Myeloproliferative Neoplasms
Summary of Key Points
Differential Diagnosis
• All three classic BCR-ABL1− MPNs may be considered as diagnoses of exclusion, because a specific diagnostic marker is currently lacking.
• The presence of a JAK2 mutation distinguishes PV from all other causes of polycythemia, and ET and PMF from reactive thrombocytosis or myelofibrosis, respectively.
Diagnostic Evaluation
• Evaluation of suspected PV should start with peripheral blood screening for JAK2V617F and serum erythropoietin (Epo) measurement.
• More than 90% of PV patients are expected to display the JAK2 mutation, whereas a low serum Epo level should capture most of the JAK2V617F− cases, which might display other JAK2 mutations such as an exon 12 mutation.
• Bone marrow examination remains essential in the diagnosis of ET and PMF.
Risk Stratification
• Both PV and ET display a near-normal life expectancy in the first decade of the disease. The major problem during this period is thrombosis that may occur in as many as 30% of the patients.
• A history of thrombosis or age older than 60 years is associated with a high-risk of thrombosis.
• Platelet count by itself has not been significantly associated with thrombosis in either PV or ET.
• The presence of advanced age, anemia, red cell transfusion-dependency, thrombocytopenia, leukocytosis, severe constitutional symptoms, circulating blasts or unfavorable karyotype are all adverse risk factors in PMF.
Treatment
• Phlebotomy, to a hematocrit target of below 45%, remains the mainstay of therapy in PV.
• Low-risk patients (age younger than 60 years and no history of thrombosis) with either PV or ET have not been shown to benefit from cytoreductive therapy.
• Treatment with hydroxyurea has been shown to reduce thrombosis risk in high-risk patients with both ET and PV.
• Microvascular symptoms, including headache and erythromelalgia (painful and burning sensation of the feet or hands associated with erythema and warmth), are easily treated with low-dose aspirin, which is indicated in the absence of extreme thrombocytosis.
• Drug therapy in PMF is currently palliative, and effective agents include corticosteroids, erythropoiesis-stimulating agents (ESAs), androgen preparations, danazol, thalidomide, lenalidomide, hydroxyurea and ruxolitinib.
• Splenectomy continues to have a palliative role in PMF.
• Involved-field radiation therapy in PMF is most effective in the setting of nonhepatosplenic extramedullary hematopoiesis.
• Hematopoietic stem cell transplantation has a therapeutic role in high-risk PMF but is associated with substantial regiment-related toxicity including death and chronic morbidity.
1. In clinical medicine the term polycythemia refers to the possible presence of an increased erythrocyte mass. This may be either true polycythemia or apparent polycythemia. True polycythemia may represent polycythemia vera (PV), of which greater than 95% is associated with a specific genetic mutation. This mutation is absent in patients with either secondary or apparent polycythemia. What is the optimal laboratory validation for a diagnosis of true PV?
A The finding of a positive BCR-ABL1 translocation
B The finding of a negative BCR-ABL1 translocation
C The finding of a JAK2V617F mutation and a serum Epo negative (low).
2. The diagnosis of essential thrombocythemia (ET) and of the presence of primary myelofibrosis (PMF) are both heavily dependent on:
A Molecular diagnostics such as exon or whole genome sequencing
C Bone marrow fluorescence in situ hybridization
D A serum Epo level and cytogenetic screening
E Clinical symptoms, molecular diagnostics, and the serum Epo level
3. The only treatment modality for patients diagnosed as having PV shown to improve survival is
1. Answer: C. More than 95% of patients with PV carry the JAK2V617F mutation. This mutation is a G-to-T somatic mutation, at nucleotide 1849, in exon 14, resulting in a phenylalanine substitution for valine at codon 617. The JAK2V617F mutation is absent in both secondary and apparent polycythemia. The measurement of the serum Epo level is important to minimize the risk of a false-positive or false-negative molecular marker test and to detect the rare cases of PV that are JAK2V617F negative. Bone marrow examination is encouraged to add further confirmation and as a baseline for future follow up.
2. Answer: B. Unlike the diagnosis of PV, mutation screening for JAK2V617F for the diagnosis of ET and PMF has a low diagnostic specificity within the myeloid neoplasms. Only approximately 50% of patients with ET and PMF carry the JAK2V617F mutation. While MPLW515L/K mutations appear specific for PMF and ET its frequency is generally seen in <5% of patients. Thus, for diagnosing ET and PMF, careful bone marrow examination is of central importance.
3. Answer: A. Phlebotomy is the cornerstone therapy for patients diagnosed with polycythemia vera and is the only therapy that has been shown to improve survival. Studies in patients with PV show a progressive increase in the incidence of vascular occlusive episodes with a hematocrit level above 44% and suboptimal cerebral blood flow with hematocrit values between 46% and 52%. Of concern in managing a patient with PV is the late onset of disease transformation into post-PV myelofibrosis and/or acute myeloid leukemia (AML). Specific treatment of PV has not had any apparent effect on preventing this natural progression. While one might expect JAK inhibitors to be useful, such treatment should be carried out only through clinical trial participation using newer pathway inhibitors. The JAK inhibitor ruxolitinib does not appear to significantly modify the natural history of PV and has significant toxicity.
