Pathophysiology of Myelofibrosis

Myelofibrosis is a hematologic neoplasm characterized by ineffective erythropoiesis and proliferation of dysfunctional megakaryocytes.1

  • Myelofibrosis is characterized by neoplastic myeloproliferation, bone marrow fibrosis, loss of hematopoietic stem cells, and impaired bone marrow function
  • This process stimulates compensatory extramedullary hematopoiesis, primarily in the liver and the spleen, which enlarges significantly
  • Ineffective erythropoiesis and proliferation of dysfunctional megakaryocytes are often associated with anemia and thrombocytosis, although patients may develop thrombocytopenia
  • High levels of circulating inflammatory cytokines, such as interleukin-6, may result in constitutional symptoms

Overactive JAK pathway is a primary driver of myelofibrosis progression2,3

JAK-STAT is a major signaling pathway that affects hematopoietic cell growth, differentiation, and death. JAK1 and JAK2 (Janus-associated kinases 1 and 2) are members of a family of intracellular, nonreceptor tyrosine kinases that act as mediators of signal transduction in the JAK-STAT pathway. Myelofibrosis is a complex disease characterized by multiple genetic, epigenetic, and cellular alterations, and an overactive JAK pathway is a primary driver of myelofibrosis disease progression.2-7

Multiple paths to overactive JAK1 and JAK2 signaling

Factors that affect JAK signaling include5,6,8-14

  • JAK2 mutations
  • Myeloproliferative leukemia virus oncogene (MPL) mutations
  • Excess cytokines
  • Increased JAK1 signaling
  • Damaged intracellular signaling mechanism (eg, those involving SOCS, or suppressor of cytokine signaling)
Chart shows the fators and multiple paths to overactive jak1 and jak2 singaling – Jakafi.com/hcp.
Expand References +
  • Lichtman MA, Tefferi A. In: Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT, eds. Williams Hematology. 8th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=6126512. Accessed October 12, 2011.
  • Verstovsek S, Kantarjian H, Mesa RA, et al. N Engl J Med. 2010;363:1117-1127.
  • Santos FPS, Verstovsek S. Hematol Oncol Clin North Am. 2012;26:1083-1099.
  • Vainchenker W, Delhommeau F, Constantinescu SN, Bernard OA. Blood. 2011;118:1723-1735.
  • Quintás-Cardama A, Vaddi K, Liu P, et al. Blood. 2010;115:3109-3117.
  • Fourouclas N, Li J, Gilby DC, et al. Haematologica. 2008;93:1635-1644.
  • Vardiman JW, Thiele, J, Arber DA, et al. Blood. 2009;114:937-951.
  • Kralovics R, Passamonti F, Buser AS, et al. N Engl J Med. 2005;352:1779-1790.
  • Levine RL, Pardanani A, Tefferi A, Gilliland DG. Nat Rev Cancer. 2007;7:673-683.
  • Scott LM, Tong W, Levine RL, et al. N Engl J Med. 2007;356:459-468.
  • Pikman Y, Lee BH, Mercher T, et al. PLoS Med. 2006;3:1140-1151.
  • Kralovics R. Leukemia. 2008;22:1841-1848.
  • Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A. J Clin Oncol. 2011;29:1356-1363.
  • Verstovsek S. Hematology Am Soc Hematol Educ Program. 2009:636-642.
  • Cervantes F, Dupriez B, Pereira A, et al. Blood. 2009;113:2895-2901.
  • Mesa RA, Niblack J, Wadleigh M, et al. Cancer. 2007;109:68-76.
  • Mesa RA. Blood. 2009;113:5697-5698.
  • Tefferi A, Barosi G, Mesa RA. Blood. 2006;108:1497-1503.
  • Barosi G. J Clin Oncol. 1999;17:2954-2970.
  • Scherber R, Dueck AC, Johansson P, et al. Blood. 2011;118:401-408.

INDICATIONS AND USAGE

Jakafi is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF and post–essential thrombocythemia MF.

IMPORTANT SAFETY INFORMATION

  • Treatment with Jakafi® (ruxolitinib) 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
  • Increases in hepatitis B viral load with or without associated elevations in alanine aminotransferase and aspartate aminotransferase have been reported in patients with chronic hepatitis B virus (HBV) infections. Monitor and treat patients with chronic HBV infection according to clinical guidelines
  • When discontinuing Jakafi, myeloproliferative neoplasm-related symptoms may return within one week. After discontinuation, some patients with myelofibrosis 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 including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations
  • Treatment with Jakafi has been associated with increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Assess lipid parameters 8-12 weeks after initiating Jakafi. Monitor and treat according to clinical guidelines for the management of hyperlipidemia
  • 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.

 
IMPORTANT SAFETY INFORMATION
 
INDICATIONS AND USAGE
Jakafi is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF and post–essential thrombocythemia MF.
IMPORTANT SAFETY INFORMATION
  • Treatment with Jakafi® (ruxolitinib) 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
  • Increases in hepatitis B viral load with or without associated elevations in alanine aminotransferase and aspartate aminotransferase have been reported in patients with chronic hepatitis B virus (HBV) infections. Monitor and treat patients with chronic HBV infection according to clinical guidelines
  • When discontinuing Jakafi, myeloproliferative neoplasm-related symptoms may return within one week. After discontinuation, some patients with myelofibrosis 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 including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations
  • Treatment with Jakafi has been associated with increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Assess lipid parameters 8-12 weeks after initiating Jakafi. Monitor and treat according to clinical guidelines for the management of hyperlipidemia
  • 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.