Hematological Adverse Drug Reactions Research Articles

Dihydropyrimidine Dehydrogenase Polymorphism c.2194G>A Screening Is a Useful Tool for Decreasing Gastrointestinal and Hematological Adverse Drug Reaction Risk in Fluoropyrimidine-Treated Patients.

Although the risk of fluoropyrimidine toxicity may be decreased by identifying poor metabolizers with a preemptive dihydropyrimidine dehydrogenase (DPYD) test, following international standards, many patients with wild-type (WT) genotypes for classic variations may still exhibit adverse drug reactions (ADRs). Therefore, the safety of fluoropyrimidine therapy could be improved by identifying new DPYD polymorphisms associated with ADRs. This study was carried out to assess whether testing for the underestimated c.2194G>A (DPYD*6 polymorphism, rs1801160) is useful, in addition to other well-known variants, in reducing the risk of ADRs in patients undergoing chemotherapy treatment. This retrospective study included 132 patients treated with fluoropyrimidine-containing regimens who experienced ADRs such as gastrointestinal, dermatological, hematological, and neurological. All subjects were screened for DPYD variants DPYD2A (IVS14+1G>A, c.1905+1G>A, rs3918290), DPYD13 (c.1679T>G, rs55886062), c.2846A>T (rs67376798), c.1236G>A (rs56038477), and c.2194G>A by real-time polymerase chain reaction (RT-PCR). In this cohort, the heterozygous c.2194G>A variant was present in 26 patients, while 106 individuals were WT; both subgroups were compared for the incidence of ADRs. This assessment revealed a high incidence of gastrointestinal and hematological ADRs in DPYD6 carriers compared to WT. Moreover, we have shown a higher prevalence of ADRs in females compared to males when stratifying c.2194G>A carrier individuals. Considering that c.2194G>A was linked to clinically relevant ADRs, we suggest that this variant should also be assessed preventively to reduce the risk of fluoropyrimidine-related ADRs.

Factors associated with hematological adverse reactions of drugs authorized via the centralized procedure

Serious hematological adverse drug reactions (HADRs) may lead to or prolong hospitalization and even cause death. The aim of this study was to determine the regulatory factors associated with HADRs caused by drugs that were authorized up to July 2023 by the European Medicines Agency (EMA) and to evaluate the frequency of HADRs. Using a cross-sectional approach, the type and frequency of HADRs were collected from the Summaries of Product Characteristics of Drugs Authorized by the EMA and analyzed within proprietary, nonproprietary, and biosimilar/biological frameworks. Multivariate statistical analysis was used to investigate the associations of generic status, biosimilar status, conditional approval, exceptional circumstances, accelerated assessment, orphan drug status, years on the market, administration route, and inclusion on the Essential Medicines List (EML) with HADRs. In total, 54.78% of proprietary drugs were associated with HADRs at any frequency, while anemia, leucopenia, and thrombocytopenia were observed in approximately 36% of the patients. The predictors of any HADR, anemia, and thrombocytopenia of any frequency are generic status, biosimilar status, and inclusion on the EML, while the only protective factor is the administration route. Biosimilars and their originator biologicals have similar frequencies of HADRs; the only exception is somatropin. Knowledge of the regulatory factors associated with HADRs could help clinicians address monitoring issues when new drugs are introduced for the treatment of patients.

Chemo-immunotherapy with dinutuximab beta in patients with relapsed/progressive high-risk neuroblastoma: does chemotherapy backbone matter?

BackgroundAddition of anti-GD2 antibodies to temozolomide-based chemotherapy has demonstrated increased antitumor activity and progression-free survival in patients with relapsed/progressive high-risk neuroblastoma. However, chemo-immunotherapy is not yet approved for this indication. This study presents the chemo-immunotherapy experience in patients with relapsed/progressive high-risk neuroblastoma treated within the off-label use program of the Neuroblastoma Committee of the French Society of Pediatric Oncology (SFCE). MethodsDinutuximab beta (dB) was administered alongside temozolomide-topotecan (TOTEM) or temozolomide-irinotecan (TEMIRI) at first disease relapse/progression or topotecan-cyclophosphamide (TopoCyclo) at further relapse/progression. Real-world data on demographics, treatment, antitumor activity and safety was collected from all patients after inclusion in SACHA-France (NCT04477681), a prospective national registry, which documents safety and efficacy data on innovative anticancer therapies prescribed to patients ≤ 25 years old as compassionate or off-label use. ResultsBetween February 2021 and July 2023, 39 patients with confirmed relapsed/progressive high-risk neuroblastoma (median age 6 years, range 1–24) were treated with dB+TopoCyclo (n = 24) or dB+TOTEM/TEMIRI (n = 15) across 17 centers. In total, 163 chemo-immunotherapy cycles were administered, main toxicities were mild or moderate, with higher incidence of hematological adverse drug reactions with dB+TopoCyclo than dB+TOTEM/TEMIRI. Objective response rate was 42% for dB+TopoCyclo (CI95% 22–63%) and 40% for dB+TOTEM/TEMIRI (CI95% 16–68%). ConclusionSimilar objective response rates for dB+TopoCyclo and dB+TOTEM/TEMIRI in patients with relapsed/progressive high-risk neuroblastoma emphasize the importance of chemo-immunotherapy, irrespective of the chemotherapy backbone.

Immune Checkpoint Inhibitor-Related Cytopenias: About 68 Cases from the French Pharmacovigilance Database.

Simple SummaryData on immune checkpoint inhibitor (ICI)-related cytopenias are scarce. The aim of the study was to further characterize grade ≥ 2 ICI-related cytopenias using the French pharmacovigilance database. Immune thrombocytopenia and autoimmune hemolytic anemia were the most frequently reported ICI-related cytopenias (50.7% and 25.3%, respectively). Nearly half were grade ≥ 4, and 4.4% of patients died from cytopenia-related complications. Using the French pharmacovigilance database, this study provides a comprehensive analysis of ICI-related cytopenias that are rare but potentially life-threatening adverse drug reactions. Early recognition and timely initiation of appropriate treatment are key in their management in clinical practice.Immune checkpoint inhibitor (ICI)-related cytopenias have been poorly described. This study aimed to further characterize ICI-related cytopenias, using the French pharmacovigilance database. All grade ≥ 2 hematological adverse drug reactions involving at least one ICI coded as suspected or interacting drug according to the World Health Organization criteria and reported up to 31 March 2022, were extracted from the French pharmacovigilance database. Patients were included if they experienced ICI-related grade ≥ 2 cytopenia. We included 68 patients (75 ICI-related cytopenias). Sixty-three percent were male, and the median age was 63.0 years. Seven patients (10.3%) had a previous history of autoimmune disease. Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) were the most frequently reported (50.7% and 25.3%, respectively). The median time to onset of ICI-related cytopenias was 2 months. Nearly half were grade ≥ 4, and three patients died from bleeding complications of refractory ITP and from thromboembolic disease with active AIHA. Out of 61 evaluable responses, complete or partial remission was observed after conventional treatment in 72.1% of ICI-related cytopenias. Among the 10 patients with ICI resumption after grade ≥ 2 ICI-related cytopenia, three relapsed. ICI-related cytopenias are rare but potentially life-threatening. Further studies are needed to identify risk factors of ICI-related cytopenias.

Adverse effects of Anticancer Chemotherapy in Childhood Cancer: A Prospective Study in a Moroccan hospital

Objective: To determine the incidence and frequency of adverse drug reactions (ADRs) induced by cancer chemotherapy in pediatric inpatients. Patients and methods: This was a six-month prospective observational study in the pediatric hematology-oncology department of the children's hospital of Rabat. This study took into account ADRs manifested by in inpatient children and undergoing cancer chemotherapy. A modified version of the Moroccan Poison Control and Pharmacovigilance Centre's notification form was used to collect demographic, clinical, cancer treatment and ADR-related data. The causality, severity and preventability were assessed for each adverse event. Results: 106 patients out of 118 followed have developed a total of 266 ADRs. The most frequent ADRs were anemia (14.3%), infections (9.4%), leukopenia (8.6%) and fever (8.3%). Vincristine (16.3%), etoposide (14%) and cytarabine (13%) were the most frequently administered products. Cytarabine followed by etoposide were the drugs most involved in ADRs. The majority of ADRs (55.6%) were probable according to the WHO method of causality assessment. Conclusion: Cancer chemotherapy is associated with a high risk of developing ADRs, particularly hematological ADRs in children. Pediatric patients receiving cytarabine and daunorubicin combinations and regimens including anthracyclines should receive more attention. Risk management plans need to be implemented by health care teams in this area.

Safety of Antibiotics in Hospitalized Children in Romania: A Prospective Observational Study.

Antibiotics are among the most prescribed drugs in pediatric inpatients and are frequently associated with adverse drug reactions (ADRs) in children. This study aimed to assess the frequency and type of ADRs related to the use of antibiotics in pediatric inpatients through a prospective observational study, conducted over 6 months, covering the winter and spring seasons when the incidence of infections peaks in Romania. ADRs were evaluated for causality, avoidability and severity. Among the 266 included children, 25 (9.4%) experienced 30 ADRs. ADR frequency tended to be higher in ≤2-year-olds (13 of 25, 52.0%) than in other age categories. Gastrointestinal and hematological ADRs were most frequently observed. Diarrhea was the most common ADR associated with antibiotics (8 of 30, 26.7%). Ceftriaxone (16 of 30, 53.3%), cefuroxime, ceftazidime and azithromycin (3 of 30, 10.0% each) were most commonly responsible for ADRs. After causality assessment, 2 (6.7%) ADRs were considered definite, 12 (40.0%) probable and 16 (53.3%) possible. One ADR was classified as definitely avoidable and one as possibly avoidable. Seven children required treatment for ADRs. Antibiotic treatment was discontinued in 4 children. Antibiotics frequently caused ADRs in ≤ 2-year-olds and were commonly associated with gastrointestinal symptoms. Close monitoring of antibiotic-associated ADRs remains important in the pediatric population.

Short-Term Adverse Drug Reactions to Antiretroviral Therapy in Children with HIV: A Cohort Study.

To carry out an active surveillance for adverse drug reactions (ADRs) in children with HIV infection newly initiated on antiretroviral therapy (ART), determine risk factors for their occurrence, and assess their influence on adherence to ART. All children newly initiated on ART from 1st March 2014 to 30th June 2019 at a tertiary care children's hospital in New Delhi, were actively monitored for ADRs to ART for a period of 6 mo after ART initiation. The frequency, spectrum, and severity of ADRs, their influence on adherence, and risk factors for their occurrence were analyzed. Among the 174 enrolled children, ADRs were observed in 78 (44.8%) children during the first 6 mo after ART initiation. Total numbers of episodes of ADR observed were 108 (0.62 episodes of ADR/child). Sixty percent of events were of grade 1 severity, 19.4% events were of grade 2 and 3 each, while 1 (0.9%) event was of grade 4 severity. Adherence to ART was adversely affected in 21.8% of ADRs. Gastrointestinal symptoms (49.1%) were most frequent among all the events observed. Zidovudine, lopinavir/ritonavir, efavirenz and nevirapine based regimes were significantly associated with hematological, gastrointestinal, neurological, and dermatological ADRs, respectively. Children with immunological suppression were at a higher risk of developing ADRs as compared to those without it [RR 1.9 (95% CI (1.1-3.2)]. ADRs to ART are very frequent; most of them are mild and self-limiting. However, they can adversely impact adherence to ART. Anticipatory guidance, ongoing monitoring, and provision of symptomatic treatment will help tide over most ADRs and reduce their adverse impact upon ART adherence.

Adverse Drug Reaction Monitoring of Anticancer Drugs in Hematology Department

Background: Cancer is among the leading causes of mortality in India. Studies have reported antineoplastic agents as the common class of drugs causing Adverse Drug Reactions (ADRs). The present study aimed to conduct active surveillance of ADRs of anticancer drugs in the hematology department. Methods: A prospective observational study was conducted in 136 patients with cancer and the incidence and frequency of ADRs were assessed. The study was conducted in 6 months in a multispecialty hospital. Results: Among 136 cancer patients, All was more prevalent (39.70%); CLL, Non- Hodgkin’s Lymphoma were less prevalent (0.73%). ADRs were more prevalent in the Pediatrics department, i.e., 18.53% of ADRs were observed in patients aged <10 years. ADRs in male patients constituted 54.39%, whereas it was 45.60% in female patients. Cytarabine caused the highest number of ADRs (34.48%). The most prevalent ADR was anemia (25.60%). Conclusion: Multiple ADRs were detected in cancer patients. We found that hematological ADRs were more prevalent. Most of the ADRs were possible reactions according to Naranjo and the World Health Organization (WHO) scales.

Pharmacovigilance Study of Anticancer Drugs in a Tertiary Care Rural Hospital in Central India

The present study has been undertaken to evaluate the pattern of adverse drug reactions (ADRs) of intravenous anticancer (i.v.) drugs with their causality and severity in a tertiary health care set up. The study was an observational cross-sectional survey over a period of 18 months. The indoor patients who were diagnosed to have cancer and receiving i.v. anticancer drugs were included in the study. The details of the patients and ADRs were recorded at the time of visit or within one-month of occurrence of ADRs using case record form and ADR reporting form. A total of 374 patients on cancer chemotherapy were included in the study and ADR was seen in 293(78.34%) patients. Out of total 812 number of ADRs, most ADRs (51.60%) were G.I. system related, followed by skin and appendages related ADRs (23.88%). The association of females in developing haematological ADRs is statistically significant (p<0.05). Most common (19.80%) cause of ADRs was the use of combination of Cisplatin, Paclitaxel and 5 Fluorouracil. Most (90.02%) of the ADRs were categorized as ‘possible’ and the remaining (9.98%) as ‘probable/likely’. The maximum number of the ADRs were classified as ‘mild’(87.68%) followed by moderate (11.45%) and severe (0.86%). The mild reactions were more common as compare to moderate & severe category in G.I & haematology related ADRs (p<0.05).

Comparative Study of Different Oral Iron Preparations in Females of Reproductive Age Group

Background: Anemia (anemia) is a decrease in the total amount of red blood cells (RBCs) or hemoglobin in the blood, or a lowered ability of the blood to carry oxygen. The commonness of iron inadequacy is high in all age bunch females. Around 32.4% of ladies have mellow iron deficiency, 14.19% ladies have direct sickliness, 2.2% have serious weakness.
 Objective: The aim of the study is to compare the efficacy and safety profile of oral iron formulations in iron deficiency anemia.
 Methods: A cross sectional study in patients with anemia receiving oral ferric ammonium citrate, folic acid, vitamin B12and iron hydroxide respectively was included. The patients were followed up once in 0 day, end of week, 1 month, for 3 months and observed for hematological improvement and adverse drug reactions (ADRs). Total 350 anemic patient were included in the study.
 Results: The data analyzed in 185 patients received ferric ammonium citrate, folic acid, 165 received, iron hydroxide,folic acid, vitamin B12 have significantly improved mean hemoglobin and anemia indices at the end of study, however, there was no significant differences between the groups when compared. “All four formulations showed similar ADR profile, there was no significant difference in adverse reactions.’’
 Conclusion: Ferric ammonium citrate can be considered as best cost-effective choice for treatment of irons deficiency anemia.

Assessment of Patient’s Response about Adverse Drug Reactions Receiving AC (Adriamycin, Cyclophosphamide) Therapy: A Survey Research

Background: Adverse drug reactions (ADRs) are most common among cancer patients receiving treatment. AC therapy which is a combination protocol of Adriamycin (doxorubicin) and Cyclophosphamide are the common therapies used for breast cancer treatment due to their effectiveness and cost of therapy breast cancer. AC combination is administered every 3 weeks, and 4 cycles are given.
 Objectives: To assess various ADRs reported by patients on AC combination therapy and their severity to ensure safe and effective treatment.
 Design: Prospective observational.
 Setting: Cancer hospital Jamshoro Pakistan.
 Patients and Methods: A hospital based observational study included 160 female patients suffering from breast cancer and receiving AC combination for treatment by purposive sampling method from June 2015- January 2018 at cancer hospital Jamshoro Pakistan. ADRs reported were compared against international standard references of drug literature such as British National Formulary (BNF) 2017 and ADR severity assessment scale (Modified Hartwig and Siegel scale).
 Main Outcome Measures: Frequency and severity of ADRs.
 Results: The common ADRs reported were, nausea and vomiting, acidity, fatigue, hair fall as common non-hematologic and leukopenia among hematologic ADRs. Those patients reported high severity ADRs according to severity scale persist for longer duration and required antidote for management with medical intervention.
 Conclusion: The present study shows that a patient’s response towards AC therapy is critical and therefore each patient must be monitored and those at high risk of developing ADRs from this therapy must be provided additional care.

Hematologic adverse effects induced by piperacillin-tazobactam: a systematic review of case reports.

Background Piperacillin/tazobactam, a semisynthetic antibiotic, is widely used to treat polymicrobial infections. Its hematologic adverse reactions are rare and the severity can be mild to life-threatening. To our knowledge, there has not been a publication reviewing hematologic abnormalities attributable to piperacillin/tazobactam. Aim of the review To evaluate the characteristic, clinical identification, mechanism and treatment of the hematologic toxicity caused by piperacillin/tazobactam. Method A search of Medline and Embase electronic databases was performed for case reports of adverse reactions of hematologic system related to piperacillin/tazobactam from inception to December 2018. Statistical analysis of demographic, clinical features, laboratory Indexes and treatments was performed using Microsoft EXCEL 2007. Results Fifty-nine referenceswere obtained involving 62 patients. The adverse drug reactions were mainly hemolytic anemia (25, 40.3%), thrombocytopenia (23, 37.1%), and neutropenia (12, 19.4%), which might be accompanied by some typical symptoms. Hemolytic anemia or thrombocytopenia was generally believed to be immune-mediated and often appeared within 10days, and neutropenia was thought to be related to bone marrow suppression and usually occurred 2weeks after the initiation of piperacillin/tazobactam. Most patients improved or recovered within a week with treatment or not, and fewer high-quality evidence-based treatments were identified. Conclusion Although part of the patients have clinical symptom, the hematologic adverse drug reactions of piperacillin/tazobactam are easily overlooked or misdiagnosed. Take special caution for patients with prolonged piperacillin/tazobactam treatment or specific disease, and prompt recognition and treatment of the adverse drug reactions are essential and can hasten recovery regardless of the type of side reactions.

Hematologic adverse drug reactions leading to hospitalization among cancer patients: A retrospective case-control study.

Cancer is one of the leading causes of death worldwide. Despite the rapid evolution of cancer treatment, chemotherapy remains the mainstay in the management of cancer. Chemotherapy can result in various adverse drug reactions (ADRs), which may lead to hospitalization and even life-threatening side-effects. Hematologic ADRs are among the most severe forms of ADR following chemotherapy, as they generally lead to hospitalization. It is important to realize the predictors and outcome of hematologic ADRs in cancer patients. We conducted a hospital-based case-control study to include all the cancer patients who were hospitalized to receive chemotherapy in Taipei Veterans General Hospital during 2013. Among them the patients rehospitalized after chemotherapy due to neutropenia, leucopenia, or pancytopenia were identified as the study group. Control subjects consisted of hospitalized cancer patients who did not display the aforementioned ADRs. The study and control groups were numbered in the ratio of 1:4 and were age- and gender-matched. Their demographic and clinical characteristics were collected through chart review. Determinants of hematologic ADRs were then analyzed. During the study period, we collected a total of 64 patients into the study group and 256 as control subjects. The mean length of hospitalization was 11 days in the study group of patients, which was 5 days longer than that in the control group (p < 0.001). Predictors of hematologic ADR-related hospitalization included history of hematologic ADRs, hypertension, cisplatin treatment, and a Charlson comorbidity score of 2 to 3. Severe outcomes of hematologic ADRs may increase healthcare costs and decrease patient productivity. Therefore, the determinants of ADR-related hospitalization identified in this study may help improve the quality of healthcare for cancer patients.

Patterns of Anthracycline-Based Chemotherapy-Induced Adverse Drug Reactions and Their Impact on Relative Dose Intensity among Women with Breast Cancer in Ethiopia: A Prospective Observational Study.

Background The breast cancer chemotherapy leads to diverse aspects of noxious or unintended adverse drug reactions (ADRs) that cause the relative dose intensity (RDI) reduced to below optimal (i.e., if the percentage of actual dose received per unit time divided by planned dose per unit time is less than 85%). Hence, this prospective observational study was conducted to evaluate chemotherapy-induced ADRs and their impact on relative dose intensity among women with breast cancer in Ethiopia. Methods The study was conducted with a cohort of 146 patients from January 1 to September 30, 2017, Gregorian Calendar (GC) at the only nationwide oncology center, Tikur Anbessa Specialized Hospital (TASH), Addis Ababa, Ethiopia. The ADRs of the chemotherapy were collected using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (version 4.03). The patients were personally interviewed for subjective toxicities, and laboratory results and supportive measures were recorded at each cycle. SPSS version 22 was used for analysis. Results Grade 3 neutropenia (23 (15.8%)) was the most frequently reported ADR among grade 3 hematological toxicity on cycle 4. However, overall grade fatigue (136 (93.2%)) and grade 3 nausea (31 (21.2%)) were the most frequently reported nonhematological toxicities on cycle 1. The majority of ADRs were reported during the first four cycles except for peripheral neuropathy. Oral antibiotics and G-CSF use (17 (11.6%)) and treatment delay (31 (21.2%)) were frequently reported on cycle 3. Overall, 61 (41.8%) and 42 (28.8%) of study participants experienced dose delay and used G-CSF, respectively, at least once during their enrollment. Of the 933 interventions observed, 95 (10%) cycles were delayed due to toxicities in which neutropenia attributed to the delay of 89 cycles. Forty-four (30.1%) of the patients received overall RDI < 85%. Pretreatment hematological counts were significant predictors (P < 0.05) for the incidence of first cycle hematological toxicities such as neutropenia, anemia, and leukopenia and nonhematological toxicities like vomiting. Conclusion Ethiopian women with breast cancer on anthracycline-based AC and AC-T chemotherapy predominantly experienced grade 1 to 3 hematological and nonhematological ADRs, particularly during the first four cycles. Neutropenia was the only toxicity that led to RDI < 85%. Thus, enhancing the utilization of G-CSF and other supportive measures will improve RDI to above 85%.

Discovery of Novel Biomarkers of Therapeutic Responses in Han Chinese Pemetrexed-Based Treated Advanced NSCLC Patients.

Pemetrexed, one of the most commonly used drugs in advanced non–small cell lung cancer (NSCLC) therapies, often leads to various therapeutic responses in patients. These therapeutic responses to pemetrexed, including adverse drug reactions (ADRs) and its intended therapeutic effects, have been demonstrated to be highly individual-specific. Such difference in therapeutic responses across individuals may be caused by the unique genetic variations in each patient. However, only a few pemetrexed-based studies have been performed using Han Chinese patients. In this study, we aimed to identify genetic signatures of therapeutic responses of pemetrexed-based treatment using 203 Han Chinese patients with advanced NSCLC. All the participants received two different types of therapies: 1) treatment with only pemetrexed and 2) treatment with both pemetrexed and platinum (mainly cisplatin and carboplatin). We then performed a genetic association analysis on 16 selected single-nucleotide polymorphisms (SNPs) in 7 genes using these 2 groups. The analysis of patients receiving only pemetrexed suggests that the SNP rs1051298 on the SLC19A1 gene (c.*746C > T) increased the risk of all ADRs (collected all types of ADRs) in different cycles of pemetrexed therapy [1-2 cycles: P = 0.0059, odds ratio (OR) = 3.143; 1-4 cycles: P = 0.0072, OR = 2.340; 1-6 cycles: P = 0.0071, OR = 2.243]. This influence of rs1051298 is particularly significant in terms of liver injury (1-4 cycles: P = 0.0056, OR = 3.863; 1-6 cycles: P = 0.0071, OR = 3.466). In all the patients, including patients who received both pemetrexed and platinum, SNP rs1801133 on the MTHFR gene (665C > T) was found to be significantly associated with hematological ADRs in 1 to 2 cycles (P = 0.0079, OR = 3.566). Additionally, we discovered that SNP rs12995526 (c.815-102T > C) in the ATIC gene and SNP rs11545077 (c.91G > T) in the GGH gene were associated with both ADRs and therapeutic effects. In summary, our study identified several potential biomarkers that were significantly associated with ADRs and therapeutic effects of pemetrexed-related treatments using Han Chinese patients. Our discoveries will provide important clues for personalized pemetrexed-based treatment design for Han Chinese NSCLC patients in the future.

Why should we monitor for hematologic adverse drug reactions to oxcarbazepine?

See the article "Evaluation of hematologic profile may be needed for patients treated with oxcarbazepine" via https://doi.org/10.3345/kjp.2019.00017.

DPYD*6 plays an important role in fluoropyrimidine toxicity in addition to DPYD*2A and c.2846A>T: a comprehensive analysis in 1254 patients

Dihydropyrimidine dehydrogenase (DPYD) is a highly polymorphic gene and classic deficient variants (i.e., c.1236G>A/HapB3, c.1679T>G, c.1905+1G>A and c.2846A>T) are characterized by impaired enzyme activity and risk of severe adverse drug reactions (ADRs) in patients treated with fluoropyrimidines. The identification of poor metabolizers by pre-emptive DPYD screening may reduce the rate of ADRs but many patients with wild-type genotype for classic variants may still display ADRs. Therefore, the search for additional DPYD polymorphisms associated with ADRs may improve the safety of treatment with fluoropyrimidines. This study included 1254 patients treated with fluoropyrimidine-containing regimens and divided into cohort 1, which included 982 subjects suffering from gastrointestinal G≥2 and/or hematological G≥3 ADRs, and cohort 2 (control group), which comprised 272 subjects not requiring dose reduction, delay or discontinuation of treatment. Both groups were screened for DPYD variants c.496A>G, c.1236G>A/HapB3, c.1601G>A (DPYD*4), c.1627A>G (DPYD*5), c.1679T>G (DPYD*13), c.1896T>C, c.1905 + 1G>A (DPYD*2A), c.2194G>A (DPYD*6), and c.2846A>T to assess their association with toxicity. Genetic analysis in the two cohorts were done by Real-Time PCR of DNA extracted from 3 ml of whole blood. DPYD c.496A>G, c.1601G>A, c.1627A>G, c.1896T>C, and c.2194G>A variants were found in both cohort 1 and 2, while c.1905+1G>A and c.2846A>T were present only in cohort 1. DPYD c.1679T>G and c.1236G>A/HapB3 were not found. Univariate analysis allowed the selection of c.1905+1G>A, c.2194G>A and c.2846A>T alleles as significantly associated with gastrointestinal and hematological ADRs (p < 0.05), while the c.496A>G variant showed a positive trend of association with neutropenia (p = 0.06). In conclusion, c.2194G>A is associated with clinically-relevant ADRs in addition to the already known c.1905+1G>A and c.2846A>T variants and should be evaluated pre-emptively to reduce the risk of fluoropyrimidine-associated ADRs.

Genotype-Guided Thiopurine Dosing Does not Lead to Additional Costs in Patients With Inflammatory Bowel Disease.

Background and AimsDecreased thiopurine S-methyltransferase [TPMT] enzyme activity increases the risk of haematological adverse drug reactions [ADRs] in patients treated with thiopurines. Clinical studies have shown that in patients with inflammatory bowel disease [IBD], pharmacogenetic TPMT-guided thiopurine treatment reduces this risk of ADRs. The aim of this study was to investigate whether this intervention impacts on healthcare costs and/or quality of life.MethodsAn a priori defined cost-effectiveness analysis was conducted in the Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics [TOPIC] trial, a randomized controlled trial performed in 30 Dutch hospitals. Patients diagnosed with IBD [age ≥18 years] were randomly assigned to the intervention [i.e. pre-treatment genotyping] or control group. Total costs in terms of volumes of care, and effects in quality-adjusted life years [QALYs], based on EuroQol-5D3L utility scores, were measured for 20 weeks. Mean incremental cost savings and QALYs with confidence intervals were calculated using non-parametric bootstrapping with 1000 replications.ResultsThe intervention group consisted of 381 patients and the control group 347 patients. The mean incremental cost savings were €52 per patient [95% percentiles −682, 569]. Mean incremental QALYs were 0.001 [95% percentiles −0.009, 0.010]. Sensitivity analysis showed that the results were robust for potential change in costs of screening, costs of biologicals and costs associated with productivity loss.ConclusionsGenotype-guided thiopurine treatment in IBD patients reduced the risk of ADRs among patients carrying a TPMT variant, without increasing overall healthcare costs and resulting in comparable quality of life, as compared to standard treatment.

Highly Active Antiretroviral Therapy Induced Hematological and Dermatological Adverse Drug Reactions in People Living with HIV in India

Introduction: In India, HIV patients are at a high risk of developing hematological and dermatological adverse drug reactions (ADRs) leading to financial burden. Materials and Methods: A prospective observational study was conducted on hematological and dermatological ADRs in a South Indian teaching hospital from October 2011 to October 2012. The definition of ADRs established by the World Health Organization (WHO) was used to assess the causality. Predictability of ADRs was assessed by Micromedex database. Preventability of ADRs was assessed using the Schumock and Thornton criteria. Results: A total of 174 HIV patients were enrolled [133 (76.4%) males and 41 (23.6%) females], who reported 99 ADRs to HAART. Of the total ADRs, 70 (70.7%) were reported in males and 29 (29.3%) in females, indicating significantly higher reporting of ADRs in males. 67 of the 99 ADRs were hematological, while the remaining 32 were dermatological. A high number of hematological [40 (59.6%)] and dermatological [15 (46.8%)] ADRs were reported for zidovudine + lamivudine + nevirapine-based HAART regimen. In most of the reported ADRs, the suspected drug was withdrawn. The reported hematological ADRs were as follows: 1) anemia with zidovudine [35 (52.2%)]; 2) pancytopenia with zidovudine [20 (29.9%)]; 3) neutropenia with lamivudine; and 4) leucopenia, bicytopenia, and eosinophilia with zidovudine. Dermatological ADRs were maculopapular rash [7 (21.8%)] with nevirapine-, tenofovir + emtricitabine + efavirenz. Conclusion: Hematological ADRs was higher than that of dermatological ADRs. Physicians must focus on routine monitoring of all possible risk factors in PLW-HIV for early prevention of hematological and dermatological ADRs to HAART.

First-wave protease inhibitors for hepatitis C genotype 1 treatment: a real-life experience in Brazilian patients.

Licensed for chronic hepatitis C treatment in 2011, the protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC), which have high sustained viral responses (SVR), ushered a new era characterized by the development of direct-action drugs against the hepatitis C virus (HCV). The aim of this study was to analyze the effectiveness and safety of BOC and TVR administered with pegylated interferon and ribavirin and to share the experience of a Brazilian reference center. A retrospective descriptive study was conducted in patients with HCV genotype 1 infection who started treatment between July 2013 and December 2015. Data were collected using a computerized system. A total of 115 subjects were included, of which 58 (50.4 %) had liver cirrhosis and 103 (89.6 %) used TVR. The overall SVR rate was 61.7 % (62.1 % for TVR and 58.3 % for BOC). The presence of cirrhosis was associated with a lower SVR rate, whereas patients who relapsed after prior therapy had a greater chance of showing SVR than did non-responders. The incidence of adverse drug reactions (ADRs) was high. Almost all patients (~100 %) presented with hematologic events. Furthermore, treatment had to be discontinued in 15 subjects (13 %) due to severe ADRs. In conclusion, the SVR rates in our study were lower than those reported in pre-marketing studies but were comparable to real-life data. ADRs, particularly hematological ADRs, were more common compared to those in previous studies and resulted in a high rate of treatment discontinuity.