History

Fact Explanation
Introduction Myelofibrosis is a myeloproliferative disorder that is derived from hematopoietic stem or early progenitor cells and is associated with increase production of mature myeloid cells. [2] It has the worst prognosis among the philadelphia chromosome-negative myeloproliferative neoplasms. [4] There is an underlying abnormal myeloproliferation and a reactive, cytokine-driven inflammatory state giving rise to various clinical symptoms and signs of myelofibrosis. [1] In myelofibrosis there is megakaryocyte proliferation and atypical morphology affecting the platelets. [2] Other features would be extensive bone marrow fibrosis, and splenomegaly secondary to extramedullary hematopoiesis. [2]
Anorexia, weight loss, night sweats [5] Constitutional symptoms are common during the course of the disease. Inflammatory cytokines, interleukin 6 and tumor necrosis factor α are involved in the pathogenesis of the constitutional symptoms. [1]
Fever There is a reactive, cytokine-driven inflammatory state as an underlying pathological process [1] and cytokine acting as pyrogens may cause fever.
Easy fatigability Anaemia is a recognized feature of the disease due to the bone marrow involvement. [1] Anaemia causes low haemoglobin level with reduced blood oxygenation leading to lack of energy production in the body.
Easy bruising, bleeding They may have either thrombocytopenia or thrombocytosis. [1] Though the number of platelets are increased it may be abnormal platelets giving rise to disordered function. [5]
Abdominal discomfort Splenomegaly may be secondary to extramedullary hematopoiesis. [2] Left subcostal abdominal discomfort may be a symptom of symptomatic splenomegaly. [1]
Difficulty in breathing May be related to the splenomegaly. [5]
Joint pain Hyperuricemia may cause gouty arthritis. [5]
References
  1. TEFFERI A, PARDANANI A. Serious Adverse Events During Ruxolitinib Treatment Discontinuation in Patients With Myelofibrosis Mayo Clin Proc [online] 2011 Dec, 86(12):1188-1191 [viewed 23 September 2014] Available from: doi:10.4065/mcp.2011.0518
  2. MERKER JD, ROSKIN KM, NG D, PAN C, FISK DG, KING JJ, HOH R, STADLER M, OKUMOTO LM, ABIDI P, HEWITT R, JONES CD, GOJENOLA L, CLARK MJ, ZHANG B, CHERRY AM, GEORGE TI, SNYDER M, BOYD SD, ZEHNDER JL, FIRE AZ, GOTLIB J. Comprehensive whole-genome sequencing of an early-stage primary myelofibrosis patient defines low mutational burden and non-recurrent candidate genes Haematologica [online] 2013 Nov, 98(11):1689-1696 [viewed 23 September 2014] Available from: doi:10.3324/haematol.2013.092379
  3. DEWAN U, KUMARI N, JAISWAL A, BEHARI S, JAIN M. Extramedullary hemopoiesis with undiagnosed, early myelofibrosis causing spastic compressive myelopathy: Case report and review Indian J Orthop [online] 2010, 44(1):98-103 [viewed 23 September 2014] Available from: doi:10.4103/0019-5413.57281
  4. KEOHANE C, RADIA DH, HARRISON CN. Treatment and management of myelofibrosis in the era of JAK inhibitors Biologics [online] 2013:189-198 [viewed 23 September 2014] Available from: doi:10.2147/BTT.S34942
  5. MASCARENHAS JO, ORAZI A, BHALLA KN, CHAMPLIN RE, HARRISON C, HOFFMAN R. Advances in myelofibrosis: a clinical case approach Haematologica [online] 2013 Oct, 98(10):1499-1509 [viewed 23 September 2014] Available from: doi:10.3324/haematol.2013.086348

Examination

Fact Explanation
Pallor Due to the associated anaemia. [1]
Plethora Myelofibrosis may be associate dwith other myeloproliferative disorders such as polycythemia vera [1] and may cause plethora secondary to polycythemia.
Petechiae and/or ecchymosis In myelofibrosis there is megakaryocyte proliferation and atypical morphology of the platelets. [3]
Febrile There is a reactive, cytokine-driven inflammatory state as an underlying pathological process [1] and cytokine acting as pyrogens may cause fever.
Cachexia Is an associated constitutional feature. [1]
Splenomegaly and hepatomegaly Splenomegaly [1] with progressive enlargement of the spleen may be due to the extramedullary haematopoiesis. [2]
Hypotension Septic shocklike syndrome with severe hypoxia may be developed after withdrawal of ruxolitinib therapy. [1]
Spastic limbs Occasionally myeloproliferative disorders may cause progressive spastic myelopathy. [2] S pinal cord compression can occur as a consequence of extramedullary haematopoiesis in the intraspinal epidural space . [2]
References
  1. TEFFERI A, PARDANANI A. Serious Adverse Events During Ruxolitinib Treatment Discontinuation in Patients With Myelofibrosis Mayo Clin Proc [online] 2011 Dec, 86(12):1188-1191 [viewed 23 September 2014] Available from: doi:10.4065/mcp.2011.0518
  2. DEWAN U, KUMARI N, JAISWAL A, BEHARI S, JAIN M. Extramedullary hemopoiesis with undiagnosed, early myelofibrosis causing spastic compressive myelopathy: Case report and review Indian J Orthop [online] 2010, 44(1):98-103 [viewed 23 September 2014] Available from: doi:10.4103/0019-5413.57281
  3. MERKER JD, ROSKIN KM, NG D, PAN C, FISK DG, KING JJ, HOH R, STADLER M, OKUMOTO LM, ABIDI P, HEWITT R, JONES CD, GOJENOLA L, CLARK MJ, ZHANG B, CHERRY AM, GEORGE TI, SNYDER M, BOYD SD, ZEHNDER JL, FIRE AZ, GOTLIB J. Comprehensive whole-genome sequencing of an early-stage primary myelofibrosis patient defines low mutational burden and non-recurrent candidate genes Haematologica [online] 2013 Nov, 98(11):1689-1696 [viewed 23 September 2014] Available from: doi:10.3324/haematol.2013.092379

Differential Diagnoses

Fact Explanation
Chronic myeloid leukemia (CML) This is a myeloproliferative disorder with a clonal hyperproliferation of myeloid cells in the bone marrow. [1] They present with fatigue, decreased appetite, and splenomegaly. Investigations may reveal leukocytosis, thrombocytosis, neutrophilia, and decreased leukocyte alkaline phosphatase (LAP) scores. [1] Philadelphia chromosome or bcr/abl rearrangement, are diagnostic markers for CML. [1]
Essential thrombocythemia (ET) Isolated thrombocytosis is found in essential thrombocythemia (ET) apart from the other clinical features of the disease. [1] World Health Organization diagnostic criteria, suggests the diagnosis of ET if the platelet count is more than 450×109/L with proliferation of megakaryocytes in the bone marrow and JAK2 V617F mutation, without any evidence of other myeloproliferative neoplasms. [1] Minor criteria includes the presence of a high lactate dehydrogenase (LDH) level, splenomegaly, and/or anemia. [2]
Polycythemia vera [2] Polycythemia vera is another disored in the spectrum of the myeloproliferative disorders that has ths Bone marrow is also helpful in diferentiating the PV from the pther disoders as there are feature like hypercellular panmyelotic marrow with pleomorphic megakaryocytes with marrow fibrosis grade 1–2. [2]
Chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia These disorders are also come under the group of myeloproliferative neoplasms [2] and are associated with same clinical features but with the elevated levels of neutrophils/eosinophils in the blood.
References
  1. BYUN YJ, PARK BB, LEE ES, CHOI KS, LEE DS. A case of chronic myeloid leukemia with features of essential thrombocythemia in peripheral blood and bone marrow Blood Res [online] 2014 Jun, 49(2):127-129 [viewed 23 September 2014] Available from: doi:10.5045/br.2014.49.2.127
  2. MASCARENHAS JO, ORAZI A, BHALLA KN, CHAMPLIN RE, HARRISON C, HOFFMAN R. Advances in myelofibrosis: a clinical case approach Haematologica [online] 2013 Oct, 98(10):1499-1509 [viewed 23 September 2014] Available from: doi:10.3324/haematol.2013.086348

Investigations - for Diagnosis

Fact Explanation
Complete blood count There may be leukocytosis or leucopenia [5] , thrombocytosis, reduced cell counts, low haemoglobin level in the blood. [1,2]
Blood picture The smear shows teardrop red blood cells, polychromatophilic RBCs [2] and bizarre platelets. [3]
Bone marrow examionation The bone marrow biopsy will show hypercellular marrow with erythroid hyperplasia, megakaryocytic clustering with ectatic sinusoids, fibrosis [5] cytopenias or cytosis, [6] and evidence of dysplasia in megakaryocytes (nucleomegaly, coarse chromatin and absence of nuclear lobation). [2] Early disease may also have changes in bone marrow examination. [2]
Polymerase chain reaction (PCR) assay or fluorescent in-situ hybridization (FISH) These investigations are able to detect bcr-abl gene rearrangement which is particularly important to differentiate chronic myeloid leukemia from other myeloproliferative diseases. [4] JAK2 mutations are present in 50% patients of myelofibrosis. [6]
Serum uric acid level May be elevated due to the increased cell breakdown and cause hyperurecaemia. [6]
References
  1. TEFFERI A, PARDANANI A. Serious Adverse Events During Ruxolitinib Treatment Discontinuation in Patients With Myelofibrosis Mayo Clin Proc [online] 2011 Dec, 86(12):1188-1191 [viewed 23 September 2014] Available from: doi:10.4065/mcp.2011.0518
  2. DEWAN U, KUMARI N, JAISWAL A, BEHARI S, JAIN M. Extramedullary hemopoiesis with undiagnosed, early myelofibrosis causing spastic compressive myelopathy: Case report and review Indian J Orthop [online] 2010, 44(1):98-103 [viewed 23 September 2014] Available from: doi:10.4103/0019-5413.57281
  3. MERKER JD, ROSKIN KM, NG D, PAN C, FISK DG, KING JJ, HOH R, STADLER M, OKUMOTO LM, ABIDI P, HEWITT R, JONES CD, GOJENOLA L, CLARK MJ, ZHANG B, CHERRY AM, GEORGE TI, SNYDER M, BOYD SD, ZEHNDER JL, FIRE AZ, GOTLIB J. Comprehensive whole-genome sequencing of an early-stage primary myelofibrosis patient defines low mutational burden and non-recurrent candidate genes Haematologica [online] 2013 Nov, 98(11):1689-1696 [viewed 23 September 2014] Available from: doi:10.3324/haematol.2013.092379
  4. BYUN YJ, PARK BB, LEE ES, CHOI KS, LEE DS. A case of chronic myeloid leukemia with features of essential thrombocythemia in peripheral blood and bone marrow Blood Res [online] 2014 Jun, 49(2):127-129 [viewed 23 September 2014] Available from: doi:10.5045/br.2014.49.2.127
  5. KEOHANE C, RADIA DH, HARRISON CN. Treatment and management of myelofibrosis in the era of JAK inhibitors Biologics [online] 2013:189-198 [viewed 23 September 2014] Available from: doi:10.2147/BTT.S34942
  6. MASCARENHAS JO, ORAZI A, BHALLA KN, CHAMPLIN RE, HARRISON C, HOFFMAN R. Advances in myelofibrosis: a clinical case approach Haematologica [online] 2013 Oct, 98(10):1499-1509 [viewed 23 September 2014] Available from: doi:10.3324/haematol.2013.086348

Investigations - Fitness for Management

Fact Explanation
Complete blood count Bone marrow may be affected with fibrosis and there can be anaemia with low haemoglobin. [1] Most of the patients are having hemoglobin values of less than 12 g/dL, and 15% have severe anemia with hemoglobin levels <8 g/dL). [2]
References
  1. DEWAN U, KUMARI N, JAISWAL A, BEHARI S, JAIN M. Extramedullary hemopoiesis with undiagnosed, early myelofibrosis causing spastic compressive myelopathy: Case report and review Indian J Orthop [online] 2010, 44(1):98-103 [viewed 23 September 2014] Available from: doi:10.4103/0019-5413.57281
  2. MITRA D, KAYE JA, PIECORO LT, BROWN J, REITH K, MUGHAL TI, SARLIS NJ. Symptom burden and splenomegaly in patients with myelofibrosis in the United States: a retrospective medical record review Cancer Med [online] 2013 Dec, 2(6):889-898 [viewed 23 September 2014] Available from: doi:10.1002/cam4.136

Investigations - Followup

Fact Explanation
Complete blood count It is important to check the blood cell counts during the follow up to assess the response to therapy and the side effects of the treatment. Eg:- cytopenia during ruxolitinib therapy. [1]
Bone marrow examination It is recomended to do the close follow-ups in early myelofibrosis. [2]
References
  1. TEFFERI A, PARDANANI A. Serious Adverse Events During Ruxolitinib Treatment Discontinuation in Patients With Myelofibrosis Mayo Clin Proc [online] 2011 Dec, 86(12):1188-1191 [viewed 23 September 2014] Available from: doi:10.4065/mcp.2011.0518
  2. DEWAN U, KUMARI N, JAISWAL A, BEHARI S, JAIN M. Extramedullary hemopoiesis with undiagnosed, early myelofibrosis causing spastic compressive myelopathy: Case report and review Indian J Orthop [online] 2010, 44(1):98-103 [viewed 23 September 2014] Available from: doi:10.4103/0019-5413.57281

Investigations - Screening/Staging

Fact Explanation
Leukocyte alkaline phosphatase (LAP) score This is important to differentiate chronic myelod leukemia from other causes of leukocytosis. This may be decreased in chronic myeloid leukaemia. [2]
Ultrasound scan of abdomen Extramedullary haematopoiesis may cause enlargement of spllen and liver. [1] Occasionally USS may be required to assess the size of these organs.
Magnetic resonance imaging (MRI) MRI of the spine is needed in cases of spastic paraplegia secondary to spinal cord compression caused by extramedullary haematopoiesis in the intraspinal epidural space. [1] There may be hypointense lesions causind spinal cord compression.
References
  1. DEWAN U, KUMARI N, JAISWAL A, BEHARI S, JAIN M. Extramedullary hemopoiesis with undiagnosed, early myelofibrosis causing spastic compressive myelopathy: Case report and review Indian J Orthop [online] 2010, 44(1):98-103 [viewed 23 September 2014] Available from: doi:10.4103/0019-5413.57281
  2. BYUN YJ, PARK BB, LEE ES, CHOI KS, LEE DS. A case of chronic myeloid leukemia with features of essential thrombocythemia in peripheral blood and bone marrow Blood Res [online] 2014 Jun, 49(2):127-129 [viewed 23 September 2014] Available from: doi:10.5045/br.2014.49.2.127

Management - General Measures

Fact Explanation
Patient education Patient should be educated about the nature of disease, potential complications and available treatment strategies. Particularly informed about the stem cell transplantation. [5]
Syupportive management Fever, pain like constitutional symptoms require attention. Nutritional support may also needed specially in anaemic patients. Psychological support is important in alleviating the anxiety, depression associated with chronic disease. [4]
Management of anaemia 15% had severe anemia which is haemoglobin less than <8 g/dL). [3] Options to manage myelofibrosis associated anemia are blood transfusions and drugs such as recombinant erythropoietin, androgens, and thalidomide. [1]
Management of thrombocytopenia Severe thrombocytopenia (platelet count of <20 × 109/L) may be found in some patients and if sever they might need platelet transfusion. [3]
Management of other associated problems Laminectomy with excision of the mass may be required in case of extramedullary haematopoiesis affecing the spine. [2]
References
  1. TEFFERI A, PARDANANI A. Serious Adverse Events During Ruxolitinib Treatment Discontinuation in Patients With Myelofibrosis Mayo Clin Proc [online] 2011 Dec, 86(12):1188-1191 [viewed 23 September 2014] Available from: doi:10.4065/mcp.2011.0518
  2. DEWAN U, KUMARI N, JAISWAL A, BEHARI S, JAIN M. Extramedullary hemopoiesis with undiagnosed, early myelofibrosis causing spastic compressive myelopathy: Case report and review Indian J Orthop [online] 2010, 44(1):98-103 [viewed 23 September 2014] Available from: doi:10.4103/0019-5413.57281
  3. MITRA D, KAYE JA, PIECORO LT, BROWN J, REITH K, MUGHAL TI, SARLIS NJ. Symptom burden and splenomegaly in patients with myelofibrosis in the United States: a retrospective medical record review Cancer Med [online] 2013 Dec, 2(6):889-898 [viewed 23 September 2014] Available from: doi:10.1002/cam4.136
  4. KOENIGS JW. Hydrogen peroxide and iron: a microbial cellulolytic system? Biotechnol Bioeng Symp [online] 1975:151-9 [viewed 23 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/97
  5. TEFFERI A, PARDANANI A. Serious Adverse Events During Ruxolitinib Treatment Discontinuation in Patients With Myelofibrosis Mayo Clin Proc [online] 2011 Dec, 86(12):1188-1191 [viewed 23 September 2014] Available from: doi:10.4065/mcp.2011.0518

Management - Specific Treatments

Fact Explanation
Hydroxyurea Hydroxyurea is a derivative of urea where a hydrogen atom is replaced by a hydroxyl group. [3] This causes marked reduction in the rate of DNA synthesis. [3] It is a cytoreductive agent used to treat the myelofibrosis. [2]
Ruxolitinib Ruxolitinib is an ATP mimetic JAK1 and JAK2 inhibitor used for the treatment of myelofibrosis. [1,2] It is effective in managing constitutional symptoms and splenomegaly. Maximum tolerated dose is 25 mg twice daily and 100 mg once daily. Ruxolitinib causes adverse effects, including moderate to severe thrombocytopenia and anemia and thrombocytopenia is the dose-limiting factor. [1] Abrupt discontinuation causes “ruxolitinib withdrawal syndrome” which is associated with acute relapse of symptoms, splenomegaly, worsening of cytopenias, and hemodynamic decompensation and septic shocklike syndrome due to rapid changes in inflammatory cytokine activity. [1]
Radiation therapy When the splenomegaly is difficult to treat with medications, they may require field radiotherapy. [1] Splenic irradiation is used for treatment of splenomegaly in advanced disease. [2]
Splenectomy [1] Extramedullary haematpoiesis may lead to splenomegaly that may cause abdominal discomfort in advanced disease. [2] These patients may require splenectomy as the treatment option.
Allogeneic stem cell transplantation Allogeneic stem cell transplantation is a treatment modality used for advanced-stage disease. It causes and is significant mortality and morbidity. [1]
References
  1. TEFFERI A, PARDANANI A. Serious Adverse Events During Ruxolitinib Treatment Discontinuation in Patients With Myelofibrosis Mayo Clin Proc [online] 2011 Dec, 86(12):1188-1191 [viewed 23 September 2014] Available from: doi:10.4065/mcp.2011.0518
  2. KEOHANE C, RADIA DH, HARRISON CN. Treatment and management of myelofibrosis in the era of JAK inhibitors Biologics [online] 2013:189-198 [viewed 23 September 2014] Available from: doi:10.2147/BTT.S34942
  3. WAWRA E, WINTERSBERGER E. Does hydroxyurea inhibit DNA replication in mouse cells by more than one mechanism? Mol Cell Biol [online] 1983 Mar, 3(3):297-304 [viewed 23 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC368538
  4. TIMSON J. Hydroxyurea: comparison of cytotoxic and antimitotic activities against human lymphocytes in vitro. Br J Cancer [online] 1969 Jun, 23(2):337-339 [viewed 23 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2008279