Myelofibrosis (MF)

The World Health Organization (WHO) classifies myelofibrosis (MF) as a myeloproliferative neoplasm. It is characterized by bone marrow fibrosis, splenomegaly, constitutional symptoms, and a tendency to transform into acute leukemia.¹

Pharmacological Interventions

JAK Inhibitors

Janus-associated kinase (JAK) inhibitors target the gain-of-function genetic mutation (VG17F) in JAK2 that is present in approximately 50% of all patients with MF.² While JAK inhibitors do not necessarily improve cytopenias in patients with MF or modify the progression of the disease in terms of blast phase transformation, JAK inhibitors decrease activation of the JAK-STAT signaling pathway that promotes inflammatory processes that exacerbate bone marrow fibrosis and triggers further genetic mutations. As both processes may contribute to disease progression, inhibition of this pathway can improve prognosis. JAK inhibitors are also associated with a reduction of splenomegaly and improvement of symptoms among patients with MF.³

Three JAK inhibitors have been approved by the US Food and Drug Administration (FDA) to treat MF, including Jakafi® (ruxolitinib), Inrebic® (fedratinib), and Vonjo® (pacritinib).^4,5 Vonjo treats intermediate- and high-risk patients with primary or secondary MF caused by underlying polycythemia vera or essential thrombocythemia.⁵

Read more about MF therapies

FGFR Inhibitors

Fibroblast growth factor receptor (FGFR) inhibitors prevent the phosphorylation and signaling activation of FGFR types 1, 2, and 3, resulting in reduced cell viability in cancer cell lines. This type of inhibitor can be used in patients with an FGFR1 rearrangement who have refractory or relapsed myeloid neoplasms such as MF.⁶

Other Pharmacological Interventions 

Many medications target the symptoms of MF. Medications such as androgens and corticosteroids may be used to treat severe anemia, a symptom of MF.⁷ Thalidomide with prednisone may help control anemia, reducing or eliminating the need for erythrocyte transfusions.⁷ Revlimid® (lenalidomide), a potent analogue of thalidomide, may reduce anemia, thrombocytopenia, and splenomegaly in patients with MF.⁷ Other chemotherapies, such as hydroxyurea, cladribine (sold as Mavenclad® or Leustatin®), interferon alfa, and busulfan, can be used primarily to treat thrombocytosis, leukocytosis, or organomegaly.⁷

Allogeneic Stem Cell Transplantation

The only potentially curative treatment for MF is allogeneic stem cell transplantation (SCT), resulting in long-lasting disease remission and regression of bone marrow fibrosis. However, due to the risk of post-transplant mortality, study results indicate that allogeneic SCT should be considered only for high-risk or intermediate-2-risk patients with MF, while lower-risk patients should receive nontransplant approaches and individual counseling.^8,9 

The international working group consisting of 23 representatives from the European Blood and Marrow Transplantation Group (EBMT) and the European LeukemiaNet (ELN) published their evidence-based best practice recommendations in 2015 regarding allogeneic SCT for patients with primary MF.¹⁰ According to the EBMT/ELN recommendations, clinicians should consider allogeneic SCT for patients with primary MF who meet the following requirements¹⁰:

• Aged <70 years with high- or intermediate-2-risk disease
• Aged <65 years with intermediate-1-risk disease who present with:
  • Refractory, transfusion-dependent anemia,
  • Adverse cytogenetics, or
  • >2% blast counts in the peripheral blood.

Pretransplant splenectomy should be considered on a case-by-case basis in candidates for allogeneic SCT.¹⁰

Read more about MF guidelines

Blood Transfusion

Intravenous blood transfusions are performed as a supportive therapy in the treatment of MF to maintain and restore healthy blood cell counts.¹¹ Patients with anemia may require red blood cell transfusions,¹² while those with thrombocytopenia may require platelet transfusions.¹³

The need for repeated transfusions may result in allergic reactions or the accumulation of iron in the body, which may damage tissues in the liver, heart, or pancreas. Chelating agents may be needed to remove excess iron in the body due to blood transfusions.¹¹

Both transfusion-dependent anemia and thrombocytopenia are poor prognostic factors in MF.^12,13 In the Dynamic International Prognostic Scoring System (DIPSS) prognostic model used for risk stratification of patients with MF, hemoglobin levels under 10 g/d are assigned 2 points of risk, whereas all other risk factors are assigned 1 point, which indicates the weighted importance of anemia in influencing patient outcomes.¹²

Read more about MF prognosis

Splenectomy

Patients with massive splenomegaly, causing symptoms of abdominal discomfort, portal hypertension, severe thrombocytopenia, and transfusion-dependent anemia, are potential candidates for splenectomy.^14,15 

Splenectomy increases the risk of morbidity and mortality due to infections, hemorrhage, and thrombosis in patients with MF. An additional risk factor following splenectomy is the higher rate of transformation of MF to acute myeloid leukemia (AML). One study reported that 26.4% of patients who underwent splenectomy experienced MF transformation to AML compared to 11.4% of patients who did not undergo the procedure.¹³ Therefore, the decision to perform a splenectomy in this patient population must be undertaken with great caution.^14,15

To help clinicians determine which patients with MF are likely to benefit the most from splenectomy, researchers have identified 4 risk factors associated with shorter postsplenectomy survival.^14,16 These factors include¹⁶:

• Age >65 years
• Continuous need for red blood cell transfusions
• ≥5% circulating blasts in the peripheral blood
• Leukocyte count >25 x 10⁹/L

Before splenectomy, clinicians should obtain a platelet count and complete blood cell count (CBC) and rule out disseminated intravascular coagulopathy (DIC). Patients with significant thrombocytosis should undergo cytoreductive therapy to reduce platelet counts to the required reference range prior to surgery. In contrast, patients with MF and thrombocytopenia may need platelet transfusions or cryoprecipitate infusions to meet coagulation parameters before surgery.¹⁴

Potential postsplenectomy complications include marked hepatomegaly and thrombocytosis, which can be treated with cytoreductive therapy and close monitoring.¹⁴

Read more about MF surgical management

Radiation Therapy

Radiation therapy may be used to treat patients with MF who experience bone pain due to tumors, periostitis, or symptomatic extramedullary hematopoiesis.¹⁷ Radiation may also be used to shrink the size of the spleen in patients with symptomatic splenomegaly or splenic infarction. However, the effects of radiation therapy are typically short-lived, with a median duration of 6 months.¹⁷ Additionally, side effects following radiation therapy include increased risks of prolonged pancytopenia and intra-abdominal hemorrhaging. Due to these serious adverse effects, splenic irradiation should be reserved for patients who are not candidates for splenectomy.¹⁷

Read more about MF complications

References

1. Tremblay D, Mascarenhas J. Next generation therapeutics for the treatment of myelofibrosis. Cells. 2021;10(5):1034. doi:10.3390/cells10051034
2. Lal A. Primary myelofibrosis treatment & management: JAK inhibitors. Medscape. Updated September 21, 2022. Accessed December 13, 2022.
3. Bose P, Verstovsek S. JAK Inhibition for the treatment of myelofibrosis: Limitations and future perspectives. Hemasphere. 2020;4(4):e424. doi:10.1097/HS9.0000000000000424 
4. Lal A. Primary myelofibrosis treatment & management: approach considerations. Medscape. Updated September 21, 2022. Accessed December 13, 2022.
5. Vonjo® (pacritinib) capsules. CTI BioPharma Corp. Accessed December 13, 2022.
6. Lal A. Primary myelofibrosis treatment & management: FGFR inhibitors. Medscape. Updated September 21, 2022. Accessed December 13, 2022.
7. Lal A. Primary myelofibrosis treatment & management: other chemotherapeutics. Medscape. Updated September 21, 2022. Accessed December 13, 2022.
8. Lal A. Primary myelofibrosis treatment & management: stem cell transplantation. Medscape. Updated September 21, 2022. Accessed December 13, 2022.
9. Kröger N, Giorgino T, Scott BL, et al. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood. 2015;125(21):3347-3350. doi:10.1182/blood-2014-10-608315
10. Kröger NM, Deeg JH, Olavarria E, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia. 2015;29(11):2126-2133. doi:10.1038/leu.2015.233
11. Blood treatments for myeloproliferative disorders. NYU Langone Health: Perlmutter Cancer Center. Accessed December 13, 2022. 
12. Pardanani A, Tefferi A. Prognostic relevance of anemia and transfusion dependency in myelodysplastic syndromes and primary myelofibrosis. Haematologica. 2011;96(1):8-10. doi:10.3324/haematol.2010.035519
13. Masarova L, Alhuraiji A, Bose P, et al. Significance of thrombocytopenia in patients with primary and postessential thrombocythemia/polycythemia vera myelofibrosis. Eur J Haematol. 2018;100(3):257-263. doi:10.1111/ejh.13005
14. Lal A. Primary myelofibrosis treatment & management: splenectomy. Medscape. Updated September 21, 2022. Accessed December 13, 2022. 
15. Malato A, Rossi E, Tiribelli M, Mendicino F, Pugliese N. Splenectomy in myelofibrosis: indications, efficacy, and complications. Clin Lymphoma Myeloma Leuk. 2020;20(9):588-595. doi:10.1016/j.clml.2020.04.015
16. Tefferi A, Mudireddy M, Gangat N, et al. Risk factors and a prognostic model for postsplenectomy survival in myelofibrosis. Am J Hematol. 2017;92(11):1187-1192. doi:10.1002/ajh.24881
17. Lal A. Primary myelofibrosis treatment & management: radiation therapy. Medscape. Updated September 21, 2022. Accessed December 13, 2022.

Reviewed by Kyle Habet, MD, on 12/20/2022.

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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.