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Therapies

Myelofibrosis (MF) is a life-threatening hematological malignancy characterized by bone marrow fibrosis, extramedullary hematopoiesis, and abnormal cytokine production.¹ Clinically, MF results in anemia and splenomegaly, leading to a variety of symptoms, including fever, night sweats, and weight loss.²

The current treatment of MF is aligned with the burden of the disease along with the disease risk category assessed using prognostic scoring systems.¹

Treatment Options for Low-Risk Patients

Interferons (peginterferon α-2a), hydroxyurea, and immunomodulatory agents such as Revlimid® (lenalidomide) can be used in the treatment of symptomatic low-risk patients with MF. Other drugs such as erythropoiesis-stimulating agents or danazol can also be used in these patients to address the anemia associated with the disease. These drugs, however, are used to target symptoms and not specifically indicated for the treatment of MF.¹

Read more about MF treatment

JAK Inhibitors

The overactive Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway has been an important target in the development of therapeutic strategies for MF.² The JAK family comprises 4 intracellular, nonreceptor tyrosine kinases, JAK1, JAK2, JAK3, and tyrosine-protein kinase 2 (TYK2). These tyrosine kinases play important roles in regulation and homeostasis in hematopoiesis and immunity by activating targets such as STAT.³ Three different JAK inhibitors are currently approved for the treatment of MF: Jakafi^® (ruxolitinib), Inrebic^® (fedratinib), and Vonjo^® (pacritinib).^2,4

Jakafi

Jakafi is a medication developed by Incyte indicated for the treatment of intermediate- or high-risk MF, including primary MF, post-polycythemia vera (PV) MF, and post-essential thrombocythemia (ET) MF in adults.⁵ Both MF and PV are known to be associated with dysregulated JAK1 and JAK2 signaling. The active ingredient in Jakafi is an oral, reversible class I kinase inhibitor, ruxolitinib, that targets both JAK1 and JAK2.^2,5

Jakafi was approved for the treatment of MF by the US Food and Drug Administration (FDA) in 2011 and by the European Medicines Agency (EMA) in 2012, based on the pivotal phase 3 COMFORT-I and COMFORT-II clinical trials.^2,3,6,7 COMFORT-I was a double-blind, placebo-controlled trial with 155 patients in the treatment group and 154 in the placebo group. COMFORT-II was an open-label study that compared 146 patients given Jakafi with 73 patients on the best available therapy (BAT), which was mainly hydroxyurea or glucocorticoids.³ These trials demonstrated the clinical efficacy of Jakafi in reducing spleen size (≥35% spleen volume reduction in 42% of the treated patients) and improving symptoms in patients with MF.^2,8

Common side effects of Jakafi include hematologic adverse reactions, such as thrombocytopenia and anemia, and nonhematologic adverse reactions, such as bruising, dizziness, headache, and diarrhea.⁵

Read more about Jakafi

Inrebic

Inrebic is a medication marketed by Bristol-Myers Squibb that is indicated for the treatment of adult patients with intermediate-2- or high-risk primary or secondary MF. The active ingredient in Inrebic is fedratinib, which is a potent oral kinase inhibitor of JAK2 and FMS-like tyrosine kinase 3 (FLT3).⁹

Inrebic was approved by the FDA in 2019.⁹The National Comprehensive Care Network (NCCN) clinical practice guidelines for the treatment of myeloproliferative neoplasms soon included Inrebic as a treatment option for patients with intermediate-2- or high-risk MF presenting with platelet counts ≥50×10⁹/L, either as initial therapy or second-line therapy for patients previously treated with Jakafi.¹

This therapy was evaluated in the pivotal trial JAKARTA, which was a phase 3, multicenter, randomized, double-blind, placebo-controlled clinical trial. It enrolled 289 patients and assessed both the safety and efficacy of Inrebic. Inrebic was shown to be effective in reducing splenomegaly (≥35% of spleen volume reduction rate compared to that with placebo) and improving MF symptoms.^1,8

The most common adverse reactions following the use of Inrebic include diarrhea, nausea, anemia, and vomiting.⁹

Read more about Inrebic

Vonjo

Vonjo is a medication marketed by CTI BioPharma Corp that is indicated for the treatment of adults with intermediate- or high-risk primary or secondary MF who have a platelet count below 50×10⁹/L.⁴ The active ingredient in Vonjo is pacritinib, which is a potent kinase inhibitor that presents a high specificity to JAK2 and interleukin-1 receptor-associated kinase 1 (IRAK1). The clinical activity of Vonjo in patients with MF results in the inhibition of two distinct pathways, JAK/STAT and toll-like receptor(TLR)/Myddosome/IRAK1.⁸

Vonjo was approved by the FDA in February 2022, and this indication was approved under accelerated approval based on spleen volume reduction.^4,8

The safety and efficacy of Vonjo were assessed in the phase 3 clinical trials PERSIST-1 and PERSIST-2.^10,11 PERSIST-1 allowed the evaluation of both the safety and efficacy of the treatment vs those of BAT in patients with high-risk primary or secondary MF who received no prior JAK2 inhibitor treatment. PERSIST-2 was a randomized, controlled study that included 311 patients with primary or secondary intermediate- or high-risk MF and moderate to severe thrombocytopenia (≤100×10⁹/L).⁸ These trials demonstrated the efficacy of Vonjo in reducing spleen size and improving symptoms in patients with MF.⁸

The most common adverse reactions deriving from Vonjo use are diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema.⁴

Read more about Vonjo

References

1. Talpaz M, Kiladjian JJ. Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis. Leukemia. 2021;35(1):1-17. doi:10.1038/s41375-020-0954-2

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

3. Ajayi S, Becker H, Reinhardt H, et al. Ruxolitinib. In: Martens UM, ed. Recent Results in Cancer Research, vol 212: Small Molecules in Hematology. 3rd ed. Cham: Springer; 2018:119-132. doi:10.1007/978-3-319-91439-8_6

4. Vonjo. Prescribing information. CTI BioPharma Corp; 2022. Accessed December 27, 2022.

5. Jakafi. Prescribing information. Incyte Corporation; 2021. Accessed December 27, 2022.

6. Controlled myelofibrosis study with oral JAK inhibitor treatment: the COMFORT-I trial. ClinicalTrials.gov. August 6, 2009. Updated March 12, 2018. Accessed December 27, 2022.

7. 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 December 27, 2022.

8. Mascarenhas J. Pacritinib for the treatment of patients with myelofibrosis and thrombocytopenia. Expert Rev Hematol. 2022;15(8):671-684. doi:10.1080/17474086.2022.2112565

9. Inrebic. Prescribing information. Bristol-Myers Squibb; 2022. Accessed December 27, 2022.

10. Pacritinib versus best available therapy to treat myelofibrosis. ClinicalTrials.gov. January 23, 2013. Updated September 29, 2020. Accessed December 27, 2022.

11. Pacritinib versus best available therapy to treat patients with myelofibrosis and thrombocytopenia (PAC326). ClinicalTrials.gov. February 5, 2014. Updated November 18, 2021. Accessed December 27, 2022.

Reviewed by Hasan Avcu, MD, on 12/29/2022.

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.

Myelofibrosis (MF)