Polycythemia vera - Emerging treatments

Ruxolitinib plus peginterferon

In one phase 2 trial including 32 patients with PV treated with ruxolitinib and pegylated interferon-alfa-2a, 31% achieved either a complete (9%) or partial (22%) hematologic remission.[150] The mean reduction in JAK2 V617F variant allele frequency was greater among patients who were previously intolerant to (61%), or had not previously been treated with, interferon alfa (65%) than patients who were previously refractory (34%). Interim findings from a study of 25 patients with newly diagnosed PV (19 at high risk and 6 at low risk) enrolled in a trial of ruxolitinib plus peginterferon alfa-2a include: a complete hematologic response in all patients; a significant reduction in JAK2 V617F variant allele frequency (median 47% [95% CI, 35 to 59] at baseline to 6% [95% CI, 3 to12] after 24 months; 4 patients achieved a JAK2 V617F variant allele frequency <1%).[151] One case of acute myocardial infarction and one patient progressed to myelofibrosis 10 months after starting treatment.[151]

Givinostat

Givinostat is a histone deacetylase inhibitor. The drug has been shown to be selectively toxic to JAK2-expressing mutant cells, and reduced JAK2 allele burden, pruritus, and splenomegaly in phase 2 trials.[152][153][154] Givinostat may be particularly effective in controlling pruritus. Interim results from a long-term study (mean follow-up 4 years) of 50 patients who continued treatment after initial phase 1/2 clinical trials indicate a consistent overall response rate >80% for the duration of follow-up, with concomitant reduction in JAK2 V617F allele burden. Adverse effects included QTc prolongation, thrombocytopenia, and diarrhea. Ten patients withdrew because of adverse effects and six because of disease progression.[155]

Bomedemstat

Lysine specific demethylase 1 (LSD1) is overexpressed in stem cells in myeloproliferative neoplasms. Bomedemstat, an investigational LSD1 inhibitor, may have potential as a disease-modifying therapy modulating the proliferation of blood cells in patients with PV. Bomedemstat is currently being evaluated in a phase 2 trial in patients with PV.[156]

Hepcidin mimetics

PV is characterized by iron deficiency, which is compounded by phlebotomy.[157] Hepcidin mimetics (e.g., rusfertide) represent a novel class of agents that may reduce or eliminate the need for phlebotomy and correct iron deficiency and resultant symptoms.[158] In phase 2 studies, rusfertide demonstrated hematocrit control (mean hematocrit <45%) and eliminated the need for phlebotomy in the 28-week dose-finding period in patients with PV. A response was observed in 60% of patients receiving rusfertide, compared with 17% receiving placebo during the 12-week randomized withdrawal period.[159] The safety and efficacy of rusfertide are being investigated in an ongoing phase 3 trial.[160]

Drugs targeting transmembrane protease serine 6 (TMPRSS6)

Treatments targeting TMPRSS6, a negative regulator of hepcidin expression, may have potential as a less invasive alternative to phlebotomy in patients with PV. TMPRSS6 negatively regulates hepcidin expression and plays a key role in iron homeostasis. Sapablursen, an investigational antisense oligonucleotide that targets TMPRSS6 mRNA, is being evaluated in a phase 2 trial of 40 patients with phlebotomy-dependent PV.[161] SLN124, an investigational synthetic, double-stranded siRNA oligonucleotide directed against TMPRSS6, is being evaluated in a phase 1/2 study in adults with PV.[162]

Direct oral anticoagulants (DOACs)

The therapeutic role of DOACs for patients with PV is currently being investigated, and has been suggested in retrospective studies.[163][164][165]