Evaluating the Frequencies of CNOT3, GRIA1, NFATC2, and PNPLA3 Variant Alleles and Their Association with L-Asparaginase Hypersensitivity in Pediatric Acute Lymphoblastic Leukemia in Addis Ababa, Ethiopia.

Introduction: L-asparaginase is a vital component for the treatment of childhood acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions and hepatotoxicity hinder its anti-neoplastic efficacy. Previous reports indicated that genetic variants in CNOT3, GRIA1, and NFATC2 genes might be associated with hypersensitivity reactions and PNPLA3 with liver function. Objective: In this study, it was investigated whether this association also exists in a pediatric ALL cohort from Ethiopia. Methods: Three variants GRIA1 rs4958351, CNOT3 rs73062673, and NFATC2 rs6021191 were genotyped in a cohort of 160 patients. Association analysis to investigate the association with hypersensitivity reactions was performed using logistic regression analyses. Besides these variants, a variant in PNPLA3 (rs738409) was genotyped to assess the association with liver function. Results: Genotype frequencies of GRIA1 rs4958351, CNOT3 rs73062673, and NFATC2 rs6021191 were higher/lower than previously reported. One hundred and forty-four patients were included in the association analysis of which, 18 (12.5%) developed L-ASP hypersensitivity. Though the frequency of hypersensitivity was higher in patients that carried the risk alleles of the three investigated genes, no statistically significant differences were observed. Association analysis between PNPLA3 rs738409 and liver function could not be investigated due to a lack of clinical information. Conclusion: In conclusion, none of the tested genes did predict L-asparaginase hypersensitivity in an Ethiopian pediatric ALL patients.

Incidence and determinants of hematotoxicity in acute lymphoblastic leukemia children who received 6-mercaptopurine based maintenance therapy in Addis Ababa, Ethiopia.

INTRODUCTION: The maintenance phase of acute lymphoblastic leukemia treatment is the final and longest stage of treatment, mainly focused on antimetabolite therapy. This phase is essential to eliminate residual leukemic clones and prevent relapse. However, dose-limiting hematotoxicity is a major problem during this phase resulting in dose reduction or treatment discontinuation. OBJECTIVE: In this cohort study, the clinical features and risk factors of hematological toxicity during the maintenance phase of treatment were analyzed in pediatric patients from Ethiopia. METHODS: A total of 160 patients from Tikur Anbessa specialized hospital were included in the study of which 142 had sufficient data available for analysis. Patient characteristics as well as information about the care-givers, sides-effects as reported by the care-givers and clinical factors were collected. Bivariable followed by multivariable analysis was performed to investigate which factors were associated with hematological toxicity during the maintenance phase. RESULTS: During the first six months of maintenance phase treatment grade 4 neutropenia was detected in 52.8% of the patients. The risk of developing grade 4 neutropenia was increased by about two fold in children with the age of 6 years and less compared to those with the age of more than 6 years. Similarly, the rate of developing grade 4 neutropenia among children with less than 4,500 maintenance day 1 white blood cell counts was significantly higher than that of children with normal maintenance day 1 white blood cell counts (AHR 2.477, 95% CI = 1.461-4.200, p = 0.001). CONCLUSION: In conclusion, child's age and day 1 maintenance white blood cell/absolute neutrophil counts significantly affected the occurrence of grade 4 hematotoxicity. Close monitoring for white blood cell and absolute neutrophil counts during maintenance phase treatment is recommended for early diagnosis of hematotoxicity.

Genetic variants of genes involved in thiopurine metabolism pathway are associated with 6-mercaptopurine toxicity in pediatric acute lymphoblastic leukemia patients from Ethiopia.

Introduction: Genetic variation in the thiopurine S-methyltransferase (TPMT) gene by and large predicts variability in 6-mercaptopurine (6-MP) related toxicities. However, some individuals without genetic variants in TPMT still develop toxicity that necessitates 6-MP dose reduction or interruption. Genetic variants of other genes in the thiopurine pathway have been linked to 6-MP related toxicities previously. Objective: The aim of this study was to evaluate the effect of genetic variants in ITPA, TPMT, NUDT15, XDH, and ABCB1 on 6-MP related toxicities in patients with acute lymphoblastic leukemia (ALL) from Ethiopia. Methods: Genotyping of ITPA, and XDH was performed using KASP genotyping assay, while that of TPMT, NUDT15, and ABCB1 with TaqMan® SNP genotyping assays. Clinical profile of the patients was collected for the first 6 months of the maintenance phase treatment. The primary outcome was the incidence of grade 4 neutropenia. Bivariable followed by multivariable cox regression analysis was performed to identify genetic variants associated with the development of grade 4 neutropenia within the first 6 months of maintenance treatment. Results: In this study, genetic variants in XDH and ITPA were associated with 6-MP related grade 4 neutropenia and neutropenic fever, respectively. Multivariable analysis revealed that patients who are homozygous (CC) for XDH rs2281547 were 2.956 times (AHR 2.956, 95% CI = 1.494-5.849, p = 0.002) more likely to develop grade 4 neutropenia than those with the TT genotype. Conclusion: In conclusion, in this cohort, XDH rs2281547 was identified as a genetic risk factor for grade 4 hematologic toxicities in ALL patients treated with 6-MP. Genetic polymorphisms in enzymes other than TPMT involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.

Stress and coping strategies among parents of children with cancer at Tikur Anbessa Specialized Hospital paediatric oncology unit, Ethiopia: a phenomenological study.

OBJECTIVE: This study explores sources of stress, conditions that help reduce stress levels and coping strategies among parents of children with cancer receiving chemotherapy at Tikur Anbessa Specialized Hospital (TASH) in Ethiopia. DESIGN: A qualitative phenomenological approach was used. SETTING: Parents of children receiving chemotherapy at the TASH paediatric oncology unit. PARTICIPANTS: Fifteen semistructured in-depth interviews were conducted with nine mothers and six fathers of children with cancer from November 2020 to January 2021. RESULTS: Sources of stress related to child's health condition as the severity of the child's illness, fear of treatment side effects and loss of body parts were identified. Parents mentioned experiencing stress arising from limited access to health facilities, long waiting times, prolonged hospital stays, lack of chemotherapy drugs, and limited or inadequate information about their child's disease condition and treatment. Other sources of stress were insufficient social support, stigmatisation of cancer and financial problems. Conditions decreasing parents' stress included positive changes in the child's health, receiving cancer treatment and access to drugs. Receiving counselling from healthcare providers, getting social support and knowing someone who had a positive treatment outcome also helped reduce stress. Coping strategies used by parents were religious practices including prayer, crying, accepting the child's condition, denial and communication with health providers. CONCLUSION: The main causes of stress identified by parents of children with cancer in Ethiopia were the severity of their child's illness, expectations of poor treatment outcomes, unavailability of cancer treatment services and lack of social/financial support. Measures that should be considered to reduce parents' stress include providing psycho-oncological care for parents and improving the counselling available to parents concerning the nature of the child's illness, its treatment, diagnostic procedures and treatment side effects. It may also be helpful to establish and strengthen family support groups and parent-to-parent communication, improve the availability of chemotherapy drugs and offer more education on coping strategies.

Identification and Resolution of Drug-Related Problems among Childhood Cancer Patients in Ethiopia.

BACKGROUND: Even though medications play a major role in the cure, palliation, and inhibition of disease, they also expose patients to drug-related problems. Drug-related problems are frequent and may result in reduced quality of life, morbidity, and mortality. OBJECTIVES: The study was aimed to identify, characterize, and resolve drug-related problems in the Pediatric Hematology/Oncology ward of Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia. METHODS: A prospective observational study was conducted from 25 June to 25 October 2018 to assess DRPs on patients admitted at the pediatric hematology/oncology ward of Tikur Anbessa Specialized Hospital, which is the highest level governmental tertiary care hospital in Ethiopia. Data were obtained from patients' medical charts, physicians, patients/caregivers, pharmacists, and nurses. All the collected data were entered and analyzed using the Statistical Package for the Social Sciences version 25e. Descriptive statistics were used to represent the data. RESULTS: Among the total 156 participants, DRPs were identified in 68.6% of the study subjects. Dosing problems which include dosage too low and high were the top ranking (39.3%) of all DRPs followed by needs additional therapy (27.2%) and nonadherence (14.0%). Systemic anti-infectives were the most common class of drugs involved in DRPs. Trimethoprim-sulfamethoxazole, methotrexate, vincristine, ondansetron, and metoclopramide were frequently involved in DRPs. The addition of drugs and change in drug dose were the two most proposed intervention types. Among the proposed interventions, 223 (92.15%) were fully accepted, 9 (3.72%) partially accepted, and 10 (4.13%) not accepted. CONCLUSION: DRPs are common among Pediatric Hematology/Oncology ward patients. The hospital should develop a pediatric dosing chart for the commonly prescribed medications to prevent drug-related morbidity and mortality. The integration of clinical pharmacists can mitigate risks associated with DRPs.