JAK Inhibitors Are Not Associated With a Reduction In Novel Markers Of Thrombosis In Myeloproliferative Neoplasms
Authors: Keohane Clodagh , Katiri Sophia , Connor Christopher , Sanchez Katy , Godfrey Roxanne , Radia Deepti H , McLornan Donal , Harrison Claire N 
Published: October 2019

Abstract

Background
Thrombosis is a common and sometimes unpredictable complication of the myeloproliferative neoplasms (MPN). MPN management is often directed by perceived thrombotic risk. Numerous factors are predictive for thrombosis including haematocrit, age and prior thrombotic event. More recently leucocyte count and JAK2V617F allele burden have been described as potentially contributing to this thrombotic risk profile. In addition, both platelet activation status and tissue factor expression have been shown to be elevated in MPN patients compared to controls and postulated to predict for thrombosis. Cytoreduction with hydroxycarbamide has been shown to decrease thrombotic risk in this population. The introduction of JAK inhibitors (JAKi) has had a profound effect upon the therapeutic landscape for MPN, however the potential effect of these drugs upon thrombotic risk is unknown. We postulated that treatment with JAKi may affect key surrogate markers for thrombosis.

Materials and Methods
Patients were recruited prior to the commencement of JAKi therapy, either with ruxolitinib or SAR302503. Baseline citrated samples were taken pre drug administration and subsequent samples were collected following a minimum of 1 month of JAKi treatment for flow cytometric analysis on a Beckman Coulter Navios instrument. Platelet-neutrophil aggregates were defined as CD15+/CD42b + and CD15+/CD62p+. Platelet-monocyte aggregates were defined as CD14+/CD42b+ and CD14/CD62p+. Platelet activation was defined by expression of CD63 and CD62p. Monocyte tissue factor expression was defined as co-expression of CD14+ and CD142+. Activated neutrophils were defined as CD15/CD63+.

Results
We evaluated 15 MPN patients (13 myelofibrosis and 2 polycythaemia vera) pre and post JAKi therapy as well as 14 MPN patients not receiving JAKi (10 patients on hydroxycarbamide, 1 on interferon-α and 3 on no treatment). Among the 15 MPN patients receiving JAKi, the median age was 64 years and the median duration of disease was 6 years and 1 month, 9 patients were JAK2V617F positive, 1 was MPLW515L positive, and 3 had a prior history of thrombosis (2 deep venous thromboses, 1 arterial thrombosis). Four patients received SAR302503 and 11 patients received ruxolitinib. At the time of sample collection, 8 patients were receiving aspirin and 1 was receiving warfarin.
We found no statistically significant difference in surrogate markers of thrombosis between MPN patients on conventional therapy and MPN patients selected to receive JAKi treatment. When comparing paired samples pre and post JAKi we found a decrease in platelet monocyte aggregates, neutrophil activation and monocyte tissue factor expression following JAKi therapy but these results did not reach statistical significance (see table). Of note, there was a significant increase in monocyte count with treatment (p=0.0078) but no significant change with respect to neutrophil, total leucocyte and platelet count. No thrombotic events occurred during the study period.

Conclusions
Given the substantial interest in the role of JAKi in MPN, it will be of key importance to evaluate the effects of these agents upon risk of thrombosis, a surrogate biomarker for that could be a demonstrated effect upon laboratory markers. In this study we were unable to detect a statistically significant effect of JAKi upon novel markers for thrombosis although the overall trend was for a decrease in monocyte activation despite an increase in monocyte count. This may be due to a number of factors including small sample size and short interval (1 month) between testing but warrants further investigation to address this important question.

Disclosures:
Harrison: Novartis: Honoraria; Sanofi : Honoraria.