Aspirin in Philadelphia-Negative Myeloproliferative Neoplasms: What Is the Optimal Dose ?
Authors: Ajzenberg Nadine , Faille Dorothee , Huisse Marie-Genevieve , Cung Anh Hong , Lamrani Lamia , Dumontier Nicolas , Jandrot-Perrus Martine , Cassinat Bruno , Chomienne Christine , Dosquet Christine 
Published: November 2019

Abstract
Background: Myeloproliferative neoplasms (MPN) are associated with an increased risk of arterial and venous thrombosis with an annual incidence varying from 1.1% to 6.6% (Patrono, Blood 2013). Comparable to that recommended in non-MPN high-risk patients, low-dose aspirin (81-100 mg/day) is recommended in primary and secondary prophylaxis of thrombosis in polycythemia vera and essential thrombocytemia (Tefferi, Am J Hematol 2012). However, the daily dose of aspirin to optimize efficacy and safety for MPN patients has never been challenged.
Aim of the study: Determine the optimal dose of aspirin to achieve biological efficacy in Philadelphia-negative MPN patients.
Methods: Patients with Philadelphia-negative MPN who were treated with low-dose aspirin 75 or 100 mg/day were enrolled in this observational study. Patients without any cytostatic drug and patients treated with either pegylated interferon alpha or hydroxyurea were eligible. Major exclusion criteria included inability to adhere to aspirin therapy and chronic oral anticoagulation. Biological efficacy to aspirin was evaluated by platelet aggregation induced by arachidonic acid 1.33 mM on platelet rich plasma and tested at trough level and 24 hours after last aspirin intake. Resistance to aspirin was defined as a maximal platelet aggregation over 20%. According to the results of platelet aggregation, aspirin dose and dosing regimen were modified as follows: from 100 mg/day to 160 mg/day or 75 mg x2/day. Patients enrolled in this have a median follow up of at least 6 months after the analysis.
Results: Between January 2012 and February 2014, 77 patients with Philadelphia-negative MPN were included. 53 were treated with aspirin 75 mg/day (69%) and 24 with aspirin 100 mg/day (31%).
Out of the 53 patients treated with aspirin 75 mg/day, 12 patients (23%) were resistant to aspirin.
Resistance to aspirin was not correlated to sex, age, presentation, JAK2 status, treatment, history of thrombotic or bleeding and hematologic values (see following table). Table 1:The MPN Grade 1 Fibrosis PhenotypePMF (N:33)PV/ET (N:58)Total (N:91)Median age63 yrs55 yrs58 yrsSex1:31:11:2JAK V617F +16/33: (49%)40/58: (69%)56/91: (62%)Median Hgb(g/dL)11.9 (range 7.9-16.4)12.5 (range 8.0-19.8)12.2 (range 7.9-19.8)Median WBC(X10 (9))26.9 (range 1.3-188)8.9 (range 3.5-51.3)10.8 (range 1.3-188 )Median Platelet(X10 (9))179 (range 18.0-1194)505 (range 67-2286)370 (range 18-2286)Leukoerythroblastic Blood Smear15/33 (45%)PV: 17 ET: 5 Total: 22/58 (38%)37/91 (41%)Splenomegaly(cm below costal margin)18/33: (55%) Median: 1025/58: (43%) Median: 643/91(48%) Median: 4Transfusion dependence6/33: (18%)2/58: (4%)8/91: (9%)Presence Of ³ 1 symptom 17/33: (52%)33/58: (57%)50/91: (55%)DIPSS risk intermediate 2 or higher13/33: (39%)17/58: (29%)30/91: (33%)2 or more prior therapies9/33: (27%)36/58: (62%)45/91: (49%)Vital Status (Alive)25/33: (76%)53/58: (91%)78/90: (86%)Median follow up time (yrs)1.9 (range 0.1-9.8)5.7 (range 0-34.5)3.1 (range 0-34.5)
An increased dose of 100 mg/day for at least 7 days overcame this biological resistance in 8 out of 8 re-tested patients. The 2 remaining 75mg resistant patients received an increased dose of aspirin but were not retested.
Out of the 24 patients under 100 mg/day, only two (8%) were resistant to aspirin. In these patients, increasing the dose to 160 mg/day did not modify their biological response. However a 75 mgx2 /day was effective to overcome biological resistance.
No thrombotic or bleeding event was observed during the 6-month follow-up regardless of the aspirin dose.
Conclusions: This is the first study to measure in standardized conditions the biological resistance of aspirin in 77 well-characterized Philadelphia-negative MPN patients. Although this does not reach statistical significance a higher proportion of patients treated with aspirin 75mg/day was resistant to anti-platelet therapy compared to patients treated with aspirin 100 mg/day. Increasing the dose of aspirin from 75 to 100 mg once daily overcomes this biological resistance without increasing bleeding side effects and seems the best compromise. Interestingly in rare cases of extreme resistance to 100mg doubling the dose twice daily (75mgX2) was better than an increase of 160mg in one take. This pilot study on a small number of patients with a limited 6-month follow up compared to the low annual incidence of thromboses in these MPNs will be followed by a prospective study on a larger number of patients with an extended follow-up period to determine if biological resistance to aspirin is correlated to the occurrence of thrombotic events.

Disclosures
No relevant conflicts of interest to declare.