Comparing the Efficacy and Safety of Ruxolitinib in Patients with Lower and Higher Risk Myelofibrosis: A Multi-Center, Single-Arm, Exploratory and Prospective Study

Introduction: The COMFORT studies assessed the efficacy and safety of ruxolitinib in patients with intermediate-2 and high risk myelofibrosis (MF), and JUMP study has broadened the investigation including patients with intermediate-1 MF in the classification of DIPSS. However, no prospective studies evaluate the efficacy and safety of patients with lower and higher risk MF in the classification of more comprehensive scoring system, including MIPSS-70, MIPSS+V2.0, DIPSS-Plus, and MYSEC-PM.

Methods: Patients aged ≥ 18 with overt primary myelofibrosis (overt-PMF), prefibrotic primary myelofibrosis (pre-PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF) were enrolled from 12 hematology centers. Lower risk was defined as MIPSS-70 ≤ 3, MIPSS+V2.0 ≤ 3, DIPSS-Plus ≤ 1, DIPSS ≤ 2 or MYSEC-PM < 14. Higher risk was defined as the opposit. The primary endpoint was the proportion of patients with a spleen length reduction of ≥ 50% from baseline at week 48. Secondary endpoints included the best spleen response, the proportion of patients with a ≥50% reduction in Total Symptom Score (TSS50) and safety.

Results: In total, 132 patients were enrolled in the study, comprising 57 (43.2%) males and 75 (56.8%) females. The median age was 66.0 years. 107 (81.8%) were JAK2V617F positive. 35 patients had next generation sequencing (NGS), the most frequent non-driver mutation were ASXL1 (11/35, 31.4%) and TET2 (11/35, 31.4%). 70 patients were classified into the lower risk group (including 9 with pre-PMF, 27 with overt-PMF, 15 with PPV-MF, and 19 with PET-MF), and 62 patients were classified into the higher risk group (including 5 with pre-PMF, 34 with overt-PMF, 9 with PPV-MF, and 14 with PET-MF). The patients in the lower risk group exhibited a younger age, higher levels of hemoglobin, platelet count, monocyte count, and hematocrit. They also showed lower percentages of blasts, lower lactate dehydrogenase levels, lower constitutional symptoms, lower transfusion dependence, and a lower incidence of chromosomal abnormalities. By Week 48, 45 (64.3%) and 34 (54.8%) patients achieved a ≥ 50% decrease in palpable spleen length in lower and higher risk groups, respectively. Additionally, 55 (78.6%) and 42 (67.7%) patients achieved a ≥ 50% reduction from baseline at any time, respectively. The median time to a spleen response was 4.2 weeks and 5.4 weeks, respectively. At Week 48, the TSS50 rates was 24.3% and 30.7%, respectively.In the lower risk group, the median hemoglobin level decreased from a baseline of 120.7 g/L to 108.6 g/L during the first 8 weeks. After 16 weeks, it stabilized at approximately 104 g/L. Median platelet counts slowly decreased from baseline of 353.0×10^9/L over the first 24 weeks, with a nadir of 290.5×10^9/L. In the higher risk groups, median hemoglobin levels decreased from baseline of 96.4g/L to a nadir of 86.8g/L by Weeks 8, and fluctuated between 94.9g/L and 88.5g/L during follow-up. Median platelet counts decreased from baseline (282.8×10^9/L) during the first 4 weeks, with a nadir of 244.5×10^9/L. The most common grade ≥ 3 hematological treatment emergent adverse events (TEAEs) were anemia (6/70, 8.6% vs. 13/62, 21.0%) and thrombocytopenia (2/70, 2.9% vs. 6/62, 9.7%) in both groups. The mostly common non-hematological TEAE was infection (10/70, 14.3% vs. 12/62, 19.4%), including pneumonia (6/70, 8.6% vs. 7/62, 11.3%), upper respiratory tract infection (2/70, 2.9% vs. 1/62, 1.6%), urinary infection (1/70, 1.4% vs. 2/62, 3.2%), and fever (1/70, 1.4% vs. 2/62, 3.2%), predominantly of grade 1 or 2. Of note, only 2 patients in the lower-risk group discontinued ruxolitinib treatment due to TEAEs. In contrast, 6 patients in the higher-risk group discontinued ruxolitinib treatment due to TEAEs, and 1 patient discontinued due to disease progression.

Conclusions: Ruxolitinib is an effective treatment for patients with lower risk MF in the classification of MIPSS-70, MIPSS+V2.0, DIPSS-Plus, DIPSS≤2 and MYSEC-PM, resulting in improved spleen and symptom responses, along with fewer hematological and non-hematological TEAEs. This trial was registered as ChiCTR2200064250 at ClinicalTrials.gov.

This research was funded by the Key R&D Program of Zhejiang (No. 2022C03137) and the Zhejiang Medical Association Clinical Medical Research special fund project (No. 2022ZYC-D09). *Correspondence to: Prof Jian Huang, E-mail: househuang@zju.edu.cn;