Objectives: The complement component 5 (C5) inhibitor ravulizumab demonstrated non-inferiority to eculizumab following 26 weeks of treatment in complement inhibitor-naïve and complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH; studies 301 and 302, respectively). This study aims to describe the results of both studies from 27 weeks to 2 years.Methods: Patients (N = 441) continued to receive ravulizumab throughout the extension period. Efficacy endpoints included lactate dehydrogenase (LDH) normalization, transfusion avoidance and fatigue score (FACIT-F). Safety analyses were also performed.Results: From 27 weeks to 2 years, improvements in LDH levels were maintained in both study populations. Transfusion avoidance was maintained in 81.9% (study 301) and 85.6% (study 302) of patients, and FACIT-F scores remained stable. Ravulizumab was well tolerated, and the incidence of adverse events (AEs) were similar between patients of both studies. Incidence of serious AEs deemed related to ravulizumab treatment was low (<3%).Conclusions: This study reports, to date, the longest period of follow-up in over 400 patients with PNH treated with ravulizumab (662 patient-years). Long-term, ravulizumab demonstrated durable efficacy and was well tolerated, highlighting the importance of C5 inhibitors as the mainstay of PNH treatment.
Background: Nilotinib, a second generation tyrosine kinase inhibitor, was proved to have high efficacy on treatment of Philadelphia chromosome positive CML patients who failed or were intolerant to imatinib. Limited data was available on its efficacy and safety in Asian population. Methods: Chronic phase CML patients who have failure, suboptimal response or intolerance to imatinib according to ELN 2009 guideline were treated with nilotinib 400 mg twice daily on 7 centers in Thailand. Prospective data collection for 24 months was performed. Results: There were 106 cases participated in this study, 2 cases with initial T315I mutation were excluded from the study, total 104 cases were analysed. The median age was 46 (16-79) years with a slight male predominance over female at the ratio of 1.4:1 respectively. Twenty five percent received imatinib less than 12 months whilst 20% received imatinib longer than 60 months. The median duration of the prior imatinib treatment was 18 months (2-142 months). Best response to imatinib treatment were major molecular response (MMR) 5.8%, complete cytogenetic response (CCyR) 26%, major cytogenetic response (MCyR) 12.5%, complete hematologic response (CHR) 47%, and no CHR 8.7%. The reasons for nilotinib switching were imatinib failure 65%, imatinib intolerance 28%, imatinib suboptimal response 7%. Sixty-eight percent were completed 24 months follow up. Of those, 32% early discontinued treatment mostly because of unsatisfactory results or adverse events. Two patients died of infection and CNS bleeding during the study period. Evaluation were made every 3 months based on ELN 2009 criteria . Best response to nilotinib treatment included MMR 57%, CCyR 16%, MCyR 6%, CHR 16%, and no CHR 5%. At 3 months, 91%, 35%, and 14% of the patients CHR,CCyR, and MMR, respectively. Achieving CCyR or MMR at 3 months predicted a chance of achieving MMR (P= 0.00001) Those who did not achieve at least CHR at 3 months never achieved MMR, while 86 % of those who achieved CCyR at 3 months achieved MMR and 100% of those achieving MMR at 3 months had sustained MMR throughout the study period (24 months). Imatinib suboptimal response had significantly better outcome as compared to imatinib failure and imatinib intolerance group (P = 0.017). All of suboptimal response cases achieved CCyR , 86% achieved MMR, no early discontinue treatment in this group. While 75% of failure group achieved CCyR, 62% achieved MMR and 62% of intolerance group achieved CCyR, 38% achieved MMR. The reason for poorer response of intolerance group was high rate of early discontinue due to side effects, 17% vs 5% in the imatinib failure group. Initial BCR-ABL mutation analysis was performed on 90 cases, mutations were found on 16 cases, 2 of them were T315I which were excluded from the study. The cases with mutation significantly had poorer response to treatment than those without mutation (P = 0.001). There was one case with initial G250E mutation, who developed T315I mutation after treatment with nilotinib. At 24 months, 1 case progressed to accelerated phase and 3 cases progressed to blastic transformation. The 2-year progression-free survival and 2-year overall survival was 96% and 98%, respectively. Skin rash, musculoskeletal pain, and infection were the three most common non-hematologic adverse events found in 18%, 13%, and 6% of the patients, respectively; however, most of them were grade 1-2, except for 4 cases with grade 3-4 infections .Grade 3-4 hematologic adverse events included thrombocytopenia (12%), neutropenia (11%), anemia (5%), and leucopenia (4%); and most of them were manageable. Although biochemical abnormalities were commonly found, most of them were mild. Grade 3-4 events found were hypophosphatemia (6%), hyperglycemia (4%), and elevated serum lipase (4%). Only 10 cases (9%) permanently discontinued nilotinib due to its adverse effects. Conclusions: Nilotinib, as a second line treatment for Thai patients with chronic phase CML showed excellent efficacy and tolerability. Indication for nilotinib treatment, initial mutation status and depth of response at 3 months after treatment can predict outcomes of the patients. Author contact: KanchanaChansung M.D. Division of Hematology, Department of Medicine, Faculty of Medicine, Khonkaen University, Khonkaen, Thailand e-mail: kchansung@gmail.com Disclosures No relevant conflicts of interest to declare.
Introduction : To date, the ELN recommendation and NCCN guidelines are the principle mile stones to follow up the treatment response and to make the decision of TKIs switching. However, in real life practice, many factors influence changing the real switching date from the date had an indication. This study aims to analyze the impact of early switching to second line TKI, nilotinib, in real life practice, for the CML patients who failed, had sub-optimal response or were intolerant to imatinib. Methods : This prospective study was conducted through 7 medical centers in Thailand between 1st of September 2009 and 31st of August 2011. Adult CML patients of age ≥ 18 years old, in chronic and accelerated phase, who had failure, suboptimal response or intolerance to imatinib, based on ELN 2009 guideline, were included and were eligible with nilotinib 400 mg twice daily. Prospective data collection for 24 months of each patient was performed. The main objective was to identify the impact of early switching to nilotinib on major molecular response (MMR). The other objectives were to observe the efficacy of nilotinib including overall survival, progression free survival and the safety. The survival results were presented as Kaplan-Meier survival curves. For the comparison of the treatment groups, the Kaplan-Meier estimator with the corresponding log-rank test for equality of survivor functions across treatment group was applied. Results : The final 108 cases were analysed. The median age was 47 (17-79) years with the proportion of male to female of 1.4:1 respectively. The median duration of the prior imatinib treatment was 18 months (2-142 months). The median duration between the date of indication and the date of real switching was 3.1 months (0-62.8 months) with 50% changing less than 3 months, 26.9% between 3 months and 12 months, and 23.1% changing longer than 12 months. The indication of switching included 63.6% failure to imatinib, 29% intolerance to imatinib and 7.4% suboptimal to imatinib. On the nilotinib switching, 70.4% completed 24 months follow-up, and 29.6% discontinued treatment mostly because of unsatisfactory results or adverse events. Evaluation was made every 3 months based on 2009 ELN recommendation. At 3 months, 57%, 20%, and 8% of the patients achieved CHR, CCyR and MMR, respectively. Those who did not achieve CHR at 3 months never achieved MMR, while 86 % of those who achieved CCyR at 3 months achieved MMR. All CML achieving MMR at 3 months had sustained MMR throughout the study period (24 months). Imatinib suboptimal response had better outcome than imatinib failure and imatinib intolerance groups. A preliminary analysis of BCR-ABL mutation was performed on 90 cases, and mutations were found on 21 cases. Two of them were T315I which were excluded from the study. The cases with mutation had poorer response to treatment than those without mutation. There was one case with initial G250E mutation developing T315I mutation after treatment with nilotinib. At 24 months, one case progressed to accelerated phase and 3 cases progressed to blastic transformation. The 2-year overall survival and 2-year progression-free survival and were 98.9% and 96.9% (figure 1 and 2), respectively. The interquatile analysis was done to identify the groups of cumulative MMR according to the duration between the date of indication and the date of real switching to nilotinib. The patients who switched to nilotinib within 12 months after date of indication could have a greater chance to achieved MMR than those who switched treatment later than 12 months (p(log-rank) = 0.002) (figure 3). Skin rash, musculoskeletal pain, and infection were the three most common non-hematologic adverse events, However, most of them were grade 1-2, except for 4 cases with grade 3-4 infections. Grade 3-4 hematologic adverse events included thrombocytopenia (12%), neutropenia (11%), anemia (5%) and leucopenia (4%), and most of them were manageable. Although biochemical abnormalities were commonly found, most of them were mild. Conclusions : Nilotinib, as a second line treatment showed excellent efficacy and tolerability. Indication for nilotinib treatment, initial mutation status and depth of response at 3 months after treatment can predict outcomes of the patients. However, the patients will have a greater chance to achieve MMR if they switched to nilotinib within 12 months after the date of indication for changing. Disclosures No relevant conflicts of interest to declare.
CML cells gain a survival advantage over normal cells due to dysregulated tyrosine kinase activity of BCR/ABL protein, which phosphorylates a number of proteins, potentially activating multiple signal transduction pathways. Imatinib specifically targets BCR/ABL protein and results in anti-proliferation and apoptosis. Even in the absence of mutation, the leukaemic clone may not be eradicated by imatinib, suggesting that leukaemic stem cells may not be absolutely reliant on BCR/ABL activity for survival. Reports on GM-CSF production by CML cells suggest a possible autocrine role, therefore we examined if GM-CSF could protect CML CD34+ cells from imatinib. CD34+ cells from peripheral blood of patients with CML in chronic phase (n=9) and from normal bone marrow donors (n=5), were labeled with CFSE (Carboxy-Fluorescein diacetate Succinimidyl Ester) to enable tracking of cell division. Normal and CML samples were cultured with and without GM-CSF (300pg/mL) to assess response to this cytokine as a single agent. CML CD34+ cells were cultured for 3 days in serum deprived medium with imatinib only, GM-CSF (300 pg/mL) + imatinib, GM-CSF (300pg/mL) + E21R (a GM-CSF analogue able to block cytokine binding) (10mg/mL), and GM-CSF (300pg/mL) + E21R (10mg/mL) + imatinib. In each condition, imatinib was titrated over the range of 0 to 10 microM. Cultures were analysed by flow cytometry to evaluate the proliferation index (PI), a ratio of final cultured cell to precursor cell number, where a PI of 1 represents no proliferation, and a PI of 2 corresponds to approximately three division cycles on average. Data are summarised in Table 1. Effect of GM-CSF and imatinib on proliferation Culture Proliferation Index Statistics using Student t test, symbols denote comparisons between culture conditions Normal Control 1.07+/−0.06 * NS Normal+GM-CSF 1.11+/−0.03 * # NS CML Control 1.43+/−0.18 ** p>0.01 #, & NS CML+GM-CSF 2.30+/−0.40 ** CML+10μM imatinib 1.18+/−0.09 *** NS CML+10μM imatinib+GM-CSF 1.54+/−0.19 @, & CML+10μM imatinib+GM-CSF+E21R 1.17+/−0.09 *** @ p>0.01 GM-CSF induced strong proliferation in all CML, but not normal samples. Imatinib reduced proliferation of CML CD34+ cells at 1 microM and above, and the addition of GM-CSF reduced this proliferative effect at concentrations of imatinib up to 10 microM. The protective effect of GM-CSF was clearly blocked using E21R. When the proliferation of CML CD34+ cells cultured within the total mononuclear fraction was compared to purified CD34+ cells, it was found that there was an approximate 40% enhancement of PI at each concentration of imatinib. This enhanced proliferation was inhibited by the addition of E21R, indicating GM-CSF may be produced by non-CD 34+ cells. ELISpot assay confirmed the production of GM-CSF by non-CD34+ CML cells (34±23%), but not CD34+ cells (0.06±0.02%). Fluorescent inhibitor of apoptosis (FLICA) assay showed that GM-CSF could reduce the proportion of cells with activated caspases induced by imatinib by over 40% during a 3 day in vitro culture, promoting increased cell survival. As the GM-CSF receptor and BCR/ABL may share common signaling pathways, during blockade of BCR/ABL activity by imatinib, GM-CSF can compensate to maintain cell viability and proliferation. These findings have implications for optimizing imatinib therapy by manipulating cytokine signaling.
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