Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors

Asciminib; Chronic myeloid leukemia; Drug intoleranceAsciminib; Leucèmia mieloide crònica; Intolerància als medicamentsAsciminib; Leucemia mieloide crónica; Intolerancia a los medicamentosBackground: Despite the prognostic improvements achieved with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), a minority of patients still fail TKIs. The recent introduction of asciminib may be a promising option in intolerant patients, as it is a first-in-class inhibitor with a more selective mechanism of action different from the ATP-competitive inhibition that occurs with TKIs. Therefore, our goal was to analyze toxicities shown with asciminib as well as to study cross-toxicity with previous TKIs. (2) Methods: An observational, multicenter, retrospective study was performed with data from 77 patients with CML with therapeutic failure to second-generation TKIs who received asciminib through a managed-access program (MAP) (3) Results: With a median follow-up of 13.7 months, 22 patients (28.5%) discontinued treatment: 32% (7/22) due to intolerance and 45% (10/22) due to resistance. Fifty-five percent of the patients reported adverse effects (AEs) with asciminib and eighteen percent grade 3-4. Most frequent AEs were: fatigue (18%), thrombocytopenia (17%), anemia (12%), and arthralgias (12%). None of the patients experienced cardiovascular events or occlusive arterial disease. Further, 26%, 25%, and 9% of patients required dose adjustment, temporary suspension, or definitive discontinuation of treatment, respectively. Toxicities under asciminib seemed lower than with prior TKIs for anemia, cardiovascular events, pleural/pericardial effusion, diarrhea, and edema. Cross-toxicity risk was statistically significant for thrombocytopenia, anemia, neutropenia, fatigue, vomiting, and pancreatitis. (4) Conclusion: Asciminib is a molecule with a good safety profile and with a low rate of AEs. However, despite its new mechanism of action, asciminib presents a risk of cross-toxicity with classical TKIs for some AEs

Association between Germline Single-Nucleotide Variants in ADME Genes and Major Molecular Response to Imatinib in Chronic Myeloid Leukemia Patients

Leucèmia mieloide crònica; Imatinib; Inhibidor de la tirosina quinasa:Chronic myeloid leukemia; Imatinib; Tyrosine kinase inhibitorLeucemia mieloide crónica; Imatinib; Inhibidor de la tirosina quinasaImatinib is the most common first-line tyrosine kinase inhibitor (TKI) used to treat chronic-phase chronic myeloid leukemia (CP-CML). However, only a proportion of patients achieve major molecular response (MMR), so there is a need to find biological factors that aid the selection of the optimal therapeutic strategy (imatinib vs. more potent second-generation TKIs). The aim of this retrospective study was to understand the contribution of germline single-nucleotide variants (gSNVs) in the achievement of MMR with imatinib. In particular, a discovery cohort including 45 CP-CML patients was analyzed through the DMET array, which interrogates 1936 variants in 231 genes related to the absorption, distribution, metabolism and excretion (ADME) process. Variants statistically significant in the discovery cohort were then tested in an extended and independent cohort of 137 CP-CML patients. Finally, a total of 7 gSNVs (ABCG1-rs492338, ABCB11-rs496550, ABCB11-rs497692, CYP2D6-rs1135840, CYP11B1-rs7003319, MAT1A-rs4934027 and SLC22A1-rs628031) and one haplotype in the ABCB11 gene were significantly associated with the achievement of MMR with first-line imatinibtreatment. In conclusion, we identified a genetic signature of response to imatinib in CP-CML patients that could be useful in selecting those patients that may benefit from starting imatinib as first-line therapy, therefore avoiding the toxicity related to second-generation TKIs

Real‑life analysis on safety and efcacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia

Asciminib; Inhibitors; LeukemiaAsciminib; Inhibidors; LeucèmiaAsciminib; Inhibidores; LeucemiaFailure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options

Safety and efficacy of asciminib treatment in chronic myeloid leukemia patients in real-life clinical practice

Chronic myeloid leukemia; Asciminib; TreatmentLeucemia mieloide crónica; Asciminib; TratamientoLeucèmia mieloide crònica; Asciminib; TractamentDespite the excellent overall survival (OS) of chronic myeloid leukemia (CML) patients, a significant proportion will fail currently available tyrosine-kinase inhibitors (TKIs) due to resistance or intolerance. Intolerant patients are usually managed successfully with alternative second-generation tyrosine-kinase inhibitors (2GTKIs). However, more than half of the patients will eventually discontinue second-line treatment due to loss of response or toxicity. Ponatinib is an effective drug in the setting of resistance to 2GTKIs, however with life-threatening side effects and varying responses. Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that potently and specifically inhibits BCR-ABL1 via binding to a pocket distinct from the ATP binding site of the kinase. Asciminib has the potential to overcome resistance to prior TKIs, and also offers the possibility of dual inhibition of BCR-ABL1 in combination with ATP-binding TKIs. Asciminib has been evaluated in a phase I study in patients with Ph-positive leukemia failing prior TKIs, with promising results. Our aim is to share the first data on the use of asciminib in CML patients in clinical practice, allowed by Novartis under a managed-access program (MAP)

Determinació de l’exposició a alcaloides de la pirrolizidina, alumini, aflatoxines i fitosanitaris pel consum de tes i herbes per a infusions a Catalunya: avaluació del risc per a la salut

Alcaloides de la pirrolizidina; Toxines naturals; PlantesAlcaloides de la pirrolizidina; Toxinas naturales; PlantasPyrrolizidine alkaloids; Natural toxins; FloorsEls objectius específics d’aquest estudi són els següents: Determinar i quantificar la presència d’alcaloides de la pirrolizidina, alumini, aflatoxines i fitosanitaris en els tes i les herbes per a infusions del mercat català. Estimar l’exposició dietètica de la població de Catalunya a alcaloides de la pirrolizidina, alumini, aflatoxines i fitosanitaris a través dels tes i herbes per a infusions. Avaluar el risc que representa l’exposició dietètica a aquestes substàncies derivada del consum de tes i herbes per a infusions. Determinar paràmetres microbiològics patògens i indicadors per avaluar l’estat higienicosanitari en els tes i herbes per a infusions

Predicting MPI Buffer Addresses *

Abstract. Communication latencies have been identified as one of the performance limiting factors of message passing applications in clusters of workstations/multiprocessors. On the receiver side, message-copying operations contribute to these communication latencies. Recently, prediction of MPI messages has been proposed as part of the design of a zero message-copying mechanism. Until now, prediction was only evaluated for the next message. Predicting only the next message, however, may not be enough for real implementations, since messages do not arrive in the same order as they are requested. In this paper, we explore long-term prediction of MPI messages for the design of a zero message-copying mechanism. To achieve long-term prediction we evaluate two prediction schemes, the first based on graphs, and the second based on periodicity detection. Our experiments indicate that with both prediction schemes the buffer addresses and message sizes of several future MPI messages (up to +10) can be predicted successfully.

Impact of BCR-ABL1 Transcript Type on Response, Treatment-Free Remission Rate and Survival in Chronic Myeloid Leukemia Patients Treated with Imatinib

Chronic myeloid leukemia; BCR-ABL1 transcripts; Response to imatinibLeucemia mieloide crónica; Transcripciones de BCR-ABL1; Respuesta al imatinibLeucèmia mieloide crònica; Transcripcions BCR-ABL1; Resposta a imatinibThe most frequent BCR-ABL1-p210 transcripts in chronic myeloid leukemia (CML) are e14a2 and e13a2. Imatinib (IM) is the most common first-line tyrosine–kinase inhibitor (TKI) used to treat CML. Some studies suggest that BCR-ABL1 transcript types confer different responses to IM. The objective of this study was to correlate the expression of e14a2 or e13a2 to clinical characteristics, cumulative cytogenetic and molecular responses to IM, acquisition of deep molecular response (DMR) and its duration (sDMR), progression rate (CIP), overall survival (OS), and treatment-free remission (TFR) rate. We studied 202 CML patients, 76 expressing the e13a2 and 126 the e14a2, and correlated the differential transcript expression with the above-mentioned parameters. There were no differences in the cumulative incidence of cytogenetic responses nor in the acquisition of DMR and sDMR between the two groups, but the e14a2 transcript had a positive impact on molecular response during the first 6 months, whereas the e13a2 was associated with improved long-term OS. No correlation was observed between the transcript type and TFR rate

Economic evaluation of treatments for patients with localized prostate cancer in Europe : a systematic review

We would like to thank Aurea Martin for her writing assistance, proofreading, manuscript editing and the submission preparation process. Financial support for this study was provided by Instituto de Salud Carlos III FEDER: Fondo Europeo de Desarrollo Regional (FIS PI08/90090 and PI13/00412); Agència d'Informació, Avaluació i Qualitat en Salut (AIAQS), 436/05/2008; Ministerio de Ciencia e Innovación (PTAT2011-04891); and DIUE of Generalitat de Catalunya (2014 SGR 748). The funding agreements ensure the authors' independence in designing the study, interpreting the data, and writing and publishing the report.Background: Our objective was to assess the efficiency of treatments in patients with localized prostate cancer, by synthesizing available evidence from European economic evaluations through systematic review. Methods: Articles published 2000-2015 were searched in MEDLINE, EMBASE and NHS EED (Prospero protocol CRD42015022063). Two authors independently selected studies for inclusion and extracted the data. A third reviewer resolved discrepancies. We included European economic evaluations or cost comparison studies, of any modality of surgery or radiotherapy treatments, regardless the comparator/s. Drummond's Checklist was used for quality assessment. Results: After reviewing 8,789 titles, 13 European eligible studies were included: eight cost-utility, two cost-effectiveness, one cost-minimization, and two cost-comparison analyses. Of them, five compared interventions with expectant management, four contrasted robotic with non robotic-assisted surgery, three assessed new modalities of radiotherapy, and three compared radical prostatectomy with brachytherapy. All but two studies scored ≥8 in the quality checklist. Considering scenario and comparator, three interventions were qualified as dominant strategies (active surveillance, robotic-assisted surgery and IMRT), and six were cost-effective (radical prostatectomy, robotic-assisted surgery, IMRT, proton therapy, brachytherapy, and 3DCRT). However, QALY gains in most of them were small. For interventions considered as dominant strategies, QALY gain was 0.013 for active surveillance over radical prostatectomy; and 0.007 for robotic-assisted over non-robotic techniques. The highest QALY gains were 0.57-0.86 for radical prostatectomy vs watchful waiting, and 0.72 for brachytherapy vs conventional radiotherapy. Conclusions: Currently, relevant treatment alternatives for localized prostate cancer are scarcely evaluated in Europe. Very limited available evidence supports the cost-effectiveness of radical prostatectomy over watchful waiting, brachytherapy over radical prostatectomy, and new treatment modalities over traditional procedures. Relevant disparities were detected among studies, mainly based on effectiveness. These apparently contradictory results may be reflecting the difficulty of interpreting small differences between treatments regarding QALY gains

Design and validation of a new screening instrument for lower urinary tract dysfunction: The bladder control self-assessment questionnaire (B-SAQ)

Objectives: To develop and validate a short patient self-assessment screening questionnaire: bladder control selfassessment questionnaire (B-SAQ) for the evaluation of lower urinary tract symptoms. This first validation study was undertaken amongst women. Patients and methods: Three hundred twenty-nine women attending general gynaecology and urogynaecology clinics completed both the B-SAQ and Kings Health questionnaire prior to medical consultation, and independent physician assessment of the presence of lower urinary tract symptoms (LUTS) and need for treatment. The psychometric properties of the B-SAQ were subsequently analysed. Results: The B-SAQ was quick and easy to complete, with 89% of respondents completing all items correctly in less than S min. The internal consistency (Cronbach's alpha score 0.90-0.91), criterion validity (Pearson's correlation values of 0.79 and 0.81, p < 0.0001 with the incontinence impact domain of the Kings Health questionnaire), and test-retest reliability of the questionnaire were good. The sensitivity and specificity of the questionnaire to identify patients with bothersome LUTS was 98% and 79%, respectively. Conclusions: LUTS are commonly underreported. Empowering patients to self-assess their bladder symptoms and the need for treatment will improve treatment- seeking behaviour. The B-SAQ is a psychometrically robust, short screening questionnaire that offers patients the ability to assess their bladder symptoms and the bother they cause, and the potential benefit of seeking medical help. (c) 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved

Additional file 1: of Economic evaluation of treatments for patients with localized prostate cancer in Europe: a systematic review

MEDLINE, EMBASE and NHS EED (NHS Economic Evaluation Database, CRD York) specific search strategies. (DOC 74 kb