Narsoplimab for severe transplant-associated thrombotic microangiopathy.

BACKGROUND: Transplantation-associated thrombotic microangiopathy (TA-TMA) is an endothelial injury syndrome linked to the overactivation of complement pathways. It manifests with microangiopathic hemolytic anemia, consumptive thrombocytopenia, and microvascular thrombosis leading to ischemic tissue injury. Mannose residues on fungi and viruses activate the mannose-binding lectin complement pathway, and hence activation of the lectin pathway could be one of the reasons for triggering TA-TMA. Narsoplimab, a human monoclonal antibody targeting MASP-2 is a potent inhibitor of the lectin pathway. We describe the transplant course of a pediatric patient who developed TA-TMA following Candida-triggered macrophage activation syndrome and was treated with Narsoplimab. The data collection was performed prospectively. CASE PRESENTATION: The six-year-old girl underwent a human leucocyte antigen (HLA) haploidentical hematopoietic stem cell transplant using post-transplant Cyclophosphamide for severe aplastic anemia. In the second week of the transplant, the patient developed macrophage activation syndrome necessitating treatment with steroids and intravenous immunoglobulin. Subsequently, USG abdomen and blood fungal PCR revealed the diagnosis of hepatosplenic candidiasis. Candida-triggered macrophage activation syndrome responded to antifungals, steroids, intravenous immunoglobulin, and alemtuzumab. However, the subsequent clinical course was complicated by thrombotic microangiopathy. The patient developed hypertension in the 2nd week, followed by high lactate dehydrogenase (1010 U/L), schistocytes (5 per hpf), low haptoglobin (< 5 mg/dl), thrombocytopenia, and anemia in the 3rd week. Ciclosporin was stopped, and the patient was treated with 10 days of defibrotide without response. The course was further complicated by the involvement of the gastrointestinal tract and kidneys. She had per rectal bleeding with frequent but low-volume stools, severe abdominal pain, and hypoalbuminemia with a rising urine protein:creatinine ratio. Narsoplimab was started in the 5th week of the transplant. A fall in lactate dehydrogenase was observed after starting Narsoplimab. This was followed by the resolution of gastrointestinal symptoms, proteinuria, and recovery of cytopenia. The second episode of TA-TMA occurred with parvoviraemia and was also successfully treated with Narsoplimab. CONCLUSION: Lectin pathway inhibition could be useful in treating the fatal complication of transplant-associated thrombotic microangiopathy.

New policies to address the global burden of childhood cancers.

Childhood cancer is a major global health issue. Every year, almost 100 000 children die from cancer before the age of 15 years, more than 90% of them in resource-limited countries. Here, we review the key policy issues for the delivery of better care, research, and education of professionals and patients. We present a key list of time-limited proposals focusing on change to health systems and research and development. These include sector and system reforms to make care affordable to all, policies to promote growth of civil society around both cancer and Millennium Development Goals, major improvements to public health services (particularly the introduction of national cancer plans), improved career development, and increased remuneration of specialist health-care workers and government support for childhood cancer registries. Research and development proposals focus on sustainable funding, the establishment of more research networks, and clinical research specifically targeted at the needs of low-income and middle-income countries. Finally, we present proposals to address the need for clinical trial innovation, the complex dichotomy of regulations, and the threats to the availability of data for childhood cancers.

The role of graft T-cell size in patients receiving alemtuzumab serotherapy for non-malignant disorders: results of an institutional protocol.

Although graft T cells assist in engraftment, mediate antiviral immune-reconstitution, and cause graft-versus-host disease, graft size is not determined by T-cell content of the graft. The conventional method of graft size determination based on CD34+ cells with alemtuzumab serotherapy is associated with delayed immune reconstitution, contributing to an increased risk of viral infections and graft failure. Alemtuzumab, a long half-life anti-CD52 monoclonal antibody is a robust T-cell depleting serotherapy, and relatively spares memory-effector T cells compared to naïve T cells. We therefore hypothesized that graft size based on T-cell content in patients receiving peripheral blood stem cell graft with alemtuzumab serotherapy would facilitate immune-reconstitution without increasing the risk of graft-versus-host disease. We retrospectively analysed twenty-six consecutive patients with non-malignant disorders grafted using alemtuzumab serotherapy and capping of graft T cells to a maximum of 600 million/kg. The graft T-cell capping protocol resulted in early immune-reconstitution without increasing the risk of severe graft-versus-host disease. Graft T-cell content correlated with CD4+ T-cell reconstitution and acute graft-versus-host disease. The course of CMV viraemia was predictable without recurrence and associated with early T-cell recovery. No patient developed chronic graft-versus-host disease. Overall survival at one year was 100% and disease-free survival was 96% at a median of 899 days (range: 243-1562). Graft size determined by peripheral blood stem cell graft T-cell content in patients receiving alemtuzumab serotherapy for non-malignant disorders is safe and leads to early T-cell immune-reconstitution with excellent survival outcomes.

Changing outcomes of stem cell transplantation in primary immunodeficiencies: Results from a tertiary-care charitable trust hospital in Mumbai.

Background: Hematopoietic stem cell transplantation in primary immunodeficiency disorders has come a long way since the first transplant in 1968. In India, pediatric stem cell transplantation long-term survival outcomes range from 62.5% to 75%, compared to 90% in high-income countries. Objective: We present single-center data of primary immunodeficiency transplants with immune-reconstitution evaluation after transplantation from a charitable trust hospital. Methods: Retrospective data of children transplanted for primary immunodeficiency disorders from March 2019 to March 2022 in a newly established transplant unit were collected. Data of pretransplant infections and comorbidities, surveillance for carbapenem-resistant Enterobacteriaceae, transplant characteristics, donor source, graft-versus-host disease, posttransplant infections, immune reconstitution, overall survival at 1 year, and immunodeficiency-free survival were collated. Results: Twenty-one patients underwent transplantation for primary immunodeficiency disorders. The median age at transplantation was 3 years and 5 months (range, 7 months to 17 years). Seventy-five percent of the cohort had organ involvement, with lung being the most common organ involved, followed by central nervous system. Fifty-two percent of children had peritransplant infections, with most of them recognized at the pretransplant assessment. Among 20 of 21 children with engraftment, 94% had complete chimerism initially, with 33% developing mixed chimerism over time. The median duration of immunosuppression was 3 months after transplantation, and only 1 child required systemic graft-versus-host disease treatment for more than a year. Immune-reconstitution showed good T-cell recovery at 3 months and naive T-cell production at 6 months. There was no regimen-related or sepsis-related mortality. Overall survival of the cohort was 95% at 1-year follow-up. Immunodeficiency-free survival was 86% after a median follow-up of 20 months. Conclusions: Immunodeficiency-free and graft-versus-host disease-free survival can be achieved in the majority of children with primary immunodeficiencies using enhanced supportive care and the latest transplantation algorithms.

Current Challenges of Asian National Children's Cancer Study Groups on Behalf of Asian Pediatric Hematology and Oncology Group.

In Asia, a few countries have a long and established history of collaborative clinical trials successfully formed national children's cancer study groups, but many still do not have such groups. The process of forming national children's cancer groups is fraught with many hurdles, which varies among the countries. One of the basic requirements for running clinical trials is an affordable health care system in which most of the children with cancer can receive the proposed treatment. The health insurance coverage for children with cancer varies from <20% to as high as 100% among Asian countries, and the operation of clinical trials must also be adjusted accordingly. Shortage of research personnel is common, including medical, nursing, research coordinators, and data managers. The establishment of the Asian Pediatric Hematology and Oncology Group aims to provide a good platform for promotion of international clinical trials in the Asian countries.

Diagnosis and Management of Acquired Aplastic Anemia: Consensus Statement of Indian Academy of Pediatrics.

JUSTIFICATION: In India, there is a lack of uniformity of treatment strategies for aplastic anemia (AA), and many children are managed only with supportive care due to non-availability of hematopoietic stem cell transplantation (HSCT). PROCESS: Eminent national faculty members were invited to participate in the process of forming a consensus statement in Hyderabad in July, 2016. Draft guidelines were circulated to all members, and comments received in a online meeting in October, 2020 were incorporated into the final draft. These were approved by all experts. Objective: To facilitate appropriate management of children with acquired aplastic anemia. RECOMMENDATIONS: Key recommendations are: i) A bone marrow biopsy is must to make a diagnosis of AA; ii) Rule out inherited bone marrow failure syndromes (IBMFS), connective tissue disorders, viral infections, paroxysmal nocturnal hemoglobinuria (PNH), drug or heavy metal induced marrow suppression in all cases of AA; iii) Conservative approach to transfusions should be followed, with a target to keep hemoglobin >6 g/dL in children with no co-morbidities; iv) HLA-matched sibling donor HSCT is the preferred choice of treatment for newly diagnosed very severe/ severe AA; v) In absence of HLA-matched family donor, a matched unrelated donor (MUD) transplant or immunosuppressive therapy (IST) should be considered as alternate choice based on physician expertise; vi) Fludarabine, cyclophos-phamide and anti-thymocyte globulin (ATG) based conditioning with cyclosporine and methotrexate as graft versus host disease (GvHD) prophylaxis is the preferred regimen; vii) Horse ATG and cyclosporine are the recommended drugs for IST. One should wait for 3-6 months for the response assessment and consideration of next line therapy.

Clinical Course of Patients With Sickle Cell Anemia and Co-inherited Hematological Disorders: Experience at a Tertiary Hematological Centre.

To study the clinical course of patients with sickle cell anemia and coinherited hematological disorders. Retrospective analysis of clinical data of patients enrolled at our hospital over last 7 years was performed. Eighty four patients of symptomatic sickling disorders were registered during this period, comprising of HbSS (n = 49), HbS-ß thalassemia (n = 28), HbS-HbD disease (n = 5), HbS-ß thalassemia with G6PD deficiency (n = 1) and HbS-hemophilia A (n = 1). Among HbS-ß thalassemia, 18% suffered from occasional pain crises and 27% required occasional blood transfusion. 40% patients with HbS-HbD disease required occasional blood transfusions, one patient was transfusion dependent, while none suffered from crisis episodes. Patient with HbS-ß thalassemia with G6PD deficiency had increased transfusion requirement during first 3 years of life, which decreased after that. Patient with HbS and severe hemophilia A had only one episode of severe bleeding, suffered from 1 crisis episode. In conclusion, HbA reduces severity of HbS in HbS-ß + thalassemia. HbS-HbD disease can manifest as a transfusion dependent illness. HbSS reduces severity of G6PD deficiency after first few years of life. HbSS and hemophilia coinheritance ameliorates symptoms of hemophilia.

Laparoscopic cholecystectomy in a 2 year old male child with choleilithiasis and recurrent right hypochondrial pain: Case report and review of literature.

INTRODUCTION: Gallstone disease has been considered an uncommon entity in children and infants, but its incidence is reportedly increasing which may be attributed to widespread use of diagnostic imaging (ultrasonography). PRESENTATION OF CASE: An apparently healthy 2 year old male child presented to our Outpatient department with chief complaint of recurrent abdominal pain. The episodes of pain were acute in onset and associated with vomiting. As per the complete examination and findings, a diagnosis of chronic calculous cholecystitis was made. A four port laparoscopic cholecystectomy was done. DISCUSSION: The incidence of gallstones in children in India has not been sufficiently studied. The incidence of gallstone disease in India was found to be 0.3% with the incidence in age group 0-10 being less than 0.1%. In contrast to adult gallstone disease, it has been found that there is no female preponderance in gallstone diseases of infancy. Also, the majority of children having increased haemoglobin turnover develop pigment stones only after 5 years of age. CONCLUSION: The probability of gallstone disease in infants and young children should not be ignored. Gall stones should always be considered as a differential diagnosis when young patients present with complaints of abdominal pain.

Study on ALL-1 gene alterations in Indian childhood acute leukemias: non-isotopic Southern blotting and molecular cytogenetics.

We carried out this study to detect ALL-1 gene alterations in Indian childhood leukemias (n-84) using non-radioactive Southern blotting and FISH techniques. 18 (21.4%) patients showed altered ALL-1 gene. All 18 patients with altered ALL-1 gene did not have high WBC count and or typical CD10-/19+ phenotype. 4/18 were infants, while 14 were of 1-12 years of age. 13/18 children were boys. 14/18 expired within 1 year. Karyotyping detected abnormal chromosome 11 only in 4/43 patients and Classical t(4:11) in one AML patient but combination of Painting FISH and LS-FISH confirmed ALL-1 gene alteration in 17/18 cases. In addition, FISH identified nine translocations and multiple copies of ALL-1 gene in three cases which conventional cytogenetics had failed to detect. Our result indicates that a combination of Southern blotting, cytogenetic and FISH techniques are useful to identify ALL-1 gene alterations in childhood leukemias.

Biological therapy for pediatric malignancy: current perspectives.

Biologicals are defined as agents that are either uniquely or partially tumor-specific. Great expectations were raised by the success in agents that target a specific genetic translocation: all-trans retinoic acid, targeting the chronic myeloid leukemia retinoic acid receptor in acute promyelocytic leukemia and imatinib, a small molecule targeting the BCR-ABL translocation in chronic myeloid leukemia (CML). Thus far, the search for similar "druggable" genetic targets in pediatric cancers has not yet resulted in such dramatic results. The rarity of pediatric cancer as well as ethical considerations necessitate that the agents for testing be carefully and rigorously selected. Biologicals present an additional challenge, as they often do not lend themselves to in vitro testing. Early approaches to specific targeting of solid tumors utilized monoclonal antibodies. The microenvironment provides an interesting new biological approach to treating tumors and alteration of the host immune response provides another avenue. Biological agents are a step forward in supportive care to reduce the hematological toxicity of high-dose chemotherapy and to manage the frequent infectious complications.

Recent advances in management of acute myeloid leukemia (AML).

Acute myeloid leukemia (AML) is the most common childhood malignancy. AML has therapeutically been difficult to treat. In 2001, the World Health Organization (WHO), in conjunction with the Society for Hematopathology and the European Association of Hematopathology, published a new classification for myeloid neoplasms. A number of chromosomal abnormalities are used to predict outcome and stratify therapeutic risk groups in children with AML. Recently, alterations in receptor tyrosine kinases, tyrosine phosphatases and in oncogenes such as RAS have been implicated in the pathogenesis of AML. This article aims to review the recent development in diagnosis, treatment and monitoring of AML. Better understanding of the molecular pathogenesis of AML has led to the development of target-specific therapies. Some of the new classes of drugs include monoclonal antibody directed against the CD33 antigen, farnesyltransferase inhibitors (FTI), and FMSlike tyrosine kinase 3 (FLT3) inhibitors. The role of allogenic SCT, particularly whether it should be done during first CR or reserved for second remission, remains the most controversial issue in pediatric AML. There is a need of collaboration with international pediatric cooperative oncology groups and definitive clinical trials in order to establish use of these newer molecules in pediatric populations.