Myeloproliferative Neoplasms Spivak, Jerry L
The New England journal of medicine,
06/2017, Letnik:
376, Številka:
22
Journal Article
Recenzirano
The myeloproliferative disorders, comprising polycythemia vera, essential thrombocytosis, and myelofibrosis, are clonal hematopoietic cancers that have an indolent course. The clinical manifestations ...of these entities overlap, as do their genetic drivers.
The myeloproliferative neoplasms — polycythemia vera, essential thrombocytosis, and primary myelofibrosis — are unique hematopoietic stem-cell disorders that share mutations that constitutively activate the physiologic signal-transduction pathways responsible for hematopoiesis (Table 1). Consequently, these disorders engage in phenotypic mimicry among themselves, as well as with myeloid neoplasms and even benign hematopoietic disorders. In contrast to the myeloid neoplasms, the myeloproliferative neoplasms have a natural history, with supportive care alone, that is usually measured in decades rather than years.
1
However, a facade of benign myeloproliferation masks a clone of transformed hematopoietic stem cells capable of expansion and transformation to an aggressive . . .
Since its discovery, polycythemia vera (PV) has challenged clinicians responsible for its diagnosis and management and scientists investigating its pathogenesis. As a clonal hematopoietic stem cell ...(HSC) disorder, PV is a neoplasm but its driver mutations result in overproduction of morphologically and functionally normal blood cells. PV arises in an HSC but it can present initially as isolated erythrocytosis, leukocytosis, thrombocytosis, or any combination of these together with splenomegaly or myelofibrosis, and it can take years for a true panmyelopathy to appear. PV shares the same JAK2 mutation as essential thrombocytosis and primary myelofibrosis, but erythrocytosis only occurs in PV. However, unlike secondary causes of erythrocytosis, in PV, the plasma volume is frequently expanded, masking the erythrocytosis and making diagnosis difficult if this essential fact is ignored. PV is not a monolithic disorder: female patients deregulate fewer genes and clinically behave differently than their male counterparts, while some PV patients are genetically predisposed to an aggressive clinical course. Nevertheless, based on what we have learned over the past century, most PV patients can lead long and productive lives. In this review, using clinical examples, I describe how I diagnose and manage PV in an evidence-based manner without relying on chemotherapy.
Polycythemia Vera Spivak, Jerry L.
Current treatment options in oncology,
02/2018, Letnik:
19, Številka:
2
Journal Article
Recenzirano
Opinion statement
Polycythemia vera (PV) is the most common myeloproliferative neoplasm (MPN), the ultimate phenotype of the
JAK2
V1617F mutation, the MPN with the highest incidence of thromboembolic ...complications, which usually occur early in the course of the disease, and the only MPN in which erythrocytosis occurs. The classical presentation of PV is characterized by erythrocytosis, leukocytosis, and thrombocytosis, often with splenomegaly and occasionally with myelofibrosis, but it can also present as isolated erythrocytosis with or without splenomegaly, isolated thrombocytosis or isolated leukocytosis, or any combination of these. When PV is present, the peripheral blood hematocrit (or hemoglobin) determination will not accurately represent the actual volume of red cells in the body, because in PV, in contrast to other disorders causing erythrocytosis, when the red cell mass increases, the plasma volume usually increases. In fact, unless the hematocrit is greater than 59%, true erythrocytosis cannot be distinguished from pseudoerythrocytosis due to plasma volume contraction. Usually, the presence of splenomegaly or leukocytosis or thrombocytosis establishes the diagnosis. However, when a patient presents with isolated thrombocytosis and a positive
JAK2
V617F assay, particularly a young woman, the possibility of PV must always be considered because of plasma volume expansion. The WHO PV diagnostic guidelines are not helpful in this situation, since the hematocrit is invariably normal and a bone marrow examination will not distinguish ET from PV. Only a direct measurement of both the red cell mass and plasma volume can establish the correct diagnosis. In managing a PV patient, it is important to remember that PV is an indolent disorder in which life span is usually measured in decades, even when myelofibrosis is present, that chemotherapy is futile in eradicating the disease but does increase the incidence of acute leukemia and that hydroxyurea is not safe in this regard nor is it antithrombotic. Phlebotomy to a sex-specific normal hematocrit is the cornerstone of therapy and there now exist safe remedies for controlling leukocytosis, thrombocytosis, and extramedullary hematopoiesis and symptoms due to inflammatory cytokines when this is necessary.
The myeloproliferative neoplasms (MPN), polycythemia vera (PV), essential thrombocytosis and primary myelofibrosis, are an unusual group of myeloid neoplasms, which arise in a pluripotent ...hematopoietic stem cell (HSC) due to gain of function driver mutations in the JAK2, CALR and MPL genes that constitutively activate JAK2, the cognate tyrosine kinase of the type 1 hematopoietic growth factor (HGF) receptors. PV is the ultimate phenotypic expression of constitutive JAK2 activation since it alone of the three MPN is characterized by overproduction of normal red cells, white cells and platelets. Paradoxically, however, although PV is a panmyelopathy involving myeloid, erythroid and megakaryocytic progenitor cells, pluripotent HSC only express a single type of HGF receptor, the thrombopoietin receptor, MPL. In this review, the basis for how a pluripotent HSC with one type of HGF can give rise to three separate types of myeloid cells will be explained and it will be demonstrated that PV is actually a hormone-sensitive disorder, characterized by elevated thrombopoietin levels. Finally, it will be shown that the most common form of acute leukemia in PV is due to the inappropriate use of chemotherapy, including hydroxyurea, which facilitates expansion of DNA-damaged, mutated HSC at the expense of their normal counterparts.
The myeloproliferative disorders polycythemia vera, essential thrombocytosis, and primary myelofibrosis are clonal disorders arising in a pluripotent hematopoietic stem cell, causing an unregulated ...increase in the number of erythrocytes, leukocytes, or platelets, alone or in combination; eventual marrow dominance by the progeny of the involved stem cell; and a tendency to arterial or venous thrombosis, marrow fibrosis, splenomegaly, or transformation to acute leukemia, albeit at widely varying frequencies. The discovery of an activating mutation (V617F) in the gene for JAK2 (Janus kinase 2), a tyrosine kinase utilized by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders. Constitutive JAK2 activation provides a growth and survival advantage to the hematopoietic cells of the affected clone. Because signaling by the mutated kinase utilizes normal pathways, the result is overproduction of morphologically normal blood cells, an often indolent course, and (in essential thrombocytosis) usually a normal life span. Because the erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor receptors are all constitutively activated, polycythemia vera is the potential ultimate clinical phenotype of the JAK2 V617F mutation and, as a corollary, is the most common of the 3 disorders. The number of cells expressing the JAK2 V617F mutation (the allele burden) seems to correlate with the clinical phenotype. Preliminary results of clinical trials with agents that inhibit the mutated kinase indicate a reduction in splenomegaly and alleviation of night sweats, fatigue, and pruritus.
To update American Society of Clinical Oncology/American Society of Hematology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer.
An Update Committee ...reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched.
The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews.
For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.
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