Ruxolitinib
JAK 1 and JAK 2 inhibitor in haematology and dermatology
Ruxolitinib is an oral inhibitor of the Janus kinases JAK 1 and JAK 2, introduced in the EU by Novartis in 2012 as Jakavi. Originally approved for the treatment of myelofibrosis, the indication spectrum has been extended over the years to polycythaemia vera (PV) and steroid refractory acute and chronic graft versus host disease (GvHD). Since 2022 a topical formulation (Opzelura cream) has also been available for the treatment of vitiligo and atopic dermatitis.
In haematology, ruxolitinib has fundamentally changed the management of myelofibrosis. Before approval, spleen size reduction and symptom relief in this progressive bone marrow disease were barely achievable with medication. The COMFORT I and COMFORT II trials documented a significant reduction in spleen size, an improvement in constitutional symptoms and a trend toward survival benefit. Robust pivotal trials also exist for GvHD and vitiligo (REACH 2 and 3, TRuE V1 and V2).
Mechanism of Action
The Janus kinases JAK 1, JAK 2, JAK 3 and TYK 2 are intracellular tyrosine kinases that mediate the signalling pathway of many cytokines and growth factors. After the cytokine binds to its receptor, JAKs phosphorylate STAT transcription factors, which translocate to the nucleus and regulate gene expression. In myeloproliferative neoplasms such as myelofibrosis and polycythaemia vera, this signalling pathway is constitutively activated by the JAK 2 V617F mutation.
Ruxolitinib reversibly inhibits the ATP binding site of JAK 1 and JAK 2. Constitutive activation in the malignant cells is attenuated, clonal proliferation decreases and inflammatory cytokines are reduced. The clinical consequences are spleen shrinkage and improvement in fatigue, night sweats, pruritus and early satiety. Ruxolitinib cannot be credited with a curative action on the underlying disease; the effect is primarily symptomatic.
In GvHD, ruxolitinib modulates the cytokine storm that, after stem cell transplantation, activates donor immune cells against recipient tissue. The reduction of interferon γ, interleukin 6 and further cytokines mitigates inflammation in skin, liver and gut. Topically in vitiligo, the substance restores immune tolerance toward melanocytes and promotes repigmentation.
Indications
- Primary and secondary myelofibrosis with symptoms or splenomegaly
- Polycythaemia vera in case of inadequate response or intolerance to hydroxyurea
- Steroid refractory acute and chronic graft versus host disease after allogeneic stem cell transplantation, from the age of 12
- Non segmental vitiligo in adults and children from 12 years of age on face and body, topical cream (Opzelura)
- Moderate atopic dermatitis topically (Opzelura), approved in some countries
Dosage and Administration
Myelofibrosis: starting dose depending on platelet count. For platelets above 200,000 per µl 20 mg twice daily, for 100,000 to 200,000 15 mg twice daily, for 50,000 to 100,000 5 mg twice daily. Dose titration every 2 to 4 weeks according to effect and toxicity. Polycythaemia vera: starting dose 10 mg twice daily, adjustment according to haematocrit and symptoms. GvHD acute and chronic: 10 mg twice daily, dose adjustment according to response and tolerability.
Opzelura cream: twice daily applied thinly to the affected skin areas, at most on 10 percent of the body surface. Duration until clinical improvement is several months up to one year, especially in vitiligo. After application wash hands thoroughly; do not apply to inflamed or infected skin.
Renal impairment: dose reduction and close monitoring in severe impairment. Hepatic impairment: dose reduction in moderate to severe impairment. Older patients: no dose adjustment based on age alone, with increased attention to infection risk and cardiovascular parameters.
Side Effects
Very common: anaemia, thrombocytopenia, neutropenia, elevation of liver enzymes, urinary tract infections, herpes zoster reactivation, respiratory infections.
Common: dizziness, headache, hypertension, weight gain, bacterial and viral infections, flatulence, constipation, elevated cholesterol values.
Uncommon to rare: severe opportunistic infections including tuberculosis reactivation, Pneumocystis pneumonia, hepatitis B reactivation, progressive multifocal leukoencephalopathy (PML, isolated cases), skin cancer including melanoma, non melanoma skin tumours, cardiovascular events, venous thromboembolism, ruxolitinib withdrawal syndrome on abrupt discontinuation with rebound of myeloproliferative symptoms.
Withdrawal syndrome: abrupt discontinuation of ruxolitinib can produce a severe cytokine storm syndrome with fever, chills, multi organ failure and sepsis like pictures. Ruxolitinib must therefore always be tapered at the end of therapy, typically over 1 to 2 weeks, with adjunctive corticosteroids if required.
Interactions
- Strong CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, clarithromycin, ritonavir): marked increase in ruxolitinib plasma levels, dose reduction by 50 percent
- Dual CYP3A4 and CYP2C9 inhibitors (fluconazole): dose reduction also recommended
- CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort): reduced plasma levels, dose increase to be considered
- Live vaccines (MMR, varicella, yellow fever, zoster): contraindicated during therapy, refresh before starting treatment
- Inactivated vaccines: possible, with partially attenuated immune response
- Other immunosuppressants, biologicals: additive infection risk, combination only for specific indications in specialist settings
Special Notes
Screening before start of therapy: tuberculosis, hepatitis B and C serology, blood count, liver values, lipids, ECG, exclusion of active infections. Review vaccination status and refresh live vaccinations before starting therapy.
Red Hand letter for JAK inhibitors 2023: the EMA has issued a warning for the entire JAK inhibitor class regarding elevated cardiovascular events, malignancies, thromboembolism and serious infections, particularly in at risk patients (age over 65, smokers, history of malignancy). For ruxolitinib in the oncological indications myelofibrosis and polycythaemia vera, benefit clearly outweighs risk; in GvHD and vitiligo individual evaluation is more important.
Skin cancer surveillance: incidence of non melanoma skin tumours and melanomas is elevated under long term ruxolitinib therapy. Annual dermatological screening, consistent sun protection and early biopsy of suspicious skin lesions are important.
Pregnancy: ruxolitinib is contraindicated. Women of childbearing potential must use effective contraception, including with topical application. Breastfeeding: not recommended with either oral or topical application because of data on systemic exposure.
Monitoring: blood count every 2 to 4 weeks in the first months, then monthly. Liver values, lipids, blood pressure at regular intervals. Annual infection history and skin examination. If active tuberculosis, severe infection or blood count changes are suspected, pause or discontinue therapy.
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Frequently Asked Questions
Does ruxolitinib cure myelofibrosis?
No. Ruxolitinib alleviates symptoms such as enlarged spleen, fatigue, night sweats and pruritus and can prolong overall survival in studies. The underlying clonal disease is not eliminated, however. The only curative option for myelofibrosis is allogeneic stem cell transplantation, for which ruxolitinib can serve as bridging therapy.
How quickly does Opzelura work in vitiligo?
Initial repigmentation typically appears after 3 to 6 months. A significant improvement on the face is achieved in studies in 30 to 50 percent of patients after 6 months; on the body the results are slower. Therapy usually lasts 12 to 24 months; regular medical follow up and combination with UV phototherapy can strengthen the effect.
Why must I not stop ruxolitinib abruptly?
Abrupt discontinuation can cause a cytokine storm syndrome with fever, chills, organ dysfunction and a sepsis like picture. The phenomenon is known as ruxolitinib withdrawal syndrome. Therapy must therefore be tapered over 1 to 2 weeks, with supportive corticosteroids if required. This rule also applies to planned operations or treatment breaks.
Which vaccinations are safe under therapy?
Inactivated vaccines such as influenza, pneumococcal, COVID 19 and HPV are possible and are expressly recommended. The immune response is partially attenuated but boosters are nevertheless important. Live vaccines such as MMR, varicella, yellow fever and the live zoster vaccine are contraindicated under ruxolitinib; review before starting therapy and refresh if needed.
Sources
- EMA, Jakavi (Ruxolitinib) EPAR
- EMA, Opzelura Ruxolitinib cream EPAR
- AWMF, Guidelines on Myeloproliferative Neoplasms and Vitiligo
- Gelbe Liste, Ruxolitinib active substance profile
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