BRADY L. STEIN (CHICAGO)
USE OF RUXOLITINIB IN ESSENTIAL THROMBOCYTHEMIA AND SPLANCHNIC
VESSEL THROMBOSIS
In the accompanying case based lecture, the use of ruxolitinib is described in patients with
Essential Thrombocytosis and/or Splanchnic Vessel thrombosis. This talk complements other
lectures in this symposium that provide an overview of ruxolitinib for Polycythemia Vera
(Professor Vannucchi) and Myelofibrosis (Professor Verstovsek).
Here, a 63 year-old patient with recently diagnosed Essential Thrombocythemia (ET) is
presented. Briefly, the goals of therapy for ET are introduced, which include symptom
management, reduction in the risk for incident or recurrent thrombosis/hemorrhage, and
ideally, delay in progression. In ET, treatment is heavily influenced by perceived vascular risk;
the main components of vascular risk assessment include JAK2 mutational status, advanced
age, and thrombosis history.1 As the presented patient is 63 years old with a JAK2 mutation,
she is classified into a high risk grouping, and consistent with routine clinical practice, is
prescribed hydroxyurea. Hydroxyurea is a commonly used front-line cytoreductive, but
approximately 20% of patients are intolerant or resistant. Such patients need to move on to
a second-line cytoreductive, but choices can be limited. As this particular patient has relative
contraindications to anagrelide (palpitations) and interferon (depression/anxiety),
considerations include a clinical trial, or another agent.
Given that ET is also driven by JAK-STAT dysregulation, and that JAK-inhibition can relieve
inflammatory symptoms and potentially address certain aspects of the thrombotic tendency,
there is rationale for considering this agent. Ruxolitinib has been previously studied in phase
2 clinical trials for patients with hydroxyurea resistance or intolerance. Two of these studies
are summarized here. The first reports on the long term follow-up from a prior phase 2 study
including 39 patients, nearly 88 months from their original diagnosis.2 Fifty-six percent of
patients received a median of 30mg daily for at least 72 months. Patients experienced prompt
reduction in the leukocyte count, and 45% experienced a platelet count of less than 600 x
109/L by week 312. Improvements in the ET symptom burden were noted and safety concerns
were comparable to those reported in PV and MF patients.2
A second phase 2 study compared ruxolitinib to best available therapy (BAT) in 110 high risk
ET patients with HU resistance or intolerance.3 Here, then mean dose intensity was 19mg
twice daily. The primary outcome, (complete hematological response rate) was similar when
comparing the ruxolitinib and BAT groups. There were no differences in overall survival,
thrombo-hemorrhagic event rates, or rates or transformation. There appeared to be better
symptom control over time in patients treated with ruxolitinib. As expected, there more
hematological adverse events and infections in ruxolitinib treated patients.3
Ruxolitinib has also been studied in patients with splanchnic vein thrombosis (SVT). Such
patients often require long term anticoagulation and cytoreduction. However, the former can
be challenging as patients often have portal hypertension and high bleeding risk in the
presence of esophageal varices. The rationale for ruxolitinib in SVT includes the possibility of
reducing spleen stiffness and volume, which theoretically could decrease portal pressures and
stabilize varices. A phase 2 investigator initiated study of 21 patients is summarized; the
primary aim including spleen size reduction and secondary aims included the rate of SVT
extension, as well as improvement in hepato-splenic stiffness and status of esophageal
varices.4 Four patients experienced a median reduction in spleen stiffness by 24%; 17
patients could not undergo reliable testing because their spleen stiffness was above the upper