Abstract 166
Imatinib mesylate combined to pegylated interferon alfa 2a (Peg-IFN) has been reported to significantly enhance the molecular responses for de novo chronic phase chronic myeloid leukemia ...(CP-CML) patients compared to Imatinib alone in a Phase 3 study (Preudhomme et al. NEJM 2010). Second generation tyrosine kinase inhibitors (TKI2) such as nilotinib induce significantly higher levels of cytogenetic and molecular responses than imatinib as front line therapy for CP-CML (Saglio et al., NEJM 2010).
Test the combination of nilotinib + Peg-IFN as front line therapy in CP-CML patients in order to check the safety and evaluate the molecular response rates (EudraCT 2010–019786–28).
In this 2-step French national study, patients were assigned first to Peg-IFN (± HU) for a month at 90 mg/wk prior to a combination of nilotinib 300 mg BID + Peg-IFN 45 mg/wk for ≥ 1 year. The primary endpoint was the rate of confirmed (on 2 datapoints) molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised for all patients and expressed as BCR-ABLIS in %.
In the first cohort, 40+1 patients (1 screen failure) were enrolled and a second cohort of 20 patients was planned once the last patient of cohort 1 attained 1 year of treatment, if the primary endpoint would have not been reached. The current median follow-up is 13.6 (10.1–16.3) months. Sokal and Euro scores were high for 12% and 2%, intermediate for 49% and 55% and low for 39% and 43% of the patients respectively. Euro score was high for one patient. The median age was 53 (23–85) years. Two patients had a masked Philadelphia chromosome, 3 a variant form, and 1 had additional chromosomal abnormalities, all patients had a “major” BCR transcript. Five percent of patients were in CHR at 1 month of Peg-IFN and 100% at month (M) 2 (after 1 month of combination therapy). The rates of Complete Cytogenetic Responses (CCyR) at 3, 6, and 12 months of combination (i. e. at 2, 5, 8 and 11 months of TKI2) were 47%, 71%, 100% respectively on evaluable samples. The incidence of molecular responses are mentioned in figure 1. Display omitted Of note, 87% of the patients had a BCR-ABLIS ≤10% at M3. The rates of molecular responses broke down by major molecular response (MMR): 27%, 4 log reduction (MR4): 36%, and ≥4.5 log BCR-ABL reduction (MR4.5, MR5 and undetectable): 21% with a total number of 84% patients in ≥MMR and beyond (17.5% and 67.5% in intention-to-treat respectively) at 1 year. Confirmed molecular results at 1 year will be presented. Nilotinib trough levels centrally analysed at M3, 6 and 12 for the vast majority of patients were ≥ 1000 ng/ml and Peg-IFN did not seem to impact on its pharmacokinetics. One patient went on unmutated myeloid blast crisis at M6 and is alive after allogeneic stem cell transplantation. Four additional patients were withdrawn from study: At M2 for non observance, at M6 for seizures related to an extra-dural hematoma, at M6 for recurrent grade 3 hepatic toxicity, at M9 for recurrent grade 3 pruritus. The median dose of Peg-IFN delivered to the patients during the first month was 90 (0–180) mg/wk, 45 mg/wk at M2, 3, 9, 12, and 33.75 mg/wk at M6. The median doses of nilotinib delivered to the patients were 600 mg daily at M2, 3, 6, 9, 12 and 15 as initially planned. The rate of grade 3–4 hematologic toxicities overall were anemia 2.5%, thrombocytopenia 41%, neutropenia 41% and pancytopenia 5%. These were observed mainly during M2 (16% neutropenia, 24% thrombocytopenia, 3% anemia), M3 (16% neutropenia, 13% thrombocytopenia, 3% pancytopenia) and M6 (12.5% neutropenia, 5% thrombocytopenia) and disappeared thereafter. Grade 3–4 toxicities occurred mostly during the first 3 months with 15% cholestatic episodes, 5% of ALAT elevation, 2.5% of lipase elevation, 2.5% arthro-myalgias, 2.5% abdominal pain without lipase elevation, 2.5% of depression. No PAO was observed and, to date, no dyslipidemia.
The combination of nilotinib and Peg-IFN seems relatively well tolerated despite frequent initial and transient hematologic and hepatic toxicities, and provides very high rates of molecular responses at 1 year and beyond. According to the initial methodology of this trial, the second cohort of patients will not be enrolled as the MR4.5 rates at M12 are beyond the initial expectations. A randomised phase III study testing nilotinib versus nilotinib + Peg-IFN is warranted.
Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Etienne:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy. Roy:Novartis, BMS: Speakers Bureau. Huguet:Novartis, BMS: Speakers Bureau. Legros:Novartis, BMS: Research Funding, Speakers Bureau. Giraudier:Novartis: Speakers Bureau. Coiteux:Novartis, BMS: Speakers Bureau. Guerci-Bresler:Novartis, BMS: Speakers Bureau. Rea:Novartis, BMS: Consultancy, Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Hermet:Novartis, BMS: Speakers Bureau. Rousselot:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy, Speakers Bureau. Guilhot:Novartis, Ariad, and BMS: Consultancy, Speakers Bureau. Mahon:Novartis, BMS: Consultancy, Speakers Bureau.
Nurses endure daily low-level exposure to cytotoxic drugs, which can lead to significant absorption with potential harmful consequences. New sterile medical devices called cytotoxic safe infusion ...systems (CSISs), intended by their manufacturers to improve safety and quality of cytotoxic drug infusions, have been made commercially available. CSISs from 3 manufacturers were tested in 2 cancer units and compared with standard infusion sets. The aim of this study is to evaluate the devices regarding occupational exposure, quality of the infusion, and economic aspects.
This phase I/II study was designed to demonstrate the tolerance and the efficacy of a combination of pegylated interferon- alpha 2a to Imatinib mesylate (IM) 600 mg daily in cytogenetically ...IM-resistant but in CHR chronic phase CML patients. The combination was generally well tolerated in the 15 evaluable patients. A significant reduction of the Ph1 super(+) BM metaphases was observed in these poor prognosis patients, with 2 long-term CCyR including 2 MMR. After a median follow-up of 43 months, 93% of patients are alive. The addition of PegIFN alpha 2a to IM600 is feasible, and able to overcome resistance within this context.
The interest of centralization of preparations of chemotherapy drugs is in addition to its economic aspect, to secure drugs circuit. The aims of this study are to determine needs in employees and ...equipments of 11 theoretical levels of production from 1,000 to 50,000 preparations per year and to determine the cost of chemotherapy's preparation for each theoretical unit. The operating cost was divided in four areas of expenditure: employees (66-78%), investment (5-15%), maintenance (3-15%) and consumables (4-16%). If we consider the 11 units, the theoretical cost varies between 27.4 € for a unit with 50,000 preparations per year and 114.1 € for a unit with 1,000 preparations per year. This study shows the importance of setting up an optimal unit of preparations according to its activity and highlights the high cost's variation in relation to the activity of the unit.
Abstract 3810
Despite frequent anemia and multiple transfusions during AML chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT), recommendations and marketing authorization ...for erythropoietin (EPO) use are still missing. In the current prospective study, as primary objective, we evaluated the effect of EPO on patient's quality of life (QOL). Secondary objective was hemoglobin (Hb) recovery. In addition, a paired matched analysis using similar population was conducted to compare platelets (Pt) and red blood cells (RBC) transfusion number.
We included adult patients with Hb level ≤11g/dl induced by 1, 2 or 3 consolidation chemotherapy for AML in complete remission (CR) (group 1); or by allo-HSCT for any hematological disease (group 2). EPO was administered Sc. once per week during a maximum period of 6 months: for group 1, ARANESP® 150μg; for group 2, NEORECORMON® 30000IU; Hb level was monitored every week. Injections were stopped once the Hb level reached 12g/dl without any transfusion. If after 4 injections, no improvement was observed, doses were doubled, and if after 8 injections, no improvement was observed, patient was taken off-study for EPO inefficiency. The QOL was measured at baseline, at 1, 2, 3 and 6 months by the Functional Assessment of Cancer Therapy–Anemia (FACT–An). EPO responders patients were defined as having Hb level ≥12g/dl (EPO CR) or a ≥ 2g/dl increase EPO partial response (EPO PR) compared with baseline value without any transfusion requirement. The matching analysis took into account: sex, age, disease status, for the two groups, associated to cytogenetics, type of chemotherapy, sequential chemotherapy number for group 1, and diagnosis, conditioning, HSC source, number of previous transplants and GVHD for group 2.
Between April 2006 and December 2009, among 261 screened patients, 55 were included in group1 and 61 in group 2, patient characteristics for each group are summarized in Table1. Main exclusion criteria were EPO contra-indication and patient refusal. The median number of EPO injections/patient was 13 (3 – 24) in group1 and 8 (2 - 28) in group 2. For the global population (111 evaluable patients 52 group1 and 59 in group 2), we have noticed a significant improvement of QOL during the 6 months follow-up according to FACT-An anemia (p=0.01). Despite a non-significant improvement for FACT-G, we observed a significant improvement in physical well-being (p<0.0001). There were 85 EPO CR (83% in group1 and 71% in group 2) and 3 (6%) EPO PR (only in group1). Among patients who reached the 6 months follow-up, 81% had a normal Hb level. Fourteen patients (13%) were withdrawn (6 in group1 and 8 in group 2) due to EPO inefficacy and 9 in group 2 for relapse or EPO related/unrelated serious adverse events (AEs). In group1: the median time to achieve an EPO CR was 34 days (17-67) after first consolidation and 41 days (12-67) after second consolidation (p=0.35). In group 2: the median time to achieve EPO CR was 39 days (14 - 180). After the pair-matched analysis, 44 patients in each group were matched with at least one case-control patient. When comparing RBC and Pt transfusions, there were 712 units and 751 units in the matched population versus 504 and 669 in the EPO population respectively 208 spared RBC (80 in group1, p=0.008 and 128 in group 2, p=0.004) and 100 spared Pt units (all in group1, p=0.001). The multivariate analysis studying different confounding factors on the cumulative incidence of EPO CR showed a significant positive impact of younger age (p=0.001) and intensive chemotherapy (p=0.03) in group1; and for group 2, the positive impact of Pt levels at baseline, the negative impact of female recipient and major ABO incompatibility. We did not find any significant difference in terms of overall (OS) and event free survival (EFS) between EPO and control groups.
This prospective study showed a real benefit of EPO administration on QOL, an achievement of a normal Hb level and a significant spare of RBC and Pt transfusions. Young AML patients, male allo-HSCT recipient, ABO compatible pairs seem to be the best candidates to benefit from EPO administration, with low AEs and no impact on OS or EFS. A cost-effectiveness study is ongoing and results will be communicated.
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No relevant conflicts of interest to declare.
L’aluminium est un contaminant environnemental ubiquitaire. L’objectif principal de cette étude était de quantifier l’exposition à l’aluminium des patients sous nutrition parentérale chronique. Les ...objectifs spécifiques comprenaient (i) la détermination des teneurs en aluminium des solutés commerciaux et des mélanges de nutrition parentérale (MNP) préparés au sein de notre pharmacie à usage intérieur, et (ii) l’évaluation de l’exposition quotidienne de chaque patient à l’aluminium comparée aux limites d’exposition fixées par les normes en vigueur et les recommandations internationales. La quantification en aluminium par spectrophotométrie d’absorption atomique électrothermique a été réalisée dans les solutés commerciaux (n=26) utilisés pour la préparation de MNP et dans MNP réalisés à l’hôpital (n=56) destinés à des patients (n=15) sous nutrition parentérale exclusive ou partielle présentant un état physiopathologique stabilisé. Quatorze solutés et l’ensemble des MNP présentaient des concentrations en aluminium supérieure à 25μg/L, concentration maximale fixée par la Food and Drug Administration. Deux tiers des patients présentaient des quantités d’aluminium par unité de masse corporelle significativement supérieures à 2μg.kg−1 par jour, valeur seuil recommandée par l’American Society of Parenteral and Enteral Nutrition. Les solutés commerciaux utilisés pour la préparation de MNP et les MNP présentaient des teneurs en aluminium nettement supérieures à celles recommandées par la FDA. Une monographie spécifiant les teneurs limites en aluminium dans les MNP et dans les solutés commerciaux pourrait servir de cadre à la rédaction d’une norme pharmaceutique européenne spécifique à la nutrition parentérale.
Aluminium is a well-known potentially hazardous contaminant in parenteral preparation for dialysis or drug delivery. The main objective of the study is to assess aluminium exposure from chronic parenteral nutrition supply. The specific objectives of the study were (i) to assess aluminium concentration in parenteral nutrition compounds (n=26) and in hospital-made parenteral nutrition mixture (n=56), (ii) to compare aluminium concentration in nutrition products to the maximum allowable concentration (i.e. 25μg/L), and finally (iii) to compare the daily rate infused per kilogram of weight to the limit value recommended by American Society of Parenteral and Enteral Nutrition (i.e. 2μg.kg−1 per day). Aluminium content, assessed by atomic absorption spectrophotometry, was determined in parenteral nutrition compounds and in hospital-made parenteral nutrition admixtures to clinically stable patients undergoing total or partial parenteral nutrition. Aluminium concentration in fourteen parenteral nutrition compounds and all parenteral nutrition admixtures excessed 25μg/L. Furthermore, two thirds of patients were exposed to a rate of aluminium significantly upper than that recommended by the American Society of Parenteral and Enteral Nutrition (i.e. 2μg.kg-1 per day). This study shows that parenteral nutrition compounds and parenteral nutrition admixtures were overloaded in aluminium. A monograph specifying acceptable aluminium content of parenteral nutrition products seems necessary for further redaction of European pharmaceutical norm or guidance.
Abstract This phase I/II study was designed to demonstrate the tolerance and the efficacy of a combination of pegylated interferon-α 2a to Imatinib mesylate (IM) 600 mg daily in cytogenetically ...IM-resistant but in CHR chronic phase CML patients. The combination was generally well tolerated in the 15 evaluable patients. A significant reduction of the Ph1+ BM metaphases was observed in these poor prognosis patients, with 2 long-term CCyR including 2 MMR. After a median follow-up of 43 months, 93% of patients are alive. The addition of PegIFNα2a to IM600 is feasible, and able to overcome resistance within this context.
Two types of circuits of injectable cytotoxic drugs still exist in our hospital: one with pharmaceutical centralization of the preparation and the other without. Our goal is to evaluate each circuit ...from two points of view: quality of patient care and protection of persons handling cytotoxics. For this evaluation, an original assessment was performed before and after centralization in the same pilot health care unit (two periods of 6 weeks each). To evaluate the prescription-preparation-administration process, six checklists consisting as a whole of 158 observable criteria have been constructed. These criteria have been weighted according to the risk of compromising the quality of patient care and the safety of persons. A total of 117 processes have been observed before centralization; after centralization, 91 were observed. From a qualitative viewpoint, we show that the cost of drugs stocked in the medicine chest of the health care unit has been reduced by 80%, that the flow of information between the different participants in the circuit varied, and that two types of dysfunctions exist: organizational and relational. From a quantitative viewpoint, we demonstrated that pharmaceutical intervention improves the quality of patient care (x2 test,
P
< 0.001) and reinforces the protection of manipulators (x2 test,
P
< 0.001). Pharmaceutical centralization of the preparation of cytotoxic drugs increases the efficiency of the circuit, from the prescription to administration.
Background
Accurate tomographic reconstructions require the knowledge of the actual acquisition geometry. Many mobile C‐arm CT scanners have poorly reproducible acquisition geometries and thus need ...acquisition‐specific calibration procedures. Most of geometric self‐calibration methods based on projection data either need prior information or are limited to the estimation of a low number of geometric calibration parameters. Other self‐calibration methods generally use a calibration pattern with known geometry and are hardly implementable in practice for clinical applications.
Purpose
We present a three‐step marker based self‐calibration method which does not require the prior knowledge of the calibration pattern and thus enables the use of calibration patterns with arbitrary markers positions.
Methods
The first step of the method aims at detecting the set of markers of the calibration pattern in each projection of the CT scan and is performed using the YOLO (You Only Look Once) Convolutional Neural Network. The projected marker trajectories are then estimated by a sequential projection‐wise marker association scheme based on the Linear Assignment Problem which uses Kalman filters to predict the markers 2D positions in the projections. The acquisition geometry is finally estimated from the marker trajectories using the Bundle‐adjustment algorithm.
Results
The calibration method has been tested on realistic simulated images of the ICRP (International Commission on Radiological Protection) phantom, using calibration patterns with 10 and 20 markers. The backprojection error was used to evaluate the self‐calibration method and exhibited sub‐millimeter errors. Real images of two human knees with 10 and 30 markers calibration patterns were then used to perform a qualitative evaluation of the method, which showed a remarkable artifacts reduction and bone structures visibility improvement.
Conclusions
The proposed calibration method gave promising results that pave the way to patient‐specific geometric self‐calibrations in clinics.
