Adding Hydroxyurea to Ruxolitinib Yields Higher Clinical Response in Myelofibrosis

Although ruxolitinib significantly reduces splenomegaly and disease-related symptoms in patients with myelofibrosis (MF), there has not been a demonstrated survival benefit, which may be due to suboptimal drug exposure from lower doses needed to mitigate hematological toxicities. However, new study findings are indicating that adding hydroxyurea to the selective inhibitor of Janus kinase 1 and 2 could elicit a high clinical response and increased ruxolitinib exposure for patients with hyperproliferative forms of MF.

Hydroxyurea has previously demonstrated its ability to reduce spleen and liver size, constitutional symptoms, pruritus, and bone pain, and to control leukocytosis and thrombocytosis.

“For these reasons, a combination of ruxolitinib and a cytoreductive agent such as hydroxyurea may be hypothesized to improved hematological response in the ‘hyperproliferative’ forms of the disease, characterized by constitutional symptoms, marked splenomegaly, leukocytosis, and/or thrombocytosis,” wrote the researchers.

Testing the hypothesis, between April 2012 and April 2017, the researchers examined the treatment combination among 20 patients aged 18 years and older with MF, post—polycythemia vera, or post–essential thrombocythemia with hyperproliferative forms of the disease and white blood cell and/or platelet counts not controlled by ruxolitinib monotherapy.

Compared with ruxolitinib monotherapy, the combination yielded significantly more clinical responses, with 8 (40%) patients achieving a clinical response on ruxolitinib monotherapy and 17 (85%) patients achieving a clinical response with the ruxolitinib-hydroxyurea combination. A reduction in at least 50% of symptoms was considered a response to treatment.

All patients received ruxolitinib orally twice daily at a dose based on platelet count, and the starting dose of hydroxyurea was based on clinician choice and modified based on white blood cell and platelet count, as well as the maximum ruxolitinib dose tolerated by each patient.

Following a median of 12.4 months on combination therapy, 16 of the 20 patients had a hematological response. Among these patients were 14 of the 17 patients who initiated combination therapy to control their white blood cell counts and 2 of the 3 patients who started the combination to reduce their platelet counts.

A spleen response was reported in 5 patients receiving ruxolitinib monotherapy and in 8 receiving the combination, and a symptoms response was reported in 6 patients receiving ruxolitinib monotherapy and in 12 receiving the combination.

“This slight difference is not statistically significant and we cannot state with certainty that the improvement in the spleen response depends on the combination or on the doses of each drug (which, in the case of ruxolitinib, increases with the combination therapy),” noted the researchers.

They added, “Indeed the rate of spleen and symptoms response was lower for the patients on low doses compared with those on intermediate and high doses. Even if this difference was not statistical significant, it could suggest that spleen and symptoms responses are also dose dependent during combination therapy.”

Notably, all 8 patients who had an increase in their ruxolitinib dose had at least 1 type of drug-related clinical response. There were 3 patients who had to reduce their ruxolitinib dose.

The researchers concluded that the findings need to be validated in a prospective and well-controlled large trial.

Reference

Pugliese N, Giordano C, Nappi D, et al. Adding hydroxyurea in combination with ruxolitinib improves clinical response in hyperproliferative forms of myelofibrosis [published online April 17, 2019]. Cancer Med. doi: 10.1002/cam4.2147.