Synonym: agnogenic myeloid metaplasia
Myelofibrosis (MF) is characterised by a clonal haemopoietic stem cell proliferation associated with a characteristic stromal pattern, a leuko-erythroblastic blood film and elevated levels of various inflammatory and pro-angiogenic cytokines. Myeloproliferative MF can present in a patient with no relevant previous illness (primary MF (PMF)) or evolve secondarily - eg, from previous polycythaemia vera or essential thrombocythaemia.
Bone marrow fibrosis is associated with the appearance of marrow stem cells in abnormal sites (myeloid metaplasia) - eg, liver and spleen.
MF may be secondary to a variety of diseases, including:
- Leukaemias: acute lymphocytic leukaemia, acute myelogenous leukaemia, acute megakaryocytic leukaemia, chronic myeloid leukaemia, hairy cell leukaemia.
- Lymphomas: Hodgkin's lymphoma and non-Hodgkin's lymphoma.
- Multiple myeloma.
- Metastatic carcinoma.
- Polycythaemia vera.
- Systemic mastocytosis.
- Infection: HIV, tuberculosis.
- Endocrine/metabolic: hyperparathyroidism, renal osteodystrophy, vitamin D deficiency.
- Connective tissue disease: systemic lupus erythematosus.
- Toxins: X-radiation, gamma radiation, benzene, thorium dioxide exposure.
The diagnosis of primary MF is based on the 2008 World Health Organization (WHO) criteria, which include histopathological, morphological, clinical and molecular-cytogenetic variables.
- This is an uncommon disease, with an annual incidence of approximately 0.4 cases per 100,000.
- The prevalence is estimated to be 4-6 per 100,000 population.
- The median age at diagnosis is 60 years and more than 90% of patients are diagnosed after age 40 years. However, MF has been reported in all age groups.
- It is more common in white people than in individuals of other races.
- An increased prevalence rate has been noted in Ashkenazi Jews.
- A slight male preponderance appears to exist; however, in younger children, girls are affected twice as frequently as boys.
The diagnosis of PMF, as defined by the WHO, is based on a combination of clinical, morphological, cytogenetic and molecular features. The diagnosis of PMF requires A1 + A2 and any two B criteria:
- A1: bone marrow fibrosis >3 (on 0-4 scale).
- A2: pathogenetic mutation (eg, in JAK2 or MPL), or absence of both BCR-ABL1 and reactive causes of bone marrow fibrosis.
- B1: palpable splenomegaly.
- B2: unexplained anaemia.
- B3: leuko-erythroblastosis.
- B4: tear-drop red cells.
- B5: constitutional symptoms: drenching night sweats, weight loss >10% over six months, unexplained fever (>37.5°C ) or diffuse bone pains.
- B6: histological evidence of extramedullary haematopoiesis.
Diagnostic criteria for post-polycythaemia vera or essential thrombocythaemia myelofibrosis: diagnosis requires A1 + A2 and any two B criteria. The criteria are the same, except for A2, which is: previous diagnosis of polycythaemia vera or essential thrombocythaemia.
- In early stages, the disease may be asymptomatic.
- The clinical features of MF are variable and include progressive anaemia, leukopenia or leukocytosis, thrombocytopenia or thrombocytosis and multi-organ extramedullary haemopoiesis, most commonly causing hepatomegaly and symptomatic splenomegaly.
- Patients with advanced disease experience severe constitutional symptoms (general malaise, weight loss, night sweats and low-grade fever), massive splenomegaly (pain, early satiety, splenic infarction, portal hypertension and dyspnoea), progressive marrow failure, pulmonary hypertension, transformation to leukaemia and early death.
- Anaemia (may occur due to ineffective erythropoiesis, erythroid hypoplasia and hypersplenism) may cause fatigue, weakness and dyspnoea.
- Splenomegaly may result in left upper quadrant discomfort. Splenic infarcts, perisplenitis, or subcapsular haematoma may cause severe left upper quadrant or left shoulder pain.
- Spontaneous bleeding may occur and vary from insignificant cutaneous petechiae to severe, life-threatening gastrointestinal tract bleeding. Platelet dysfunction, acquired factor V deficiency, thrombocytopenia, disseminated intravascular coagulation, oesophageal varices and peptic ulcer disease may occur.
- Extramedullary haematopoiesis may cause symptoms, depending on the organ or site of involvement. The condition may result in spinal cord compression, focal seizures, symptoms related to brain tumours, ascites, haematuria, pericardial effusion, pleural effusion, haemoptysis and respiratory failure.
- Splenomegaly (may be massive).
- Petechiae and ecchymosis.
- Neutropenia may cause opportunistic infection - eg, oral thrush.
- Signs of portal hypertension.
- Peripheral blood film: leuko-erythroblastosis with teardrop poikilocytosis. Large platelets and megakaryocyte fragments may also be seen. May be anaemia and leukopenia. Thrombocytosis is more common than thrombocytopenia.
- Disseminated intravascular coagulation (15% of patients) is usually clinically silent but may cause decreased platelets, decreased clotting factors and increased fibrin degradation products.
- Bone marrow aspiration is usually dry. A bone marrow biopsy is required to show fibrosis. Fibrosis may not be uniformly distributed and so the biopsy may need to be repeated at a different site.
- Skeletal radiographs: increased bone density (may be patchy and result in a mottled appearance) and a prominence of bony trabeculae.
- MRI scan: help to assess the severity and progression of disease. Marrow patterns observed on an MRI examination of the proximal femur appear to correlate with clinical severity.
- Investigation of possible underlying cause (see above) - eg, parathyroid hormone, antinuclear antibodies.
- Cytogenetic studies help to exclude chronic myeloid leukaemia, myelodysplastic syndrome, or other chronic myeloid disorders.
- In patients with MF, cytogenetic studies reveal chromosomal abnormalities in about half of all patients. The presence of an abnormal karyotype is associated with a poorer prognosis.
- JAK2 V617F mutation screening should be carried out routinely in patients with PMF. JAK2 V617F mutation is present in approximately 45-68% of patients.
- BCR-ABL1 rearrangement (diagnostic of chronic myeloid leukaemia) should be excluded in cases with atypical trephine biopsy features, or if the patient lacks a mutation in JAK2 or MPL.
- PDGFRA and PDGFRB rearrangements should be excluded in the presence of significant eosinophilia.
- Screening for other mutations remains a research tool and routine screening cannot be justified, apart from in cases of diagnostic difficulty where detection of a clonal abnormality would be informative.
- Idiopathic MF is a chronic myeloproliferative disorder, along with chronic myeloid leukaemia, polycythaemia rubra vera and essential thrombocytosis.
- Myeloproliferative diseases are a group of disorders characterised by cellular proliferation of one or more blood cell lines distinct from acute leukaemia.
- In some patients, conditions overlap and one condition may evolve into one of the other myeloproliferative conditions and/or transform to acute myeloid leukaemia.
- Allogeneic stem cell transplantation (SCT) represents the only treatment modality with curative potential.[11, 12]
- Treatment, therefore, is otherwise generally palliative and guided by the predominant symptoms associated with anaemia and splenomegaly.
- Asymptomatic low-risk patients may be observed without intervention.
- Patients with haemolysis should take folic acid supplements. Allopurinol should be used for hyperuricaemia.
- Hydroxyurea has traditionally been the preferred and most commonly used agent - moderately effective at improving splenomegaly, leukocytosis and thrombocytosis.
- Interferon alfa and other drug treatments have shown some benefit but need further evaluation.
- Management of constitutional symptoms in PMF is very difficult and there is no evidence of benefit for any of the conventional treatments for PMF.
- JAK inhibitors (eg, ruxolitinib) have recently shown important and promising benefits in the treatment of MF.
- Although ruxolitinib and other JAK inhibitors are effective in controlling splenomegaly and alleviating constitutional symptoms, their benefit in reversing bone marrow fibrosis or inducing complete or partial remissions appears to be limited.
- Other agents that do not directly target JAK2 and have shown benefit include pomalidomide, which appears to be particularly effective against MF-associated anaemia.
- First-line: hydroxycarbamide (in the absence of cytopenias). Thalidomide and prednisolone may be considered in the presence of cytopenias; lenalidomide may be considered if the patient is anaemic with a platelet count >100 x 109/L).
- Second-line: consideration should be given to the use of JAK inhibitors, either as part of a clinical trial or via patient access protocols.
- Routine splenectomy is inappropriate and should be restricted to patients with refractory haemolysis, symptomatic splenomegaly, significant splenic infarction, severe portal hypertension and severe hypercatabolic symptoms.
- Radiotherapy may be considered for patients with symptomatic splenomegaly who have an adequate platelet count (>50 x 109/L) and who are not suitable for surgical intervention. Platelet transfusions may be required after treatment. Radiotherapy may also be indicated for extramedullary haematopoiesis involving vital organs and severe bone pain.
- Post-splenectomy myeloproliferation: cytoreductive therapy (hydroxycarbamide). Cladribine can be considered in selected patients.
- Red cell transfusions are recommended in PMF patients with symptomatic anaemia. Iron chelation therapy is not routinely recommended.
- A trial of recombinant erythropoietin therapy should be considered in anaemic PMF patients with inappropriately low erythropoietin levels.
- Danazol should be considered as a therapeutic option to improve the haemoglobin concentration of patients with MF and transfusion-dependent anaemia.
- Hydroxycarbamide is the first-line choice for the control of the hyperproliferation manifestations of MF.
- Anagrelide should be used with caution in patients with established MF.
- Use of interferon alfa in PMF patients should be restricted to cases with early-phase disease with more proliferative disease features.
- Potentially curative therapy and long-lasting, complete remissions have been reported. Requires high-dose chemotherapy to destroy the bone marrow before SCT. The high-dose chemotherapy may have severe adverse effects. Studies are focused on ways to avoid the need for such high-dose chemotherapy.
- A bone marrow transplant-eligible patient is defined as one deemed fit enough to undergo the procedure with manageable comorbidities and having an HLA-matched sibling or unrelated donor available.
- Transplant-eligible patients less than 45 years of age, with an International Prognostic Scoring System (IPSS) risk of Intermediate 2 or High, especially with transfusion dependence and/or adverse cytogenetic abnormalities, should be considered for myeloablative allogeneic SCT. See 'Prognosis' section below for details of IPSS.
- Transplant-eligible patients with an IPSS risk of Intermediate 2 or High, especially with transfusion dependence and/or adverse cytogenetic abnormalities, together with an HSCT comorbidity index >3, or who are over the age of 45, should be considered for reduced-intensity conditioning allogeneic HSCT.
- Patients should be transplanted before they have received more than 20 units of red cells.
- Conventional myeloablative regimens such as cyclophosphamide combined with total body irradiation, or busulfan, may achieve good overall survival rates.
- JAK2 V617F mutated patients who do not achieve molecular remission or who relapse post-transplant are candidates for donor lymphocyte infusions in the absence of graft-versus-host disease.
Blast phase of MF (BP-MF)
- The blast phase of MF is synonymous with acute myeloid leukaemia. Despite treatment, individuals with BP-MF will survive less than one year, with many dying within six months.
- Cure for BP-MF requires the success of induction chemotherapy with a return to a chronic phase disease, and an immediate allogeneic SCT.
- Azacitidine can lead to responses of a palliative, or possibly life-prolonging, nature for patients who will not be candidates for allogeneic SCT.
- BP-MF has a poor prognosis and consideration should be given to strictly supportive care.
- Portal hypertension may result in variceal bleeding, ascites and hepatic encephalopathy. Hepatic or portal vein thrombosis may also occur.
- Splenic infarction: usually self-limited and treated with fluids and opiate analgesics. Refractory cases may require splenectomy or splenic irradiation.
- Osteosclerosis, hypertrophic osteoarthropathy and periostitis: may cause severe joint and bone pain.
- Abnormalities of humoral immunity: variety of autoantibodies and circulating immune complexes may be detected and amyloidosis may develop. Infections, commonly pneumonia, may occur as a result of immune deficiency.
- Leukaemic transformation to acute myeloid leukaemia may occur.
- Extramedullary hematopoiesis may involve any organ and may result in gastrointestinal bleeding, spinal cord compression, seizures, haemoptysis, and/or effusions. These can be controlled with low-dose radiation.
- Gout or urate renal calculi due to uric acid overproduction.
- MF is an incurable disease for patients who are not successful recipients of allogeneic SCT.
- The IPSS estimates survival from the time of diagnosis, based on five risk factors: age >65 years, haemoglobin concentration <100 g/L, leukocyte count >25 x 109/L, circulating blasts >1% and the presence of constitutional symptoms.
- Based on the presence of 0 (low risk), 1 (intermediate risk-1), 2 (intermediate risk-2) or 3 or more (high risk) of these variables, four risk groups have been identified with median survivals of 135, 95, 48 and 27 months respectively.
- The IPSS has been modified for use at any time during the disease course (Dynamic IPSS) and the addition of three additional independent risk factors (transfusion dependence, unfavourable karyotype and platelet count <100 x 109/L) has been shown to provide greater discrimination between the risk groups (DIPPS Plus).
- Leukocytosis and abnormal karyotype are associated with increased risk of transformation to acute myeloid leukaemia.
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