clinical topic updates
Traditional and Nontraditional Risk Factors in Patients With Myeloproliferative Neoplasms
The risk of vascular complications in patients with myeloproliferative neoplasms (MPN) may be predicted by older age, history of thrombosis, and other established factors. Additionally, recent evidence supports the prognostic value of newer markers, including leukocytosis, the Janus kinase 2 gene, JAK2, V617F mutation, and other driver gene mutations.
“The traditional thinking that age and prior thrombosis are the only important risk factors in PV has been challenged by more recent findings.”
We have been basing our treatment plan for patients with MPN on traditional risk factors such as older age and prior thrombotic events for many years. However, recent data suggest that other nontraditional risk factors and clinical markers are also important, challenging the traditional thinking that age and prior thrombosis are the only important risk factors in polycythemia vera (PV). For instance, leukocytosis is an independent predictive factor for thrombosis and for negative outcomes in both PV and essential thrombocythemia. Leukocytosis may increase the risk of thrombosis in individuals with PV through adhesion to the vascular endothelium and inflammation (ie, the leukocytosis is causing the thrombosis). Additionally, those patients with a more proliferative phenotype of MPN and leukocytosis may have a unique biology that contributes to this risk. Essentially, they may be more likely to progress to myelofibrosis or to transform to acute myeloid leukemia. Interestingly, the conventional thinking has been that one should not be too concerned about leukocytosis in asymptomatic patients with PV and that one should not initiate treatment based on the leukocytosis, but findings are emerging that challenge the dogma that leukocytosis in PV is essentially benign. Individuals with PV and leukocytosis are not the same as those with PV without the leukocytosis, and this is something that I consider when evaluating the need for cytoreductive therapy. Bone marrow studies may identify additional risk markers. In community settings, most patients with PV are diagnosed without bone marrow studies, and karyotype analysis is not usually performed at diagnosis in patients with PV. In the academic setting, however, I think that it is always beneficial to obtain bone marrow studies at diagnosis in those with PV to establish a baseline.
Genetic testing comes into play much more in the risk assessment of myelofibrosis. The JAK2 V617F allele burden varies considerably in patients with PV, and a JAK2 V617F allele burden greater than 50% is an independent risk factor for progression to myelofibrosis. In individuals with primary myelofibrosis, the prognostic models include the International Prognostic Scoring System (IPSS), the dynamic IPSS, and the dynamic IPSS-plus, which include clinical variables such as age, anemia, constitutional symptoms, and leukocytosis. Other models such as the Mutation-Enhanced International Prognostic Scoring System and the Mutation-Enhanced International Prognostic Scoring System for Transplant-Age Patients use both clinical and molecular variables. For example, calreticulin gene, CALR, type 1 and type 1-like mutations are associated with better outcome. ASXL transcriptional regulator 1 gene, ASXL1, and serine and arginine rich splicing factor 2 gene, SRSF2, mutations are associated with poor prognosis in patients with primary myelofibrosis. The management of MPN is still currently guided by both traditional and nontraditional markers of risk.
Barbui T, Masciulli A, Marfisi MR, et al. White blood cell counts and thrombosis in polycythemia vera: a subanalysis of the CYTO-PV study. Blood. 2015;126:560-561.
Horvat I, Boban A, Zadro R, et al. Influence of blood count, cardiovascular risks, inherited thrombophilia, and JAK2 V617F burden allele on type of thrombosis in patients with Philadelphia chromosome negative myeloproliferative neoplasms. Clin Lymphoma Myeloma Leuk. 2019;19(1):53-63.
Mascarenhas J. A concise update on risk factors, therapy, and outcome of leukemic transformation of myeloproliferative neoplasms. Clin Lymphoma Myeloma Leuk. 2016;16 Suppl:S124-S129.
Tefferi A, Guglielmelli P, Nicolosi M, et al. GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis. Leukemia. 2018;32(7):1631-1642.
Vannucchi AM, Guglielmelli P, Rotunno G, et al. Mutation-Enhanced International Prognostic Scoring System (MIPSS) for primary myelofibrosis: an AGIMM & IWG-MRT project. Blood. 2014;124(21):405.