Clinical Pearls & Morning Reports

Published May 31, 2017

What therapies reduce splenomegaly in patients with a myeloproliferative neoplasm?

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. These disorders engage in phenotypic mimicry among themselves, as well as with myeloid neoplasms and even benign hematopoietic disorders. In addition to phenotypic mimicry, each type of myeloproliferative neoplasm is capable of evolving to another type, making diagnosis, risk assessment, and therapeutic choices difficult. Read the new review on this topic.

Clinical Pearls

Q. What are the most common myeloproliferative neoplasm driver genes?

A. Recently, driver mutations have been identified in more than 90% of patients with myeloproliferative neoplasms, providing substantial insight into their pathogenesis. Janus kinase 2 (JAK2) is the most common myeloproliferative neoplasm driver gene. The most common myeloproliferative neoplasm mutation, JAK2 V617F, an exon 14 point mutation in the JAK2 JH2 pseudokinase domain, impairs its physiologic inhibitory influence on the JH1 kinase domain. CALR, the gene that encodes calreticulin, is the second most common myeloproliferative driver gene. MPL, a truncated form of the thrombopoietin receptor gene, is the oncogene of the MPLV retrovirus, which causes murine polycythemia vera. MPL mutations are the least common myeloproliferative neoplasm driver mutations.

Q. What genetic variants increase susceptibility to the myeloproliferative neoplasms?

A. Genomewide association studies have identified single-nucleotide variants that increase the probability that myeloproliferative neoplasms will develop. For example, in one study, a single-nucleotide variant haplotype, designated 46/1 (GGCC) and located in cis on the JAK2 allele, was associated with an increase by a factor of 3 in the risk of a JAK2-activating mutation; in other studies, other single-nucleotide variants were associated with mutations in the genes encoding calreticulin (CALR) and the thrombopoietin receptor (MPL), or the individual myeloproliferative neoplasms. A single-nucleotide variant in TERT, which is linked to activated myeloid hematopoiesis, is associated with all three myeloproliferative neoplasms but most significantly with their familial forms, and this variant, in combination with 46/1 and other single-nucleotide variants, has an additive effect on susceptibility to myeloproliferative neoplasms.

Morning Report Questions

Q: What is the risk of acute leukemia in patients with a myeloproliferative neoplasm?

A: Acute myeloid leukemia occurs spontaneously in patients with myeloproliferative neoplasms and has a poor prognosis. Estimates of the incidence of acute myeloid leukemia range from 1.5% in patients with essential thrombocytosis and 7.0% in patients with polycythemia vera to 11% in patients with primary myelofibrosis. However, such estimates are confounded by age-related de novo acute leukemia and chemotherapy; chemotherapy increases the incidence to 20%. Acute leukemia in patients with myeloproliferative neoplasms can involve the founding hematopoietic stem-cell clone but more often involves a subclone, as occurs in cases of de novo acute leukemia in patients without such neoplasms.

Q: What therapies reduce splenomegaly in patients with a myeloproliferative neoplasm?

A: Ruxolitinib, an inhibitor of JAK1 and JAK2, durably alleviates symptoms, reduces splenomegaly, corrects blood counts, and is effective in patients with hydroxyurea-refractory polycythemia vera. Suppression of inflammatory cytokine production and hematopoietic progenitor-cell proliferation appear to be the major effects of ruxolitinib. Hematopoietic stem cells are not appreciably affected, and neither is leukemic transformation. Whether the presence of additional mutations impairs the effectiveness of ruxolitinib is disputed. Interferon is currently the only agent that specifically targets hematopoietic stem cells in patients with myeloproliferative neoplasms; its pegylated derivative alleviates symptoms, reduces splenomegaly, and induces hematologic remission. Durable complete molecular remission has been achieved in 18% of patients with polycythemia vera or essential thrombocytosis, and marrow fibrosis has been ameliorated in some patients with primary myelofibrosis. The influence of nondriver mutations on the effectiveness of interferon is unclear. Neither interferon nor its pegylated derivative is uniformly effective in all patients, and clinically significant side effects, such as immunosuppression, myelotoxicity, and neurotoxicity, limit the use of these drugs in some patients.

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