Assessing the Safety and Efficacy of Ruxolitinib in a Multicenter, Open-Label, Expanded-Access Study in Japanese Patients with Myelofibrosis (MF)
Authors: Kirito Keita , Komatsu Norio , Shimoda Kazuya , Okada Hikaru , Amagasaki Taro , Yonezu Toshio , Akashi Koichi 
Published: October 2019

Abstract
BACKGROUND: Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor that has demonstrated durable improvements in splenomegaly and MF-related symptoms, and has been associated with improved overall survival in patients (pts) with MF in randomized clinical trials. Results from the phase 2 Asian multinational study (NCT01392443) supported these findings in Asian pts, including 30 Japanese pts. The current study was initiated to collect further data on the safety and efficacy of ruxolitinib in pts with MF and included intermediate (Int)-1-risk pts and those with a platelet (PLT) count of 50 to < 100 × 109/L, 2 pt populations not included in the phase 3 COMFORT studies or the phase 2 Asian study.
METHODS: Pts with primary MF (PMF), post-polycythemia vera (PPV) MF, or post-essential thrombocythemia (PET) MF classified as high-risk, Int-2 risk, or Int-1 risk with a palpable spleen (≥ 5 cm from costal margin) were included. The primary objective was to assess safety of ruxolitinib. Efficacy endpoints included changes in spleen size and patient-reported outcomes (EORTC QLQ-C30 symptoms and functional scales and the 7-day modified MFSAF v2.0). All pts were to receive ruxolitinib for 24 wk with the starting dose based on PLT count at baseline (50 to ˂ 100 × 109/L, 5 mg twice daily [bid]; 100 to 200 × 109/L, 15 mg bid; ˃ 200 × 109/L, 20 mg bid) and adjusted for each pt to maximize safety and efficacy (minimum, 5 mg bid; maximum, 25 mg bid). The primary analysis occurred when all pts completed 24 wk or discontinued.
RESULTS: Overall, 51 pts (PMF, n = 23; PPV-MF, n = 14; PET-MF, n = 14) were treated. Most pts were Int-2 (33.3%) or high risk (54.9%); 11.8% were classified as Int-1. The median age was 65 years (range, 44-85 years), and 52.9% (n = 27) were male. The median palpable spleen length was 16.5 cm (range, 2-30 cm), and the median spleen volume was 2028.7 cm3 (range, 480-4682 cm3). Median hemoglobin at baseline was 99.0 g/L (range, 62-141 g/L), and median PLT count was 247 × 109/L (range, 57-1265 × 109/L); 13.7% of pts had a baseline PLT count of 50 to < 100 × 109/L. Most pts received a starting dose of 20 mg bid (62.7%; n = 32) or 15 mg bid (23.5%; n = 12); the rest started treatment at 5 mg bid.
Most pts completed treatment as per protocol (86.3%; n = 44); 9.8% (n = 5) discontinued due to adverse events (AEs). Other reasons for discontinuation included disease progression and loss to follow-up (2.0% each). The most common hematologic AEs were anemia (62.7%; grade 3/4, 47.1%) and thrombocytopenia (29.4%; grade 3/4, 7.8%). Nonhematologic AEs in ≥ 10% of pts included constipation (13.7%; grade 3/4, 0%), abnormal hepatic function (11.8%; grade 3/4, 3.9%), and nasopharyngitis (11.8%; grade 3/4, 0%). No deaths occurred on study.
At wk 24, 30.0% of evaluable pts (15/50) experienced ≥ 50% reduction in palpable spleen length from baseline; 26.0% (13/50) had a ≥ 35% reduction in spleen volume. The majority of pts (52.0%; 26/50) had a ≥ 50% reduction in palpable spleen length from baseline at any time by wk 24; 38.0% (19/50) had a ≥ 35% reduction in spleen volume by wk 24. Ruxolitinib treatment led to clinically significant improvements in symptoms, with 75.0% of evaluable pts (30/40) achieving a ≥ 50% reduction from baseline in MFSAF total symptom score at wk 24. Improvements were also observed in quality of life and role functioning (as assessed by the EORTC-QLQ), with pts reporting reductions in MF-related symptoms, including fatigue, pain, and appetite loss. Overall, IgM, CD3, CD4, and CD8 levels remained stable during treatment; IgG levels decreased slightly in the first 4 wk but then increased to near baseline levels (Figure).
CONCLUSIONS: As observed in other studies of ruxolitinib, most pts in this study experienced spleen size reductions and improvement in symptoms. The most common AEs were anemia and thrombocytopenia, consistent with previous reports. Additionally, this study evaluated the effect of ruxolitinib on the levels of different immune markers, an analysis not conducted in previous studies with ruxolitinib, and identified no negative effects on the levels of these markers during the course of treatment. The safety and efficacy of ruxolitinib here is consistent with the phase 3 COMFORT studies and the phase 2 Asian study. These findings indicate that ruxolitinib is a safe and effective therapy in Japanese pts with MF, including Int-1-risk pts and those with PLT counts 50 to < 100 × 109/L.

Disclosures
Kirito: Novartis Pharma KK: Honoraria. Shimoda:Novartis: Consultancy, Honoraria. Okada:Novartis Pharma K.K.: Employment. Amagasaki:Novartis Pharma K.K.: Employment. Yonezu:Novartis Pharma K.K.: Employment. Akashi:Asahi Kasei: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau.