Previous studies have shown ruxolitinib effective in symptom relief and hematocrit control for hydroxyurea-resistant polycythemia vera, but its role in disease progression is not yet clear.
The most prominent medication for polycythemia vera (PV) is hydroxyurea (HU), but a significant subset of patients develops resistance or intolerance to HU, potentially leading to poor disease control and a higher risk of thrombosis. The Janus kinase (JAK) inhibitor ruxolitinib is approved for use in HU-resistant patients, but its impact on thrombosis risk and disease progression is unknown.
A recent study published in Cancer examined ruxolitinib vs the best available therapy (BAT) in HU-resistant PV.
PV is a chronic myeloproliferative neoplasm that carries an increased risk of thrombosis and bleeding, as well as a risk of transformation into myelofibrosis and acute myeloid leukemia (AML). Although HU helps with disease control in most cases, approximately 20% to 30% of patients develop resistance or intolerance to the drug. Patients with PV who are resistant to HU often carry mutations in TP53 or chromatin or splicing genes and are at a greater risk of AML and myelofibrosis.
Ruxolitinib is considered the best available option for hematocrit control, symptom relief, and spleen size reduction in HU-resistant PV given findings from the RESPONSE and RESPONSE-2 studies. But many of those patients crossed over to ruxolitinib early, meaning vascular events, disease transformation, and survival could not be compared in those studies.
The current retrospective, real-world study compared additional outcomes with ruxolitinib vs BAT in HU-resistant patients with PV, using data from the Spanish Registry of Polycythemia Vera. Of 2245 patients in the registry, 1784 were treated with HU, 431 (24%) of whom developed resistance.
The ruxolitinib cohort included 105 patients who received the drug within the first year after developing resistance or intolerance to HU, while 272 patients were in the BAT group. The remaining 54 HU-resistant patients were excluded because they started ruxolitinib more than 1 year after developing HU resistance or intolerance.
Main outcomes were rates of survival, thrombosis, bleeding, myelofibrosis, AML, and second cancers in patients treated with ruxolitinib vs BAT, calculated with incidence rates. The BAT cohort comprised patients treated with HU (60%), busulfan (15%), anagrelide (9%), interferon (4%), melphalan (2%), radioactive phosphorous (1%), other treatment (2%), and no medication (8%).
Patients treated with ruxolitinib saw better hemoglobin values and hematocrit control than patients in the BAT cohort, which is in line with previous studies. The ruxolitinib cohort also saw a smaller proportion of patients with pruritus and microvascular and constitutional symptoms over time vs the BAT group, in which the proportion stayed stable.
Overall, there were 46 reported thrombotic events in 1523 person-years of follow-up. After adjusting for time treated with anticoagulation and antiplatelet drugs, patients in the ruxolitinib group had a lower rate of arterial thrombosis than the BAT cohort. This trend remained after adjusting for propensity to have received the drug. There were no significant differences in rates of venous thrombosis and major bleeding between groups after adjustment for whether they were on anticoagulant or antiplatelet medications at the time of the event.
Treatment with ruxolitinib was not associated with a higher rate of second primary cancers. Overall, 11 patients, all in the BAT group, had disease progression to AML (n = 9) or myelodysplastic syndrome (n = 2). Thirty-four patients—6 in the ruxolitinib cohort and 28 in the BAT cohort—progressed to myelofibrosis. There were no significant differences in survival between the ruxolitinib and BAT cohorts.
Study limitations included that the cohorts were not contemporaneous; most of the BAT group had a longer follow-up because ruxolitinib was approved later. The study authors only considered the first 8 years after patients in the BAT group developed resistance to mitigate potential effects of this difference. The study is also observational, meaning causal effects could not be determined.
The study authors concluded that although the study results suggest ruxolitinib may reduce the incidence of arterial thrombosis in HU-resistant PV patients, they were unable to show a disease-modifying effect of ruxolitinib. The relatively short follow-up and retrospective design could have affected these results, although the authors note that most of the events that shape the natural history of PV occur in the first years after patients show resistance or intolerance to HU.
Alvarez-Larrán A, Garrote M, Ferrer-Marín F, et al. Real-world analysis of main clinical outcomes in patients with polycythemia vera treated with ruxolitinib or best available therapy after developing resistance/intolerance to hydroxyurea. Cancer. Published online April 13, 2022. doi:10.1002/cncr.34195