MYELOPROLIFARATIVE NEOPLASMS Dr. Hasan Fahmawi, MRCP(UK), FRCP(Edin).
These are a group of chronic conditions characterised by clonal proliferation of marrow precursor cells. PRV, essential thrombocyathaemia, and myelofibrosis are the non-leukaemic myeloproliferative neoplasms. Some have overlapping features and there is progression from one to another. A mutation in the gene on chromosome 9 signal transduction molecule JAK-2 which has been found in more than 95% of PRV cases and 50% of those with essential thrombocyathaemia and 50% in myelofibrosis.
Myeloproliferative Neoplasm AML Acute Myeloid Leukaemia Haematopoietic Stem Cell
Myelofibrosis The marrow is initially hypercellular, with an excess of abnormal megakaryocytes, producing platelet-derived growth factor to the marrow microenvironment, resulting in a reactive proliferation of fibroblasts, leading finally to fibrosis. Clinically: age over 50 yrs., and complain of lassitude, weight loss and night sweats. Spleen can be massively enlarged due to extramedullary haematopoiesis and painful due to splenic infarct. Blood picture-leucoerythroblastic anaemia, with reticulocytes, nucleated RBC and myelocytes. RBC show teardrop poikilocytes, and giant platelets might be seen in the blood. WBC vary from low to moderately high, as well as platelets might be high normal or low. Urates level may be high due to increased cell breakdown. Folate deficiency is common. Bone marrow is difficult to aspirate(dry tap), megakaryocytes increase in number, as well as reticulin and fibrous tissue. Jak2 mutation support the diagnosis.
Treatment RBC transfusions for anaemia, folic acid, Hydroxycarbamide, may help control spleen size, WBC count and systemic symptoms. Splenectomy for grossly enlarged one, or symptomatic pancytopaenia due to hypersplenism and splenic pooling. HSCT for young patients. Ruxolitinib, an inhibitor of JAK-2 is effective for reducing systemic manifestations and splenomegaly.
Essential Thrombocythaemia Uncontrolled proliferation of megakaryocytes results in raised circulating levels of platelets that are often dysfunctional, reactive causes must be excluded. JAK2, CALR or rarely MPL mutations support the diagnosis but not universal. Presentations; age 60 yrs., vascular occlusion, bleeding or with an asymptomatic isolated platelets count. 5% transform to acute leukaemia and others to myelofibrosis, most patients benefit from low dose aspirin to reduce the risk of occlusive vascular events. Low risk patients(age less than 40yrs and platelet count less than 1.5 millions and no bleeding or thrombosis) may not need treatment to reduce platelet count. If above 1.5 millions with symptoms or other risk factors for thrombosis in e.g. hypertension or DM, treatment should be given, Hydroxycarbamide or anagrelide, an inhibitor of platelet maturation and intravenous radioactive phosphorous in old age.
High Haemoglobin-Polycythaemia Patients with persistently raised haematocrit, (Hct above 0.52 males or 0.48 females)for more than 2 months should be investigated. True polycythaemia indicate an excess of RBC, while relative or low volume polycythaemia is due to a decreased plasma volume. These include increase erythropoiesis in the bone marrow, either due to primary increase of in marrow activity, or in response to increased erythropoietin(epo levels) in secondary type(in hypoxia), or due to inappropriate secretion of Epo. Athletes who seek to increase oxygen carrying capacity have been known to use Epo. To achieve this. Low volume is polycythaemia associated with hypertension, diuretic use, smoking, and alcohol. Males and females with Hct values of over0.6 and 0.56 respectively, can be assumed to have erythrocytosis. PRV is a high risk for arterial thrombosis (stroke) and VTE, they may have aquagenic pruritus, hepatosplenomegaly and gout(due to high RBC turnover.
Polycyathaemia rubra vera Age over 40 yrs., present as an incidental finding or with symptoms of hyperviscosity, such as lassitude, lack of concentration, headache, dizziness, blackouts, pruritus and epistaxis. Peripheral arterial or cerebrovascular disease, VTE, peptic ulcer disease sometimes complicated with bleeding. Patients are often plethoric and may have a palpable spleen at diagnosis. Investigations; high haematocrit, presence of JAK-2 V617F mutation (positive in 95% of patients). In absence of mutation raised RBC mass and absence of causes of secondary erythrocytosis must be established. Splenomegaly, neutrophil and platelet count are frequently raised. Treatment; venesection, Hydroxycarbamide, interferon alpha to suppress platelet count, which may reduce the risk of vascular occlusion, control spleen size and reduce myelofibrosis transformation. In old age radioactive phosphosphorus which carry 6-10 times increased risk in acute leukaemia. May convert to any myeloproliferative disorder, and 15% progress to acute leukaemia. CVA or coronary artery disease develop in 60% of patients.
Chronic Myeloid Leukaemia CML CML is a shortened chromosome 22 (Philadelphia) resulting from reciprocal translocation material with chromosome 9, (Break Point Cluster Region, BCR, ABL oncogene). It is a myeloproliferative stem cell disorder resulting in haematopoietic lineage but manifesting predominantly in the granulocytic series. Maturation of cells proceed normally. Age 55 yrs., incidence 1.8/100000, accounts for 20% of all leukaemias. A chronic phase; disease is responsive to treatment and is easy to control, which lasts 2-3 yrs., with imatinib therapy life expectancy is normal in many patients. Accelerated phase; in which disease control become more difficult. Blast crises; in which disease turn to either(70% )myeloblastic or (30%) lymphoblastic leukaemia, which is refractory to treatment. This is the cause of death in the majority of cases.
Clinical features Lethargy, weight loss. Abdominal pain, gout and sweating, but about 25% are a symptomatic at diagnosis. Signs; splenomegaly in 90% of cases. A friction rub might be heard in splenic infarcts. Hepatomegaly in 50%, but lymph adenopathy is unusual. Investigations; normocytic normochromic anaemia, WBC 10-600, and the full range of granulocytes precursors, from myeloblasts to mature neutrophils are seen in the blood film. Myeloblasts are less than 10%.There is increased eosinophils, basophils and nucleated RBC. In one third of patients platelets are high and can be 2000. LDH and uric acid are high. Bone marrow should be obtained to confirm diagnosis and phase by morphology. Management; Tyrosine Kinase Inhibitors, imanitib, nilotinib and dasanitib are first line treatment. HSCT
MYELODYSPLASIA MDSs constitute a group of clonal haematopoietic disorders with the common features off ineffective blood cell production and a tendency to progress to AML, as such they are pre-leukaemic. MDS presents with consequences of bone marrow failure, (anaemia, recurrent infection or bleeding)usually in older people(median age of diagnosis is 73 yrs.) Incidence 30/100000 in people over 70yrs. Blood film characterised by cytopaenia and abnormal looking (dysplastic) blood cells including macrocytic RBC (high MCV), hypogranular neutrophils with hypo- or hypersegmentation. The bone marrow is hypercellular, with dysplastic changes in at least 10% of cells of one or more cell lines. The blast cells might be increased but don t reach the 20% level that indicates acute leukaemia. Chromosomes frequently reveals abnormalities, particularly chromosome 5 or7. Prognosis; natural history of MDS is progressive, and worsening of dysplasia leading to bone marrow failure or AML in 30% of cases. The time of progression varies from months to years. Management; for the vast majority patients who are elderly, the disease is incurable, and supportive care with packed RBCs and platelets transfusions is the main stay of treatment. Allogenic bone marrow transplant. Azacytidine has improved survival for 9 months in high-risk patients who are not eligible for transplant.