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1.
Expert Rev Anticancer Ther ; 24(7): 613-622, 2024 Jul.
Article de Anglais | MEDLINE | ID: mdl-38761169

RÉSUMÉ

INTRODUCTION: This study aimed to estimate the toxicities of PARP inhibitors (PARPis), based on randomized controlled trials (RCTs) and the FDA Adverse Event Reporting System (FAERS) database. METHODS: Four electronic databases were searched from inception to 16 April 2024, for RCTs of approved PARPis. The primary and secondary outcomes were grade 3-5 adverse events (AEs) and grade 3-5 hematological AE, respectively. We conducted network meta-analyses to calculate the relative risks (RRs) and 95% confidence intervals (CIs) of outcomes. A disproportionality analysis was conducted to estimate the signals of hematological AEs associated with PARPis from the FAERS database. RESULTS: Overall, 27 RCTs involving 11,067 patients with cancer were included. Olaparib had the best safety profile for any grade 3-5 AEs and hematological AEs among four approved PARPis. Olaparib did not increase the risk of thrombocytopenia (RR: 1.48; 95%CI: 0.64-3.39), but other PARPis did. Furthermore 14,780 hematological AE reports associated with PARPis were identified in the FAERS database, and all PARPis were associated with strong hematological AE signals. Hematological AEs mainly occurred within the first 3 months (80.84%) after PARPi initiation. CONCLUSION: Olaparib had the best safety profile among five PARPis. PARPi-associated hematological AEs mainly occurred within the first 3 months. REGISTRATION: PROSPERO (CRD42022385274).


Sujet(s)
Hémopathies , Tumeurs , Pharmacovigilance , Inhibiteurs de poly(ADP-ribose) polymérases , Essais contrôlés randomisés comme sujet , Humains , Inhibiteurs de poly(ADP-ribose) polymérases/effets indésirables , Inhibiteurs de poly(ADP-ribose) polymérases/administration et posologie , Tumeurs/traitement médicamenteux , Hémopathies/induit chimiquement , Hémopathies/épidémiologie , Systèmes de signalement des effets indésirables des médicaments/statistiques et données numériques , Antinéoplasiques/effets indésirables , Antinéoplasiques/administration et posologie , Bases de données factuelles , Phtalazines , Pipérazines
2.
Cancer Chemother Pharmacol ; 94(1): 103-108, 2024 Jul.
Article de Anglais | MEDLINE | ID: mdl-38652271

RÉSUMÉ

OBJECTIVE: BRCA1/2 are integral to the DNA repair mechanism and their germline pathogenic variants (gBRCA) result in a high risk for developing breast and ovarian cancer. Patients with gBRCA mutations showed increased sensitivity to DNA cross-linking agent but might have increased treatment-related toxicities. Thus, we hypothesized that gBRCA mutation ovarian cancer patients who underwent platinum-based chemotherapy might be at higher risk of developing chemotherapy-induced hematologic toxicity. METHODS: This study enrolled 160 patients with ovarian cancer who received frontline platinum-based chemotherapy between 2011 and 2019 in Kyungpook National University Chilgok Hospital. Incidence rate and severity of chemotherapy-induced hematologic toxicity (neutropenia, anemia, thrombocytopenia) was compared for BRCA mutation and wild patients. RESULTS: 160 women, including 62 BRCA1/2 (38 BRCA1, and 25 BRCA2) mutation group, and 98 noncarriers, were analyzed. A higher frequency of G2 anemia was noted in the BRCA -mutant group (22% vs. 1%, p = 0.07). Furthermore, G3 anemia was significantly common among BRCA group (12.9% vs. 3%, p = 0.02). In the subgroup analysis according to BRCA1/2 status, BRCA1 mutated patients showed a significantly higher frequency of G1 anemia than BRCA2 (89% vs. 60%, p = 0.01). In terms of neutropenia and thrombocytopenia, BRCA mutated patients and noncarriers had similar hematologic toxicity. CONCLUSION: Germline BRCA mutations were associated with a higher frequency of G2/3 anemia in ovarian cancer patients who underwent first-line platinum-based chemotherapy. Moreover, the BRCA1 mutation appeared to be more strongly associated with the incidence of chemotherapy-induced anemia. Our findings warrant further investigation in larger, prospective studies to confirm these current findings and determine whether preventive interventions may be necessary.


Sujet(s)
Protéine BRCA1 , Protéine BRCA2 , Tumeurs de l'ovaire , Humains , Femelle , Tumeurs de l'ovaire/traitement médicamenteux , Tumeurs de l'ovaire/génétique , Adulte d'âge moyen , Protéine BRCA1/génétique , Protéine BRCA2/génétique , Sujet âgé , Adulte , Mutation germinale , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Anémie/induit chimiquement , Anémie/génétique , Études rétrospectives , Thrombopénie/induit chimiquement , Thrombopénie/épidémiologie , Thrombopénie/génétique , Hémopathies/induit chimiquement , Hémopathies/épidémiologie , Mutation
3.
Leuk Lymphoma ; 65(8): 1117-1126, 2024 Aug.
Article de Anglais | MEDLINE | ID: mdl-38626450

RÉSUMÉ

Knowledge of the SARS-CoV-2 antibody titers induced by tixagevimab-cilgavimab in patients with hematologic diseases remains insufficient. Here, we performed a single-center, prospective study to reveal the changes in antibody titer after administration of tixagevimab-cilgavimab in 78 patients with hematologic diseases. The median peak titer was 155.4 U/mL, and the median AUC was 46556 days·U/mL. First, we compared several characteristics between patients with low titers (peak titer ≤ 155.4 U/mL) and high titers (peak titer > 155.4 U/mL). We extracted 6 factors (patient age, sex, ECOG-PS, serum albumin level, and cross-sectional area and computed tomographic number of the psoas major muscle) as candidates influencing the antibody titers. Multiple regression analysis revealed that antibody titer was closely associated with these 6 factors (contribution rate = 0.76, p = 0.02). Our data support the inability of tixagevimab-cilgavimab to induce sufficient antibody titers against SARS-CoV-2, especially in older, frailer, female patients.


Sujet(s)
Anticorps monoclonaux humanisés , Anticorps antiviraux , COVID-19 , Hémopathies , SARS-CoV-2 , Humains , Femelle , Mâle , Études prospectives , Adulte d'âge moyen , Sujet âgé , SARS-CoV-2/immunologie , Hémopathies/immunologie , Hémopathies/induit chimiquement , COVID-19/immunologie , COVID-19/sang , Anticorps antiviraux/sang , Anticorps antiviraux/immunologie , Adulte , Anticorps monoclonaux humanisés/administration et posologie , Anticorps monoclonaux humanisés/usage thérapeutique , Sujet âgé de 80 ans ou plus
4.
CNS Oncol ; 13(1): CNS107, 2024 Jun 06.
Article de Anglais | MEDLINE | ID: mdl-38456492

RÉSUMÉ

Aim: Adult medulloblastomas (MB) are rare, and optimal post-craniospinal irradiation (CSI) chemotherapy is not yet defined. We investigated hematological toxicity in patients treated with platinum-etoposide (EP) post-CSI. Methods: Retrospective, single-institution study to determine hematological toxicity in adult MB patients treated with EP (1995-2022). Results: Thirteen patients with a median follow-up of 50 months (range, 10-233) were analyzed. Four discontinued treatment due to toxicity, one after 1, 3 after 3 cycles. Hematological toxicities included grade 3 (5 patients) and grade 4 (6 patients). Two patients experienced post-treatment progression and died 16 and 37 months from diagnosis. Conclusion: Post-CSI EP demonstrates acceptable hematological toxicity in adult MB. However, the small cohort precludes definitive survival outcome conclusions. Prospective studies for comprehensive comparisons with other regimens are needed in this context.


Our study aimed to understand the effect of a chemotherapy combination (platinum and etoposide) on blood counts in adult patients with medulloblastoma after craniospinal radiation. Medulloblastoma is a rare brain cancer in adults. We analyzed data from 13 adult patients with medulloblastoma. The results show that the treatment leads to significant blood count-related side effects. Four of the patients discontinued their treatment early. Blood counts improved again after completion of treatment. Two patients had the tumor grow back after treatment and died later. Overall, the effect from this chemotherapy combination on blood counts was felt to be acceptable. The number of patients in this study was small, and more research is needed to determine the overall effectiveness of this treatment.


Sujet(s)
Tumeurs du cervelet , Étoposide , Médulloblastome , Humains , Mâle , Études rétrospectives , Adulte , Femelle , Médulloblastome/radiothérapie , Médulloblastome/traitement médicamenteux , Étoposide/effets indésirables , Étoposide/administration et posologie , Jeune adulte , Adulte d'âge moyen , Tumeurs du cervelet/radiothérapie , Tumeurs du cervelet/traitement médicamenteux , Tumeurs du cervelet/thérapie , Hémopathies/induit chimiquement , Hémopathies/étiologie , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Études de suivi , Adolescent , Irradiation craniospinale/effets indésirables , Platine/usage thérapeutique
5.
J Infect Chemother ; 30(6): 504-510, 2024 Jun.
Article de Anglais | MEDLINE | ID: mdl-38097040

RÉSUMÉ

INTRODUCTION: This study aimed to identify factors responsible for changes in blood concentrations of a liposomal formulation of amphotericin B (AMPH-B, L-AMB) and analyze the relationships between blood concentrations and efficacy or toxicity. METHODS: L-AMB was administered to 30 patients being treated for hematological diseases. AMPH-B plasma concentrations were determined right before the initiation (Cmin) and at the end (Cmax) of infusion on at least 1 day, beginning on Day 3 of L-AMB treatment. The relationships of Cmin divided by dose (C/D ratio) to body weight, age, hepatic function, renal function, serum albumin, C-reactive protein (CRP), response, hypokalemia, and renal impairment were evaluated. RESULTS: C/D ratio was not correlated with age, hepatic function, renal function, or serum albumin. Body weight adjusted C/D ratio was negatively correlated with CRP. Cmax and Cmin were compared between responders and non-responders, those with or without hypokalemia, and those with or without renal impairment. A higher Cmax in patients with hypokalemia was the only significant difference seen. CONCLUSIONS: The negative correlation between CRP and plasma concentrations was likely caused by higher distribution of L-AMB from the blood to infected tissue in patients with a greater degree of infection, with a resulting decrease in plasma concentrations. AMPH-B plasma concentrations were not related to response. Higher Cmax of AMPH-B were observed in patients with hypokalemia, but no relationship between plasma concentration and renal toxicity was observed, suggesting that AMPH-B plasma concentrations appear to be minimally related to PD when used as L-AMB.


Sujet(s)
Hémopathies , Hypokaliémie , Humains , Amphotéricine B/effets indésirables , Antifongiques/effets indésirables , Hypokaliémie/induit chimiquement , Hypokaliémie/traitement médicamenteux , Hémopathies/induit chimiquement , Sérumalbumine , Protéine C-réactive , Poids
6.
Clin Exp Med ; 23(4): 1285-1291, 2023 Aug.
Article de Anglais | MEDLINE | ID: mdl-35976516

RÉSUMÉ

The effectiveness and safety of trimethoprim/sulfamethoxazole (TMP/SMX) desensitization therapy is insufficiently evaluated in hematological diseases. From 2002 to 2019, we retrospectively analyzed 112 patients with hematological diseases who underwent desensitization therapy after TMP/SMX prophylaxis withdrawal due to adverse events. They orally started TMP/SMX at 0.4 mg/2 mg, which was then increased daily to 80 mg/400 mg for 5 or 9 days. Eighty-eight patients (79%) had complete desensitization, and the major reason for failure was rash seen in 21 cases (19%). The cause of desensitization and reasons for failure matched in 22 cases (92%). Pneumocystis pneumonia was not observed throughout the study. In the failure group, the number of eosinophils and alanine aminotransferase (ALT) levels were significantly increased after desensitization. In particular in the failure group, the slight increase in eosinophils was seen through the beginning to halfway during desensitization (36/µL (0-900/µL) and 48/µL (0-2560/µL), respectively, p = 0.025). These data show that TMP/SMX desensitization therapy is effective and safe in hematological diseases. The recurrence of adverse events could help predict desensitization success.


Sujet(s)
Hémopathies , Pneumonie à Pneumocystis , Humains , Association triméthoprime-sulfaméthoxazole/effets indésirables , Études rétrospectives , Études de faisabilité , Pneumonie à Pneumocystis/traitement médicamenteux , Pneumonie à Pneumocystis/prévention et contrôle , Pneumonie à Pneumocystis/étiologie , Hémopathies/thérapie , Hémopathies/induit chimiquement , Hémopathies/complications
7.
Int J Immunopathol Pharmacol ; 36: 3946320221145520, 2022.
Article de Anglais | MEDLINE | ID: mdl-36565299

RÉSUMÉ

OBJECTIVE: The haematopoietic cytopenia (HC) of the cyclin-dependent kinase (CDK)4/6 inhibitors was evaluated using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHOD: Data from 1 January 2015 to 31 December 2021 has been retrieved from the FAERS database. Disproportionality analysis and Bayesian analysis were utilized in the data mining. The reporting odds ratio (ROR) with 95% confidence interval (CI) for HC was calculated for each CDK 4/6 inhibitor agent. Clinical features of the patients were collected and compared between death outcome and non-death outcome groups. Time to onset (TTO), proportion of deaths, life-threatening and hospitalizations of CDK 4/6 inhibitors-associated HC were also studied. RESULTS: A total of 17,235 cases of HC associated with CDK 4/6 inhibitors were identified with a median age of 65 years (interquartile range [IQR] 57-73). Palbociclib appeared the strongest signal, with the highest (ROR 9.64, 95% CI 9.46-9.83), followed by ribociclib (ROR 6.38, 95% CI 6.04-6.73) and then abemaciclib (ROR 2.72, 95% CI 2.49-2.97). Patients aged 18-64 had a higher proportion of deaths than those aged 65-84 (12.21% vs. 9.91%, p = 0.001). In Africa and Asia, the proportions of deaths were higher (31.65% and 26.13%, respectively). The median TTO was 26 days (IQR 14-65) for abemaciclib, 33 days (IQR 15-134) for palbociclib and 23 days (IQR 14-69) for ribociclib, respectively. The highest proportion of deaths, life-threatening and hospitalizations all occurred in abemaciclib (13.00%, 5.42% and 44.04%, respectively). CONCLUSIONS: Greater proportions of deaths occurred in Africa and Asia. HC may occur early in any CDK 4/6 inhibitor regimen. Abemaciclib had the highest proportion of deaths, life-threatening and hospitalizations. Health care workers should be more concerned about CDK 4/6 inhibitors. The higher proportions of serious events, including deaths, from Africa and Asia, as well as for abemaciclib, deserve further investigations through additional pharmacoepidemiological approaches.


Sujet(s)
Antinéoplasiques , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Hémopathies , Hématopoïèse , Inhibiteurs de protéines kinases , Sujet âgé , Humains , Théorème de Bayes , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , États-Unis/épidémiologie , Food and Drug Administration (USA) , Hémopathies/induit chimiquement , Hémopathies/épidémiologie , Hémopathies/mortalité , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/effets indésirables , Inhibiteurs de protéines kinases/usage thérapeutique , Antinéoplasiques/effets indésirables , Antinéoplasiques/usage thérapeutique , Hématopoïèse/effets des médicaments et des substances chimiques , Afrique/épidémiologie , Asie/épidémiologie , Mâle , Femelle , Adolescent , Jeune adulte , Adulte , Adulte d'âge moyen , Sujet âgé de 80 ans ou plus
8.
J Biochem Mol Toxicol ; 36(11): e23183, 2022 Nov.
Article de Anglais | MEDLINE | ID: mdl-35924411

RÉSUMÉ

The present study investigated the relationship between MLH1, MSH2, MSH3, and MSH6 polymorphisms and toxicity due to platinum-based doublet chemotherapy for North Indian lung cancer patients. Polymerase chain reaction-restriction fragment length polymorphism technique was used to assess the polymorphism. For MSH2 IVS1 + 9G > C polymorphism variant type genotype reported a 1.4-fold increased risk of anemia (AOR = 1.4; 95% CI = 0.98-1.99; p = 0.04) and decreased risk of developing gastrointestinal toxicity (diarrhea) (AOR = 0.53; 95% CI = 0.28-1.01; p = 0.04). Further, we also reported a 10-fold increased risk of developing severe grade anorexia in combined genotype (GC + CC) (AOR = 9.18; 95% CI = 0.98-86.1; p = 0.05). For MSH2 T > C/-6 polymorphism, variant type reported a 3-fold and 2-fold increased risk of developing severe grade leukopenia (AOR = 3.37; 95% CI = 1.44-7.88; p = 0.005) and neutropenia respectively (AOR = 2.23; 95% CI = 1.07-4.66; p = 0.03). For MSH3 G > A polymorphism, heterozygous (GA) and combined genotype (GA + AA) reported a 7-fold and 6-fold increased risk of developing anemia (AOR = 7.23; 95% CI = 1.51-34.6; p = 0.01, AOR = 6.39; 95% CI = 1.53-26.6; p = 0.01). Our results suggest that polymorphisms in DNA mismatch repair genes are associated with hematological, and gastrointestinal toxicities and might be considered a predictor for pretreatment evaluation in lung cancer patients.


Sujet(s)
Antinéoplasiques , Réparation de mésappariement de l'ADN , Tumeurs du poumon , Protéine-2 homologue de MutS , Composés du platine , Humains , Réparation de mésappariement de l'ADN/génétique , Protéines de liaison à l'ADN/génétique , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/génétique , Protéine-2 homologue de MutS/génétique , Polymorphisme de nucléotide simple , Composés du platine/effets indésirables , Composés du platine/usage thérapeutique , Antinéoplasiques/effets indésirables , Antinéoplasiques/usage thérapeutique , Hémopathies/induit chimiquement , Maladies gastro-intestinales/induit chimiquement
9.
Haematologica ; 107(12): 2870-2883, 2022 12 01.
Article de Anglais | MEDLINE | ID: mdl-35770534

RÉSUMÉ

Hepatitis E virus is increasingly being reported to cause chronic infection in immunocompromised patients. However, less is known about patients with an underlying hematologic disease. In particular, the impact of hepatitis E infection on oncological therapy has been poorly described. In this retrospective single-center study, we analyzed 35 hematologic patients with hepatitis E, including 20 patients under active oncological treatment and 15 patients who were in the posttreatment follow-up or under active surveillance. The primary aim was to describe the clinical courses with particular focus on any hepatitis E-related therapy modifications of cancer-directed therapy. In the majority (60%) of patients who were under active oncological treatment, hepatitis E-related therapy modifications were made, and 25% of deaths were due to progression of the hematologic disease. In patients receiving concomitant oncological treatment, no hepatitis Erelated deaths occurred. In contrast, two patients in the follow-up group died from hepatitis E-associated acute-onchronic liver failure. Chronic hepatitis E was observed in 34% of all cases and 43% received ribavirin therapy; of those, 27% achieved a sustained virological response. CD20-directed therapy was the only independent risk factor for developing chronic hepatitis E. We conclude that CD20-directed treatment at any time point is a risk factor for developing chronic hepatitis E. Nevertheless, since mortality from the progression of hematologic disease was higher than hepatitis E-related mortality, we suggest careful case-by-case decisions on modifications of cancer treatment. Patients in the posttreatment follow-up phase may also suffer from severe courses and hepatitis E chronicity occurs as frequently as in patients undergoing active therapy.


Sujet(s)
Hémopathies , Virus de l'hépatite E , Hépatite E , Humains , Hépatite E/complications , Hépatite E/diagnostic , Hépatite E/traitement médicamenteux , Études rétrospectives , Antiviraux/usage thérapeutique , Ribavirine/effets indésirables , Hémopathies/complications , Hémopathies/induit chimiquement , Résultat thérapeutique
10.
Med Oncol ; 39(2): 25, 2022 Jan 04.
Article de Anglais | MEDLINE | ID: mdl-34982283

RÉSUMÉ

There are no optimal regimens for advanced thymic epithelial tumors (TETs) when frontline chemotherapy fails. In this study, we aimed to assess the activity of Bevacizumab in combination with a routine chemotherapeutic regimen. Patients with advanced TETs who had failed after previous chemotherapy were enrolled in this study. Paclitaxel (160 mg/m2) and cisplatin (70 mg/m2) or carboplatin (area under the curve, 6) plus Bevacizumab (7.5 mg/kg) were intravenously injected on day 1.The treatment was repeated every 3 weeks until the disease progressed or intolerable toxicities occurred. Between March 2018 and August 2020, a total of 49 patients (21 thymoma and 28 thymic carcinoma) received the new treatment. There were 28 men and 21 women with a median age of 50 years (range: 21-73 years). The median number of cycles was 3 (range: 1-6) per patient. The objective response rate (ORR) for all patients was 43% (21/49). The ORRs for thymoma and thymic carcinoma were 24% and 57%, respectively. The median progression-free survival for thymoma and thymic carcinoma was 6 and 8 months, respectively. Hematological toxicities were the main side effects. Paclitaxel and platinum plus Bevacizumab showed promising effects in refractory or relapsed advanced TETs without severe toxicity. Even when applied as salvage therapy, this regimen resulted in a better ORR than frontline chemotherapy.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/administration et posologie , Bévacizumab/administration et posologie , Carboplatine/administration et posologie , Tumeurs épithéliales épidermoïdes et glandulaires/traitement médicamenteux , Paclitaxel/administration et posologie , Tumeurs du thymus/traitement médicamenteux , Adulte , Sujet âgé , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Bévacizumab/effets indésirables , Carboplatine/effets indésirables , Femelle , Hémopathies/induit chimiquement , Humains , Mâle , Adulte d'âge moyen , Paclitaxel/effets indésirables , Études rétrospectives , Analyse de survie , Résultat thérapeutique , Jeune adulte
11.
Anticancer Drugs ; 33(1): e477-e485, 2022 01 01.
Article de Anglais | MEDLINE | ID: mdl-34261917

RÉSUMÉ

We aimed to compare the efficacy and the safety of the FOLFOX and the FLOT regimens in metastatic gastric cancer (mGC) as first-line treatment. It was a retrospective multicenter observational study. The comparisons between groups were conducted in terms of progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and hematologic adverse events. Seventy-nine patients, diagnosed with mGC between March 2012 and December 2019, treated with FOLFOX (n = 43) or FLOT (n = 36) regimens as first-line treatment were included in the study. The mPFS was 10.9 months [95% confidence interval (CI), 5.8-16.1] in the FLOT arm and 7.1 months (95% CI, 5.1-9.1) in the FOLFOX arm (P < 0.001). The ORR was 63.9% in the FLOT arm and 30.2% in the FOLFOX arm (P = 0.003). The mOS was 13.3 months (95% CI, 11.3-15.4) in the FLOT arm and 10.9 months (95% CI, 8.2-13.5) in the FOLFOX arm (P = 0.103). The hematologic adverse events in all grades were 88.4% (n = 38) in the FOLFOX arm compared with 80.6% (n = 29) in the FLOT arm (P = 0.335). The FLOT regimen might be a preferred option in mGC with an improved PFS and ORR compared with the FOLFOX regimen.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Docetaxel/usage thérapeutique , Tumeurs de l'estomac/traitement médicamenteux , Sujet âgé , Protocoles de polychimiothérapie antinéoplasique/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Docetaxel/administration et posologie , Docetaxel/effets indésirables , Jonction oesogastrique/anatomopathologie , Femelle , Fluorouracil/usage thérapeutique , Hémopathies/induit chimiquement , Humains , Leucovorine/usage thérapeutique , Mâle , Adulte d'âge moyen , Métastase tumorale , Composés organiques du platine/usage thérapeutique , Oxaliplatine/usage thérapeutique , Études rétrospectives , Tumeurs de l'estomac/anatomopathologie , Analyse de survie
12.
CNS Neurol Disord Drug Targets ; 21(4): 316-325, 2022.
Article de Anglais | MEDLINE | ID: mdl-34382515

RÉSUMÉ

PURPOSE: Although Valproate (VPA) has several advantages in controlling seizures, it may cause serious hematological consequences. Hematotoxicity of VPA is particularly important in pediatrics because patients at this age are at a growing risk of leukemia. For a conclusive agreement about the toxicity of VPA, in this study, we systematically reviewed the literature in which the hematological consequences of VPA had been emphasized. METHODS: A systematic literature search was performed in June 2021 on electronic databases to find original research on the association between VPA therapy and hematotoxicity in pediatric patients. For this purpose, the following search terms "hematotoxicity", "valproic acid" and "pediatrics" with different spellings and similar terms, were searched in the title, keywords, and abstracts of articles. The data were collected and used for qualitative data description. RESULTS: A total of 36 relevant articles with an overall 1381 study population were included. The results showed that VPA could cause severe hematotoxicity in children even at therapeutic doses. Neutropenia, thrombocytopenia, and bone marrow depression are the most common complications associated with VPA therapy. Also, findings showed that after discontinuation of VPA and starting other antiepileptic drugs or reducing the administered VPA dose, hematologic damages were entirely resolved, and all the hematological parameters improved during two weeks. CONCLUSION: This review showed that VPA therapy could cause hematotoxicity in children; hence, it is recommended to monitor hematological indices during VPA therapy. Also, according to the suggested mechanistic pathways of VPA side effects, a combination of VPA with antioxidants may reduce hematological side effects.


Sujet(s)
Anticonvulsivants/toxicité , Hémopathies/induit chimiquement , Acide valproïque/toxicité , Adolescent , Enfant , Enfant d'âge préscolaire , Femelle , Humains , Nourrisson , Mâle , Crises épileptiques/traitement médicamenteux , Jeune adulte
14.
Ann Hematol ; 100(11): 2745-2754, 2021 Nov.
Article de Anglais | MEDLINE | ID: mdl-34333665

RÉSUMÉ

The Vulnerable Elders Survey-13 (VES-13) is a well-studied simplified frailty screening tool for elderly patients in the oncology setting. We conducted a prospective clinical trial to evaluate the efficacy and safety of dose-adjusted treatment based on the VES-13 in transplant-ineligible patients with newly diagnosed multiple myeloma (MM). In the Fit group (VES-13 <3), patients were treated with 4 cycles of standard-dose VCD (bortezomib, cyclophosphamide, and dexamethasone) followed by 4 cycles of standard-dose VTD (bortezomib, thalidomide, and dexamethasone). In the Frail group (VES-13 ≥3), patients were treated with 4 cycles of reduced-dose VCD followed by 4 cycles of reduced-dose VTD. The median age was 75 years (66-86 years), and 34% of the cases were classified as PS 3. Among the Fit group (n=16), the overall response rate (ORR) was 87.5%. Among the Frail group (n=31), the ORR was 87.1%. There were no significant differences in progression-free survival (PFS) and overall survival (OS) between the Fit and Frail groups (3-year PFS: 68.8% vs 53.3%, P = 0.658; 3-year OS: 70.0% vs 77.6%, P = 0.919). Personalized VCD-VTD sequential therapy based on the VES-13 was associated with high response rates and showed acceptable safety in elderly frail patients with MM. The study is registered as UMIN000011235.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Personne âgée fragile , Myélome multiple/traitement médicamenteux , Sujet âgé , Sujet âgé de 80 ans ou plus , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Bortézomib/administration et posologie , Bortézomib/effets indésirables , Cyclophosphamide/administration et posologie , Cyclophosphamide/effets indésirables , Dexaméthasone/administration et posologie , Dexaméthasone/effets indésirables , Femelle , Hémopathies/induit chimiquement , Humains , Hyponatrémie/induit chimiquement , Japon , Estimation de Kaplan-Meier , Mâle , Neuropathies périphériques/induit chimiquement , Médecine de précision , Survie sans progression , Études prospectives , Thalidomide/administration et posologie , Thalidomide/effets indésirables , Résultat thérapeutique
15.
Rev Neurol ; 73(2): 39-49, 2021 Jul 16.
Article de Espagnol | MEDLINE | ID: mdl-34254659

RÉSUMÉ

INTRODUCTION: The prevalence of pathologies that generate chronic pain is high (10-40%), as is the use of opioids. In Colombia, these drugs rank among the first in terms of prescriptions and the number of deaths related to their consumption is rising (0.71/1,000,000 inhabitants). This study seeks to characterise opioid-related problems (ORP) and the variables associated with their resolution. MATERIALS AND METHODS: It is a study based on secondary information. Incidences were calculated using Ministry of Health data and characteristics related to non-recoverable adverse reactions (ADRs) were determined. RESULTS: Altogether 4,437 problems were identified in 3,063 patients (39.51%, male), adults (45 years old; IQR: 29-62). The most common opioids were tramadol (46.49%, 5 mg; IQR: 5-5) and morphine (19.65%, 3 mg; IQR: 2.6-5). The majority of ORP were ADRs (93.15%) and of these, 32.28% were severe. Women had proportionally more gastrointestinal and neurological disorders, while men had a higher frequency of vascular, psychiatric, urinary and haematological problems (p < 0.05). These reactions did not resolve in 8.39%, and prognosis was associated with oral administration - odds ratio (OR): 9.24; 95% confidence interval (CI 95%): 6.36-13.42; severity (OR: 3.96; CI 95%: 2.71-5.76); age (OR: 1.01; CI 95%: 1.001-1.01); weak opioids (OR: 0.57; CI 95%: 0.4-0.84); and neurological-cardiovascular reactions (OR: 0.36; CI 95%: 0.21-0.61). CONCLUSIONS: Interventions to optimise the prescription of opioids should be encouraged to prevent ADRs with poor prognosis. Studies should be conducted to further investigate the impact of gender and route of administration on the occurrence of ADRs, as well as the severity of skin and gastrointestinal problems, which may be underestimated.


TITLE: Problemas y reacciones adversas relacionadas con analgésicos opioides en Colombia.Introducción. Las patologías que generan dolor crónico tienen alta prevalencia (10-40%), así como el consumo de opioides. En Colombia, estos medicamentos ocupan los primeros lugares de prescripción y existe un incremento en las muertes relacionadas con su consumo (0,71/1.000.000 habitantes). Este estudio busca caracterizar los problemas relacionados con opioides (PRM) y las variables asociadas con su resolución. Materiales y métodos. Es un estudio basado en información secundaria. Se calcularon las incidencias con datos del Ministerio de Salud y se determinaron las características relacionadas con reacciones adversas (RAM) no recuperables. Resultados. Se identificaron 4.437 problemas en 3.063 pacientes (39,51%, hombres), adultos (45 años; RIC: 29-62). Los opioides más comunes fueron tramadol (46,49%, 5 mg; RIC: 5-5) y morfina (19,65%, 3 mg; RIC: 2,6-5). La mayoría de los PRM fueron RAM (93,15%), y de éstas, el 32,28% fueron graves. Las mujeres presentaron proporcionalmente más alteraciones gastrointestinales y neurológicas, mientras que los hombres tuvieron una mayor frecuencia de problemas vasculares, psiquiátricos, urinarios y hematológicos (p menor de 0,05). Estas reacciones no se resolvieron en el 8,39% y el pronóstico se asoció con la administración oral ­odds ratio (OR): 9,24; intervalo de confianza al 95% (IC 95%): 6,36-13,42­, gravedad (OR: 3,96; IC 95%: 2,71-5,76), edad (OR: 1,01; IC 95%: 1,001-1,01), opioides débiles (OR: 0,57; IC 95%: 0,4-0,84) y reacciones neurológicas-cardiovasculares (OR: 0,36; IC 95%: 0,21-0,61). Conclusiones. Se sugiere fomentar intervenciones para optimizar la prescripción de opioides y así prevenir RAM con pobre pronóstico. Deben realizarse estudios que profundicen en el impacto del sexo y la vía de administración sobre la ocurrencia de RAM, así como la gravedad de los problemas cutáneos y gastrointestinales, que podría subestimarse.


Sujet(s)
Analgésiques morphiniques/effets indésirables , Adulte , Sujet âgé , Colombie/épidémiologie , Femelle , Maladies gastro-intestinales/induit chimiquement , Maladies gastro-intestinales/épidémiologie , Hémopathies/induit chimiquement , Hémopathies/épidémiologie , Humains , Incidence , Mâle , Troubles mentaux/induit chimiquement , Troubles mentaux/épidémiologie , Adulte d'âge moyen , Maladies du système nerveux/induit chimiquement , Maladies du système nerveux/épidémiologie , Gestion de la douleur , Études rétrospectives , Troubles mictionnels/induit chimiquement , Troubles mictionnels/épidémiologie , Maladies vasculaires/induit chimiquement , Maladies vasculaires/épidémiologie , Jeune adulte
16.
Br J Haematol ; 194(1): 69-77, 2021 07.
Article de Anglais | MEDLINE | ID: mdl-34121184

RÉSUMÉ

Idelalisib (IDL) is an oral first-in-class phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for chronic lymphocytic leukaemia (CLL) alongside rituximab (R) since 2014. However, little data exist on routine practice. The RETRO-idel was a protocol-led, retrospective study of 110 patients [n = 27 front-line (1L)] who received IDL-R. The primary end-point was clinical overall response rate (ORR). The median (range) follow-up of the whole cohort was 30·2 (0·1-51·9) months. The median (range) age was 72 (48-89) years. Tumour protein p53-disruption was common [100% 1L, 32·5% relapsed/refractory (R/R)]. The best ORR (intention-to-treat) was 88·2% (1L 96·3%, R/R 85·5%). Overall, the median event-free survival (mEFS) was 20·3 months and time-to-next treatment was 29·2 months. The mEFS for 1L patients was 18·7 months and R/R patients was 21·7 months. The 3-year overall survival was 56·1% (95% confidence interval 45·7-65·3). IDL was discontinued in 87·3% (n = 96). More patients discontinued due to adverse events in the front-line setting (1L 63·0% vs. R/R 44·6%) and due to progressive disease in R/R patients (20·5% vs. 3·7% in 1L). Lower respiratory tract infection/pneumonia were reported in 34·5% (Grade ≥3, 19·1%), diarrhoea in 30·9% (Grade ≥3, 6·4%), and colitis in 9·1% (Grade ≥3, 5·5%). Overall, these data describe clear efficacy for IDL-R in routine practice. No new safety signals were identified, although careful management of known toxicities is required.


Sujet(s)
Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Leucémie chronique lymphocytaire à cellules B/traitement médicamenteux , Sujet âgé , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Femelle , Maladies gastro-intestinales/induit chimiquement , Hémopathies/induit chimiquement , Humains , Irlande/épidémiologie , Estimation de Kaplan-Meier , Leucémie chronique lymphocytaire à cellules B/épidémiologie , Mâle , Adulte d'âge moyen , Inhibiteurs des phosphoinositide-3 kinases/administration et posologie , Survie sans progression , Purines/administration et posologie , Purines/effets indésirables , Quinazolinones/administration et posologie , Quinazolinones/effets indésirables , Maladies de l'appareil respiratoire/induit chimiquement , Études rétrospectives , Rituximab/administration et posologie , Rituximab/effets indésirables , Thérapie de rattrapage , Résultat thérapeutique , Royaume-Uni/épidémiologie
18.
Int J Cancer ; 149(7): 1463-1472, 2021 10 01.
Article de Anglais | MEDLINE | ID: mdl-34109630

RÉSUMÉ

Chemotherapy-induced myelosuppression is an acute, dose-limiting toxicity of chemotherapy regimens used in the treatment of extensive-stage small cell lung cancer (ES-SCLC). Trilaciclib protects haematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection). To assess the totality of the myeloprotective benefits of trilaciclib, including analysis of several clinically relevant but low-frequency events, an exploratory composite endpoint comprising five major adverse haematological events (MAHE) was prospectively defined: all-cause hospitalisations, all-cause chemotherapy dose reductions, febrile neutropenia (FN), prolonged severe neutropenia (SN) and red blood cell (RBC) transfusions on/after Week 5. MAHE and its individual components were assessed in three randomised, double-blind, placebo-controlled Phase 2 trials in patients receiving a platinum/etoposide or topotecan-containing chemotherapy regimen for ES-SCLC and in data pooled from the three trials. A total of 242 patients were randomised across the three trials (trilaciclib, n = 123; placebo, n = 119). In the individual trials and the pooled analysis, administering trilaciclib prior to chemotherapy resulted in a statistically significant reduction in the cumulative incidence of MAHE compared to placebo. In the pooled analysis, the cumulative incidences of all-cause chemotherapy dose reductions, FN, prolonged SN and RBC transfusions on/after Week 5 were significantly reduced with trilaciclib vs placebo; however, no significant difference was observed in rates of all-cause hospitalisations. Additionally, compared to placebo, trilaciclib significantly extended the amount of time patients remained free of MAHE. These data support the myeloprotective benefits of trilaciclib and its ability to improve the overall safety profile of myelosuppressive chemotherapy regimens used to treat patients with ES-SCLC.


Sujet(s)
Cytoprotection , Hémopathies/prévention et contrôle , Tumeurs du poumon/traitement médicamenteux , Cellules myéloïdes/effets des médicaments et des substances chimiques , Pyrimidines/administration et posologie , Pyrroles/administration et posologie , Carcinome pulmonaire à petites cellules/traitement médicamenteux , Sujet âgé , Méthode en double aveugle , Femelle , Études de suivi , Hémopathies/induit chimiquement , Humains , Tumeurs du poumon/anatomopathologie , Mâle , Adulte d'âge moyen , Pronostic , Études prospectives , Pyrimidines/effets indésirables , Pyrroles/effets indésirables , Carcinome pulmonaire à petites cellules/anatomopathologie
19.
AAPS J ; 23(4): 77, 2021 05 20.
Article de Anglais | MEDLINE | ID: mdl-34018069

RÉSUMÉ

Quantitative Systems Toxicology (QST) models, recapitulating pharmacokinetics and mechanism of action together with the organic response at multiple levels of biological organization, can provide predictions on the magnitude of injury and recovery dynamics to support study design and decision-making during drug development. Here, we highlight the application of QST models to predict toxicities of cancer treatments, such as cytopenia(s) and gastrointestinal adverse effects, where narrow therapeutic indexes need to be actively managed. The importance of bifurcation analysis is demonstrated in QST models of hematologic toxicity to understand how different regions of the parameter space generate different behaviors following cancer treatment, which results in asymptotically stable predictions, yet highly irregular for specific schedules, or oscillating predictions of blood cell levels. In addition, an agent-based model of the intestinal crypt was used to simulate how the spatial location of the injury within the crypt affects the villus disruption severity. We discuss the value of QST modeling approaches to support drug development and how they align with technological advances impacting trial design including patient selection, dose/regimen selection, and ultimately patient safety.


Sujet(s)
Antinéoplasiques/effets indésirables , Développement de médicament/méthodes , Maladies gastro-intestinales/épidémiologie , Hémopathies/épidémiologie , Modèles biologiques , Simulation numérique , Maladies gastro-intestinales/induit chimiquement , Maladies gastro-intestinales/prévention et contrôle , Hémopathies/induit chimiquement , Hémopathies/prévention et contrôle , Humains , Appréciation des risques/méthodes , Analyse des systèmes
20.
J Clin Pharmacol ; 61(10): 1376-1385, 2021 10.
Article de Anglais | MEDLINE | ID: mdl-33974709

RÉSUMÉ

Most patients experience severe hematological toxicity during treatment with gemcitabine; thus, preventing such toxicity would improve the treatment effects and patient quality of life. We analyzed 13 polymorphisms in the transporters, metabolizing enzymes, targets, and genes involved in DNA damage and the folate pathway among 132 patients treated with gemcitabine and studied their association with the severity of the hematological toxicities. Single-locus analysis showed that the single-nucleotide polymorphisms (SNPs) RRM1 rs12806698 and rs11031918 and DCTD rs7663494 were significantly associated with severe neutropenia, hENT1 rs760370 and hCNT3 rs7867504 and rs4877831 were associated with severe leukopenia, CDA rs2072671, DCTD rs7663494, and WEE1 rs3910384 were associated with severe anemia, and MTHFR rs1801133 was associated with severe thrombocytopenia after stringent Bonferroni correction (P < .0038). The gene-gene interaction analysis identified the overall best models, including a 2-way interaction model (hCNT3 rs7867504 and dCK rs12648166) for severe leukopenia (P = .0022) and a 3-locus model (CDA rs207671, DCTD rs7663494, and WEE1 rs3910384) for severe anemia with a strong synergistic effect (P = .0001). The association with hematological toxicity was further strengthened by the results of a haplotype analysis, in which the homozygous genotype combination of rs3910384 CC, rs2072671 AA, rs12648166 GG, rs7867504 CC, and rs7663494 TT conferred high genetic susceptibility to severe thrombocytopenia. Our results suggest that the gene-gene interaction of gemcitabine metabolic pathway genes and WEE1 contributes to susceptibility to gemcitabine-induced hematological toxicity. Moreover, we propose a promising data-mining analysis approach (generalized multifactor dimensionality reduction) to detect and characterize gene-gene interactions.


Sujet(s)
Antimétabolites antinéoplasiques/effets indésirables , Protéines du cycle cellulaire/génétique , Désoxycytidine/analogues et dérivés , Hémopathies/induit chimiquement , Protéines de transport membranaire/génétique , Protein-tyrosine kinases/génétique , Sujet âgé , Désoxycytidine/effets indésirables , Femelle , Régulation de l'expression des gènes tumoraux , Humains , Modèles logistiques , Mâle , Adulte d'âge moyen , Acuité des besoins du patient , Polymorphisme de nucléotide simple , Gemcitabine
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