Clinical & Economic Implications of Hydroxyurea Intolerance in Polycythemia Vera in Routine Clinical Practice in Israel
Authors: Ellis Martin H. , Tadmor Tamar , Chodick Gabriel , Yekutiel Naama , Levi Moti , Sharf Giora , Feine Oren , Leef Raanan , Ben Zvi Nana , Shavit Oren 
Published: November 2020

Background: Hydroxyurea (HU) is an effective and common therapy for high-risk Polycythemia Vera (PV). Some patients may demonstrate resistance or intolerance to HU, but the consequences of these warrant further studies.
Objective: Evaluate the clinical and economic implications of HU resistance/intolerance, in routine clinical practice in Israel.
Methods: A retrospective analysis of Maccabi Health Services' (MHS) database was performed. MHS is a Non-for-Profit healthcare insurer and provider in Israel, with over 2.2 million members.
Patients were included in the study if they had a recorded PV diagnosis or complete blood count indicative of PV, and had purchased HU for at least 3 months between 2000-2015. Enrolled patients were divided into 3 groups: A) Resistant to HU (patients prescribed 2g/day of HU); B) Intolerant of HU (patients who stopped HU, transitioned to another line of therapy or who developed HU related cytopenias); C) Stable on HU.
A mid-time point was added to "Stable" to compensate for the time required for transition in the "Intolerant" group. Only patients who developed Intolerance within 5 years were included. Collected data pertained to demographics, clinical outcomes, resource utilization and expenditure data.
Results: A total of 830 patients were identified. Only 3 met criteria for Resistance and were disregarded for further analysis, while 318 (38%) were defined as "Intolerant" and 509 (61%) as "Stable". At baseline, there were no significant differences between "Intolerant" and "Stable" groups, apart from platelet counts (431 vs. 495, respectively) and red cell distribution width (RDW) (18.4 vs. 17.6, respectively).
Intolerance was determined based on HU-related cytopenias (n=144, 45% of Intolerant), transition to other treatment line (n=52, 16%) or stopping HU (n=122, 38%). These results indicate some patients continue HU treatment despite lack of disease control.
"Intolerant" patients who had transitioned by 5 years from first HU purchase (N=173) and "Stable" patients who met the mid-point of time to transition (N=487) were eligible for comparison. Median follow up time was 4.9 and 5.5 years for "Intolerant" and "Stable" groups, respectively. Thrombotic events occurred in 8% of the "Intolerant" group compared with 3% of "Stable" (p=0.003) and event rate per 100 patient-years was 1.6 versus 0.5 (p&lt;0.001). Progression to MF occurred in 28% versus 5% (p&lt;0.001), and progression to AML occurred in 6% compared with 1% (p&lt;0.001) among "Intolerant" and "Stable", respectively. Interestingly no significant difference was found regarding major arterial thrombotic complications, (myocardial infarction, acute coronary syndrome, cerebrovascular accident or limb ischemia).
During study follow up, hospitalization occurred in 84% versus 69% (p&lt;0.001), and hospitalization days were 5.3 vs 1.9 per year (p=0.004) among "Intolerant" and "Stable" groups, respectively. Death occurred in 58% of "Intolerant" compared with 30% of "Stable"(p&lt;0.001).
Treatment costs for an Intolerant patient in the first year after intolerance were 2.6-fold higher than those for a Stable patient, driven mainly by hospitalization costs being 3.6-fold higher (data available from 2010).
Conclusions: The results of this analysis indicate that intolerance to HU treatment in PV patients is associated with serious clinical and economic implications, indicating a need for improved treatment for these patients.

Disclosures
Ellis: Novartis Pharma AG: Consultancy, Honoraria, Other: Institutional research grant; BMS: Consultancy, Other: Institutional research grant; Gilead: Other: Institutional research grant. Tadmor:AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Medison: Consultancy, Speakers Bureau; Neopharm: Consultancy, Speakers Bureau; 6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Consultancy, Speakers Bureau. Chodick:Novartis Pharma AG: Other: Institutional grant. Yekutiel:Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Other: Institutional grant. Sharf:Novartis Pharma AG: Consultancy, Other: Institutional Grant; Leukaemia Patient Advocates Foundation: Ended employment in the past 24 months, Membership on an entity's Board of Directors or advisory committees; Israeli CML Patient Organisation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Other: Institutional grant; AbbVie: Consultancy, Other: Institutional Grant; Amgen: Consultancy, Other: Institutional grant; Bristol Mayers Squibb: Consultancy, Other: Institutional Grant; Celgene: Consultancy, Other: Institutional Grant; AOP Orphan: Other: Institutional grant; CTI: Other: Institutional grant; Medison: Other; Roche: Other; Jansseb: Other; Pfizer: Consultancy, Other; Takeda: Other; Gilead: Other. Feine:Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Current Employment. Leef:Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Current Employment. Ben Zvi:Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Current Employment. Shavit:6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Current Employment.