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The huge development that Advanced Therapy Medicinal Products (AMTPs) have experienced in recent years, both commercial and research, represent a challenge for Hospital Pharmacy at all levels. The aim of this article is to describe the implementation of an Advanced Therapies Unit (AUT) and the process of preparation of the AMTPs according to the "good manufacturing practices" (GMP), as well as the results obtained in a tertiary hospital, as an example of the challenges posed by MTA's academic production. The AUT meets the requirements established in the GMP by guaranteeing that the medicines produced therein are of the quality required for the use for which they are intended, and also provides support to various research groups involved in the development of AMTPs. The AUT is composed of a highly qualified multidisciplinary team, qualified and trained in GMP, and is authorized for the preparation of five types of AMTPs consisting of allogeneic virus-specific T cells (VST) with various viral specificities. A circuit has been established in collaboration between the UTA and the Pharmacy Service with the Hematology Service for the assessment of the clinical indication, the request and preparation of VST, which allows the treatment of patients receiving hematopoietic stem cell transplants who present viral reactivations resistant or refractory to standard treatment, or who cannot tolerate it due to toxicity. Preliminary results from these AMTPs suggest that VSTs are an effective and safe alternative. Academic AMTPs have special interest in orphan indications or in the absence of alternative treatments, and their production through the "hospital exemption" can favor early access in the initial phases of development and at a lower cost. It is essential to promote the training of hospital pharmacists in GMP and their participation in collaboration with other clinicians and researchers to develop AMTPs that meet all logistical and regulatory requirements.
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Serviço de Farmácia Hospitalar , Humanos , Serviço de Farmácia Hospitalar/organização & administração , Terapias em EstudoRESUMO
The huge development that advanced therapy medicinal products (AMTPs) have experienced in recent years, both commercial and research, represent a challenge for hospital pharmacy at all levels. The aim of this article is to describe the implementation of an advanced therapies unit (AUT) and the process of preparation of the AMTPs according to the "good manufacturing practices" (GMP), as well as the results obtained in a tertiary hospital, as an example of the challenges posed by MTA's academic production. The AUT meets the requirements established in the GMP by guaranteeing that the medicines produced therein are of the quality required for the use for which they are intended, and also provides support to various research groups involved in the development of AMTPs. The AUT is composed of a highly qualified multidisciplinary team, qualified and trained in GMP, and is authorized for the preparation of 5 types of AMTPs consisting of allogeneic virus-specific T cells (VST) with various viral specificities. A circuit has been established in collaboration between the UTA and the pharmacy service with the hematology service for the assessment of the clinical indication, the request, and preparation of VST, which allows the treatment of patients receiving hematopoietic stem cell transplants who present viral reactivations resistant or refractory to standard treatment, or who cannot tolerate it due to toxicity. Preliminary results from these AMTPs suggest that VSTs are an effective and safe alternative. Academic AMTPs have special interest in orphan indications or in the absence of alternative treatments, and their production through the "hospital exemption" can favor early access in the initial phases of development and at a lower cost. It is essential to promote the training of hospital pharmacists in GMP and their participation in collaboration with other clinicians and researchers to develop AMTPs that meet all logistical and regulatory requirements.
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Serviço de Farmácia Hospitalar , Humanos , Serviço de Farmácia Hospitalar/organização & administração , Terapias em EstudoRESUMO
INTRODUCTION: Activity wristbands have been shown to be effective in relation to self-monitoring activity levels and increasing exercise adherence. However, previous reports have been based on short-term follow-ups in people with haemophilia (PWH). AIM: (1) To evaluate compliance with physical activity (PA) recommendations in PWH during a 1-year follow-up period using activity wristbands to record daily steps and intensity; (2) To determine the effect of PA self-monitoring on clinical outcomes. METHODS: A prospective observational study was conducted in 27 adults with severe haemophilia undergoing prophylactic treatment. The Fitbit Charge HR was used to track daily PA for an entire year. The participants were encouraged to try to reach a goal of 10,000 steps/day and to track their progress. The pre- and post-evaluation included quality of life (A36 Hemophilia-QoL Questionnaire), joint health (Haemophilia Joint Health Score), functionality (Timed Up and Go test), and muscle strength. RESULTS: A total of 323.63 (95%CI: 194-364) valid days (i.e., > 2000 steps) were recorded. The annual average number of steps per day taken by participants was 10,379. Sixteen (59%) PWH reached 10,000 steps/day at baseline and 17 (63%) at 1 year follow-up, with no significant differences (x2 = .33; p = .56). A statistically significant improvement was observed in daily moderate activity time (p = .012) and in the 'physical health' quality of life subscale (mean difference: 2.15 points; 95%CI: .64-3.65; p = .007). CONCLUSION: Our results suggest that patients with severe haemophilia who self-managed their PA can improve their long-term quality of life in the domain of physical health and also the daily time spent in moderate-intensity PA.
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Exercício Físico , Hemofilia A , Qualidade de Vida , Humanos , Hemofilia A/terapia , Estudos Prospectivos , Adulto , Masculino , Seguimentos , Feminino , Adulto Jovem , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
The incidence of cardiac morbimortality in acute myeloid leukemia (AML) is not well known. We aim to estimate the cumulative incidence (CI) of cardiac events in AML patients and to identify risk factors for their occurrence. Among 571 newly diagnosed AML patients, 26 (4.6%) developed fatal cardiac events, and among 525 treated patients, 19 (3.6%) experienced fatal cardiac events (CI: 2% at 6 months; 6.7% at 9 years). Prior heart disease was associated with the development of fatal cardiac events (hazard ratio (HR) = 6.9). The CI of non-fatal cardiac events was 43.7% at 6 months and 56.9% at 9 years. Age ≥ 65 (HR = 2.2), relevant cardiac antecedents (HR = 1.4), and non-intensive chemotherapy (HR = 1.8) were associated with non-fatal cardiac events. The 9-year CI of grade 1-2 QTcF prolongation was 11.2%, grade 3 was 2.7%, and no patient had grade 4-5 events. The 9-year CI of grade 1-2 cardiac failure was 1.3%, grade 3-4 was 15%, and grade 5 was 2.1%; of grade 1-2, arrhythmia was 1.9%, grade 3-4 was 9.1%, and grade 5 was 1%. Among 285 intensive therapy patients, median overall survival decreased in those experiencing grade 3-4 cardiac events (p < 0.001). We observed a high incidence of cardiac toxicity associated with significant mortality in AML.
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INTRODUCTION: FLT3 inhibitors (FLT3i) are drugs in which there is limited experience and not yet enough information on the mechanisms of absorption, transport, and elimination; but especially on the potential drug-drug interactions (DDIs). There are therefore risks in the management of FLT3i DDIs (i.e. sorafenib, ponatinib, crenolanib, midostaurin, quizartinib, and gilteritinib) and ignoring them can compromise therapeutic success in acute myeloid leukemia (AML) treatment, in complex patients and secondary pathologies. AREAS COVERED: This review summarizes the DDIs of FLT3i with P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting (OAT), organic cationic transporting (OCT), cytochrome P450 (CYP) subunits, and other minor metabolic/transport pathways. EMBASE, PubMed, the Cochrane Central Register and the Web of Science were searched. The last literature search was performed on the 14 February 2022. EXPERT OPINION: FLT3i will be combined with other therapeutic agents (supportive care, doublet, or triplet therapy) and in different clinical settings, which means a greater chance of controlling and even eradicating the disease effectively, but also an increased risk to patients due to potential DDIs. Healthcare professionals should be aware of the potential interactions that may occur and be vigilant in monitoring those patients who are receiving any potentially interacting drug.
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Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Antineoplásicos/efeitos adversos , Proteínas de Neoplasias/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Interações Medicamentosas , Leucemia Mieloide Aguda/tratamento farmacológico , Tirosina Quinase 3 Semelhante a fms , MutaçãoRESUMO
Advanced therapy drugs have emerged in recent years as new pharmacotherapeutic strategies. In this context, hospital pharmacy services have had to adapt to the new challenges posed by the inclusion of advanced therapies in their roster of services against the background of the complex pharmacotherapeutic process patients typically go through.All the activities carried out in the hospital pharmacy services must abide by the rules established in the Spanish legislation and ensure both the quality of the different drugs they manage and the safety of every single patient.Advanced therapy drugs are associated certain peculiarities, including the need to select and evaluate potential candidates to receive them; recourse to financing mechanisms based on risk sharing; and their extreme fragility, which means that the personnel in charge of handling them must be properly trained to maintain their viability and that special storage conditions, involving temperatures below 180 ºC in the case of chimeric antigen receptor T cell therapies, must be maintained. In addition, use of advanced therapy medications in the clinical setting has made it necessary for scientific societies to produce consensus documents recognizing the pivotal role of hospital pharmacists as indispensable members of the multidisciplinary healthcare team and ensuring the same traceability, conservation, custody and pharmacotherapeutical monitoring standards imposed on other drugs to provide for adequate pharmaceutical care. Scientific societies have also highlighted the importance of intensifying clinical research, an essential requirement for the safe incorporation of new therapeutic targets. The present document is intended to describe the challenges pharmacists may face when using advanced therapy drugs at the different stages or processes in the patient's clinical journey.
Los medicamentos de terapia avanzada han emergido en los últimos años como nuevas estrategias farmacoterapéuticas. En este contexto, los servicios de farmacia hospitalaria nos hemos tenido que adaptar al nuevo reto que ha supuesto su inclusión en nuestra cartera de servicios dentro del complejo proceso farmacoterapéutico en el que están inmersos los pacientes. Todas las actividades que se desarrollan en los servicios de farmacia hospitalaria cumplen con una base legal establecida en nuestra legislación y garantizan la calidad y seguridad tanto de los pacientes atendidos como de todos y cada uno de los medicamentos que se gestionan. Los medicamentos de terapia avanzada tienen unas características especiales a considerar que van desde las fases iniciales de selección y evaluación de los pacientes candidatos y su modelo de financiación, basado en riesgo compartido, hasta una fragilidad en su manipulación que requiere de una adecuada y adaptada formación del personal implicado en la logística para mantener su viabilidad, al necesitar unas condiciones de conservación, en ocasiones, a temperaturas de menos 180 ºC, en el caso de las células T con receptores quiméricos de antígenos. Además, la utilización clínica de los medicamentos de terapia avanzada ha necesitado de documentos de consenso de las sociedades científicas que pongan en valor el posicionamiento del farmacéutico hospitalario, como miembro indispensable dentro del equipo multidisciplinar asistencial, y que garanticen, como en cualquier otro medicamento, la trazabilidad, la correcta conservación y custodia y el seguimiento farmacoterapéutico asociado a una adecuada atención farmacéutica de nuestros pacientes, sin olvidar la importancia de la creciente investigación clínica, necesaria e imprescindible para una incorporación segura de nuevas dianas terapéuticas. Por todo ello, consideramos necesario el presente documento, en donde se ponen de manifiesto los retos o necesidades, desde el punto de vista farmacéutico, en cada una de las etapas o procesos a considerar en la utilización de los medicamentos de terapia avanzada dentro de nuestro amplio arsenal terapéutico.
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Antineoplásicos , Serviço de Farmácia Hospitalar , Consenso , Humanos , Conduta do Tratamento Medicamentoso , FarmacêuticosRESUMO
Antineoplastic uptake by blast cells in acute myeloid leukemia (AML) could be influenced by influx and efflux transporters, especially solute carriers (SLCs) and ATP-binding cassette family (ABC) pumps. Genetic variability in SLC and ABC could produce interindividual differences in clinical outcomes. A systematic review was performed to evaluate the influence of SLC and ABC polymorphisms and their combinations on efficacy and safety in AML cohorts. Anthracycline intake was especially influenced by SLCO1B1 polymorphisms, associated with lower hepatic uptake, showing higher survival rates and toxicity in AML studies. The variant alleles of ABCB1 were related to anthracycline intracellular accumulation, increasing complete remission, survival and toxicity. Similar findings have been suggested with ABCC1 and ABCG2 polymorphisms. Polymorphisms of SLC29A1, responsible for cytarabine uptake, demonstrated significant associations with survival and response in Asian populations. Promising results were observed with SLC and ABC combinations regarding anthracycline toxicities. Knowledge of the role of transporter pharmacogenetics could explain the differences observed in drug disposition in the blast. Further studies including novel targeted therapies should be performed to determine the influence of genetic variability to individualize chemotherapy schemes.
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BACKGROUND: Information regarding the impact on healthcare systems of secondary acute myeloid leukemia (sAML) is scarce. METHODS: A retrospective review of medical charts identified patients aged 60-75 years with sAML between 2010 and 2019. Patient information was collected from diagnosis to death or last follow-up. Outpatient resource use, reimbursement, frequency and duration of hospitalization, and transfusion burden were assessed. Forty-six patients with a median age of 64 years were included. Anthracycline plus cytarabine regimens were the most common induction treatment (39 patients, 85%). The ratio of the total days hospitalized between the total follow-up was 29%, with a sum of 204 hospitalizations (average four/patient; average duration 21 days). The total average reimbursement was EUR 90,008 per patient, with the majority (EUR 77,827) related to hospital admissions (EUR 17,403/hospitalization). Most hospitalizations (163, mean 22 days) occurred in the period before the first allogeneic hematopoietic stem cell transplant (alloHSCT), costing EUR 59,698 per patient and EUR 15,857 per hospitalization. The period after alloHSCT (in only 10 patients) had 41 hospitalizations (mean 21 days), and a mean reimbursement cost of EUR 99,542 per patient and EUR 24,278 per hospitalization. In conclusion, there is a high consumption of economic and healthcare resources in elderly patients with sAML receiving active treatments in Spain.
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INTRODUCTION: The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with Acute Myeloid Leukemia (AML). Midostaurin, quizartinib, and gilteritinib have been approved in the last years for the treatment of AML, and more Tyrosine Kinase Inhibitors (TKIs) targeting FLT3 are being developed such as crenolanib. AREAS COVERED: In this systematic review, we will analyze the available clinical data on FLT3 inhibitors in development and describe the potential role that these FLT3-TKIs may play in the future management of FLT3-mutated (FLT3mut) AML. EXPERT OPINION: Although several aspects may challenge the use of FLT3 inhibitors in AML (resistance mechanisms, on- and off-target toxicities or drug-drug interactions), these drugs are generally well tolerated, particularly if we compare their safety profile with classical chemotherapy agents or even with newer immunotherapies, thus enabling their use in fit and unfit AML patients, alone or combined. As AML is a polyclonal disease and FLT3 mutations are a late leukemogenic event, combinations of these FLT3 inhibitors with other antileukemic agents (like venetoclax or hypomethylating agents) seem a necessary research pathway.
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Antineoplásicos , Leucemia Mieloide Aguda , Antineoplásicos/efeitos adversos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/uso terapêuticoRESUMO
Acquired thrombocytopenic thrombotic purpura (aTTP) is an autoantibody-mediated disease against the enzyme A Disintegrin and Metalloprotease domain with ThromboSpondin-1 type motif 13, which until now has been treated with plasma exchange (PEX) and corticosteroids. A 29-year-old female patient, who presented with aTTP in the context of pregnancy, has developed multiple relapses after treatment with PEX, corticosteroids, and rituximab. Recently, caplacizumab, a nanobody against von Willebrand factor, has been approved for the treatment of aTTP. In our patient, caplacizumab achieved better disease control, with a lower platelet count restoration time, days of PEX and hospitalization duration, as compared to standard therapy, reproducing the results of clinical trials. Caplacizumab represents a significant advance in the treatment of aTTP, especially in cases of recurrent relapses.
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Troca Plasmática , Complicações Hematológicas na Gravidez/terapia , Púrpura Trombocitopênica Trombótica/terapia , Anticorpos de Domínio Único/administração & dosagem , Adulto , Feminino , Humanos , Gravidez , Complicações Hematológicas na Gravidez/sangue , Púrpura Trombocitopênica Trombótica/sangueRESUMO
OBJECTIVES: To analyse the effectiveness and safety of baricitinib for severe COVID-19 in cytokine storm syndrome based on its potential role as an anti-inflammatory immunomodulator and inhibitor of viral endocytosis. METHODS: This was an observational retrospective study of hospitalised patients treated with baricitinib for severe COVID-19. Outcomes were clinical improvement on an ordinal scale of 1-8 on day 1 of baricitinib compared with day 14 (where 8=death and 1=not hospitalised with no limitations of activities), overall survival, time to recovery since baricitinib treatment started (days until hospital discharge) and laboratory parameters related to COVID-19 poor prognosis. Adverse events related to baricitinib during the admission period were also reported. RESULTS: Forty-three patients (70% men, mean age 70 years (IQR 54-79)) treated with baricitinib daily for 6 days (IQR 5-7) were included. Thirty-six patients were treated with corticosteroids (84%). Clinical improvement was 3 points (IQR 1-4) in patients on an ordinal scale of 4-6, overall survival was 100% at day 30 and day 60 with a mean time to recovery of 12 days (IQR 9-25) from start of baricitinib treatment. No adverse events of interest were found and all poor prognosis risk factors improved at day 14: interleukin-6, C-reactive protein, ferritin, lymphocytes, platelets and D-dimers. CONCLUSIONS: Patients treated with baricitinib for severe COVID-19 showed improvements in clinical and analytical values without relevant adverse events and 100% overall survival. Clinical randomised trials are needed to confirm the clinical benefit of baricitinib.
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Tratamento Farmacológico da COVID-19 , Idoso , Azetidinas , Feminino , Humanos , Masculino , Purinas , Pirazóis , Estudos Retrospectivos , SARS-CoV-2 , SulfonamidasRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection produces higher morbidity and mortality in hematological malignancies, but evidence in acute myeloid leukemia (AML) is scarce. A multicenter observational study was conducted to determine the clinical outcomes and assess the impact of therapeutic approaches in adult AML patients with SARS-CoV-2 infection in the first wave (March-May 2020). Overall, 108 patients were included: 51.9% with active leukemia and 70.4% under therapeutic schedules for AML. Signs and symptoms of SARS-CoV-2 were present in 96.3% of patients and 82.4% received specific treatment for SARS-CoV-2. The mortality rate was 43.5% and was correlated with age, gender, active leukemia, dyspnea, severe SARS-CoV-2, intensive care measures, neutrophil count, and D-dimer levels. A protective effect was found with azithromycin, lopinavir/ritonavir, and normal liver enzyme levels. During the SARS-CoV-2 first wave, our findings suggested an increased mortality in AML in a short period. SARS-CoV-2 management could be guided by risk factors in AML patients.
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COVID-19 , Leucemia Mieloide Aguda , Adulto , Humanos , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/terapia , Lopinavir , Fatores de Risco , SARS-CoV-2RESUMO
INTRODUCTION: Individual pharmacokinetic (PK) profiling in hemophilia A (HA) helps to individualize prophylaxis using population PK models (popPK). A specific popPK model for plasma-derived factor VIII containing von-Willebrand Factor (pdFVIII/VWF) was developed. AIM: To compare standard versus PK-driven prophylaxis, using a generic or a specific popPK model for pdFVIII/VWF. MATERIALS AND METHODS: A prospective study conducted in HA patients in prophylaxis with pdFVIII/VWF (Fanhdi®) comparing three one-year study periods: (1) standard prophylaxis, (2) PK-guided prophylaxis using a generic pdFVIII popPK model which described FVIII activity irrespective of FVIII concentrate, and (3) PK-guided prophylaxis with specific pdFVIII/VWF popPK model. PK parameters analyzed were half-life, trough levels (TL) at 24, 48 and 72 h, and time to reach FVIII levels of 1, 2, 5% (T5%). Clinical outcomes were dose/kg, FVIII consumption, annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), spontaneous and traumatic bleeds. RESULTS: Of the 30 analyzed patients, 28 had severe HA and the median age was 31.2. Fifteen patient's prophylaxis doses were PK-adjusted. After the generic PK-guided prophylaxis period, younger patients showed more joint bleeds, a shorter half-life, and lower TL48, TL72 and T5%. Using the specific pdFVIII/VWF popPK model compared with standard prophylaxis, a lower spontaneous AJBR was observed in the entire cohort and in patients aged >15 years. Additionally, lower spontaneous ABR was reported in patients aged ≤15 years comparing specific and generic models. CONCLUSIONS: PK-guided prophylaxis with a specific pdFVIII/VWF popPK model allowed treatment individualization and improved bleeding control in routine clinical practice, especially in younger patients with short pdFVIII/VWF half-lives.
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Hemofilia A , Fator de von Willebrand , Adulto , Teorema de Bayes , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Humanos , Estudos ProspectivosRESUMO
We have analyzed treatment patterns and outcomes of relapsed/refractory(R/R) FLT3mut AML adult patients registered in our institutional data base between 1998 and 2018. Overall, 147 patients were evaluable: 34 from 1998 to 2009, 113 from 2010 to 2018. Salvage treatments were intensive chemotherapy (n = 25, 74%), and supportive care (n = 9, 26%) in the 1998-2009 period, and intensive chemotherapy (n = 63, 56%), hypomethylating agent (n = 7, 6%), low-dose cytarabine-based (n = 8, 7%), clinical trial (n = 16, 14%) and supportive care (n = 19, 17%) in the 2010-2018 period. Complete remission (CR) or with incomplete recovery (CRi) rate was 44%, 49% among patients treated intensively (vs 30% with non-intensive p = 0.005). Median overall survival since first R/R was 5.8 months, and 16.3 months in subjects receiving an allo-HSCT in CR/CRi after first salvage (vs 3.8 in the remaining patients p < 0.0001). Clinical outcomes of R/R FLT3mut AML remain unsatisfactory. Inclusion in clinical trials and expanding options could lead to improved outcomes.
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Leucemia Mieloide Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Indução de Remissão , Terapia de Salvação , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
BACKGROUND: This study assessed pharmacoeconomic costs associated with extracorporeal photopheresis (ECP) compared with other available second-line therapies for chronic graft-vs-host disease (cGvHD) in a tertiary Spanish institution. METHODS: Patients (≥18 years) diagnosed with steroid-refractory cGvHD were eligible. Data were collected retrospectively from index date until 1 year or relapse. Patients were distributed in two cohorts (ECP vs non-ECP), matched by age (≤ or > 40), hematopoietic stem cell transplant (HLA-identical sibling donor or other) and number of previous immunosuppressive lines (1, 2, or ≥ 3). Costs were assigned using the 2016 diagnosis-related group (DRG) system: DRG 579 (22 383) overnight stay due to major complication (ie, sepsis, pneumonia, parenteral nutrition, or respiratory failure), and DRG 875 (5154) if no major complication. The primary endpoint was healthcare resource utilization per patient. RESULTS: Forty patients (n = 20 per cohort) were included. Median age was 49, and 37.5% were female. Mean total cost per patient was 25 319 (95% CI: 17 049-33 590) across the two cohorts, with a slightly lower mean cost per ECP-treated patient (23 120) compared with the non-ECP cohort (27 519; P = .597). Twenty-seven inpatient hospitalizations occurred among ECP-treated patients, vs 33 in the non-ECP cohort. Day hospital and external consultations were more frequent in the ECP cohort. However, fewer inpatient admissions included DRG 579 compared with the non-ECP cohort (44% vs 58%). Inpatient length of stay was slightly shorter in the ECP cohort (30 vs 49 days; P = .298). CONCLUSIONS: ECP treatment may yield economic savings in Spain through resource savings and moving costs toward outpatient care.
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Doença Enxerto-Hospedeiro/tratamento farmacológico , Hospitais , Fotoferese/economia , Fotoferese/métodos , Esteroides/uso terapêutico , Adulto , Idoso , Doença Crônica , Farmacoeconomia , Feminino , Doença Enxerto-Hospedeiro/economia , Transplante de Células-Tronco Hematopoéticas/métodos , Hospitalização , Humanos , Imunossupressores , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Estudos Retrospectivos , Risco , Espanha/epidemiologia , Resultado do Tratamento , Adulto JovemRESUMO
Prognosis for relapsed or refractory (R/R) acute myeloid leukemia (AML) despite salvage therapy is dismal. This phase I dose-escalation trial assessed the safety and preliminary clinical activity of selinexor, an oral exportin-1 (XPO1) inhibitor, in combination with FLAG-Ida in younger R/R AML patients. The aim was to find the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD). Fourteen patients were included, and selinexor dosage was 60 mg (3 patients), 80 mg (3 patients), and 100 mg (7 patients) weekly. No dose-limiting toxicities were reported. Grade ≥3 non-hematologic adverse events (AEs) occurred in 78.6% of patients. Two patients were non MTD evaluable due to early death, and overall, 3 out of 14 patients (21.4%) had fatal AEs. Five out of 12 (42%) response and MTD evaluable patients achieved a complete remission (CR; n=4) or CR with incomplete hematologic recovery (CRi, n=1), and 4 patients (33%) subsequently underwent allogeneic transplantation. The median overall survival (OS) and event-free survival (EFS) were 6.0 (range 0.9-19.3) and 1.1 months (range 0.7-19.3), respectively. Using selinexor 100 mg/weekly, CR/CRi rate of 66.7%, OS 13.6 months (range, 1.6-19.3), and EFS 10.6 months (range, 0.9-19.3). At last follow-up, 3 patients were alive. Selinexor 100 mg/weekly with FLAG-Ida combination in R/R AML showed acceptable tolerability and efficacy, establishing the RP2D of this regimen in future clinical trials. ClinicalTrials.gov Identifier: NCT03661515.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hidrazinas/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Triazóis/uso terapêutico , Vidarabina/análogos & derivados , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Idarubicina/administração & dosagem , Idarubicina/efeitos adversos , Idarubicina/uso terapêutico , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Resultado do Tratamento , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/uso terapêuticoRESUMO
OBJECTIVES: Genetic variability in anthracycline metabolism could modify the response and safety of acute myeloid leukemia (AML) induction. METHODS: Polymorphisms in genes that encodes enzymes of anthracyclines metabolic pathway (CBR3: rs1056892, rs8133052, NQO1: rs1800566, NQO2: rs1143684, NOS3: rs1799983, rs2070744) were evaluated in 225 adult de novo AML patients. RESULTS: The variant CBR3 rs8133052 was associated with lower hepatotoxicity (P = 0.028). Wild-type genotype of NQO2 rs1143684 was related to higher complete remission (P = 0.014), and the variant allele with greater gastrointestinal toxicity (P = 0.024). However, the variant genotype of NQO1 rs1800566 was associated with mucositis (P = 0.018), but heterozygous genotype showed less gastrointestinal toxicity (P = 0.028) and thrombocytopenia (P = 0.009). Protective effects against nephrotoxicity and thrombocytopenia were reported with variant NOS3 rs1799983 (P = 0.006, P = 0.014), whereas carriers of NOS3 rs2070744 showed higher hepatotoxicity and thrombocytopenia (P = 0.017, P = 0.013). CONCLUSIONS: This study supports the influence of genetic variability of idarubicin metabolizing could be critical in predicting anthracycline-induced toxicities.
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Quimioterapia de Indução , Leucemia Mieloide Aguda , Adulto , Alelos , Antraciclinas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Polimorfismo GenéticoRESUMO
BACKGROUND: Information regarding impact on healthcare systems of relapsed or refractory (R/R) FLT3 mutated (FLT3mut) acute myeloid leukemia (AML) is scarce. OBJECTIVE: To assess the time and reimbursement associated with hospitalizations of patients with R/R FLT3mut AML in a tertiary Spanish hospital. METHODS: Retrospective review of medical charts identified patients aged ≥ 18 years with R/R FLT3mut AML between 1998 and 2018. Data were collected from the date of first diagnosis of R/R FLT3mut AML (index) until death or loss to follow-up. The primary end point was duration and frequency of hospitalization, use of outpatient resources and transfusion burden. Reimbursement associated with hospitalizations (including associated chemotherapy) was also assessed. RESULTS: Thirty-eight patients were eligible for inclusion. Their median age was 52 years, and 30 (79%) received intensive salvage chemotherapy; FLAG-IDA-based regimens were the most frequent (24 patients, 63%). Overall, there were 150 hospitalizations (mean 3.9/patient; mean duration 21 days). Patients spent a mean of 24% of the study period in hospital. Total mean reimbursement was 108 293 per patient; the majority (89 834) attributable to inpatient stays (22 576 /hospitalization). During chemotherapy period (prior to first alloHSCT), there were 73 hospitalizations (mean duration 22 days); mean reimbursement was 19 776 per hospitalization and 49 819 per patient. AlloHSCT (n = 16) involved 77 hospitalizations (mean duration 21 days), mean reimbursement 25 231/hospitalization and 131 515 per patient. CONCLUSION: Data from this study suggest that there is a substantial healthcare resource utilization and cost burden on R/R FLT3mut AML patients in Spain receiving active treatments.
Assuntos
Recursos em Saúde , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/genética , Mutação , Aceitação pelo Paciente de Cuidados de Saúde , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Resistencia a Medicamentos Antineoplásicos , Feminino , Custos de Cuidados de Saúde , Hospitalização , Humanos , Reembolso de Seguro de Saúde , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Masculino , Recidiva , Estudos Retrospectivos , Espanha/epidemiologia , Centros de Atenção TerciáriaRESUMO
OBJECTIVE: The rise in the development of monoclonal antibodies has brought about a revolution in the pharmacotherapy of inflammatory bowel disease (Crohn's disease and ulcerative colitis). Systematic plasma concentrations monitoring of these biological drugs in anticipation of potential clinical failures of treatment is known as proactive therapeutic drug monitoring. New pharmacogenetic analysis techniques have recently been developed that can predict response to these treatments even before they are administered. The goal of this systematic review is to analyze the potential benefits of proactive therapeutic drug monitoring and of the harmacogenetic analysis of biological drugs in inflammatory bowel disease patients in terms of clinical remission. METHOD: A systematic search was performed in the MEDLINE/Pubmed, Embase and Cochrane Library databases using the escriptors proactive drug monitoring, biological drugs, inflammatory bowel disease and pharmacogenetics. Only randomized clinical trials published between January 2015 and May 2021 were included; all articles whose main topic was not related to the topic were excluded by hand. The quality of the articles was assessed using the Jadad scale and risk of bias was assessed using the Cochrane Collaboration tool. RESULTS: After applying inclusion and exclusion criteria, seven of the 228 retrieved articles were selected for review. Almost all the studies measured the same clinical variables (Harvey-Bradshaw index for Crohn's disease and Mayo score for ulcerative colitis). Only in two of the included studies was proactive therapeutic drug monitoring superior to reactive monitoring- or no level-guided dose adjustments. No pharmacogenetic analyses were found that met the criteria defined. Conclusions: This review shows that the data supporting the use of proactive therapeutic drug monitoring in inflammatory bowel disease is limited and of low quality. Although pharmacogenetic analysis can be a useful tool for personalizing treatment, further and better designed randomized clinical trials are needed to determine the role of proactive drug monitoring strategies in clinical practice.
OBJETIVO: El auge del desarrollo de los anticuerpos monoclonales supuso una revolución en la farmacoterapia de la enfermedad inflamatoria intestinal, principalmente enfermedad de Crohn y colitis ulcerosa. La monitorización de niveles plasmáticos de estos fármacos biológicos de forma programada y anticipada a un posible fracaso clínico del tratamiento se conoce como monitorización farmacocinética proactiva. Además, recientemente se han puesto a punto nuevas técnicas para el análisis farmacogenético que pueden predecir la respuesta a estos tratamientos, incluso antes de ser administrados. El objetivo de esta revisión sistemática es analizar los posibles beneficios de la monitorización proactiva y del análisis farmacogenético de fármacos biológicos en pacientes con enfermedad inflamatoria intestinal en términos de remisión clínica.Método: Se buscó en las bases de datos Medline/PubMed, Embase y Cochrane Library con los descriptores "Proactive drug monitoring", biological drugs", "inflammatory bowel disease" y "pharmacogenetics". Se incluyeron únicamente ensayos clínicos aleatorizados publicados entre enero de 2015 y mayo de 2021, y se excluyeron las publicaciones cuyo tema principal no era el de la búsqueda. La calidad de los artículos se evaluó mediante la escala de Jadad y además se evaluaron los riesgos de sesgo por la herramienta de la Colaboración Cochrane. RESULTADOS: Tras aplicar los criterios de inclusión y exclusión, se seleccionaron para la revisión 7 de las 228 referencias recuperadas. Casi todos los estudios coincidían en las variables clínicas medidas (índice de Harvey- Bradshaw en enfermedad de Crohn e índice de Mayo en colitis ulcerosa). Sólo en dos de los estudios incluidos la monitorización proactiva era superior a la reactiva o al no realizar ajustes de dosis guiados por niveles. No se encontraron ensayos clínicos con los criterios de búsqueda definidos acerca del análisis farmacogenético. CONCLUSIONES: Esta revisión muestra que los datos que apoyan el uso de la monitorización farmacocinética proactiva en enfermedad inflamatoria intestinal son limitados y de baja calidad. El análisis armacogenético puede ser una herramienta útil para ofrecer a los pacientes el tratamiento más personalizado, pero son necesarios más ensayos clínicos aleatorizados con mejor diseño para determinar el lugar de estas estrategias en la práctica clínica.
Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Monitoramento de Medicamentos/métodos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Testes FarmacogenômicosRESUMO
OBJECTIVE: The management of surgeries in patients with hemophilia is complex and requires adequate clotting factor adjustment to avoid bleeding complications and excessive factor consumption. The aim of this systematic review is to analyze the pharmacokinetic studies published on surgery in hemophilic patients, the methodologies used, the main pharmacokinetic covariates applied, and the recommendations made by clinical guidelines. METHOD: A structured search was performed in Pubmed, the Cochrane Library, and the Database of Abstracts of Reviews of Effects using the search terms hemophilia (or haemophilia), surgery and pharmacokinetics (or PK). No date or language limits were established. Results: The search yielded 186 results, from which 34 articles were selected. Many of these analyzed the use of continuous infusions with the aim of achieving stable factor VIII or IX levels and reducing overall factor consumption. However, continuous infusions have fallen into disuse. For decades, clinical guidelines have recommended the performance of comprehensive pharmacokinetic studies prior to surgery (9-11 samples). The clearance rate obtained is used to adjust the presurgical factor dose (or the infusion rate in case of continuous perfusion). Another approach is the use of population pharmacokinetic models, which allow adjustments to be made based on a more limited number of samples. However, the validity of these presurgical pharmacokinetic estimates ceases as soon as the surgical procedure is initiated, making it necessary to adjust the dose based on periodic peak and trough levels. In addition, depending on the type of surgery, clinical guidelines recommend maintaining factor VIII and IX levels above specific thresholds for certain periods of time, which makes it essential to use pharmacokinetics during the pre- and post-surgical process. In recent years, specific factor VIII and factor IX pharmacokinetic population models have been developed for surgery. The main covariates of these population pharmacokinetic models are age, blood type, and type of surgery for factor VIII; and age and body weight for factor IX. CONCLUSIONS: Pharmacokinetic estimation could allow individual and standardized intraoperative dose adjustments to be conducted in patients with hemophilia. The development of specific population pharmacokinetic models for surgery, including those based on extended half- life factors, will allow an optimization of current treatments, potentially reducing factor consumption and hospital stays.
OBJETIVO: El manejo de las cirugías en pacientes hemofílicos es complejo y requiere de un ajuste adecuado de los factores de coagulación para evitar complicaciones hemorrágicas y un consumo elevado. El objetivo de esta revisión sistemática es analizar los estudios farmacocinéticos publicados en cirugía en pacientes con hemofilia, las metodologías empleadas, las principales covariables farmacocinéticas y las recomendaciones de las guías clínicas.Método: Se ha realizado una búsqueda estructurada sin restricciones de fecha ni idioma en Pubmed, Cochrane y Database of Abstracts of Reviews of Effects empleado los mismos términos de búsqueda: (hemophilia or haemophilia), surgery y (pharmacokinetics or PK). Resultados: La búsqueda sistemática obtuvo 186 resultados, de los que seleccionamos 34 artículos. Muchos estudios analizaban el uso de erfusiones continuas con el objetivo de lograr niveles estables de factor VIII o IX y reducir el consumo global, aunque su empleo ha caído en desuso. Durante décadas las guías clínicas recomendaban realizar estudios farmacocinéticos completos previos a la cirugía (9-11 muestras), según los cuales se ajusta la dosis prequirúrgica, así como la velocidad de infusión en caso de perfusión continua basándose en el aclaramiento calculado. Otra aproximación es el empleo de modelos poblacionales farmacocinéticos, ajustando con un número más limitado de muestras. Estas estimaciones farmacocinéticas prequirúrgicas pierden validez tan pronto como se inicia un procedimiento quirúrgico, y tienen que ajustarse con niveles pico y valle periódicos. Además, las guías clínicas recomiendan, en función del populationtipo de cirugía, mantener los niveles de factores VIII y IX por encima de los umbrales específicos durante periodos, por lo que resulta fundamental emplear la farmacocinética durante el proceso pre y postquirúrgico. En los últimos años se han desarrollado modelos poblacionales farmacocinéticos de factores VIII y IX específicos para cirugía. Las principales covariables de estos modelos son la edad, el grupo sanguíneo y el tipo de cirugía para el factor VIII, y la edad y el peso corporal para el factor IX. CONCLUSIONES: La farmacocinética puede permitir ajustar de forma individual y protocolizada las cirugías en pacientes hemofílicos. El desarrollo de modelos farmacocinéticos poblacionales específicos para cirugía, incluyendo los factores de vida media extendida, permitirá optimizar estos tratamientos, con potencial reducción del consumo y las estancias hospitalarias.