Adverse events associated with Pegaspargase biosimilar in pediatric patients with acute lymphoblastic leukemia: A prospective single-center study.

BACKGROUND: While Pegaspargase is an essential component of the treatment of acute lymphoid leukemia (ALL) in children, it causes adverse events (AEs) that sometimes make full use impossible. OBJECTIVE: The objective was to investigate the safety of Pegaspargase biosimilar in pediatric ALL patients undergoing treatment according to ICiCLe ALL-14 protocol. METHOD AND MATERIALS: A prospective study was carried out in a university teaching hospital located in the state of Maharashtra, India. Data on clinical factors and adverse reaction characteristics were gathered from hospital medical records. Suspected AEs were classified according to causality and severity. RESULTS: During the study period, 72 children had 52 suspicions of AEs during treatment with biosimilar Pegaspargase. The odds ratio of 1.11 (95%CI, 0.41-2.98) suggested that males and females were both equally likely to experience adverse drug events, despite the fact that the frequency of suspected AEs was higher in boys (66%) than in girls (33%). None of the patients experienced allergic reactions. The high-risk category had the highest number of suspected AEs (56%), followed by intermediate risk (20%) and standard risk (20%). These patients showed a high frequency of suspected AEs during the induction phase (43%) followed by the consolidation phase (26%). Sixty percent of the reactions were classified as grade 1 or 2. ALL cell type (p = 0.02), risk category (p = 0.04) and length of hospitalization (p = 0.003) were significantly correlated with suspected AEs. CONCLUSION: Bio-similar Pegaspargase in combination with chemotherapy was safe and tolerable in the pediatric ALL patients treated according to ICiCLe ALL-14 protocol. Suspected AEs ranged from mild to moderate and hepatic failure and hyperglycemia being severe.

Clinical and Molecular Findings in Mendelian Susceptibility to Mycobacterial Diseases: Experience From India.

Mendelian Susceptibility to Mycobacterial diseases (MSMD) are a group of innate immune defects with more than 17 genes and 32 clinical phenotypes identified. Defects in the IFN-γ mediated immunity lead to an increased susceptibility to intracellular pathogens like mycobacteria including attenuated Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) vaccine strains and non-tuberculous environmental mycobacteria (NTM), Salmonella, fungi, parasites like Leishmania and some viruses, in otherwise healthy individuals. Mutations in the IL12RB1 gene are the commonest genetic defects identified. This retrospective study reports the clinical, immunological, and molecular characteristics of a cohort of 55 MSMD patients from 10 centers across India. Mycobacterial infection was confirmed by GeneXpert, Histopathology, and acid fast bacilli staining. Immunological workup included lymphocyte subset analysis, Nitro blue tetrazolium (NBT) test, immunoglobulin levels, and flow-cytometric evaluation of the IFN-γ mediated immunity. Genetic analysis was done by next generation sequencing (NGS). Disseminated BCG-osis was the commonest presenting manifestation (82%) with a median age of presentation of 6 months due to the practice of BCG vaccination at birth. This was followed by infection with Salmonella and non-typhi Salmonella (13%), Cytomegalovirus (CMV) (11%), Candida (7%), NTM (4%), and Histoplasma (2%). Thirty-six percent of patients in cohort were infected by more than one organism. This study is the largest cohort of MSMD patients reported from India to the best of our knowledge and we highlight the importance of work up for IL-12/IL-23/ISG15/IFN-γ circuit in all patients with BCG-osis and suspected MSMD irrespective of age.

High-dose methotrexate-induced fulminant hepatic failure and pancytopenia in an acute lymphoblastic leukaemia paediatric patient.

Methotrexate treatment has been associated with an array of liver-related adverse events like asymptomatic transaminase elevations, fatal necrosis and fibrosis. Here we present a child with relapse Pre B cell acute lymphoblastic leukaemia who developed and died of fulminant hepatic failure and pancytopenia soon after the administration of high-dose MTX. This case is unusual due to a series of adverse events that led to severe toxicity. The child received 1 g/m2 dose of methotrexate infusion for 36 hours. The patient developed drowsiness with altered sensorium in the 72 hours after starting the infusion. Investigations revealed severe pancytopenia along with grossly deranged liver function tests and coagulation profile. On the fourth day of paediatric intensive care unit admission, the child went into cardiac arrest and could not be revived.

Serum Methotrexate Level and Side Effects of High Dose Methotrexate Infusion in Pediatric Patients with Acute Lymphoblastic Leukaemia (ALL).

Methotrexate (MTX) is an extensively prescribed antimetabolite especially in the treatment of several pediatric cancers, though managing toxicities associated with methotrexate in high dose continues to be a challenge. A prospective study was carried out from April 2017 to October 2018. Children of either sex below 18 years at the time of enrolment and receiving high dose Methotrexate intravenous infusion over 24 h as a 2 g/m2, 3 g/m2 and 5 g/m2 dose was included in the study. The serum methotrexate level was estimated after the start of 48 h HDMTX infusion by using the ARCHITECT methotrexate assay. Toxicity due to HDMTX was assessed by Common Terminology Criteria for Adverse Events v.5.0. A total of 244 HDMTX infusions were delivered to 62 ALL patients. From the total of 244 cycles, serum methotrexate level in 35 cycles after the start of 48 h HDMTX infusion was found to be ≥ 1.0 µmol/L with reported toxicities among 31 cycles (88.6%). In 209 cycles MTX level was found to be less than 1.0 is statistically significant as compared to other cycles (p < 0.0001). Highest toxicities reported were in cycle I (38.8%). The toxicities such as oral mucositis, neutropenia, the elevation of liver enzymes, dermatological toxicities were found more in cycles whose methotrexate level are greater than 1.0 µmol/L. Dose reduction, increased the length of stay and treatment delay occurred in patients with severe toxicities. Severe toxicities of methotrexate can be interrelated with serum methotrexate levels at 48 h after the start of HDMTX infusion.

Case report on hypersensitivity to methotrexate infusion in a pediatric acute lymphoblastic leukaemia patient.

Methotrexate is extensively used in the treatment of various malignancies and autoimmune conditions. Methotrexate is associated with several toxicities, while hypersensitivity reactions to methotrexate are unusual, but have been reported in adult cancer patients. Hereby, we detail the case of a child with acute lymphoblastic leukaemia who developed a hypersensitivity reaction to high-dose methotrexate infusion (HDMTX) during the fourth cycle of HDMTX. The child was rechallenged with another brand of methotrexate; she started complaining of itching on trunk within 5 min of infusion. Few studies have reported that desensitization has been helpful in children with hypersensitivity reactions allowing the continuation of HDMTX. However, it was decided to omit parenteral methotrexate for this child. Cranial radiotherapy was given for CNS prophylaxis. In conclusion, unexpected hypersensitivity with methotrexate should be kept in mind during the treatment especially with high-dose infusion.

'Quality of Life' of Parents of Children Suffering from Pediatric Malignancies in a Low Income Setting.

OBJECTIVES: To evaluate the impact of pediatric malignancies on quality of life (QOL) and psychological status of parents and to correlate it with well-matched controls and socioeconomic status. METHODS: A prospective comparative cross-sectional study was conducted. Seventy parents of children diagnosed with pediatric malignancies within the last three months were enrolled in the study group (SG) and 50 matched parents of healthy children as the control group (CG). Assessment was done by WHOQOL-BREF questionnaire, Depression Anxiety Stress Score (DASS) scale and Kuppuswamy scale. Data analysis was done by using Statistical Package for social sciences (SPSS) version 20.0. p value <0.05 considered as significant. RESULTS: Mean score of QOL for SG in physical health domain (D1), psychological health (D2), social relationships (D3) and environment health (D4) was 48.64, 43.07, 47.36, and 40.58 respectively whereas that of CG was 79.38, 76.32, 80.58 and 72.86 respectively and the difference was statistically significant (p value <0.001). The environmental domain (D4) had the lowest mean score amongst all domains in the SG. QOL was maximally affected by the parameter sleep, depression, personal relationship and lack of information in the respective domains. Mean depression, anxiety and stress score of SG was 23.43, 20.33, 23.56 respectively whereas that of the CG was 7.1, 8.06 and 8.54 respectively and this was statistically significant (p value <0.001). The QOL of SG in D1 for the lower socioeconomic class was 48.86 and for the upper class was 63 and this difference was statistically significant (p value <0.015). Similarly in D2 and D4 the QOL scores went higher with the socioeconomic class and this was statistically significant (p value < 0.007 and p value <0.030 respectively). CONCLUSIONS: SG had poorer QOL and were significantly more depressed, anxious and stressed. It is concluded that effective interventions are needed to aid these families to improve outcomes by delivering the benefit of vastly improved therapeutic strategies in this field.

Human Leukocyte Antigen-B27: The Genetic Predisposition Leading to Reactive Arthritis during Induction Phase Chemotherapy for Acute Myeloid Leukemia.

We report a case of reactive arthritis (ReA) during induction phase chemotherapy of a 15-year-old male patient with acute myeloid leukemia (AML) M4 with inv(16), most probably due to a genetic predisposition of being human leukocyte antigen b27 (HLA-B27) positive. The episode of ReA recurred during consolidation therapy; however, the patient was asymptomatic after the completion of treatment. The link between HLA-B27 and a large family of inflammatory rheumatic diseases is a well-established fact, but interestingly, there is also a molecular link between HLA-B27 and hematological malignancies. This case brings to our notice, the common immunological, molecular, and microbiological link between AML, HLA-B27, and ReA. It also emphasizes the fact that clinicians should have a high index of suspicion of HLA-B27 positivity, if a case of AML develops arthritis during chemotherapy, since early introduction of immunosuppressive medications for arthritis may reduce morbidity and prevent delay in the administration of further chemotherapy cycles.

Juvenile granulosa cell tumor associated with Ollier disease.

Juvenile granulosa cell tumor (JGCT) is a rare neoplasm of childhood. Interestingly, it is known to be associated with Ollier disease, which is a rare bone disease characterized by multiple enchondromatosis. There is paucity of literature about the co-occurence of these two conditions. However, this association is noteworthy because these two conditions share a common pathogenesis. We report a case of JGCT in a 2.5-year-old female child in which multiple enchondromas mimicking bony metastasis were an incidental finding during routine workup for tumor staging, thus leading to a diagnosis of Ollier disease.