The salient features of AHA and treatment outcomes of the patients in this study are similar to those of other patients. Two independent factors (the use of a Rb regimen and platelet < 1.5 × 10(11)/L) were significantly associated with TRS.

Background The selective tyrosine kinase inhibitor (TKI) nilotinib has been approved for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) globally, including Taiwan. The NOVEL-1st study was conducted to examine the long-term safety and efficacy of nilotinib in this group of patients in routine clinical practice in Taiwan. Methods The NOVEL-1st study was a non-interventional, multi-center study. A total of 129 patients with newly diagnosed and previously untreated Ph+ CML-CP were enrolled from 11 centers across Taiwan between January 2013 and June 2016. The follow-up period was 36 months. The primary objective was to collect long-term safety data on nilotinib. Secondary objectives were to evaluate the efficacy of nilotinib by clinical response, disease progression, and survival. Results The median age of the enrolled patients was 49.7 (20.2-89.6) years of whom 58.3% were males. The median duration from CML diagnosis to study enrolment was 25.5 days. Of the 129 enrolled patients, 59 (45.7%) had completed the study, 29 (22.5%) had withdrawn from the study and other patients are still under follow up. The most common reasons included adverse events (AE) (n = 8), discontinuing nilotinib (n = 6), and death (n = 4). All 129 patients were included in the safety analysis, while 122 patients in whom molecular response data were collected were included in the efficacy assessment. At the time of data cut-off, a total of 1,278 AEs were reported by 120 (93.0%) patients, of which 140 (11.0%) AEs in 41 (34.2%) patients were serious and 499 (39.0%) AEs in 40 (33.3%) patients were drug-related. Non-hematological and hematological AEs were consistent with other reports, with no new safety signal detected. Common hematological AEs (incidence ≥ 10 %) included thrombocytopenia (29.5%), anemia (19.4%), and leukopenia (14.0%). Frequent non-hematological AEs (incidence ≥ 10 %) included rash (21.7%), upper respiratory tract infection (19.4%), pruritus (18.6%), cough (17.1%), constipation (14.7%), diarrhea (12.4%), increased alanine aminotransferase (11.6%), increased bilirubin (10.1%), and insomnia (10.1%). Compared to previous studies, we observed lower rates of cardio- or cerebrovascular events (1.6%), fluid retention (2.3%), and hyperglycemia (2.3%) of all grades, but a higher rate of hepatotoxicity (20.9%) was seen in the study population. Five (3.9%) patients expired during the study of whom 2 were due to CML progression. The efficacy outcomes were comparable to other first-line studies of nilotinib. From 3 to 36 months, the rates of clinical response increased over time, from 67.4% to 91.5% for complete hematological response (CHR), 45.0% to 86.0% for complete cytogenetic response (CCyR), 15.5% to 79.1% for major molecular response (MMR), 3.9% to 56.6% for MR4.0 (BCR-ABL ≥ 4 log reduction), and 2.3% to 38.8% for MR4.5 (BCR-ABL ≥ 4.5 log reduction). The median time to CHR, CCyR, MMR, and MR4.0 were 4, 5, 9, and 25 months, respectively (not reached for MR4.5). Early molecular response (EMR), defined as BCR-ABL ≤ 10% at Month 3, was seen in 88.7% of patients. MR4.0 and MR4.5 were significantly higher for patients with deeper EMR, confirming an association between early and long-term deep molecular response. To date, the median OS and PFS were not reached as death and disease progression were only observed in 5 and 2 patients, respectively. Conclusions The initial results of NOVEL-1st were comparable to other published first-line studies of nilotinib and demonstrated that nilotinib as a first-line treatment for Ph+ CML-CP patients was well-tolerated and efficacious in the real-world setting. Clinical response was observed as early as 3 months. Early molecular response is a potential predictor of long-term clinical outcome. The final analysis will be conducted when all patients have completed the study. Disclosures No relevant conflicts of interest to declare.

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Background Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved for the treatment of patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) globally, including Taiwan. However, the real-world evidence regarding the long-term safety (primary) and effectiveness (secondary) of nilotinib in newly diagnosed untreated Ph+ CML-CP is limited in Taiwan. Methods The NOVEL-1st study was a non-interventional, multi-center study. A total of 129 patients with newly diagnosed and previously untreated Ph+ CML-CP were enrolled from 11 centers. The objective was to collect the long-term safety (primary) and effectiveness (secondary) data in patients treated with nilotinib under the real clinical practice for up to three years. Results Of the 129 enrolled patients, 32 patients (24.8%) discontinued the study, predominately due to AEs (n = 8; 6.2%), discontinuing nilotinib or switching to other treatments (n = 7; 5.4%), and death (n = 5; 3.9%). The median age of the study population was 49 years (range, 20 - 53 years), of whom 77 were male (59.7%). At enrollment, the median time from initial CML diagnosis was 22 days (range, 0.0 - 602 days), and three of them had their CML diagnosed for more than one year. Across the 3-year observational period, a total of 1,466 AEs were reported in 127 (98.4%) patients, of which 151 AEs in 44 (34.6%) patients were serious adverse events (SAEs) and 524 AEs in 37 (29.1%) patients were nilotinib-related. The most commonly reported non-hematological AEs (regardless of relationship to nilotinib, incidence ≥ 20 %) were rash (24.8%); while that for hematological AEs were thrombocytopenia (31.0%; Grade 3 or above: 13.2%) (Table 1). Nilotinib discontinuation, and dose reduction or interruptions were only reported in 9 (7.1%) and 11 (8.7%) patients, respectively. Five (3.9%) patients expired, of whom 2 were due to CML progression. Favorable efficacy outcomes were observed in this real-world study. From 3 to 36 months, the rates of clinical response increased over time, from 72.5% to 98.3% for complete hematological response (CHR), from 48.3% to 92.5% for complete cytogenetic response (CCyR), from 16.7% to 85.8% for major molecular response (MMR), from 4.2% to 65.0% for MR4.0 (BCR-ABL ≥ 4 log reduction), and from 3.3% to 45.0% for MR4.5 (BCR-ABL ≥ 4.5 log reduction) (Figure 1). The median time to CHR, CCyR, MMR, and MR4.0 were 4, 5, 9, and 25 months, respectively (not reached for MR4.5). Early molecular response (EMR), defined as BCR-ABL ≤ 10% at Month 3, was seen in 87.6% of patients. Non-hematological and hematological AEs were comparable with previous studies, with no new safety signal detected. This NOVEL-1st study demonstrated a lower percentage of patients withdrawing nilotinib owing to AEs (NOVEL-1st vs. prior: 7.1% vs. 10.0%) and an extremely lower incidence of AEs leading to dose reduction or interruption (8.7% vs. 37 - 55%). It was inferred that the high tolerability and patient adherence further contributed to high treatment response in terms of complete molecular response (CMR [i.e., MR4.5], 45% vs. 32%), molecular response 4.0 (MR4.0, 65% vs. 50%), and major molecular response (MMR, 85.5% vs. 73%) at 3 years. Over the 3 years of follow-up, there was no newly onset of hepatitis or hepatitis B flare. This NOVEL-1st study also reported lower incidence rates of CV events (NOVEL-1st vs. prior: 2.3% vs. 3.5 - 6.0%), diabetes (2.3% vs. 20.2%), and hyperglycemia (3.1% vs. 42.1%) than prior studies. None of them was judged as related to nilotinib treatment (Table 1). Conclusions Across the 3-year observational period, nilotinib demonstrated comparable efficacy and had lower risk of hepatitis flare, CV event, diabetes and hyperglycemia among Ph+CML-CP patients in a real world setting in Taiwan. Long-term good patient adherence and holistic care could contribute to good treatment outcome in this chronic disease under the first-line treatment with nilotinib. Disclosures Chen: Novartis: Current Employment. Lee:Novartis: Current Employment. Ku:Novartis: Current Employment.

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.