GVHD relapse-free survival after peripheral blood hematopoietic cell transplantation for hematologic malignancies.

The preferred choice for hematopoietic cell transplantation (HCT) donors in India is a matched related donor (MRD) followed by a haploidentical (haplo) donor for patients with hematological malignancies. International data in the haplo-HCT setting is mainly using bone marrow as a source. Almost all HCTs in India use peripheral blood stem cells (PBSC), which increases the risk of graft-versus-host disease (GVHD). In this single-center prospective study from 2017 to 2021, we sought to compare these outcomes prospectively in adult patients with hematological malignancies. Patient, disease, donor, and HCT details were prospectively recorded. GVHD prophylaxis included cyclosporine + methotrexate in MRD-HCT and post-transplant cyclophosphamide (PTCy) based in haplo-HCT. The primary endpoint GVHD relapse-free survival (GRFS) was defined as the time post-HCT without any of the following events: grade III-IV acute GVHD, chronic GVHD requiring systemic immunosuppressive treatment, disease relapse, or death from any cause. A total of 41 MRD and 33 haplo-HCT recipients were included in the study. Both cohorts were matched for age, sex, diagnosis, disease risk index, donor age, sex and CMV mismatches, and CD34 counts. A lower proportion of MRD-HCT recipients than haplo-HCT received myeloablative conditioning (39% vs. 76%, p = 0.002). There was no difference in the cumulative incidence of grade III-IV acute GVHD (16% vs. 27%, p = 0.2) or moderate-to-severe chronic GVHD (58% vs. 71%, p = 0.5). The one-year GRFS was not significantly different (53% vs. 38%, p = 0.2), with median GRFS of 420 and 274 days. The relapse incidence (22% vs. 19%, p = 0.6) and non-relapse mortality (25% vs. 35%, p = 0.4) did not differ. There was no difference in overall survival at one year (60% vs. 52%, p = 0.3). Despite a higher proportion of myeloablative conditioning in the haplo-HCT cohort, all outcomes, including GRFS, were comparable to those of the MRD-HCT cohort. This should encourage patients without an MRD to undergo haplo-HCT.

A Well-Curated Cost-Effective Next-Generation Sequencing Panel Identifies a Diverse Landscape of Pathogenic and Novel Germline Variants in a Bone Marrow Failure Cohort in a Resource-Constraint Setting.

The current study is a 4-year experience in diagnosis and screening of inherited and immune bone marrow failure cases using a targeted sequencing panel. A total of 171 cases underwent targeted next-generation sequencing and were categorized as suspected inherited bone marrow failure syndrome (IBMFS) group (106; 62%) and immune/idiopathic aplastic anemia (IAA) group (65; 38%) based on clinical and laboratory criteria. A total of 110 (64%) were pediatric (aged 0 to 12 years) patients and 61 (36%) were adolescent and adult (aged 13 to 47 years) patients. In suspected IBMFS group, 47 (44%), and in IAA group, 8 (12%) revealed a likely germline pathogenic variation. Whole-exome sequencing performed in 15 of 59 suspected IBMFS group cases was negative on targeted panel, and revealed a clinically important variation in 3 (20%) cases. A total of 11 novel variants were identified. The targeted panel helped establish a diagnosis in 44% (27/61) of unclassified bone marrow failure syndrome cases and led to amendment of clinical diagnosis in 5 (4.7%) cases. Overall, diagnostic yield of this well-curated small panel was comparable to Western studies with larger gene panels. Moreover, this was achievable at a much lower cost, making it suitable for resource-constraint settings. In addition, high frequency (>10%) of cryptic pathogenic IBMFS gene variations in IAA cohort suggests routine incorporation of targeted next-generation sequencing screening in these cases.

Utility of eGVHD App for bedside GVHD assessment in a high-volume BMT center.

Assessing acute and chronic graft-versus-host disease (GVHD) is challenging because there are several classification systems. The European Society for Blood and Marrow Transplantation and the Center for International Bone Marrow Transplantation Registry task force recommends using the eGVHD application (App) to score acute GVHD according to the Mount Sinai Acute GvHD International Consortium (MAGIC) criteria and chronic GVHD according to the National Institutes of Health 2014 criteria. We prospectively used the eGVHD App at each follow-up visit in a large-volume bone-marrow transplant center in India from 2017 to 2021. We retrospectively evaluated the discrepancy in scoring GVHD severity by physicians not using the App from the same patient charts. The App user satisfaction and experience were recorded using the technology acceptance model (TAM) and the Post-Study System Usability Questionnaire (PSSUQ). In 100 consecutive allogeneic hematopoietic cell transplantation recipients, there was more discrepancy in scoring the severity of chronic GVHD (38%) than acute GVHD (9%) without using the App. The median TAM and PSSUQ scores were six (IQR:1) and two (IQR:1), respectively, indicating high perceived usefulness and user satisfaction. The eGVHD App is an excellent learning tool for hematology/BMT fellows and helps manage GVHD in high-volume BMT centers.

Cerebrospinal fluid cytology in a toddler with a posterior fossa space-occupying lesion.

An atypical teratoid rhabdoid tumour (AT/RT) is an extremely rare malignant neoplasm. Cerebrospinal fluid (CSF) involvement at presentation indicates intracranial dissemination and is associated with an aggressive course and worse outcomes. We present the characteristic cytomorphological features of AT/RT in the cerebrospinal fluid from a toddler presenting with a posterior fossa space-occupying lesion.

Adherence to long-term follow-up preventive practices in allogeneic hematopoietic cell transplantation survivors from North India.

Introduction: There are existing international guidelines for long-term follow-up (LTFU) care of allogeneic hematopoietic cell transplantation (allo-HCT) survivors. However, implementing these guidelines represents a unique challenge in resource-challenged settings. Methods: This study aimed to evaluate adherence to recommended surveillance in allo-HCT survivors at an academic center in North India and study the incidence of late effects. This single-center, retrospective study analyzed records of allo-HCT recipients from 2016 to 2020. Survivors were screened in our LTFU clinic at day +100 and +365 using cardiometabolic parameters (screening for hypertension, dyslipidemia, hyperglycemia, 24-hour urine protein, thyroid function), pulmonary function test (PFT), bone mineral density (BMD), and initiation of revaccination. Results: A total of 40/80 (50%) allo-HCT survivors were alive at a median of 888 days (IQR 515-1,306). The adherence to home-based screening parameters such as blood pressure and blood glucose was highest (>75%), followed by lab-based parameters (45-70%), and lowest for specialized tests such as PFT (<50%) at both day +100 and +365 time points. Adherence to the initiation of revaccination was only 67%. At least one cardiometabolic parameter was out of range in 55% and 63% of survivors at day +100 and +365, respectively. Conclusion: The adherence to recommended surveillance measures for allo-HCT survivors in an academic LTFU clinic at one year was only 75% overall. Cardiometabolic abnormalities were noted in more than half of the survivors. This study emphasizes the need for a structured LTFU clinic in all centers performing HCT.

Small Cell Carcinoma of Ovary, Hypercalcemic Type: Cytologic, Histopathologic, and Immunohistochemical Landscapes of a Rare Case.

BACKGROUND: Small cell carcinoma of ovary, hypercalcemia type (SCCOHT), also known as the malignant rhabdoid tumor of the ovary, is a rare and highly aggressive malignancy affecting younger women. The pathogenesis involves mutations in SWI/SNF-related, matrix-associated, actin-dependent regulator chromatin group A4 (SMARCA4)/Brahma-related gene 1 (BRG1) and/or SWI/SNF-related, matrix-associated, actin-dependent regulator chromatin group A2 (SMARCA2)/Brahma homolog (BRM). CASE: A 10-year-old girl presented with lower abdominal pain and a mass for the past 2 weeks. She underwent ultrasound-guided fine needle aspiration and core needle biopsy from the pelvic mass followed by surgery. On the basis of the characteristic morphologic and immunohistochemical features, a diagnosis of SCCOHT was rendered. Chemotherapy was started, however, she succumbed to the disease.

Pediatric bone marrow failure: Clinical, hematological and targeted next generation sequencing data.

OBJECTIVE: In this study, clinico-hematological, genetic and outcome profile of children with BMF was evaluated to delineate the underlying genotype and phenotype. DESIGN: Cases were evaluated as two groups: Group 1 (n = 56; DBA-23, FA-18, DC-2, UBMFS-13) included children with suspected IBMFS based on clinical phenotype and accessible lab investigations and Group 2 (n = 53) included children with IAA treated with IST. Targeted NGS was carried out in a subset of these children (n = 42) and supplemented with WES wherever required. RESULTS: We identified causative mutation in overall 15 of 27 tested children (55.5%) in group 1 and 2 of 15 tested children (13.3%) in group 2. In DBA, a mutation was noted in 50% cases with involvement of RPS 19 (75%) and RPL5 (25%) genes. Phenotypic abnormalities were present in 69.5% and response to steroids in 68.4% of cases at a median follow up of 33 months. In children with IAA, overall response (complete + partial) was present in 51% at a median follow up of 23 months. The 3-year OS and FFS for the cohort of IAA were 68% and 48% respectively. Targeted sequencing could also pick up germline mutations in 50% of UBMFS cases and nearly 19% of IAA cases.

Cytotoxic T- Lymphocyte Antigen-4 (CTLA4) Gene Expression and Urinary CTLA4 Levels in Idiopathic Nephrotic Syndrome.

OBJECTIVES: To detect Cytotoxic T- Lymphocyte Antigen-4 (CTLA4) single nucleotide polymorphisms (SNPs) at +49A/G (rs231775) and -318C/T (rs5742909) positions in children with idiopathic nephrotic syndrome (INS) and also assay urinary soluble CTLA4 (sCTLA4) levels in children with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and steroid sensitive nephrotic syndrome (SSNS) in remission. METHODS: The study included 59 patients of INS (MCD-23, FSGS-15 and SSNS in remission-21) and 35 healthy controls. The CTLA4 SNPs profiling was done in peripheral blood mononuclear cells and urinary sCTLA4 level was assayed by ELISA kit. RESULTS: Although frequency of homozygous +49 GG (rs4553808) genotype (26.3% vs. 11.4%; p = 0.231) and G allele (52.6% vs. 40%; p = 0.216) were found to be higher in INS as compared to controls, the differences were statistically non-significant. Genotypes GG, AG, AA and alleles A and G frequencies were comparable among MCD, FSGS and controls. SNP at -318 C/T (rs5742909) did not show homozygous TT genotype both in INS as well as controls. Median urinary sCTLA4/creatinine level was significantly higher in MCD as compared to FSGS (p = 0.027), SSNS in remission (p = 0.001) and controls (p = 0.003). CONCLUSIONS: The positive associations of +49 GG genotype and G allele in patients with nephrotic syndrome were not observed. The frequencies did not differ significantly among MCD, FSGS and controls. Urinary sCTLA4 level was significantly increased in MCD; suggesting its possible role in the pathogenesis of disease.