Philadelphia-negative classical MPNs: clinical, morphological, and molecular features
| Nosologic entity . | Clinical and morphological features . | Driver genes . | Relationships between genotype, phenotype, and clinical outcome . |
|---|---|---|---|
| PV | Erythrocytosis frequently combined with thrombocytosis and/or leukocytosis (that is, polycythemia) and typically associated with suppressed endogenous erythropoietin production. Bone marrow hypercellularity for age with trilineage growth (that is, panmyelosis) | • JAK2 (V617F) in about 96% of patients • JAK2 exon 12 mutations in about 4% of patients (isolated erythrocytosis in most of these patients) • Patients with wild-type JAK2 extremely rare, if any | • PV patients are at increased risk of thrombosis • PV may progress to myelofibrosis and less commonly to a blast phase similar to AML, sometimes preceded by a myelodysplastic phase |
| ET | Thrombocytosis. Normocellular bone marrow with proliferation of enlarged megakaryocytes | • JAK2 (V617F) in 60%-65% of patients • CALR exon 9 indels in 20%-25% of patients • MPL exon 10 mutations* in about 4%-5% of patients • Noncanonical MPL mutations* in <1% of patients • About 10% of patients do not carry any of the above somatic mutations (the so-called triple-negative cases) | • ET involves increased risk of thrombosis and bleeding, and may progress to more aggressive myeloid neoplasms • JAK2 (V617F)-mutant ET involves a high risk of thrombosis, and may progress to PV or myelofibrosis • CALR-mutant ET involves lower risk of thrombosis and higher risk of progression to myelofibrosis • Triple-negative ET is an indolent disease with low incidence of vascular events |
| PMF | Prefibrotic PMF • Various abnormalities of peripheral blood • Granulocytic and megakaryocytic proliferation in the bone marrow with lack of reticulin fibrosis | • JAK2 (V617F) in 60%-65% of patients • CALR exon 9 indels in 25%-30% of patients • MPL exon 10 mutations* in about 4%-5% of patients • Noncanonical MPL mutations* in <1% of patients • About 5%-10% of patients do not carry any of the above somatic mutations (the so-called triple-negative cases) | • PMF is associated with the greatest symptom burden and the worst prognosis within MPNs, with a variable risk of progression to AML • CALR-mutant PMF is associated with longer survival compared with other genotypes • JAK2 (V617F)- and MPL-mutant PMF have worse prognosis than CALR-mutant PMF • Triple-negative PMF is an aggressive myeloid neoplasm characterized by prominent myelodysplastic features and high risk of leukemic evolution |
| Overt PMF • Various abnormalities of peripheral blood. Bone marrow megakaryocytic proliferation with atypia, accompanied by either reticulin and/or collagen fibrosis grades 2/3. Abnormal stem cell trafficking with myeloid metaplasia (extramedullary hematopoiesis in the liver and/or the spleen) |
| Nosologic entity . | Clinical and morphological features . | Driver genes . | Relationships between genotype, phenotype, and clinical outcome . |
|---|---|---|---|
| PV | Erythrocytosis frequently combined with thrombocytosis and/or leukocytosis (that is, polycythemia) and typically associated with suppressed endogenous erythropoietin production. Bone marrow hypercellularity for age with trilineage growth (that is, panmyelosis) | • JAK2 (V617F) in about 96% of patients • JAK2 exon 12 mutations in about 4% of patients (isolated erythrocytosis in most of these patients) • Patients with wild-type JAK2 extremely rare, if any | • PV patients are at increased risk of thrombosis • PV may progress to myelofibrosis and less commonly to a blast phase similar to AML, sometimes preceded by a myelodysplastic phase |
| ET | Thrombocytosis. Normocellular bone marrow with proliferation of enlarged megakaryocytes | • JAK2 (V617F) in 60%-65% of patients • CALR exon 9 indels in 20%-25% of patients • MPL exon 10 mutations* in about 4%-5% of patients • Noncanonical MPL mutations* in <1% of patients • About 10% of patients do not carry any of the above somatic mutations (the so-called triple-negative cases) | • ET involves increased risk of thrombosis and bleeding, and may progress to more aggressive myeloid neoplasms • JAK2 (V617F)-mutant ET involves a high risk of thrombosis, and may progress to PV or myelofibrosis • CALR-mutant ET involves lower risk of thrombosis and higher risk of progression to myelofibrosis • Triple-negative ET is an indolent disease with low incidence of vascular events |
| PMF | Prefibrotic PMF • Various abnormalities of peripheral blood • Granulocytic and megakaryocytic proliferation in the bone marrow with lack of reticulin fibrosis | • JAK2 (V617F) in 60%-65% of patients • CALR exon 9 indels in 25%-30% of patients • MPL exon 10 mutations* in about 4%-5% of patients • Noncanonical MPL mutations* in <1% of patients • About 5%-10% of patients do not carry any of the above somatic mutations (the so-called triple-negative cases) | • PMF is associated with the greatest symptom burden and the worst prognosis within MPNs, with a variable risk of progression to AML • CALR-mutant PMF is associated with longer survival compared with other genotypes • JAK2 (V617F)- and MPL-mutant PMF have worse prognosis than CALR-mutant PMF • Triple-negative PMF is an aggressive myeloid neoplasm characterized by prominent myelodysplastic features and high risk of leukemic evolution |
| Overt PMF • Various abnormalities of peripheral blood. Bone marrow megakaryocytic proliferation with atypia, accompanied by either reticulin and/or collagen fibrosis grades 2/3. Abnormal stem cell trafficking with myeloid metaplasia (extramedullary hematopoiesis in the liver and/or the spleen) |
AML, acute myeloid leukemia.
Canonical MPL exon 10 mutations include W515L/K/A/R, S505N/C, and V501A (transmembrane domain of MPL); noncanonical MPL mutations (outside exon 10) include T119I, S204F/P, E230G, Y252H (extracellular domain) and Y591D/N (intracellular domain).12