UNDERSTANDING THE JAK PATHWAY IN MYELOFIBROSIS
One important signal transduction pathway is the JAK-STAT pathway. Why is it important?
Janus kinases (JAKs) are cytoplasmic kinases that play significant roles in important physiological processes, including hematopoiesis, cell proliferation and proper immune function.
JAK signaling begins when a cytokine or growth factor binds to its transmembrane receptor. This activates specific JAK proteins which subsequently recruit the STATs (Signal Transducers and Activators of Transcription). Once activated, STATs dimerize and travel to the nucleus, where they modulate gene expression.
The unique combination of cytokine or growth factor, receptor, JAK protein and STAT determines a specific cellular response. For instance, JAK1 is believed to signal the cell to produce cytokines, and JAK2 is implicated in cell proliferation.
What happens when JAK signaling goes wrong?
JAK signaling is complex, and may become dysregulated for many reasons, including
- JAK2 mutations
- Receptor mutations (eg, MPL mutations)
- Increased JAK1 signaling
- Excess cytokines
- Damaged intracellular signaling mechanisms (eg, those involving SOCS)
- JAK dysregulation may lead to excessive transcription, cell proliferation and increased levels of inflammatory cytokines. Inhibiting one component of aberrant JAK may reduce dysregulated JAK signaling in general.
Ruxolitinib, the first FDA-approved JAK inhibitor
Ruxolitinib, a kinase inhibitor, inhibits JAK1 and JAK2, which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function.
Jakafi® (ruxolitinib) is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.
IMPORTANT SAFETY INFORMATION
- Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose‐related effects. Perform a pre‐treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated
- Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary
- Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi
- Severe neutropenia (ANC <0.5 X 109/L) was generally reversible by withholding Jakafi until recovery
- Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly
- Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk‐benefit determination
- Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate
- Advise patients about early signs and symptoms of herpes zoster and to seek early treatment
- When discontinuing Jakafi, myelofibrosis symptoms generally return within one week. After discontinuation, some patients have experienced fever, respiratory distress, hypotension, DIC, or multi‐organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation
- Non‐melanoma skin cancers have been reported. Periodic skin examination is recommended for patients who are at increased risk for skin cancer
- The three most frequent non‐hematologic adverse reactions (incidence >10%) were bruising, dizziness and headache
- A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or fluconazole or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy
- Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast‐feed
Please see Full Prescribing Information for Jakafi.