Phlebotomy and Hydroxyurea Are Underused in Patients With Polycythemia Vera

Treatment with phlebotomy or hydroxyurea was associated with lower mortality among older patients with polycythemia vera (PV) who were considered at high thrombotic risk, compared with patients who received neither treatment, according to results from a population-based cohort study published in Blood Advances. Each treatment also lowered risks of thrombosis but, despite these benefits, the authors, led by Nikolai A. Podoltsev, MD, PhD, from Yale University School of Medicine, found that these treatments were underused in the population of older patients with PV.

“These findings suggest that patients in our study cohort were undertreated according to European LeukemiaNet and National Comprehensive Cancer Network guidelines,” which recommend hydroxyurea as the first-line cytoreductive treatment in the high-risk PV setting, the researchers explained. “Improved dissemination and implementation of the guidelines may translate to better patient outcomes.”

To evaluate the effectiveness of phlebotomy and hydroxyurea on a population basis, the authors conducted a retrospective study of 3,173 adults at least 65 years old who were diagnosed with PV between 2007 and 2013, using the linked Surveillance, Epidemiology, and End Results (SEER) Medicare database. People who died within 30 days of PV diagnosis were excluded (n=12), as were those who had noncontinuous Medicare part D coverage (n=811), noncontinuous Medicare part A/B coverage (n=216), health maintenance organization insurance (n=840), or a diagnosis of PV only on a death certificate or autopsy report (n=474). In total, 74.1 percent of identified patients were excluded.

A total of 820 patients (median age = 77 years; interquartile range = 71-83 years) were included in the analysis and followed through December 31, 2014 or death – whichever occurred first.

During the study period, 336 patients (41.1%) received both phlebotomy and hydroxyurea, either concurrently or sequentially, while 189 (23%) underwent phlebotomy only, 161 (19.6%) received hydroxyurea only, and 134 (16.3%) received neither.

Those who underwent phlebotomy had a median of seven phlebotomies (range = 3-12) from diagnosis to the end of follow-up, with a median of 2.3 phlebotomies per year (range = 1.1-4.1).

Among people prescribed hydroxyurea, adherence was calculated as the percentage of days from diagnosis to the end of follow-up covered by a hydroxyurea prescription, or proportion of days covered (PDC).

The median PDC by hydroxyurea was 61.6 percent (range = 35.2-80.1%). Other cytoreductive treatments were used infrequently but included ruxolitinib (n=17; 2%) and interferons (n=11; 1.3%).

During a median follow-up of 2.75 years (range = 1.58-4.67 years), evolution to myelofibrosis, acute myeloid leukemia (AML), or either myelofibrosis or AML occurred in 19 (2.3%), 18 (2.2%), and 36 patients (4.3%), respectively. There was no association between disease progression and use of hydroxyurea or phlebotomy.

A total of 305 patients (37.2%) died during follow-up. Overall, median survival was longer for people who received either treatment, alone or in combination, than for those who did not undergo treatment:

  • phlebotomy users vs. nonusers: 6.29 years vs. 4.5 years (p<0.01)
  • hydroxyurea users vs. nonusers: 6.02 years vs. 5.25 years (p<0.01)

The authors then performed multivariable Cox hazard models that accounted for patient age at diagnosis, sex, race, disability status, receipt of low-income subsidy, influenza vaccination in the 12 months prior to PV diagnosis, comorbidity burden, and history of thrombosis.

They reported that phlebotomy was associated with a lower risk of death (hazard ratio [HR] = 0.65; 95% CI 0.51-0.81; p<0.01). As phlebotomy intensity (defined as number of phlebotomies per year) increased, risk of death appeared to decrease (HR=0.71; 95% CI 0.65-0.79; p<0.01).

A similar relationship also was observed for hydroxyurea users: Every 10-percent increase of hydroxyurea PDC was associated with a 9-percent lower risk of death (TABLE).

Other factors associated with a higher mortality risk included: older age, male sex, comorbidities, and potential underuse of the health-care system (measured by no receipt of flu vaccination in the year prior to PV diagnosis).

Thrombotic events were recorded in 296 patients (36.1%) and, as with the survival analysis, those who received treatment were less likely to experience a thrombotic event:

  • phlebotomy users vs. nonusers: 142 (29.3%) vs. 154 (46.0%; p<0.01)
  • hydroxyurea users vs. nonusers: 118 (27.6%) vs.178 (45.4%; p<0.01)

Both phlebotomy intensity and PDC of hydroxyurea were associated with lower thrombotic risks. Comorbidity burden and low-income subsidy were the only factors associated with an increased thrombotic risk (TABLE).

In sensitivity analyses, there were no significant differences between overall survival or thrombosis between those who received either hydroxyurea or phlebotomy (p=0.52 and p=0.28, respectively).

This observational study was limited by the inability to capture data about therapies such as aspirin that were not covered by Medicare and not mentioned in Medicare claims. Also, because ruxolitinib was approved by the U.S. Food and Drug Administration as a second-line treatment for patients with PV that is refractory to or intolerant of hydroxyurea only in December 2014, after the conclusion of the study period, its use could not be adequately evaluated in this study.

“In addition, the SEER Medicare database did not contain information on the results of laboratory tests, such as hematocrit level and leukocyte count, so we could not incorporate these important clinical parameters into the analysis,” the authors added. Study results also may not be generalizable to people with previously treated PV or younger or lower-risk patients.

The authors report financial relationships with Alexion, Pfizer, Boehringer Ingelheim, Astellas, Daiichi Sankyo, Sunesis, Celator, Pfizer, Astex Pharmaceuticals, CTI BioPharma, Celgene, Genentech, and LAM Therapeutics.


Podoltsev NA, Zhu M, Zeidan AM, et al. The impact of phlebotomy and hydroxyurea on survival and risk of thrombosis among older patients with polycythemia vera. Blood Advances. 2018;2:2681-90.