Essential Thrombocythemia Tefferi, Ayalew; Pardanani, Animesh
The New England journal of medicine,
11/2019, Letnik:
381, Številka:
22
Journal Article
Recenzirano
Essential thrombocythemia is associated with increased risks of bleeding and thrombosis. Estimation of the risk of thrombosis is based on history of thrombosis, presence of the
JAK2
V617F mutation, ...age, and cardiovascular risk. Treatment commonly involves low-dose aspirin; therapy is used in patients with high thrombotic risk.
Disease Overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features ...include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation.
Diagnosis: Bone marrow morphology remains the cornerstone of diagnosis. In addition, the presence of JAK2 mutation is expected in PV while approximately 90% of patients with ET express mutually exclusive JAK2, CALR, or myeloproliferative leukemia mutations. In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis.
Survival: Median survivals are 14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Certain mutations (mostly spliceosome) and abnormal karyotype might compromise survival in PV and ET. Life‐expectancy in ET is inferior to the control population. Driver mutations have not been shown to affect survival in ET. Risk of thrombosis is higher in JAK2‐mutated ET. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV.
Thrombosis Risk: In PV, 2 risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors); in ET, 4 risk categories are considered: very low (age ≤ 60 years, no thrombosis history, JAK2 wild‐type), low (same as very low but JAK2 mutation present), intermediate (age > 60 years, no thrombosis history, JAK2 wild‐type) and high (thrombosis history present or age > 60 years with JAK2 mutation).
Risk‐Adapted Therapy: The main goal of therapy in both PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once‐ or twice‐daily aspirin (81 mg), in the absence of contraindications. Very low‐risk ET might not require therapy while aspirin therapy is advised for low‐risk disease. Cytoreductive therapy is recommended for high‐risk ET and PV but it is not mandatory for intermediate‐risk ET. First‐line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second‐line drugs of choice are interferon‐α and busulfan. We do not recommend treatment with ruxolutinib in PV, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs.
William Vainchenker discovered the gain-of-function mutation in the gene encoding Janus kinase (JAK) 2 (
JAK2
V617F) in early 2004 (reported in 2005)
1
and subsequently described its association with
...BCR-ABL1
–negative myeloproliferative neoplasms and its ability to induce erythrocytosis in mice. At that time, many researchers hoped that a specific targeted agent would be developed for these neoplasms, similar to imatinib for chronic myeloid leukemia. This particular prospect was bolstered by the detection of other activating mutations that are relevant to JAK–signal transducer and activator of transcription (STAT) (e.g.,
MPL
W515L and
JAK2
K539L) in patients with
JAK2
V617F–negative disease. . . .
Polycythemia vera (PV) is a relatively indolent myeloid neoplasm with median survival that exceeds 35 years in young patients, but its natural history might be interrupted by thrombotic, fibrotic, or ...leukemic events, with respective 20-year rates of 26%, 16%, and 4%. Current treatment strategies in PV have not been shown to prolong survival or lessen the risk of leukemic or fibrotic progression and instead are directed at preventing thrombotic complications. In the latter regard, two risk categories are considered: high (age >60 years or thrombosis history) and low (absence of both risk factors). All patients require phlebotomy to keep hematocrit below 45% and once-daily low-dose aspirin, in the absence of contraindications. Cytoreductive therapy is recommended for high-risk or symptomatic low-risk disease; our first-line drug of choice in this regard is hydroxyurea but we consider pegylated interferon as an alternative in certain situations, including in young women of reproductive age, in patients manifesting intolerance or resistance to hydroxyurea therapy, and in situations where treatment is indicated for curbing phlebotomy requirement rather than preventing thrombosis. Additional treatment options include busulfan and ruxolitinib; the former is preferred in older patients and the latter in the presence of symptoms reminiscent of post-PV myelofibrosis or protracted pruritus. Our drug choices reflect our appreciation for long-term track record of safety, evidence for reduction of thrombosis risk, and broader suppression of myeloproliferation. Controlled studies are needed to clarify the added value of twice- vs once-daily aspirin dosing and direct oral anticoagulants. In this invited review, we discuss our current approach to diagnosis, prognostication, and treatment of PV in general, as well as during specific situations, including pregnancy and splanchnic vein thrombosis.
To update oncologists on pathogenesis, contemporary diagnosis, risk stratification, and treatment strategies in BCR-ABL1-negative myeloproliferative neoplasms, including polycythemia vera (PV), ...essential thrombocythemia (ET), and primary myelofibrosis (PMF). Recent literature was reviewed and interpreted in the context of the authors' own experience and expertise. Pathogenetic mechanisms in PV, ET, and PMF include stem cell-derived clonal myeloproliferation and secondary stromal changes in the bone marrow and spleen. Most patients carry an activating JAK2 or MPL mutation and a smaller subset also harbors LNK, CBL, TET2, ASXL1, IDH, IKZF1, or EZH2 mutations; the precise pathogenetic contribution of these mutations is under investigation. JAK2 mutation analysis is now a formal component of diagnostic criteria for PV, ET, and PMF, but its prognostic utility is limited. Life expectancy in the majority of patients with PV or ET is near-normal and disease complications are effectively (and safely) managed by treatment with low-dose aspirin, phlebotomy, or hydroxyurea. In PMF, survival and quality of life are significantly worse and current therapy is inadequate. In ET and PV, controlled studies are needed to show added value and justify the risk of unknown long-term health effects associated with nonconventional therapeutic approaches (eg, interferon-alfa). The unmet need for treatment in PMF dictates a different approach for assessing the therapeutic value of new drugs (eg, JAK inhibitors, pomalidomide) or allogeneic stem-cell transplantation.
JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses both hereditary and acquired conditions. A systematic diagnostic approach begins with documentation of historical hematocrit ...(Hct)/hemoglobin (Hgb) measurements and classification of the process as life-long/unknown duration or acquired. Further investigation in both categories is facilitated by determination of serum erythropoietin level (EPO). Workup for hereditary/congenital erythrocytosis requires documentation of family history and laboratory screening for high-oxygen affinity hemoglobin variants, 2, 3 biphosphoglycerate deficiency, and germline mutations that are known to alter cellular oxygen sensing (e.g., PHD2, HIF2A, VHL) or EPO signaling (e.g., EPOR mutations); the latter is uniquely associated with subnormal EPO. Acquired erythrocytosis is often elicited by central or peripheral hypoxia resulting from cardiopulmonary disease/high-altitude dwelling or renal artery stenosis, respectively; EPO in the former instance is often normal (compensated by negative feed-back). Other conditions associated with acquired erythrocytosis include EPO-producing tumors and the use of drugs that promote erythropoiesis (e.g., testosterone, erythropoiesis stimulating agents). "Idiopathic erythrocytosis" loosely refers to an otherwise not explained situation. Historically, management of non-PV erythrocytosis has been conflicted by unfounded concerns regarding thrombosis risk, stemming from limited phenotypic characterization, save for Chuvash polycythemia, well-known for its thrombotic tendency. In general, cytoreductive therapy should be avoided and phlebotomy is seldom warranted where frequency is determined by symptom control rather than Hct threshold. Although not supported by hard evidence, cardiovascular risk optimization and low-dose aspirin use are often advised. Application of modern genetic tests and development of controlled therapeutic intervention trials are needed to advance current clinical practice.
Disease overview
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an ...inherent risk for leukemic transformation (~15% over 3‐5 years).
Diagnosis
Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 109/L; monocytes ≥10%), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ~ 30% of patients, while >90% have gene mutations. Mutations involving TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%) and the oncogenic RAS pathway (~30%) are frequent; while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact over‐all survival.
Risk stratification
Molecularly integrated prognostic models include; the Groupe Français des Myélodysplasies (GFM), Mayo Molecular Model (MMM) and the CMML specific prognostic model (CPSS‐Mol). Risk factors incorporated into the MMM include presence of nonsense or frameshift ASXL1 mutations, absolute monocyte count>10 × 109/L, hemoglobin <10 g/dL, platelet count <100 × 109/L and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into four groups; high (≥3 risk factors), intermediate‐2 (2 risk factors), intermediate‐1 (1 risk factor) and low (no risk factors), with median survivals of 16, 31, 59 and 97 months, respectively.
Risk‐adapted therapy
Hypomethylating agents such as 5‐azacitidine and decitabine are commonly used, with overall response rates of ~40%‐50% and complete remission rates of ~7%‐17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option, but is associated with significant morbidity and mortality.
PDF
