Overview
Myelofibrosis (MF) is a life-threatening blood cancer associated with progressive, debilitating symptoms that can severely impact quality of life and shorten survival.[i],[ii] MF is characterized by bone marrow scarring (fibrosis), an enlarged spleen (splenomegaly) and debilitating consequences, including fatigue, fever, night sweats, itchy skin, bone pain, abdominal pain or discomfort, and weight loss.[iii],[iv]
MF is a type of “myeloproliferative neoplasms” (MPNs), a group of diseases in which blood cells are overproduced in the body and disrupt normal functioning.[v] Other MPNs include essential thrombocythemia (ET) and polycythemia vera (PV), which can lead to MF (called “secondary MF”) within the course of the disease.[vi],[vii]
Characteristics of Myelofibrosis
The exact prevalence of MF is uncertain, and depends on the population sampled. In Canada, MF is estimated to affect about two out of every 1,000,000 people and is typically diagnosed in people between 50 and 80 years old, although the disease can arise at any age.[viii] Both men and women are affected.[ix]
A physician may consider a diagnosis of MF when a routine medical examination shows an enlarged spleen (found in almost all patients) and abnormal levels of red blood cells, white blood cells and platelets.[x] Diagnosis is usually determined by a bone marrow aspiration and biopsy.[xi]
The Impact of Myelofibrosis
In people with MF, too many blood cells are produced in the bone marrow – the spongy insides of bone where blood cells develop. This causes scar tissue to build up in the marrow,[xii] eventually leading to a decrease in the number of normal red blood cells, white blood cells and platelets produced. To compensate, the spleen and liver may enlarge, as these organs take on the role of making more blood cells. The spleen of a person with MF can grow to ten times normal size, causing discomfort in the stomach or shoulder pain.[xiii],[xiv],[xv] Serious complications of the disease severely impact the quality of life of people with MF and shorten survival.[xvi],[xvii]
The Treatment Challenge
Until now, there were no Health Canada approved treatments for people with MF. The goal of traditional therapies for MF is to reduce spleen size, relieve symptoms and decrease the risk of complications.[xviii],[xix],[xx] Potential side effects of older therapies include progression to leukemia, enlarged liver (hepatomegaly), drowsiness, constipation, fatigue, burning or prickling sensation (paresthesias), and low white blood cell count (neutropenia).[xxi]
The only potential curative treatment is stem cell transplantation, but this procedure involves potentially life-threatening risks and is usually only attempted in those under age 55. The five-year survival rate after transplantation is approximately 30 per cent.[xxii]
Controlling the JAK pathway: The hidden key?
MF develops from overactive signaling in the JAK (“Janus kinase”) pathway, which regulates blood cell production and inflammation.[xxiii],[xxiv],[xxv] This over-activity may arise from a number of genetic mutations. While not all MF patients have one of the mutations currently known to lead to overactive JAK signalling, it is believed that the JAK pathway is nonetheless overactive in all patients with MF.[xxvi],[xxvii],[xxviii]
The goal of MF therapies that target the JAK pathway is to manage overactive JAK signalling in order to reduce spleen volume, control clinical symptoms and improve quality of life.
Glossary of Terms
Essential thrombocythemia: A disease in which the number of thrombocytes (platelets) in the blood is above normal, without known cause.
Myelofibrosis: A blood cancer in which the bone marrow is replaced by fibrous tissue and is no longer able to produce adequate numbers of normal blood cells.
Myeloproliferative neoplasms: A group of blood cancers – including myelofibrosis, polycythemia vera and essential thrombocythemia – in which large numbers of abnormal red blood cells, white blood cells or platelets grow and spread in the bone marrow and the blood.
Platelet: A small piece of cell in the blood that forms blood clots.
Polycythemia vera: A disease in which the number of red blood cells in the bone marrow and blood is above normal.
Splenomegaly: An enlargement of the spleen beyond its normal size with symptoms including fatigue, the inability to eat a large meal and pain on the upper left side of the abdomen.
Used with Permission from National Public Relations
[i] Mesa RA, Schwager S, Radia D, et al. The Myelofibrosis Symptom Assessment Form (MFSAF):
anevidence-based brief inventory to measure quality of life and symptomatic response to treatment
in myelofibrosis. Leukemia research. Sep 2009;33(9):1199-1203.
[ii] The Leukemia & Lymphoma Society. Idiopathic myelofibrosis. 2007. Available at http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/idiopathicmyelofibrosis.pdf. Accessed January 20, 2012.
[iii] Mesa RA, Schwager S, Radia D, et al. The Myelofibrosis Symptom Assessment Form (MFSAF):
anevidence-based brief inventory to measure quality of life and symptomatic response to treatment
in myelofibrosis. Leukemia research. Sep 2009;33(9):1199-1203.
[iv] The Leukemia & Lymphoma Society. Idiopathic myelofibrosis. 2007. Available at http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/idiopathicmyelofibrosis.pdf. Accessed January 20, 2012.
[v] Koopmans SM, van Marion AMW, Schouten HC. Myeloproliferative neoplasia: a review of clinical criteria and treatment. Neth J Med. 2012;70:159-67.
[vi] Thiele J, Kvasnicka HM. The 2008 WHO diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Current Hematol Malig Reports. 2009;4:33-40.
[vii] Vannucchi AM. Management of myelofibrosis. Hematology Am Soc Hematol Educ Program. 2011;2011:222-30.
[viii] The Leukemia & Lymphoma Society. Incidence. Updated March, 2011. Available at http://www.llscanada.org/#/diseaseinformation/myeloproliferativediseases/incidence/. Accessed June 4, 2012.
[ix] Leukemia & Lymphoma Society. Incidence. Updated March, 2011. Available at http://www.llscanada.org/#/diseaseinformation/myeloproliferativediseases/incidence/. Accessed June 4, 2012.
[x] Leukemia & Lymphoma Society. Idiopathic myelofibrosis. Available at: http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/idiopathicmyelofibrosis.pdf Accessed June 2011.
[xi] Leukemia & Lymphoma Society. Idiopathic myelofibrosis. Available at: http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/idiopathicmyelofibrosis.pdf Accessed June 2011.
[xii] The Leukemia & Lymphoma Society. Idiopathic myelofibrosis. 2007. Available at http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/idiopathicmyelofibrosis.pdf. Accessed January 20, 2012.
[xiii] Mesa RA. How I treat symptomatic splenomegaly in patients with myelofibrosis. Blood. 2009;113(22):5394-5400.
[xiv] Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and Efficacy of JAK1 & JAK2 Inhibitor, INCB018424, in Myelofibrosis. New Eng J Med. 2010;16(363):1117-1127.
[xv] Leukemia & Lymphoma Society. Idiopathic myelofibrosis. Available at: http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/idiopathicmyelofibrosis.pdf Accessed April 2011.
[xvi] Mesa, R.A., et al., The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res, 2009. 33(9): p. 1199-203.
[xvii] The Leukemia & Lymphoma Society. Idiopathic myelofibrosis. 2007. Available at http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/idiopathicmyelofibrosis.pdf. Accessed January 20, 2012.
[xviii] The Leukemia & Lymphoma Society. Idiopathic myelofibrosis. 2007. Available at http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/idiopathicmyelofibrosis.pdf. Accessed January 20, 2012.
[xix] Hellman AJ. Myeloproliferative syndromes: diagnosis and therapeutic options. Pol Arch Med Wewn. 2008;118:756-759.
[xx] Tefferi A. Allogeneic hematopoietic cell transplantation versus drugs in myelofibrosis: the risk-benefit balancing act. Bone Marrow Transpl. 2010;45(3):419-421.
[xxi] Abdel-Wahab OI, Levine RL. Primary myelofibrosis: update on definition, pathogenesis, and treatment. Annu Rev Med. 2009;60:233-245.
[xxii] Patriarca F, Bacigalupo A, Sperotto A, et al. Allogeneic hematopoietic stem cell transplantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Haematologica. 2008;93(10):1514-1522.
[xxiii] Morgan KJ, Gilliland DG. A role for JAK2 mutations in myeloproliferative diseases. Annu Rev Med. 2008;59:213-222.
[xxiv] Delhommeau F, Jeziorowska D, Marzac C, Casadevall N. Molecular aspects of myeloproliferative neoplasms. Int J Hematol. 2010;91(2):165-173.
[xxv] Quintás-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115(15):3109-3117.
[xxvi] Quintás-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115(15):3109-3117.
[xxvii] Abdel-Wahab OI, Levine RL. Primary myelofibrosis: update on definition, pathogenesis, and treatment. Annu Rev Med. 2009;60:233-245.
[xxviii] Verstovsek S. Therapeutic potential of Janus-activated kinase-2 inhibitors for the management of myelofibrosis. Clin Cancer Res. 2010;16(7):1988-1996.
