Trial-in-Progress: A Phase 2 Study of Ruxolitinib in Low-Risk Essential Thrombocythemia and Polycythemia Vera Patients with High Symptom Burden
Authors: How Chi-Joan , Liu Yiwen , Gallagher Kathleen , Logan Emma K , Mullally Ann , Neuberg Donna S. , Reardon Thomas , Watson Alyssa , DeAngelo Daniel J. , Patell Rushad , Hobbs Gabriela S. 
Published: December 2024

Background: Essential thrombocythemia (ET) and polycythemia vera (PV) are myeloproliferative neoplasms (MPNs) characterized by increased risk of thrombotic events and progression to more aggressive leukemias. Risk stratification in ET and PV is based on thrombotic risk, and patients at high risk of thrombosis (i.e. patients &gt;60 years of age, those with a prior history of thrombosis, and patients &gt; 60 with a JAK2 mutation in ET) are often started on cytoreduction for thrombosis prevention. However, in addition to thrombotic risk, ET and PV patients experience significant symptoms due to activation of the JAK/STAT signaling pathway resulting in an increase in inflammatory cytokines. These symptoms include fatigue, itching, night sweats, bone pain, and brain fog. Symptoms occur in MPN patients regardless of thrombotic risk; in low-risk patients, many of whom are younger and of working age, symptoms can be severe and adversely impact functioning and quality of life.
Ruxolitinib is a JAK1/2 inhibitor currently approved in myelofibrosis (MF) and as a second-line agent in PV. It has been demonstrated to significantly improve symptom burden based on its ability to ameliorate inflammation through JAK/STAT inhibition. Ruxolitinib is not approved in ET or as a first-line agent in PV. However, it is a rational therapy to address symptom control in ET and PV patients who have high symptom burden.
The purpose of this trial is to evaluate the preliminary efficacy of ruxolitinib in improving symptom burden in ET and PV patients who are low risk for thrombosis but experience significant MPN-related symptoms.
Study Design and Methods: This is a multi-center, non-randomized, two-stage phase 2 trial evaluating ruxolitinib in low-risk, symptomatic ET and PV patients (NCT04644211). Enrollment is currently open at Dana-Farber Cancer Institute, Massachusetts General Hospital, and Beth Israel Deaconess Medical Center. Ruxolitinib is dosed at 10 mg BID and dose-escalated to a maximum of 25 mg BID based on symptoms and tolerability.
Eligible patients include adults (age &gt;18) with a diagnosis of ET and PV by World Health Organization 2016 criteria. ET patients must be very low, low, or intermediate risk by Revised International Prognostic Score for Thrombosis (R-IPSET), and PV patients must be low risk by National Comprehensive Cancer Network (NCCN) criteria. Patients must have high symptom burden to be eligible, as defined by a baseline MPN Symptom Assessment Form (SAF) Total Symptom Score (TSS) &gt;10 with at least one individual component of the MPN SAF TSS &gt;5. Patients remain eligible if they have had prior cytoreduction for symptom control.
The primary objective of this study is to evaluate ruxolitinib's efficacy in improving symptom burden as measured by the percentage of patients who achieve &gt;50% improvement of baseline symptoms at week 12 MPN-SAF TSS score. Secondary objectives of this study are to evaluate the efficacy of ruxolitinib in achieving (1) hematologic remission, as defined by International Working Group (IWG) criteria; (2) change in percentage spleen volume by imaging, in patients with baseline splenomegaly; and (3) other quality of life metrics including the modified Patient-Reported Outcomes Measurement Information System (mPROMIS-57) and Patient Global Impression of Change (PGIC). Exploratory objectives include evaluation of ruxolitinib's effect on inflammatory cytokine production and its relationship with symptom burden. We will also perform next-generation-sequencing to evaluate the effect of ruxolitinib on driver and non-driver mutation burden.
A total of 30 patients will be enrolled in a Simon two-stage design where the first 15 patients are assessed at week 12. If &gt;3 responses occur in the first stage, an additional 15 patients will be enrolled. The study is considered promising if &gt;6 responses are recorded in 30 patients. The first patient consented to the study in March 2022, and as of this writing 15 patients have enrolled (7 ET, 8 PV; median age 49.2 years; 13/15 female), with confirmed responses in at least 3 patients. The trial is therefore currently enrolling an additional 15 patients for Stage 2.