Myelofibrosis (MF)

Jakafi® (ruxolitinib) is a medication indicated for the treatment of intermediate- or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF, in adults.¹ Jakafi was approved for MF treatment by the US Food and Drug Administration (FDA) in 2011 and the European Medicines Agency (EMA) in 2012.²

Myelofibrosis is a rare blood malignancy characterized by bone marrow fibrosis, extramedullary hematopoiesis, and an overactive Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway.³ Patients with MF experience splenomegaly, cytopenia, and constitutional symptoms that are often debilitating, such as fever, night sweats, bone and abdominal pain, and weight loss.^3,4

Mechanism of Action 

JAK1 and JAK2 signaling is overactive in myelofibrosis, causing an abnormal and observable level of proinflammatory cytokines.² JAKs can phosphorylate and activate downstream targets such as STAT, and they play an important role in mediating the signaling of cytokines and growth factors in hematopoiesis and the immune system.^1,2 

The active ingredient in Jakafi is ruxolitinib, which is a potent and selective oral inhibitor of JAK1 and JAK2.^1-3 This inhibition starts a downstream attenuation of inflammation caused by constitutive JAK–STAT activation by decreasing the amount of circulating inflammatory cytokines.¹

Read more about MF pathophysiology

Administration

All patients are required to have complete blood count (CBC) testing done immediately prior to the initiation of treatment, as dosage of Jakafi is based on platelet count. A CBC should be performed every 2 to 4 weeks until the dosage is established or as clinically indicated.¹

Each patient’s dosage should be decided through a strict comparison of serum platelet levels and the prescribing recommendations. Doses range from 5 mg twice daily to 20 mg twice daily, though recommendations include therapy interruptions when platelet levels are too low. These recommendations also include guidance on treatment interruption and restarting treatment, treatment modifications for insufficient response or toxicity, and modifications for bleeding, concomitant CYP3A4 inhibitor administration, hepatic impairment, and renal impairment.¹

Get full prescribing information for Jakafi at MPR

Adverse Effects 

Common side effects following Jakafi administration include hematologic (such as thrombocytopenia and anemia) and nonhematologic adverse reactions (including bruising, dizziness, headache, and diarrhea).¹ The use of Jakafi has been associated with severe infections, including opportunistic infections and viral (re)activation, therefore requiring careful monitoring of patients while undergoing treatment.²

Read more about MF complications

Warnings and Precautions 

Jakafi therapy can cause anemia, thrombocytopenia, and neutropenia. These complications are generally reversible through dosage reductions or therapy interruptions, though platelet transfusions may be necessary. Treatment may be linked with increases in lipid parameters, such as total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. These levels should be monitored and treated as needed.¹ 

Several risks have shown an increased incidence, including risk of infection, risk of nonmelanoma skin cancer, secondary malignancies, risk of major adverse cardiovascular events (MACE), and thrombosis.¹

If therapy with Jakafi is interrupted or discontinued, symptoms may intensify. This can be managed with supportive care until treatment may be continued.¹  

Read more about MF prognosis

Safety and Efficacy in Trials

Jakafi was first studied in a phase 1/2 clinical trial involving 153 adult patients with MF.⁵ A reduction in spleen size was observed in this study, and the majority of patients treated with this medication at doses of 10, 15, and 25 mg twice per day presented with at least a 50% improvement in symptoms associated with the disease.⁶ A long-term study of 107 patients who were included in this clinical trial revealed that the median duration of a meaningful reduction in spleen size was approximately 2 years.^2,7

Following this phase 1/2 trial, two phase 3 studies were performed, COMFORT-I and COMFORT-II,^8,9 which led to the approval of Jakafi for the treatment of patients with MF.^2,3 The COMFORT studies included intermediate-2- and high-risk patients who also had palpable splenomegaly at least 5 cm below the costal margin.¹

COMFORT-I (NCT00952289) was a double-blind, randomized, placebo-controlled trial with 155 patients in the Jakafi group and 154 patients in the placebo group. The primary endpoint of this trial was the proportion of patients achieving a ≥35% reduction in spleen volume at 24 weeks. COMFORT-II (NCT00934544) was an open-label, randomized study that studied the clinical efficacy of Jakafi in 146 patients against the best available therapy (BAT; mainly hydroxyurea or glucocorticoids) in 73 patients. The primary endpoint of this trial was the proportion of patients achieving a ≥35% reduction in spleen volume at 48 weeks.^2,3

Both the COMFORT-I and COMFORT-II trials demonstrated the clinical efficacy of Jakafi in reducing spleen size in almost every treated patient. In COMFORT-I, a spleen volume reduction of at least 35% was reported in 41.9% of the treated patients compared to 0.7% in the placebo group. In COMFORT-II, this reduction was observed in 28% of the treated patients, compared to 0% in the BAT group.^4,10 A survival benefit was observed in patients receiving Jakafi in COMFORT-I when compared to those in the placebo group.^2,7

In addition to spleen volume reduction, treatment with Jakafi led to an improvement in MF-related symptoms in both trials. The proportion of patients with a 50% reduction in total symptom score at 24 weeks as measured by the modified Myelofibrosis Symptom Management Form was a secondary endpoint included in COMFORT-I, which was achieved by 46% of the patients treated with Jakafi and 5% of the patients in the placebo group.⁴ Similar results were reported in COMFORT-II.¹⁰

Read more about MF clinical trials

References

1. Jakafi. Prescribing information. Incyte Corporation; 2021. Accessed January 3, 2023.

2. Ajayi S, Becker H, Reinhardt H, et al. Ruxolitinib. In: Martens UM, ed. Small Molecules in Hematology. Recent Results in Cancer Research, vol 212. Springer;2018:119-132. Accessed January 3, 2023.

3. Tremblay D, Mascarenhas J. Next generation therapeutics for the treatment of myelofibrosis. Cells. 2021;10(5):1034. doi:10.3390/cells10051034

4. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/NEJMoa1110557

5. Open label ruxolitinib (INCB018424) in patients with myelofibrosis and post polycythemia vera/essential thrombocythemia myelofibrosis. ClinicalTrials.gov. August 1, 2007. Updated March 12, 2018. Accessed January 3, 2023.

6. Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117-1127. doi:10.1056/NEJMoa1002028

7. Verstovsek S, Kantarjian HM, Estrov Z, et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood. 2012;120(6):1202-1209. doi:10.1182/blood-2012-02-414631

8. Controlled myelofibrosis study with oral JAK inhibitor treatment: the COMFORT-I trial. ClinicalTrials.gov. August 6, 2009. Updated March 12, 2018. Accessed January 3, 2023.

9. Controlled myelofibrosis study with oral Janus-associated kinase (JAK) inhibitor treatment-II: the COMFORT-II trial. ClinicalTrials.gov. July 8, 2009. Updated August 19, 2019. Accessed January 3, 2023.

10. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798. doi:10.1056/NEJMoa1110556

Reviewed by Kyle Habet, MD, on 1/10/2023.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.