Novel Clinical, Laboratory, Molecular and Pathological (2018 CLMP) Criteria for the Differential Diagnosis of three Distinct JAK2, CALR and MPL Mutated Myeloproliferative Neoplasms: The Role of Driver Mutation Analysis and Bone Marrow Histology

Abstract

The broad spectrum of JAK2V617F mutated trilinear phenotypes varies from essential thrombocythemia (ET), prodromal polycythemia vera (PV), masked PV, erythrocythemic PV, classical PV, and PV complicated by splenomegaly and myelofibrosis (MF). ET heterozygous for the JAK2V617F mutation is associated with normal life expecancy. JAK2V617F mutation load increases from low to 40% in ET, from below to above 50% in early stage PV and above 50% up to 100% in overt and advanced PV and MF. Pretreatment bone marrow morphology and cellularity distinguish JAK2V617F mutated trilinear MPN from calreticulin (CALR) and MPL mutated MPN. The morphology of clustered mature enlarged pleomorphic megakaryocytes with hyperlobulated nuclei are similar in JAK2V67F ET and PV patients. MPL515 mutated thrombocythemia is featured by monolinear proliferation of large to giant mature megakaryocytes with hyperlobulated nuclei in a normocellular or hypocellular bone marrow. CALR mutated thrombocythemia shows characteristic bone marrow features of primary dual megakaryocytic granulocytic myeloproliferation (PMGM) in a normocellular or hypercellular bone marrow without features of PV. JAK2V617F, CALR and MPL515 allele burden slowly increases to values around 50% together with the degree of splenomegaly, myelofibrosis and constitutional symptoms during life long follow-up. Natural history and life expectancy relate to the degree of splenomegaly, bone marrow fibrosis, anemia and the acquisition of epigenetic mutations at increasing age predict unfavorable outcome in JAK2V617F, CALR and MPL515 mutated MPN. Low dose aspirin in JAK2V617F mutated ET and PV and phlebotomy on top of aspirin in PV is mandatory to prevent platelet-mediated microvascular circulation disturbances. Pegylated interferon is the first line myeloreductive treatment option in prodromal and early stage JAK2V617F mutated PV and in CALR and MPL mutated thrombocythemia to postpone the use of hydroxyurea and ruxolitinib as long as possible.