Combined or Sequential Treatment with Immune Checkpoint Inhibitors and Car-T Cell Therapies for the Management of Haematological Malignancies: A Systematic Review.

The aim of this paper was to review the available evidence on the efficacy and safety of combined or sequential use of PD-1/PD-L1 immune checkpoint inhibitors (ICI) and CAR-T cell therapies in relapsed/refractory (R/R) haematological malignancies. A systematic literature review was performed until 21 November 2022. Inclusion criteria: cohort studies/clinical trials aimed at evaluating the efficacy and/or safety of the combination of CAR-T cell therapy with PD-1/PD-L1 inhibitors in R/R haematological malignancies, which had reported results. Those focusing only on ICI or CAR-T separately or evaluating the combination in other non-hematological solid tumours were excluded. We used a specific checklist for quality assessment of the studies, and then we extracted data on efficacy or efficiency and safety. A total of 1867 articles were identified, and 9 articles were finally included (early phase studies, with small samples of patients and acceptable quality). The main pathologies were B-cell acute lymphoblastic leukaemia (B-ALL) and B-cell non-Hodgkin's lymphoma (B-NHL). The most studied combination was tisagenlecleucel with pembrolizumab. In terms of efficacy, there is great variability: the combination could be a promising option in B-ALL, with modest data, and in B-NHL, although hopeful responses were received, the combination does not appear better than CAR-T cell monotherapy. The safety profile could be considered comparable to that described for CAR-T cell monotherapy.

Subgroup analysis in haematologic malignancies phase III clinical trials: A systematic review.

AIMS: To assess the appropriateness of the use and interpretation of subgroup analysis in haematology randomized clinical trials (RCTs). METHOD: A systematic review of Medline, including haematology phase III RCTs published between January 2013 and October 2019, was carried out to identify reported subgroup analysis. Information related to trial characteristics, subgroup analysis and claims of subgroup difference were collected. RESULTS: The initial search identified 1622 studies. A total of 98 studies reporting subgroup analyses were identified. Of those, 24 RCT reported 46 claims of subgroup difference. Among them, 44 were claims for the primary outcome, of which 25 were considered strong claims and 17 were considered suggestions of a possible effect. Authors included subgroup variables for the primary outcome measured at baseline for 38 claims (n = 86.36%), used a subgroup variable as a stratification factor at randomization for 15 (34.09%), clearly prespecified their hypothesis for 11 (25%), the subgroup effect was one of a small number of hypothesised effects tested (≤ 5) for 17 (38.64%), carried out a test of interaction that provide statistically significant for 18 (40.91%), documented replication of a subgroup effect with previously related studies for 11 (25%), identified the consistency of a subgroup effect across related outcome for 10 (22.72%) and provided a biological rationale for the effect for 8 (18.18%). Of the 44 claims for the primary outcome, 34 (77.27%) met four or fewer of the 10 credibility criteria. CONCLUSION: The subgroup claims reported in haematology RCTs lack credibility, even when the claims are strong. Information about subgroup difference should be interpreted cautiously.

Pharmacotherapeutic management of advanced therapy drugs.

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.

Influence of Performance Status on the Effectiveness of Pembrolizumab Monotherapy in First-Line for Advanced Non-Small-Cell Lung Cancer: Results in a Real-World Population.

The KEYNOTE-024 clinical trial showed promising results for pembrolizumab in the first-line of treatment of advanced non-small-cell lung cancer (NSCLC). However, the profile of patients in real-world practice differs from those included in this clinical trial. Here, an observational single-center retrospective study was performed through a comparative analysis of clinical outcomes after pembrolizumab therapy according to the Eastern Cooperative Oncology Group Stage Performance Status (ECOG PS). Moreover, univariate and multivariate analyses were carried out to detect prognostic factors. In our cohort, 63.7% of patients had an ECOG PS of 0-1. Regarding response rate, 31.8% of patients had a partial response (PR), 19.3% had stable disease (SD) and 23.9% had progression disease. On the other hand, patients with ECOG PS ≥ 2 showed a significantly lower rate of PR and SD to pembrolizumab than patients with a PS of 0-1. The rate of response, median overall survival (OS) and progression-free survival (PFS) were significantly higher in patients with ECOG PS 0-1 than in those with ECOG PS ≥ 2. In the current study, we found ECOG PS as the only independent predictor of OS and PFS. Due to the ECOG PS scale being a subjective parameter, other tools are needed to identify treatment effectiveness to each patient.

Effectiveness and safety of pemetrexed for non-small cell lung cancer in the Andalusian Public Health System.

OBJECTIVE: To evaluate effectiveness and safety profile of pemetrexed in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) when it´s used on real clinical practice in Andalusia (a Spanish region with 8.5 million inhabitants, 2014 census data). METHODS: An observational multicentre retrospective study was conducted. Adult patients with locally advanced/metastatic NSCLC who received pemetrexed in any hospital in the Andalusian Public Health System during the last term of 2011 were included. We collected patients´ baseline characteristics, diagnostic and treatment data, effectiveness variables (response to treatment with pemetrexed and overallsurvival) and main adverse reactions detected. RESULTS: 172 patients from 17 hospitals were included (77.33% were men), median age 63 years old (between 34 and 83). The predominant histology was adenocarcinoma (84.30%) and 85.20% were diagnosed of lung cancer with IV-stage. 78.49% had been smokers at some point in their lives. Median overall survival from the start of pemetrexed was 9 months (95%CI, 4.1-13.9). Progression of the disease was the most frequent response (33.14%), only one patient had complete response. Stable disease was associated with a higher probability of survival. Main adverse reactions detected were asthenia, haematological reactions, gastrointestinal reactions and dermal o mucous toxicity. No patients discontinued treatment for serious toxicity. CONCLUSIONS: Pemetrexed resulted quite effective in NSCLC when it was used on real clinical practice, with higher survival in non-squamous histology and patients with the best score of Eastern Cooperative Oncology Group scale. The toxicity profile was well tolerated. Prospective studies would be needed to confirm the effect of prognostic factors observed.

Objetivo: Evaluar la efectividad y el perfil de seguridad del pemetrexed en pacientes con cáncer de pulmón no microcítico (CPNM) localmente avanzado o metastásico en la práctica clínica real en Andalucía (una región española con 8,5 millones de habitantes según los datos del censo de 2014). Métodos: Se realizó un estudio retrospectivo multicéntrico observacional, incluyendo aquellos pacientes adultos con CPNM localmente avanzado/metastásico que hubiesen recibido pemetrexed en cualquier hospital del Sistema Sanitario Público de Andalucía durante el último trimestre de 2011. Se revisaron las características basales de los pacientes, los datos relativos al diagnóstico y al tratamiento, las variables de efectividad (en términos de respuesta al tratamiento con pemetrexed y supervivencia global) y las principales reacciones adversas detectadas. Resultados: Se incluyeron un total de 172 pacientes procedentes de 17 hospitales (77,33% hombres), con una mediana de edad de 63 años (rango: 34 y 83). La histología predominante fue el adenocarcinoma (84,30%) y el 85,20% fueron diagnosticados de cáncer de pulmón en estadio IV. El 78,49% habían sido fumadores en algún momento de sus vidas. La mediana de supervivencia global desde el inicio del pemetrexed fue de 9 meses (IC del 95%, 4,1-13,9). La progresión de la enfermedad fue la respuesta al tratamiento más frecuente (33,14%) y solo un paciente tuvo una respuesta completa. La presencia de enfermedad estable se asoció con una mayor probabilidad de supervivencia. Las principales reacciones adversas detectadas fueron astenia; reacciones hematológicas, gastrointestinales y dermatológicas o toxicidad mucosa. Ninguno de los pacientes interrumpió el tratamiento por toxicidad grave. Conclusiones: El pemetrexed resultó bastante efectivo en el CPNM cuando fue utilizado en la práctica clínica real, con una mayor supervivencia en histología no escamosa y en los pacientes con mejor puntuación en la escala Eastern Cooperative Oncology Group. El perfil de toxicidad fue bien tolerado. Serían necesarios estudios prospectivos para confirmar el efecto de los factores pronósticos observados.

Nadolol for the treatment of infantile hemangioma.

PURPOSE: The successful use of nadolol as an alternative to propranolol therapy in three cases of infantile hemangioma is reported. SUMMARY: Infantile hemangioma is a benign vascular neoplastic disorder that affects up to 10% of newborns and can lead to deformity or local complications in severe cases. Propranolol, administered alone or in combination with corticosteroids, is increasingly used to treat infantile hemangioma, but its ability to cross the blood-brain barrier and potentially cause central nervous system adverse effects has prompted research on alternative ß-blocker therapies for the disorder that have more favorable safety profiles, including nadolol. This article describes the use of nadolol to treat three pediatric patients with a buccal or genital hemangioma who developed adverse reactions (mainly, irritability and sleep disturbances) or resistance to initial treatment with propranolol. The patients were 10 months, 12 months, and 4 years of age, respectively, when hemangioma treatment was initiated. The results of nadolol therapy were favorable, with involution of lesions and gradual disappearance of propranolol-associated adverse effects occurring in all three cases. As with any use of ß-blocker therapy in a pediatric patient, a cardiac workup is advised before the start of nadolol therapy; blood pressure and heart rate monitoring should be performed at one and two hours after the first dose and continued during dose escalation. CONCLUSION: Nadolol was an effective alternative to propranolol in three pediatric patients with hemangiomas.

Use of pemetrexed for non-small cell lung cancer in the Andalusian public health system.

The aim of this study is to determine the profile of the use of pemetrexed in metastatic or locally advanced NSCLC in Andalusia and its variation over 2 years (2010-2011). A prescription-indication observational retrospective multicenter study was conducted. Adult patients with locally advanced/metastatic NSCLC who received pemetrexed in any hospital in the Andalusian Public Health System during the first term of 2010 or the last term of 2011 were included. We collected patients' baseline characteristics, tumour histology and stage, pemetrexed indication and performance status at the start of treatment. In all, 107 and 170 patients (62 ± 11 years old) from 17 hospitals were included in 2010 and 2011, respectively. The predominant histology was adenocarcinoma (85%), 88% of patients had stage IV tumours and 52% Eastern Cooperative Oncology Group stage (ECOG) 1. Pemetrexed indications in 2010 and 2011 were: First line combined with platinum (28.97-37.64%); first line combined with platinum and maintenance with pemetrexed (24.30-28.82%); second line mono-therapy (12.15-7.65%) and maintenance (2.15-7.05%). Off-label use was detected in 22.43% (2010) and 18.84% (2011). In conclusion, pemetrexed combined with platinum is mainly used as first-line treatment in NSCLC patients with stage IV, adenocarcinoma histologic subtype and good performance status. Off-label use is high (especially in 2010). An adequate therapeutic positioning for pemetrexed based on effectiveness and safety analysis should be defined, so that NSCLC patients could be beneficiated with the most cost-effective chemotherapy treatment.

Systematic review of efficacy and safety of pemetrexed in non-small-cell-lung cancer.

INTRODUCTION: Lung cancer accounts for 20 % of cancer deaths in Spain. The most frequent subtype (87 %) is non-small cell lung cancer (NSCLC). Pemetrexed is a recently marketed drug added to NSCLC therapeutic arsenal. It seems to have become one of the most used options for the treatment of this condition over the last 3 years. AIM OF THE REVIEW: To evaluate the efficacy and safety of pemetrexed in NSCLC, in the different therapy lines. Method A systematic search of published literature was conducted using the main databases (MEDLINE, EMBASE, the Cochrane Library and the Center for Reviews and Dissemination) and subsequently a search of referenced literature was performed. We included clinical trials, meta-analyses and systematic reviews. The evaluation of the quality of the articles was performed by pairs using specific assessment scales, Critical Appraisal Skills Program (CASP) adapted for CASP Spain. Then we extracted data on efficacy and safety according to the treatment line assessed. RESULTS: We identified 277 references. Finally, nine clinical trials and a meta-analysis complied with inclusion criteria. In first-line induction, treatment with pemetrexed associated with a platinum was similar in terms of efficacy to other alternative chemotherapy regimens, except in patients with non-squamous histology, in whom survival was higher in the experimental group. In maintenance treatment, greater efficacy was seen with pemetrexed in patients with non-squamous histology. In second-line treatment, there were no significant differences in terms of efficacy and safety for pemetrexed treatment versus other chemotherapy options. The most frequent adverse reactions were: hematological, gastrointestinal and neurological. All were significantly less frequent with pemetrexed versus other alternative therapies, except for liver toxicity. CONCLUSIONS: Due to the high degree of uncertainty as to its efficacy in certain subgroups of patients, including conflicting data; to its recent incorporation, and therefore lack of safety data in the medium and long term, and the high budgetary impact of its incorporation into health systems, it seems reasonable to optimize its use, identifying those patients who may benefit most.

[Out-patient determination of glycosylated haemoglobin in the monitoring and control of diabetes mellitus: systematic review of the literature]. / Determinación ambulatoria de glucohemoglobina en el seguimiento y el control de la diabetes mellitus: revisión sistemática de la literatura.

OBJECTIVE: To compare out-patient determination of HbA(1c) with lab figures, by measuring metabolic control, quality of life and hypoglycaemia episodes, in adults with type-1 or -2 diabetes mellitus. DESIGN: Systematic review. DATA SOURCES: MEDLINE (1966-August 2006), EMBASE (2000-August 2006), bases held by the Center for Reviews and Dissemination (DARE, INAHTA, NHS-EED), Cochrane Library (number 3, 2006), European Medication Agency, Food and Drug Administration and the European Network of Emerging Technologies. A manual search was made in Point of Care and in the register of trials, (ClinicalTrials.gov). METHODS: Inclusion criteria were studies with type-1 or -2 diabetics who used portable out-patient devices and with comparison with lab references. Studies of minors, of any other kind of diabetes, of patients without a portable device and where the comparator did not include reference methods were excluded. Those that a priori met the criteria were recovered fully. A quality analysis was run according to the CASPe programme criteria and data were extracted with specific formulae. As meta-analysis was not possible, a qualitative synthesis was made. RESULTS: Twenty publications were selected. The values of most devices correlated well (R(2)=0.85 and R(2)=0.059; P< .001). Some studies described increase in glycaemia control, with drop in HbA(1c) of 0.1%-1.5% (P< .01); therapy control was more intense (95% CI, 0.95-1.52) and visits to the doctor decreased. CONCLUSIONS: Out-patient evaluations are rapid and comfortable, increasing patients' metabolic control. However, they possess certain limitations.