Myelofibrosis - Clinicals, Diagnosis, and Management

Hematology

Clinicals - 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. It has the worst prognosis among the philadelphia chromosome-negative myeloproliferative neoplasms. There is an underlying abnormal myeloproliferation and a reactive, cytokine-driven inflammatory state giving rise to various clinical symptoms and signs of myelofibrosis. In myelofibrosis there is megakaryocyte proliferation and atypical morphology affecting the platelets. Other features would be extensive bone marrow fibrosis, and splenomegaly secondary to extramedullary hematopoiesis. 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. It has the worst prognosis among the philadelphia chromosome-negative myeloproliferative neoplasms. There is an underlying abnormal myeloproliferation and a reactive, cytokine-driven inflammatory state giving rise to various clinical symptoms and signs of myelofibrosis. In myelofibrosis there is megakaryocyte proliferation and atypical morphology affecting the platelets. Other features would be extensive bone marrow fibrosis, and splenomegaly secondary to extramedullary hematopoiesis.
Anorexia, weight loss, night sweats 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. Anorexia, weight loss, night sweats
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.
Fever There is a reactive, cytokine-driven inflammatory state as an underlying pathological process and cytokine acting as pyrogens may cause fever. Fever
There is a reactive, cytokine-driven inflammatory state as an underlying pathological process and cytokine acting as pyrogens may cause fever.
Easy fatigability Anaemia is a recognized feature of the disease due to the bone marrow involvement. Anaemia causes low haemoglobin level with reduced blood oxygenation leading to lack of energy production in the body. Easy fatigability
Anaemia is a recognized feature of the disease due to the bone marrow involvement. 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. Though the number of platelets are increased it may be abnormal platelets giving rise to disordered function. Easy bruising, bleeding
They may have either thrombocytopenia or thrombocytosis. Though the number of platelets are increased it may be abnormal platelets giving rise to disordered function.
Abdominal discomfort Splenomegaly may be secondary to extramedullary hematopoiesis. Left subcostal abdominal discomfort may be a symptom of symptomatic splenomegaly. Abdominal discomfort
Splenomegaly may be secondary to extramedullary hematopoiesis. Left subcostal abdominal discomfort may be a symptom of symptomatic splenomegaly.
Difficulty in breathing May be related to the splenomegaly. Difficulty in breathing
May be related to the splenomegaly.
Joint pain Hyperuricemia may cause gouty arthritis. Joint pain
Hyperuricemia may cause gouty arthritis.

Clinicals - Examination

Fact Explanation
Pallor Due to the associated anaemia. Pallor
Due to the associated anaemia.
Plethora Myelofibrosis may be associate dwith other myeloproliferative disorders such as polycythemia vera and may cause plethora secondary to polycythemia. Plethora
Myelofibrosis may be associate dwith other myeloproliferative disorders such as polycythemia vera and may cause plethora secondary to polycythemia.
Petechiae and/or ecchymosis In myelofibrosis there is megakaryocyte proliferation and atypical morphology of the platelets. Petechiae and/or ecchymosis
In myelofibrosis there is megakaryocyte proliferation and atypical morphology of the platelets.
Febrile There is a reactive, cytokine-driven inflammatory state as an underlying pathological process and cytokine acting as pyrogens may cause fever. Febrile
There is a reactive, cytokine-driven inflammatory state as an underlying pathological process and cytokine acting as pyrogens may cause fever.
Cachexia Is an associated constitutional feature. Cachexia
Is an associated constitutional feature.
Splenomegaly and hepatomegaly Splenomegaly with progressive enlargement of the spleen may be due to the extramedullary haematopoiesis. Splenomegaly and hepatomegaly
Splenomegaly with progressive enlargement of the spleen may be due to the extramedullary haematopoiesis.
Hypotension Septic shocklike syndrome with severe hypoxia may be developed after withdrawal of ruxolitinib therapy. Hypotension
Septic shocklike syndrome with severe hypoxia may be developed after withdrawal of ruxolitinib therapy.
Spastic limbs Occasionally myeloproliferative disorders may cause progressive spastic myelopathy. S pinal cord compression can occur as a consequence of extramedullary haematopoiesis in the intraspinal epidural space . Spastic limbs
Occasionally myeloproliferative disorders may cause progressive spastic myelopathy. S pinal cord compression can occur as a consequence of extramedullary haematopoiesis in the intraspinal epidural space .

Investigations - Diagnosis

Fact Explanation
Complete blood count There may be leukocytosis or leucopenia , thrombocytosis, reduced cell counts, low haemoglobin level in the blood. Complete blood count
There may be leukocytosis or leucopenia , thrombocytosis, reduced cell counts, low haemoglobin level in the blood.
Blood picture The smear shows teardrop red blood cells, polychromatophilic RBCs and bizarre platelets. Blood picture
The smear shows teardrop red blood cells, polychromatophilic RBCs and bizarre platelets.
Bone marrow examionation The bone marrow biopsy will show hypercellular marrow with erythroid hyperplasia, megakaryocytic clustering with ectatic sinusoids, fibrosis cytopenias or cytosis, and evidence of dysplasia in megakaryocytes (nucleomegaly, coarse chromatin and absence of nuclear lobation). Early disease may also have changes in bone marrow examination. Bone marrow examionation
The bone marrow biopsy will show hypercellular marrow with erythroid hyperplasia, megakaryocytic clustering with ectatic sinusoids, fibrosis cytopenias or cytosis, and evidence of dysplasia in megakaryocytes (nucleomegaly, coarse chromatin and absence of nuclear lobation). Early disease may also have changes in bone marrow examination.
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. JAK2 mutations are present in 50% patients of myelofibrosis. 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. JAK2 mutations are present in 50% patients of myelofibrosis.
Serum uric acid level May be elevated due to the increased cell breakdown and cause hyperurecaemia. Serum uric acid level
May be elevated due to the increased cell breakdown and cause hyperurecaemia.

Investigations - Management

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. 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.
Bone marrow examination It is recomended to do the close follow-ups in early myelofibrosis. Bone marrow examination
It is recomended to do the close follow-ups in early myelofibrosis.
Complete blood count Bone marrow may be affected with fibrosis and there can be anaemia with low haemoglobin. 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). Complete blood count
Bone marrow may be affected with fibrosis and there can be anaemia with low haemoglobin. 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).
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. 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.
Ultrasound scan of abdomen Extramedullary haematopoiesis may cause enlargement of spllen and liver. Occasionally USS may be required to assess the size of these organs. Ultrasound scan of abdomen
Extramedullary haematopoiesis may cause enlargement of spllen and liver. 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. There may be hypointense lesions causind spinal cord compression. 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. There may be hypointense lesions causind spinal cord compression.

Management - Supportive

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. Patient education
Patient should be educated about the nature of disease, potential complications and available treatment strategies. Particularly informed about the stem cell transplantation.
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. 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.
Management of anaemia 15% had severe anemia which is haemoglobin less than <8 g/dL). Options to manage myelofibrosis associated anemia are blood transfusions and drugs such as recombinant erythropoietin, androgens, and thalidomide. Management of anaemia
15% had severe anemia which is haemoglobin less than <8 g/dL). Options to manage myelofibrosis associated anemia are blood transfusions and drugs such as recombinant erythropoietin, androgens, and thalidomide.
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. 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.
Management of other associated problems Laminectomy with excision of the mass may be required in case of extramedullary haematopoiesis affecing the spine. Management of other associated problems
Laminectomy with excision of the mass may be required in case of extramedullary haematopoiesis affecing the spine.

Management - Specific

Fact Explanation
Hydroxyurea Hydroxyurea is a derivative of urea where a hydrogen atom is replaced by a hydroxyl group. This causes marked reduction in the rate of DNA synthesis. It is a cytoreductive agent used to treat the myelofibrosis. Hydroxyurea
Hydroxyurea is a derivative of urea where a hydrogen atom is replaced by a hydroxyl group. This causes marked reduction in the rate of DNA synthesis. It is a cytoreductive agent used to treat the myelofibrosis.
Ruxolitinib Ruxolitinib is an ATP mimetic JAK1 and JAK2 inhibitor used for the treatment of myelofibrosis. 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. 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. Ruxolitinib
Ruxolitinib is an ATP mimetic JAK1 and JAK2 inhibitor used for the treatment of myelofibrosis. 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. 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.
Radiation therapy When the splenomegaly is difficult to treat with medications, they may require field radiotherapy. Splenic irradiation is used for treatment of splenomegaly in advanced disease. Radiation therapy
When the splenomegaly is difficult to treat with medications, they may require field radiotherapy. Splenic irradiation is used for treatment of splenomegaly in advanced disease.
Splenectomy Extramedullary haematpoiesis may lead to splenomegaly that may cause abdominal discomfort in advanced disease. These patients may require splenectomy as the treatment option. Splenectomy
Extramedullary haematpoiesis may lead to splenomegaly that may cause abdominal discomfort in advanced disease. 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. 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.

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