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, cyclophosphamide 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.

Pediatric Hemophagocytic Lymphohistiocytosis - A Single Center Study

Objective: To describe the epidemiological features, outcomes and prognostic factors in diagnosis of pediatric hemophagocytic lymphohistiocytosis (HLH). Methods: 118 children fulfilling the inclusion criteria for HLH were identified from review of hospital records for period January, 2010 to December, 2019. Result: Median age at diagnosis was 4 years (range13 days-15 years). Presenting features were fever (100%), hepatosplenomegaly (91%), neurological symptoms (23%), bicytopenia (76%), transaminitis (67.3%), increased soluble interleukin-2 receptor) (sIL-2R) (78%) and hemophagocytosis on bone marrow (75%). Median follow-up duration was 13.5 months (3 days to 102 months). Primary HLH was identified in 27 (23%) patients. Etiology of secondary HLH was infections in 53 (45%), rheumatologic illnesses in 21 (18%) and malignancies in 8 (6%) children. Treatment modalities were steroid only (25%), anti-infectious agent (58%), multi-agent chemotherapy (43%) and HSCT (40%); mortality among above treatment groups were 25%, 58%, 43% and 40%, respectively. 15 patients (13%) had relapsed/refractory HLH who were treated with salvage chemotherapy and hematopoietic stem cell transplantation (HSCT). The overall mortality rate was 39%; mortality within 30 days seen in 23%. Estimated overall survival (OS) and event free survival (EFS) at 3 years were 62% and 61%, respectively. Conclusion: Pediatric HLH is an aggressive disease with high mortality. Hyponatremia, hyperbilirubinemia, coagulopathy and increased sIL2 receptor level at diagnosis predicts poor outcome.

Consensus Statement of the Indian Academy of Pediatrics in Diagnosis and Management of Hemophilia

Justification: Despite having standard principles of management of hemophilia, treatment differs in various countries depending onavailable resources. Guideline for management of hemophilia in Indian setting is essential.Process: Indian Academy of Pediatrics conducted a consultative meeting on Hemophilia on 18th September, 2016 in New Delhi, whichwas attended by experts in the field working across India. Scientific literature was reviewed, and guidelines were drafted. All expertcommittee members reviewed the final manuscript.Objective: To bring out consensus guidelines in diagnosis and management of Hemophilia in India.Recommendations: Specific factor assays confirm diagnosis and classify hemophilia according to residual factor activity (mild 5-40%,moderate 1-5%, severe <1%). Genetic testing helps in identifying carriers, and providing genetic counseling and prenatal diagnosis.Patients with hemophilia should be managed by multi-specialty team approach. Continuous primary prophylaxis (at least low-doseregimen of 10-20 IU/kg twice or thrice per week) is recommended in severe hemophilia with dose tailored as per response. Factorreplacement remains the mainstay of treating acute bleeds (dose and duration depends on body weight, site and severity of bleed).Factor concentrates (plasma derived or recombinant), if available, are preferred over blood components. Other supportive measures(rest, ice, compression, and elevation) should be instantly initiated. Long-term complications include musculoskeletal problems,development of inhibitors and transfusion-transmitted infections, which need monitoring. Adequate vaccination of children withhemophilia (with precautions) is emphasized

Umbilical Cord Blood Banking: Consensus Statement of the Indian Academy of Pediatrics

Justification: Practitioners and people need information about the therapeutic potential of umbilical cord blood stem cells and pros andcons of storing cord blood in public versus private banks.Process: Indian Academy of Pediatrics conducted a consultative meeting on umbilical cord blood banking on 25th June 2016 in Pune,attended by experts in the field of hematopoietic stem cell transplantation working across India. Review of scientific literature was alsoperformed. All expert committee members reviewed the final manuscript.Objective: To bring out consensus guidelines for umbilical cord banking in India.Recommendations: Umbilical cord blood stem cell transplantation has been used to cure many malignant disorders, hematologicalconditions, immune deficiency disorders and inherited metabolic disorders, even when it’s partially HLA mismatched. Collectionprocedure is safe for mother and baby in an otherwise uncomplicated delivery. Public cord blood banking should be promoted over privatebanking. Private cord blood banking is highly recommended when an existing family member (sibling or biological parent) is sufferingfrom diseases approved to be cured by allogenic stem cell transplantation. Otherwise, private cord blood banking is not a ‘biologicalinsurance’, and should be discouraged. At present, autologous cord stem cells cannot be used for treating diseases of genetic origin,metabolic disorders and hematological cancers. Advertisements for private banking are often misleading. Legislative measures arerequired to regularize the marketing strategies of cord blood banking.

Health Related Quality of Life in Patients with Transfusion-dependent Thalassemia.

Patients with transfusion-dependent thalassemia are expected to have an unfavorable quality of life due to multiple factors. We studied the quality of life in 72 patients (age 5-39 y) with transfusion-dependent thalassemia in the era of improved care, and assessed different parameters affecting it.

Plasma Epstein-Barr Virus (EBV) DNA as a Biomarker for EBV-associated Hodgkin lymphoma.

Objective: To assess plasma Epstein-Barr virus (EBV) DNA as a biomarker of tumour burden at diagnosis and during therapy in children with Hodgkin lymphoma. Design: Case-control study, with prospective follow-up of the Hodgkin lymphoma cohort (2007-2012). Setting: Pediatric Hematology Oncology unit of a tertiary care hospital in Delhi. Patients: Thirty children with Hodgkin lymphoma and 70 sex and age-matched controls (benign lymphadenopathy 19, non-lymphoid malignancy 29, Burkitt lymphoma 5, healthy children 17). Intervention: Positive EBV-staining on immunohistochemistry was defined as EBV-associated Hodgkin lymphoma. Plasma EBV real-time quantitative polymerase chain reaction (PCR) was tested at presentation, after first and last chemotherapy cycles, and on follow-up. Main outcome measures: Plasma EBV quantitative PCR was compared between cases and controls. Its kinetics was assessed during and after chemotherapy. Results: EBV quantitative PCR was positive in 19 (63%) Hodgkin lymphoma cases (range 500–430,000 copies/mL), with 87.5% accuracy (kappa=0.69) as compared with EBVimmunohistochemistry. Sensitivity and specificity of the quantitative PCR were 87.5% and 81.8%, respectively. Only boys showed positive EBV immunohistochemistry and/or quantitative- PCR positivity. All controls were quantitative-PCR negative. All quantitative-PCR positive cases with follow-up blood sample showed EBV clearance after the first cycle. A quantitative-PCR negative case in long-term remission became positive at relapse. EBV status did not influence survival. Conclusion: Plasma EBV-DNA, detectable in EBV-associated Hodgkin lymphoma, becomes undetectable early after initiating therapy. It can be used as a biomarker of treatment response in EBV-associated Hodgkin lymphoma.

Serum Vascular Endothelial Growth Factor-A Levels During Induction Therapy in Children with Acute Lymphoblastic Leukemia.

Objective: To evaluate serum vascular endothelial growth factor (VEGF) levels in children with acute lymphoblastic leukemia (ALL) during the induction phase of chemotherapy. Design: Prospective sudy. Setting: Hospital-based study over 18 months. Patients: 30 children with ALL and 17 healthy age- and sexmatched controls. Intervention: Serum concentration of VEGF-A–165 isoform (s- VEGF) was measured by enzyme-linked immunoabsorbant assay at diagnosis and at the end of induction chemotherapy. Main outcome measures: s-VEGF was compared with markers of tumor burden. Kinetics of s-VEGF was assessed in response to induction chemotherapy. Results: Median VEGF was significantly lower in untreated patients than in controls (17.0 vs. 42.6 pg/mL, P=0.004). s-VEGF levels were fairly correlated with WBC count (r=-0.56, P=0.004) and LDH (r=-0.52, P=0.02) at diagnosis. All patients but one were in morphologic remission at the end of induction. Median s-VEGF concentration on day 29/33 was significantly higher than on day 1 (44.2 pg/mL, P=0.009). Conclusion: Untreated children with ALL have significantly lower s-VEGF concentration than controls. At the end of the induction therapy, s-VEGF increased to levels similar to controls. The role of ligand-receptor interaction between VEGF and VEGF receptors on leukemia cells needs to be further delineated.