Chapter 6: Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

KEY CONCEPTS

• Polycythemia vera (PV) is the most common of the Ph-negative myeloproliferative neoplasms (MPNs). Virtually all cases are driven by activating JAK2 mutations, and elevation of all three cell counts is typical. Life expectancy is good but shorter than that of an age- and sex-matched population. Thrombosis is the major clinical concern, and prevention of the same is the principal goal of therapy. PV can progress to myelofibrosis (MF) or transform to acute myeloid leukemia (AML). All patients need aspirin unless it is contraindicated. Low-risk patients are typically treated with phlebotomy, whereas high-risk patients need cytoreductive therapy. The target hematocrit level for all patients is to be less than 45%. Leukocytosis is clearly associated with mortality and leukemic transformation; its relationship with thrombotic risk is less certain. Hydroxyurea (HU) and interferon (IFN) are both reasonable frontline options for cytoreductive therapy; ruxolitinib is approved for use after failure of HU.

• Essential thrombocythemia (ET) is the most indolent of the classic Ph-negative MPNs. Careful distinction of ET from prefibrotic primary myelofibrosis (pre-PMF) is necessary. Life expectancy in ET is the same as, or only slightly lower than, that of an age- and sex-matched population. Driver mutations in JAK2 underlie approximately half the cases, with CALR and MPL mutations accounting for most of the remainder. ET can progress to MF and rarely transform to AML. Thrombosis and bleeding are the main clinical concerns, and the goal of therapy is to mitigate these risks. Patients are risk stratified for thrombosis by age, JAK2 mutation status, thrombosis history, and cardiovascular risk factors. The platelet count does not correlate with thrombotic risk. HU or IFN are the cytoreductive agents of choice; anagrelide is commonly used as a second-line therapy. Aspirin is generally recommended, but should be avoided in the presence of acquired von Willebrand disease.

• Myelofibrosis can be primary (PMF) or arise as a complication of PV or ET (post-PV/ET MF). Overt MF is usually characterized by anemia, splenomegaly, a variety of symptoms, leukoerythroblastosis, and markedly reduced survival compared with PV and ET. Pre-PMF is more indolent but carries a worse prognosis than ET. The distribution of driver mutations in PMF is generally similar to that in ET, but mutations in “nondriver” genes are much more common. The risk of leukemic transformation is much higher in MF than in ET or PV. Accurate prognosis for patients with MF is critical for decisions about stem cell transplant (SCT) and depends on several clinical and genomic factors. JAK inhibitors represent the cornerstone of therapy; in some patients, anemia-directed therapy with or without JAK inhibitors may be appropriate.

• Chronic eosinophilic disorders/hypereosinophilic syndromes (CED/HES) are heterogeneous disorders characterized by hypereosinophilia in the blood and possible eosinophilic organ infiltrations. Diagnosis requires exclusion of secondary causes. Evaluation for end-organ damage is always needed. Primary CED/HES include myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRα, PDGFRβ, FGFR1, or with PCM1-JAK2. Patients might have various nonspecific symptoms or serious organ involvement (gastrointestinal system, heart, skin, lungs). ...