Cytoreductive Treatment in 'Real Life' - Interim-Analysis of 434 Polycythemia Vera Patients in Germany

Treatment recommendations for cytoreductive treatment of patients with polycythemia vera (PV) are well established. However, the clinical use and limitation of phlebotomies remain a matter of current debate (Barbui et al, Leukemia, 32; Heidel et al, Leukemia, 32).

While multicenter trials investigating therapeutic strategies for PV have been conducted at specialized academic centers, the majority of patients is treated in an outpatient (ambulatory) setting. The aim of this study is to evaluate the 'real live' situation especially in regard to the use of phlebotomy and cytoreductive therapy in a cohort of 1500 patients from a survey conducted at private practices and primary care centers.

Eligible centers treating patients with MPN in Germany were recruited to participate in a paper-pencil based ongoing survey conducted from December 2018 and planned until December 2019. Hematologists were asked to report from patient charts. Descriptive analyses were conducted to assess for therapeutic interventions and outcomes and examined by reported prognostic risk scores, symptom scores, and clinical response criteria.

For this interim analysis (data cutoff on May 31, 2019) a total of 11 centers participated in a retrospective survey and provided data on 434 patients. Gender was balanced with 211 (48.6%) male and 223 (51.4%) female patients. Most patients were of older age (mean 71.4 years; 62.7 years at diagnosis and 63,4% over the age of 60), which is a main risk factor according to published criteria (Tefferi et al, Am J Hematol, 94). 154 patients (35.5%) had a disease history of more than 10 years, 95 pts (21.9%) 6 to 10 years and 42.6% less than 6 years.

Thromboembolic complications were reported in 100 patients (23.0%) at time of diagnosis and for 61 (14.1%) during treatment. Additional cardiovascular (CV) risk-factors were reported for 320 patients (73.7%), whereas 107 (24.7%) had none (and no data available in 1,6% (n=7) of cases). Hypertension was the most prevalent CV risk factor with 86.9% (n=278) affected, followed by hypercholesteremia 18.8% (n=60), diabetes mellitus 16.2% (n=52) and smoking 15.9% (n=51).

Phlebotomy was the primary therapy in 301 patients (69.4%). Of those, 83 (27.6%) received 1-3 phlebotomies/year, 113 (37.5%) 4-6/year, 71 (23.6%) 7-12 times/year and 8 pts (2,6%) >13 times/year.

Main triggers to start pharmacologic cytoreduction included the presence of high-risk criteria (53.2%) and insufficient disease control (22.6%). Of note, asymptomatic iron deficiency (5.6%), symptomatic iron deficiency (9.3%) and intolerance to phlebotomy (5.3%) have been reported in a significant number of patients and contributed to the limitation of phlebotomy treatment.

Choice of cytoreductive agents included hydroxycarbamide (n=320; 73.3%), JAK-inhibitors (n=80, 18.4%), Interferon alpha (n=15; 3,5%), IMIDEs (n=2; 0.5%) and other cytoreductive agents (n=6; 1.4%). While 11 patients (2.5%) required combination of cytoreductive agents, 137 (31.3%) patients had a persistent need for phlebotomy.

In summary, the patient population investigated here was older than in published large multicenter trials. Age was the main factor accounting for the majority of patients being categorized as 'high risk'. Although the majority of patients (>60%) presented as 'high risk' according to international guidelines, 69.4% of patients received phlebotomy as primary therapeutic approach, in part at high frequency (>25% with more than 7 phlebotomies per year). The low number of primary cytoreductive treatment and occurrence of symptomatic iron deficiency in 9.3% and of intolerance in 5.3% of patients indicates the need to reconsider indication and limitations of phlebotomy.

We conclude that phlebotomy as a prophylactic measure of risk reduction should result in mild iron-deficient erythropoiesis and hematocrit control without inducing a severe iron-deficiency syndrome as indicated by increased levels of soluble transferrin-receptor or Zn-protoporphyrin. Pharmacologic cytoreduction is necessary for high risk patients older than 60 years or with previous thromboembolic complications. For patients, who require permanent phlebotomies at high frequency for sufficient hematocrit control (<45%), pharmacologic intervention should be discussed even in the low-risk situation to balance the looming risk of iron-deficiency symptoms with potential side effects of pharmacologic compounds.