Polycythemia vera treatment
It has long been underlined that there are differences in treatment patterns in routine practice. Therapeutic strategies have also expanded, and in recent years the JAK1/JAK2 inhibitor ruxolitinib has emerged as a second line therapeutic option in patients who are intolerant to or resistant to hydroxyurea. Determining the impact of changes on practice patterns is of interest, especially for aspects that lack detailed guidance for management.
In order to gain insights into treatment patterns by clinicians treating patients with PV in Italy, we carried out a survey of 60 hematologists and transfusion specialists. The questions covered: treatment of low-risk patients, definition of significant leukocytosis, splenomegaly and excessive phlebotomies, resistance/intolerance to hydroxyurea, use of ruxolitinib, cytoreductive therapy and vaccines.
In general, the results of the survey indicate that there is a large heterogeneity in management of patients with PV across these areas.
While helping to provide greater understanding of treatment patterns for patients with PV in Italy, the survey highlights the need for additional clinical studies to obtain more precise guidance for the routine care of patients with PV 1).
Phlebotomy
Ruxolitinib
Ferroportin inhibitor
Stetka et al. examined the influence of iron availability on MPN phenotype in mice expressing JAK2-V617F and in mice expressing JAK2 with an N542-E543del mutation in exon 12 (E12). At baseline on the control diet, all JAK2-mutant mouse models with PV-like phenotype displayed iron deficiency, although E12 mice maintained more iron for augmented erythropoiesis than JAK2-V617F mutant mice. In contrast, JAK2-V617F mutant mice with an ET-like phenotype had normal iron stores comparable to wild-type (WT) mice. On the low-iron diet, JAK2-mutant mice and WT controls increased platelet production at the expense of erythrocytes. Mice with PV phenotype responded to parenteral iron injections by decreasing platelet counts and further increasing hemoglobin and hematocrit, whereas no changes were observed in WT controls. Alterations of iron availability primarily affected the pre-megakaryocyte erythrocyte progenitors (pre-MegE), which constitute the iron-responsive stage of hematopoiesis in JAK2-mutant mice. The orally administered ferroportin inhibitor vamifeport and the minihepcidin PR73 normalized hematocrit and hemoglobin levels in JAK2-V617F and E12 mutant mouse models of PV, suggesting that ferroportin inhibitors and minihepcidins could be used in the treatment of PV patients 2).
Rusfertide
Rusfertide Development of hepcidin therapeutics has been a ground-breaking discovery in restoring iron homeostasis in several haematological disorders. The hepcidin mimetic, rusfertide, is in late-stage clinical development for treating polycythemia vera patients with a global phase 3 trial [NCT05210790] currently underway. Rusfertide serves as the first possible noncytoreductive therapeutic option to maintain hematocrit control and avoid phlebotomy for polycythemia vera patients.
Handa in a comprehensive review, discuss the pathobiology of dysregulated iron metabolism in polycythemia vera, provide the rationale for targeting the hepcidin-ferroportin axis and elaborate on the preclinical and clinical trial evidence supporting the role of hepcidin mimetics in polycythemia vera.
Recent findings: Recently, updated results from two phase 2 clinical trials [NCT04057040 & NCT04767802] of rusfertide (PTG300) demonstrate that the drug is highly effective in eliminating the need for therapeutic phlebotomies, normalizing haematological parameters, repleting iron stores and relieving constitutional symptoms in patients with polycythemia vera. In light of these findings, additional hepcidin mimetic agents are also being evaluated in polycythemia vera patients.
Summary: Hepcidin agonists essentially serve as a 'chemical phlebotomy' and are poised to vastly improve the quality of life for phlebotomy-requiring polycythemia vera patients 3)