Interim Analysis of Registry of Ruxolitinib Treatment in Patients with Intermediate-2 or High Risk Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF) in Taiwan
Authors: Hou Hsin-An , Lin Chien-Chin , Kuo Ming-Chung , Lin Shyuann-Yuh , Gau Jyh-Pyng , Wang Ming-Chung , Chang Ming-Chih , Chen Tsung-Chih , Yeh Su-Peng , Chen Yeu-Chin , Huang Cih-En , Chen Chieh-Wen , Lee Yee-Ming , Ku Fan-Chen , Shih Lee-Yung 
Published: November 2019

Background
Ruxolitinib, an oral JAK 1/JAK 2 inhibitor, has been approved for the treatment of intermediate-2 or high-risk myelofibrosis, including primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), and post-essential thrombocythemia myelofibrosis (PET-MF) in Taiwan since 2014. This registry aimed to examine the real-world safety profile and treatment pattern of ruxolitinib in Taiwan.
Methods
This is an observational, multi-center, post-marketing registry study. A total of 98 patients with intermediate-2 or high-risk PMF, PPV-MF, or PET-MF and receiving ruxolitinib (73.5%) or newly initiating ruxolitinib (26.5%) per clinical judgment were enrolled and analyzed in a 2-year follow-up. The primary objective was to collect the safety profile of ruxolitinib under routine practice in Taiwan.
Results
This interim analysis included results of 98 patients who had received ruxolitinib treatment. The median age was 68.1 years (range, 38 -87 years), 50.0% of patients were male. Of the 98 patients, 51.0% were diagnosed with PMF, 27.1% were PET-MF, and 21.9% were PPV-MF; 70.4% were categorized as Dynamic International Prognostic Scoring System (DIPSS) intermediate-2-risk group and 28.6% were high-risk group when ruxolitinib was initiated. JAK2 mutation was identified in 77.8% of 63 patients examined, while CALR mutation was identified in 6 of the 14 (42.9%) JAK2-unmutated cases. At the time of data cut-off, 23 patients (23.2%) discontinued the study mainly due to death (9.1%), adverse events (2.0%), withdrawal of consent (2.0%), and interruption of ruxolitinib ≥ 3 months (2.0%).
The median exposure to ruxolitinib was 14.2 months (range, 0.8 - 37.9 months) from the time of study enrollment. At baseline, 75.4% of patients receiving a starting dose of > 5 - 10 mg bid, 11.2 % receiving > 10 - 15 mg bid, 10.2% receiving 20 mg bid. The prescription appeared to be more conservative than the suggested dose. The dose of 5 - 10 mg bid was prescribed for most patients at study enrollment regardless of different platelet counts (56.5% with platelet counts > 200 × 109/L, 54.5% with platelet counts 100 - 200 × 109/L, 50.0% with platelet counts < 100 × 109/L). The median dose after 6 months was maintained at 10 mg bid.
At the time of data cut-off, adverse events (AE) were reported in 77.6% of patients and serious AEs (SAE) observed in 35.7% of patients. The most common non-hematologic AEs (≥ 5% of patients) were infections (pneumonia [9.2%], upper respiratory tract infection [8.2%], urinary tract infection [7.1%]), pyrexia (9.2%), diarrhea (8.2%), hyperkalemia (6.1%), and cough (5.1%). The infections were mainly grade 1/2, without tuberculosis or hepatitis B reactivation reported. Consistent with findings from other ruxolitinib studies, the most common hematologic AEs were anemia (10.2%) and thrombocytopenia (10.2%). However, we observed a lower incidence of anemia and thrombocytopenia compared to other studies (42.2 - 56.3%) and no one discontinued the treatment, indicating that these AEs were tolerable and manageable. Ten patients died but none of them was related to ruxolitinib.
Over 48 weeks, ruxolitinib provided a sustained clinical benefit (n = 59), with a significant reduction in MPN-10 total score from 21.4 to 12.0 (P < 0.001). The improvement of symptoms was particularly prominent in naïve patients (change in total score: -12.8, P < 0.001) compared to non-naïve patients (change in total score: -6.1, P = 0.023), especially in itching (-2.7 vs. -0.5, respectively), problems with concentration (-1.8 vs. -0.9, respectively), and filling up quickly when eating (-2.2 vs. -1.1, respectively). In addition, the spleen size was reduced from baseline by 10.9 % in 27 evaluable patients at Week 12 and 16.4% in 13 evaluable patients at Week 24.
Conclusions
The interim analysis demonstrated that ruxolitinib for patients with intermediate-2 or high-risk myelofibrosis, was well-tolerated in the real-world setting in Taiwan. With a lower starting dose, the incidence of hematological AEs and infection rate appeared to be lower than previous reports. The safety profile was consistent with published data, with neither new safety signal, tuberculosis, nor hepatitis B reactivation detected. Ruxolitinib also provided continuous symptom improvement; however, spleen size reduction, an important goal of ruxolitinib therapy of myelofibrosis, was relatively modest, highlighting the need for dose optimization.

Disclosures
Hou: Celgene: Research Funding; Abbvie, Astellas, BMS, Celgene, Chugai, Daiichi Sankyo, IQVIA, Johnson & Johnson, Kirin, Merck Sharp & Dohme, Novartis, Pfizer, PharmaEssential, Roche, Takeda: Honoraria. Chen:Novartis: Employment. Lee:Novartis: Employment. Ku:Novartis: Employment.