20,21​.  

The degree of immunosuppression appears greater with agents that inhibit JAK1, reflecting its role in interferon signalling^​20,21​. Pre-treatment screening for latent infections, vaccination review and ongoing vigilance are essential.

Haematological toxicity (i.e. cytopenias)

Cytopenias are among the most common adverse effects of JAKis and represent on-target suppression of normal haematopoiesis, particularly via JAK2 inhibition^​22​. Anaemia is frequently observed, particularly early in treatment with ruxolitinib and fedratinib. Thrombocytopenia and neutropenia may also occur and can be dose-limiting^​22​. These effects may necessitate dose reduction, interruption or supportive measures such as transfusion.

In contrast, momelotinib may mitigate anaemia through ACVR1 inhibition and suppression of hepcidin, improving iron availability and erythropoiesis. Pacritinib demonstrates reduced myelosuppression and is suitable for patients with severe thrombocytopenia^​22​.

Malignancy risk

Long-term JAKi therapy has been associated with an increased incidence of malignancy, particularly non-melanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma^​23​. This is thought to reflect impaired immune surveillance, which is secondary to cytokine pathway inhibition. There is also emerging evidence of increased risk of lymphoproliferative disorders and selected solid tumours, although causality remains incompletely defined. Regular dermatological review, sun protection and adherence to routine cancer screening are recommended.

Cardiovascular and thrombotic risk

Patients with MPNs are inherently at increased risk of thrombosis owing to abnormal blood counts, endothelial dysfunction and systemic inflammation. Although JAKis reduce inflammatory cytokines, major adverse cardiovascular events, including myocardial infarction and stroke, have been observed in broader JAKi populations^​21​. Risk assessment and optimisation of modifiable cardiovascular risk factors should form part of routine care.

Ruxolitinib withdrawal syndrome

Abrupt discontinuation of ruxolitinib may result in withdrawal syndrome, which is characterised by rapid recurrence of constitutional symptoms, splenomegaly and rebound cytokine activation. In severe cases, this may resemble a cytokine storm–like syndrome^​21​. This phenomenon reflects sudden reactivation of suppressed JAK–STAT signalling pathways. Gradual dose tapering, careful monitoring and structured transition to alternative therapy are recommended.

Neurological toxicity: Wernicke’s encephalopathy

Fedratinib is associated with a rare but serious risk of Wernicke’s encephalopathy, which is a neurological condition caused by thiamine deficiency^​24​. Mechanistically, fedratinib interferes with thiamine transport across the blood–brain barrier via inhibition of SLC19A transporters. Clinical features include confusion, ataxia and ophthalmoplegia. Risk is increased in patients with malnutrition, chronic gastrointestinal losses or alcohol misuse. Monitoring of thiamine status and supplementation in at-risk individuals is recommended. Sensory peripheral neuropathy was reported in 10% of patients on momelotinib in SIMPLIFY-1^​17​. Neuropathy is often resolvable or partially resolvable on discontinuation of the drug.

Renal and hepatic impairment

JAKis are variably metabolised via hepatic pathways and cleared renally. Ruxolitinib and fedratinib require dose adjustment in renal impairment. Hepatic dysfunction may increase drug exposure and toxicity. Baseline and periodic monitoring of renal and hepatic function is recommended.

Metabolic effects

Metabolic changes observed with prolonged JAKi use include:

• Weight gain; 
• Dyslipidaemia; 
• Mild hyperglycaemia. 

These effects may reflect reduced inflammatory catabolism and altered metabolic signalling pathways — for example by blocking leptin signalling. Monitoring of metabolic parameters and lifestyle advice should be incorporated into long-term care.

Drug interactions 

JAKis are subject to clinically significant pharmacokinetic interactions, primarily mediated through hepatic metabolism and drug transport pathways. While CYP3A4 metabolism is a shared feature, the relative contribution of metabolic enzymes and transporters differs between agents, resulting in distinct interaction profiles that are relevant to clinical practice. 

Mechanistic overview

Key pathways influencing JAKi pharmacokinetics include:

• CYP3A4 — primary metabolic pathway for most agents; 
• CYP2C9 — secondary pathway (notably for ruxolitinib);
• P-glycoprotein (P-gp) — efflux transporter affecting drug absorption and distribution; 
• Breast cancer resistance protein (BCRP) — efflux transporter; 
• Organic anion transporting polypeptides (OATP1B1/1B3) — hepatic uptake transporters. 

Differences in reliance on these pathways underpin drug-specific interaction risks.

Agent-specific interaction profiles

Ruxolitinib

Ruxolitinib is metabolised predominantly by CYP3A4, with a secondary contribution from CYP2C9:

• CYP3A4 inhibitors (e.g. azole antifungals and clarithromycin)
  lead to increased ruxolitinib exposure, resulting in increased risk of cytopenias; 
• CYP3A4 inducers (e.g. rifampicin and carbamazepine)
  leads to decreased exposure resulting in reduced efficacy. 

Dose reduction is recommended when co-administered with strong CYP3A4 inhibitors.

Fedratinib

Fedratinib is primarily metabolised by CYP3A4 and also acts as a moderate CYP3A4 inhibitor:

• Susceptible to CYP3A4 inhibitors and inducers; 
• May increase exposure of co-administered CYP3A4 substrates. 

In addition, fedratinib inhibits:

• P-gp; 
• BCRP. 

This raises the potential for increased exposure of transporter substrates, including certain anticoagulants and chemotherapeutics.

Momelotinib

Momelotinib demonstrates a broader interaction profile, involving both metabolic enzymes and transporters. It is metabolised via:

• CYP3A4 (primary); 
• Contributions from CYP2C8 and CYP2C9. 

In addition, momelotinib inhibits:

• OATP1B1 and OATP1B3, which are hepatic uptake transporters; 
• BCRP; 
• Weak inhibition of P-gp. 

This creates a clinically relevant risk of interaction with drugs dependent on hepatic uptake transport, particularly:

• Statins (e.g. simvastatin and atorvastatin); 
• Certain anticancer agents. 

Unlike ruxolitinib, momelotinib’s interaction profile extends beyond metabolism into transporter-mediated effects, which may influence both efficacy and toxicity of co-administered drugs.

Pacritinib

Pacritinib is metabolised primarily by CYP3A4 and also exhibits:

• CYP3A4 inhibitory activity; 
• Interaction with P-gp substrates. 

Given its use in thrombocytopenic populations, particular caution is required when co-administered with drugs that increase bleeding risk. For a summary of the pharmacokinetic interaction profiles of JAKis, see Table 2.

Table 2: Pharmacokinetic interaction profiles of JAKis

Role of the pharmacist in monitoring therapy 

Infections monitoring:

• Ensure patient is offered antiviral and PCP prophylaxis as per the trust’s local guidelines; 
• Ensure patient’s vaccination status is checked/liaise with the GP for any boosters;
• Community pharmacists can be important in reinforcing the importance of prophylactic medication.

Malignancy risk:

• Encourage patients to wear sun protection;
• Advise patients to monitor and report skin changes (e.g. basal and squamous cell carcinoma risks);
• Low threshold for screening, if signs or symptoms of secondary malignancies during therapy.

Thrombotic events:

• Assess risk factors and consider anticoagulation/antiplatelet therapy if necessary;
• Liaise with the anticoagulation team for multidisciplinary team discussion, if necessary.

Cytopenias:

• Monitor patient’s symptoms together with regular bloods to monitor for anaemia, neutropenia and thrombocytopenia while on treatment. 

Cardiovascular events:

• Assess risk factors for long-term cardiovascular events (e.g. myocardial infarction and stroke, especially in patients >65 years with additional risk factors);
• Consider cardio-oncology review, if appropriate.

Renal/hepatic impairment:

• Monitor renal and hepatic function, follow protocol guidance and recommend dose adjustments if necessary.

Weight gain and metabolic effects:

• Monitor lipid profile and HbA1C on a periodic basis, as appropriate;
• Dietary counselling, where relevant.

Drug interactions and contraindications:

• Advise on drug interactions and where appropriate consider dose adjustments.

Miscellaneous:

• Remind patients to not stop taking their medication to avoid a withdrawal syndrome.

Combination therapeutic strategies

JAKis in combination with epigenetic therapies

Epigenetic dysregulation is an imporant feature of MPN biology. Combining JAK inhibition with hypomethylating agents aims to target both signalling and transcriptional dysregulation. Examples include:

• Ruxolitinib + azacitidine; 
• Ruxolitinib + decitabine. 

These combinations are particularly relevant in advanced-phase disease and aim to improve disease control and reduce clonal burden.

JAKis in combination with BCL-2 inhibition

Targeting apoptotic pathways represents a rational strategy to overcome resistance. Examples include:

• Ruxolitinib + venetoclax;
• Ruxolitinib + navitoclax.

Navitoclax combinations have demonstrated improvements in spleen volume, symptom burden, and potential reductions in fibrosis and allele burden.

JAKis in combination with anti-fibrotic/microenvironment-targeting agents

Targeting the bone marrow microenvironment and fibrosis is an emerging therapeutic focus. Examples include:

• Ruxolitinib + pelabresib (BET inhibitor); 
• Combinations targeting TGF-β signalling; 
• Agents targeting extracellular matrix remodeling pathways. 

These strategies aim to address disease biology beyond symptom control and may contribute to reversal of fibrosis.

Clonal monitoring and precision medicine

Integration of next-generation sequencing (NGS) into clinical practice is enabling increasingly precise characterisation of clonal architecture and disease evolution in MPNs. This includes:

• Monitoring of driver mutation allele burden, often expressed as variant allele frequency (VAF), which is the proportion of DNA carrying a specific mutation; 
• Identification of high-risk co-mutations (e.g. ASXL1, SRSF2, EZH2) associated with disease progression;
• Early detection of clonal evolution and transformation. 

Changes in VAF over time may provide insights into clonal dominance and treatment response, although reductions in allele burden with current JAKis are typically modest, reflecting their role as pathway modulators rather than disease-eradicating therapies.

Emerging strategies aimed to incorporate molecular monitoring into clinical decision-making, including:

• Identification of patients at higher risk of progression; 
• Dynamic treatment adaptation based on clonal evolution; 
• Integration of mutation profiles into prognostic scoring systems. 

At present, routine use of VAF to guide treatment decisions remains investigational, but it is likely to play an increasingly important role as disease-modifying and mutation-targeted therapies evolve.

Conclusion

JAKis have transformed the management of MPNs by targeting both aberrant signalling and cytokine-driven inflammation.

Their clinical efficacy reflects modulation of both proliferative and inflammatory pathways, resulting in improved symptom control, reduced splenomegaly and enhanced quality of life.

However, these benefits must be balanced against a complex safety profile requiring careful monitoring and multidisciplinary management.

Future developments — including mutation-specific inhibitors and combination strategies — hold promise for improved disease control and potential disease modification.

Pharmacists, pharmacy technicians and support teams play a central role in supporting safe and effective use through monitoring, education and integration of emerging therapies into clinical practice.