Disease overview
Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) respectively characterized by clonal 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 MPL mutations (so called driver mutations). In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis.
Survival
Median survivals are approximately 15 years for PV and 18 years for ET; the corresponding values for patients age 40 or younger were 37 and 35 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 but risk of thrombosis is higher in JAK2 mutated cases. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV.
Thrombosis risk
In PV, two risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors). In ET, four 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‐daily 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.
New treatment directions
Controlled studies are needed to confirm the clinical outcome value of twice‐daily vs once‐daily aspirin dosing and the therapeutic role of pegylated interferons and direct oral anticoagulants.
Mutations in the calreticulin (CALR) gene were recently discovered in patients with essential thrombocythemia (ET) lacking the JAK2V617F and MPLW515 mutations, but no information is available on the ...clinical correlates. In this series, CALR mutations were found in 15.5% of 576 World Health Organization–defined ET patients, accounting for 48.9% of JAK2 and MPL wild-type (wt) patients. CALR-mutated patients were preferentially male and showed higher platelet count and lower hemoglobin and leukocyte count compared with JAK2- and MPL-mutated patients. Patients carrying the CALR mutation had a lower risk of thrombosis than JAK2- and MPL-mutated patients; of interest, their risk was superimposable to patients who were wt for the above mutations. CALR mutation had no impact on survival or transformation to post-ET myelofibrosis. Genotyping for CALR mutations represents a novel useful tool for establishing a clonal myeloproliferative disorder in JAK2 and MPL wt patients with thrombocytosis and may have prognostic and therapeutic relevance.
•CALR mutations occur in half of JAK2 and MPL wt patients with ET and associate with some distinctive phenotypic traits.•Patients with ET harboring CALR mutations are at significantly lower risk of thrombosis compared with JAK2- and MPL-mutated patients.
Treatments for high-risk essential thrombocythemia (ET) address thrombocytosis, disease-related symptoms, as well as risks of thrombosis, hemorrhage, transformation to myelofibrosis, and leukemia. ...Patients resistant/intolerant to hydroxycarbamide (HC) have a poor outlook. MAJIC (ISRCTN61925716) is a randomized phase 2 trial of ruxolitinib (JAK1/2 inhibitor) vs best available therapy (BAT) in ET and polycythemia vera patients resistant or intolerant to HC. Here, findings of MAJIC-ET are reported, where the modified intention-to-treat population included 58 and 52 patients randomized to receive ruxolitinib or BAT, respectively. There was no evidence of improvement in complete response within 1 year reported in 27 (46.6%) patients treated with ruxolitinib vs 23 (44.2%) with BAT (P = .40). At 2 years, rates of thrombosis, hemorrhage, and transformation were not significantly different; however, some disease-related symptoms improved in patients receiving ruxolitinib relative to BAT. Molecular responses were uncommon; there were 2 complete molecular responses (CMR) and 1 partial molecular response in CALR-positive ruxolitinib-treated patients. Transformation to myelofibrosis occurred in 1 CMR patient, presumably because of the emergence of a different clone, raising questions about the relevance of CMR in ET patients. Grade 3 and 4 anemia occurred in 19% and 0% of ruxolitinib vs 0% (both grades) in the BAT arm, and grade 3 and 4 thrombocytopenia in 5.2% and 1.7% of ruxolitinib vs 0% (both grades) of BAT-treated patients. Rates of discontinuation or treatment switching did not differ between the 2 trial arms. The MAJIC-ET trial suggests that ruxolitinib is not superior to current second-line treatments for ET. This trial was registered at www.isrctn.com as #ISRCTN61925716.
•After hydroxycarbamide therapy in high-risk ET, ruxolitinib showed no improvement for complete or partial response rates compared with BAT.•Ruxolitinib significantly improved some disease-related symptoms, but rates of thrombosis, hemorrhage, or transformation were not different.
Philadelphia-negative classical myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 revision of the WHO ...Classification of Tumours of Haematopoietic and Lymphoid Tissues includes new criteria for the diagnosis of these disorders. Somatic mutations in the 3 driver genes, that is, JAK2, CALR, and MPL, represent major diagnostic criteria in combination with hematologic and morphological abnormalities. PV is characterized by erythrocytosis with suppressed endogenous erythropoietin production, bone marrow panmyelosis, and JAK2 mutation. Thrombocytosis, bone marrow megakaryocytic proliferation, and presence of JAK2, CALR, or MPL mutation are the main diagnostic criteria for ET. PMF is characterized by bone marrow megakaryocytic proliferation, reticulin and/or collagen fibrosis, and presence of JAK2, CALR, or MPL mutation. Prefibrotic myelofibrosis represents an early phase of myelofibrosis, and is characterized by granulocytic/megakaryocytic proliferation and lack of reticulin fibrosis in the bone marrow. The genomic landscape of MPNs is more complex than initially thought and involves several mutant genes beyond the 3 drivers. Comutated, myeloid tumor-suppressor genes contribute to phenotypic variability, phenotypic shifts, and progression to more aggressive disorders. Patients with myeloid neoplasms are at variable risk of vascular complications, including arterial or venous thrombosis and bleeding. Current prognostic models are mainly based on clinical and hematologic parameters, but innovative models that include genetic data are being developed for both clinical and trial settings. In perspective, molecular profiling of MPNs might also allow for accurate evaluation and monitoring of response to innovative drugs that target the mutant clone.
Mutations in the MPL gene encoding the human thrombopoietin receptor (TpoR) drive sporadic and familial essential thrombocythemias (ETs). We identified 2 ET patients harboring double mutations in cis ...in MPL, namely, L498W-H499C and H499Y-S505N. Using biochemical and signaling assays along with partial saturation mutagenesis, we showed that L498W is an activating mutation potentiated by H499C and that H499C and H499Y enhance the activity of the canonical S505N mutation. L498W and H499C can activate a truncated TpoR mutant, which lacks the extracellular domain, indicating these mutations act on the transmembrane (TM) cytosolic domain. Using a protein complementation assay, we showed that L498W and H499C strongly drive dimerization of TpoR. Activation by tryptophan substitution is exquisitely specific for position 498. Using structure-guided mutagenesis, we identified upstream amino acid W491 as a key residue required for activation by L498W or canonical activating mutations such as S505N and W515K, as well as by eltrombopag. Structural data point to a common dimerization and activation path for TpoR via its TM domain that is shared between the small-molecule agonist eltrombopag and canonical and novel activating TpoR mutations that all depend on W491, a potentially accessible extracellular residue that could become a target for therapeutic intervention.
•H499C and H499Y mutations enhance activation of TpoR by novel L498W and canonical S505N mutations.•Activation of TpoR by eltrombopag and the L498W, S505N, and W515K mutants depends on W491, which might be accessible on the cell surface.
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Patients with essential thrombocythemia may carry JAK2 (V617F), an MPL substitution, or a calreticulin gene (CALR) mutation. We studied biologic and clinical features of essential thrombocythemia ...according to JAK2 or CALR mutation status and in relation to those of polycythemia vera. The mutant allele burden was lower in JAK2-mutated than in CALR-mutated essential thrombocythemia. Patients with JAK2 (V617F) were older, had a higher hemoglobin level and white blood cell count, and lower platelet count and serum erythropoietin than those with CALR mutation. Hematologic parameters of patients with JAK2-mutated essential thrombocythemia or polycythemia vera were related to the mutant allele burden. While no polycythemic transformation was observed in CALR-mutated patients, the cumulative risk was 29% at 15 years in those with JAK2-mutated essential thrombocythemia. There was no significant difference in myelofibrotic transformation between the 2 subtypes of essential thrombocythemia. Patients with JAK2-mutated essential thrombocythemia and those with polycythemia vera had a similar risk of thrombosis, which was twice that of patients with the CALR mutation. These observations are consistent with the notion that JAK2-mutated essential thrombocythemia and polycythemia vera represent different phenotypes of a single myeloproliferative neoplasm, whereas CALR-mutated essential thrombocythemia is a distinct disease entity.
•JAK2 (V617F)-mutated essential thrombocythemia and polycythemia vera are different phenotypes in the evolution of a single neoplasm.•CALR-mutated essential thrombocythemia is a distinct disease entity not only at the molecular level, but also with respect to clinical outcomes.
Since its approval in 2011, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea ...resistant or intolerant polycythemia vera (PV) is steadily increasing. Several other JAK2 inhibitors have entered clinical testing, but none have been approved and many have been discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, in which survival is short. Many such combinations are being explored, as are other novel agents, some of which could successfully be combined with JAK2 inhibitors in the future. In addition, new JAK2 inhibitors with the potential for less myelosuppression continue to be investigated. Given the proven safety and efficacy of ruxolitinib, it is likely that ruxolitinib-based combinations will be a major way forward in drug development for MF. If approved, less myelosuppressive JAK2 inhibitors such as pacritinib or NS-018 could prove to be very useful additions to the therapeutic armamentarium in MF. In PV, inhibitors of histone deacetylases and human double minute 2 have activity, but their role, if any, in the future treatment algorithm is uncertain, given the availability of ruxolitinib and renewed interest in interferons. Ruxolitinib is in late-phase clinical trials in essential thrombocythemia, in which it could fill an important void for patients with troublesome symptoms.
The authors identified calreticulin mutations in the majority of patients with essential thrombocythemia and myelofibrosis who did not have
JAK2
mutations. The mutation alters calreticulin protein, ...and cells expressing the mutant protein are more responsive to growth factors.
Philadelphia chromosome–negative myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia, and primary myelofibrosis.
1
A unique gain-of-function mutation in the Janus kinase 2 gene (
JAK2
) is found in about three quarters of patients in whom these disease entities have been diagnosed.
2
,
3
The valine-to-phenylalanine (V617F) alteration constitutively activates JAK2, resulting in increased phosphorylation of its substrates and leading to increased cytokine responsiveness of myeloid cells. The
JAK2
V617F mutation is present in approximately 95% of patients with polycythemia vera and in 50 to 60% of those with essential thrombocythemia or primary myelofibrosis.
4
In addition, somatic mutations of
JAK2
exon 12 . . .
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