Ruxolitinib


Continuing Education Activity

Ruxolitinib is a medication used to manage and treat myelofibrosis, polycythemia vera, and steroid-refractory acute graft-versus-host disease. It is in the Janus Kinase inhibitor class of medications. This activity reviews the indications, action, and contraindications for ruxolitinib as a valuable agent in managing myelofibrosis, polycythemia vera, and steroid-refractory acute graft-versus-host disease. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent for members of the interprofessional team in managing patients with myelofibrosis, polycythemia vera, and steroid-refractory acute graft-versus-host disease and their related conditions.

Objectives:

  • Identify the indications for ruxolitinib therapy.
  • Identify the most common adverse events associated with ruxolitinib therapy.
  • Explain the importance of monitoring for patients on ruxolitinib, including complete blood count.
  • Summarize some interprofessional strategies that can improve therapeutic outcomes when using ruxolitinib therapy.

Indications

Ruxolitinib is a Janus-activated kinase inhibitor (JAK) that selectivity inhibits the JAK1 and JAK2 protein kinases.[1] It is an oral medication approved by the FDA to treat myelofibrosis, patients with polycythemia Vera who are intolerant or resistant to hydroxyurea and steroid-refractory acute graft-versus-host disease.[1][2][3] In 2011, based on the results from both the COMFORT–I and COMFORT–II trials, the FDA approved ruxolitinib as a treatment for myelofibrosis. At the time, it was the only therapy that was approved for treating intermediate and high-risk myelofibrosis.[4] 

In 2019 the FDA approved ruxolitinib for steroid-refractory acute graft-versus-host disease for patients older than 12 years old based on the results from STUDY INCB 18424-271, which was a trial involving forty-nine patients. This made ruxolitinib the first-ever drug to be approved for patients with steroid-refractory acute graft-versus-host disease.[5] Ruxolitinib is recently being studied as a potential treatment for coronavirus disease; however, this is still ongoing with no firm approval.[6][7]

Mechanism of Action

Ruxolitinib falls under the drug class known as Janus kinase inhibitors (JAK Inhibitors). It is an inhibitor of the JAK1 and JAK2 protein kinases and works by competitively inhibiting the ATP-binding catalytic site on JAK1 and JAK2.[4] The result of this inhibition is a decrease in proinflammatory cytokines and chemokines, which are usually elevated in myelofibrosis and other inflammatory conditions. Furthermore, JAK1 is involved with regulating interleukin 2 and 6 and TNF alpha, while JAK2 is involved with many cellular functions that include proliferation and differentiation.

Due to its anti-JAK activity, ruxolitinib has been reported to improve splenomegaly that is seen in myelofibrosis and other constitutional symptoms such as fevers, pruritus, and night sweats. However, ruxolitinib is not known to alter the actual bone marrow in any way or cause prolonged survival in myelofibrosis.[4] Moreover, in mice models, ruxolitinib has been shown to decrease inflammation as well as decrease T-cell activation and neutrophil activity.[8]

Administration

Ruxolitinib is taken orally and is available in 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg tablets. The dosing regimen is based on the patient’s individual situation as well as blood results. For example, when treating myelofibrosis, the dose is dependent on the patient’s baseline platelet counts. Patients with myelofibrosis who have a platelet count between 50 to 100 x 10^9/L can take up to a maximum of 5 mg twice daily, while patients with a platelet count of above 100 x 10^9/L can take a maximum of 15 mg twice daily.

In contrast, patients with polycythemia vera should be started on 10 mg twice daily as a starting dose. In non-responders dose can be increased to 25 mg twice daily if hemoglobin, neutrophil counts, and platelets are normal. It is important to keep in mind that ruxolitinib should not be taken with grapefruit or grapefruit juice due to possible interaction causing increased exposure to ruxolitinib; however, patients can take it with other food or without depending on patient preference.[9]

Adverse Effects

During the COMFORT trials, the most common nonhematologic adverse events included ecchymosis, headache, dizziness, abdominal pain, fatigue, and diarrhea. The most common hematological adverse events seen with ruxolitinib during the trials included anemia and thrombocytopenia due to the inhibition of JAK2, which plays a role in erythropoietin and thrombopoietin signaling.[9] 

It has been reported that patients taking ruxolitinib experience higher rates of herpes zoster infection and basal-cell and squamous-cell carcinomas.[10] One study analyzing ruxolitinib in patients with steroid-refractory acute graft-versus-host disease mentioned patients developing anemia, thrombocytopenia, and cytomegalovirus infection while on ruxolitinib.[11]

Contraindications

There are no specific contraindications when it comes to prescribing ruxolitinib; however, there are medications and foods that should be used with caution alongside ruxolitinib. For example, as previously mentioned, grapefruit and grapefruit juice should not be taken alongside ruxolitinib due to possible interaction. Further, when taking strong CYP3A4 inhibitors such as clarithromycin, nelfinavir, and voriconazole alongside ruxolitinib, the ruxolitinib dose should be reduced as all these medications cause increased exposure to ruxolitinib.

Moving on, careful consideration needs to be taken when fluconazole is taken alongside ruxolitinib as it inhibits both CYP3A4 and CYP2C9 and causes increased exposure to ruxolitinib. Hence, the dose of fluconazole should not exceed 200 mg daily when taken alongside ruxolitinib.[9]    

Monitoring

Patients starting or continuing ruxolitinib need to be monitored in multiple domains. Due to the increased risk of infection, all patients require monitoring for signs of infection throughout treatment while taking ruxolitinib. Studies have shown increased rates of urinary tract infections, hepatitis, pneumonia, tuberculosis, and herpes zoster infection; therefore, clinicians should keep this in mind, and patients should be screened for signs of infection.[12] 

Clinicians should perform tuberculosis screening in patients deemed high risk to investigate for any active or latent tuberculosis infection prior to starting ruxolitinib treatment. It is also recommended to check complete blood count in patients with myelofibrosis before starting ruxolitinib and to continue to check this every two to four weeks until the dose of ruxolitinib has stabilized. Once drug levels have stabilized, a complete blood count only needs to be done when clinical suspicion warrants it.[9]

Toxicity

Toxicities that are seen with ruxolitinib mainly include hematological toxicities, which encompass cytopenia and anemia. In one study looking at the efficacy of ruxolitinib in patients with corticosteroid-refractory graft-versus-host disease when cytopenia occurred, it required a dose reduction, interruption in treatment, or permanent cessation of ruxolitinib.[12] Furthermore, when patients’ platelet count drops below 50 x 10^9/L with an original baseline greater than 100 x 10^9/L, ruxolitinib needs to be stopped to avoid further toxicity. The same can be said for patients with a baseline platelet count of 50 x 10^9/L that drops below 25 x 10^9/L. Ruxolitinib can be restarted once counts normalize.

Also, during the COMFORT trials, hemoglobin levels in patients decreased in the first eight to twelve weeks; however, levels improved after twelve weeks. Moreover, patients with renal impairment should have their ruxolitinib dose reduced, as should patients with any hepatic impairment.[9] Lastly, one study looking at the relationship between ruxolitinib and cardiac repolarization found no evidence of ruxolitinib affecting the QT interval.[13]

Enhancing Healthcare Team Outcomes

Ruxolitinib is a medication that is currently being used to treat three different medical conditions and was the first medication for treating patients with steroid-refractory acute graft-versus-host disease. Hence, all healthcare professionals should be aware of its indications and monitoring requirements.

Due to the adverse effects and hematological toxicities associated with ruxolitinib, patients need to be monitored closely by all interprofessional healthcare team members, including clinicians, mid-level practitioners, nurses, and pharmacists. Due to hematological toxicities, it is crucial to monitor complete blood count in these patients until ruxolitinib doses stabilize. All team members should also be asking patients about possible signs of infection due to increased infection rates with ruxolitinib and so that ruxolitinib can be stopped if needed. By working together, the interprofessional healthcare team can allow for optimal treatment and monitoring that will allow patients to carry through with their long-term treatment with ruxolitinib. [Level 5]


Article Details

Article Author

Mawiyah Haq

Article Editor:

Ghufran Adnan

Updated:

5/2/2021 12:21:22 PM

PubMed Link:

Ruxolitinib

References

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[11]

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