Survey-based assessment of hematopoietic stem cell graft manipulation (minimal) by cell therapy labs supporting hematopoietic stem cell transplants in India.

BACKGROUND AIMS: Hematopoietic stem cell transplants (HSCTs) are increasingly being offered to patients in India for various conditions. The Indian Stem Cell Transplant Registry shows that a total of 2533 transplants were done in India in 2019. METHODS: An epidemiological descriptive cross-sectional survey (55 questions) of centers providing HSCT in India was planned to analyze variations in policies and practices regarding HSCT graft manipulation (i.e., plasma reduction, red blood cell [RBC] depletion and cryopreservation). A total of 63 of 102 centers responded to the survey (response rate, 61.7%), mostly from the northern part of India (27 of 63 [42.8%]). RESULTS: The majority of responding centers reported performing >50 HSCTs annually (n = 24 [38%]), and 92% (58 of 63) performed stem cell collections from a pediatric donor/patient (age <18 years). A total of 56 of 63 responding centers indicated that they did product manipulations involving cryopreservation (n = 45), plasma reduction (n = 42) and RBC depletion (n = 28). Cryopreservation was primarily done by blood centers (27 of 45 [60%]), with dimethyl sulfoxide (DMSO) being the primary constituent, used most commonly at a concentration of 5-10% (28 of 45 centers). Dump freezing was most commonly used (27 of 45) with a -80°C deep freezer. A 7-aminoactinomycin D based viability assessment was also most commonly used (30 of 45). Thawing of the product was done mainly at the bedside (30 of 45) using a wet-type thawer (36 of 45), and washing of DMSO was done by a few centers (seven of 45). Plasma reduction and RBC depletion were primarily done for ABO incompatibility at blood centers. CONCLUSIONS: This survey demonstrates the lack of standardization and uniformity in the minimal manipulation of hematopoietic stem cell grafts in centers supporting HSCT in India. This work also highlights the need for more studies and country-specific recommendations to establish best practices.

Cost-effectiveness analysis of emicizumab prophylaxis in patients with haemophilia A in India.

INTRODUCTION: Emicizumab is the initial subcutaneously administered bispecific antibody approved as a prophylactic treatment for patients with haemophilia A (PwHA). AIM: This study assessed the economic evaluation of emicizumab treatment for non-inhibitor severe haemophilia A (HA) patients in India. METHODS: A Markov model evaluated the cost-effectiveness of emicizumab prophylaxis compared to on-demand therapy (ODT), low-dose prophylaxis (LDP; 1565 IU/kg/year), intermediate-dose prophylaxis (IDP; 3915 IU/kg/year) and high-dose prophylaxis (HDP; 7125 IU/kg/year) for HA patients without factor VIII inhibitors. Inputs from HAVEN-1 and HAVEN-3 trials included transition probabilities of different bleeding types. Costs and benefits were discounted at a 3.5% annual rate. RESULTS: In the base-case analysis, emicizumab was cost-effective compared to HDP, with an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-years (QALY) of Indian rupees (INR) 27,869. Compared to IDP, ODT and LDP, emicizumab prophylaxis could be considered a cost-effective option if the paying threshold is >1 per capita gross domestic product (GDP) with ICER/QALY values of INR 264,592, INR 255,876 and INR 305,398, respectively. One-way sensitivity analysis (OWSA) highlighted emicizumab cost as the parameter with the greatest impact on ICERs. Probabilistic sensitivity analysis (PSA) indicated that emicizumab had a 94.7% and 49.4% probability of being cost-effective at willingness-to-pay (WTP) thresholds of three and two-times per capita GDP. CONCLUSION: Emicizumab prophylaxis is cost-effective compared to HDP and provides value for money compared to ODT, IDP, and LDP for severe non-inhibitor PwHA in India. Its long-term humanistic, clinical and economic benefits outweigh alternative options, making it a valuable choice in resource-constrained settings.

Answers to common questions about COVID-19 vaccines in children with cancer.

BACKGROUND: The SARS-CoV-2 outbreak in 2020 evolved into a global pandemic, and COVID-19 vaccines became rapidly available, including for pediatric patients. However, questions emerged that challenged vaccine acceptance and use. We aimed to answer these questions and give recommendations applicable for use in pediatric patients with cancer by healthcare professionals and the public. METHODS: A 12-member global COVID-19 Vaccine in Pediatric Oncology Working Group made up of physicians and nurses from all world regions met weekly from March to July 2021. We used a modified Delphi method to select the top questions. The Working Group, in four-member subgroups, answered assigned questions by providing brief recommendations, followed by a discussion of the rationale for each answer. All Working Group members voted on each recommendation using a scale of 1 to 10, 10 being complete agreement. A "pass" recommendation corresponded to an agreement ≥7.5. RESULTS: We selected 15 questions from 173 suggested questions. Based on existing published information, we generated answers for each question as recommendations. The overall average agreement for the 24 recommendations was 9.5 (95% CI 9.4-9.6). CONCLUSION: Top COVID-19 vaccine-related questions could be answered using available information. Reports on COVID-19 vaccination and related topics have been published at record speed, aided by available technology and the priority imposed by the pandemic; however, all efforts were made to incorporate emerging information throughout our project. Recommendations will be periodically updated on a dedicated website.

A comprehensive molecular study identified 12 complementation groups with 56 novel FANC gene variants in Indian Fanconi anemia subjects.

Fanconi anemia (FA) is a rare autosomal or X-linked genetic disorder characterized by chromosomal breakages, congenital abnormalities, bone marrow failure (BMF), and cancer. There has been a discovery of 22 FANC genes known to be involved in the FA pathway. This wide number of pathway components makes molecular diagnosis challenging for FA. We present here the most comprehensive molecular diagnosis of FA subjects from India. We observed a high frequency (4.42 ± 1.5 breaks/metaphase) of chromosomal breakages in 181 FA subjects. The major clinical abnormalities observed were skin pigmentation (70.2%), short stature (46.4%), and skeletal abnormalities (43.1%), along with a few minor clinical abnormalities. The combination of Sanger sequencing and Next Generation Sequencing could molecularly characterize 164 (90.6%) FA patients and identified 12 different complementation groups [FANCA (56.10%), FANCG (16.46%), FANCL (12.80%), FANCD2 (4.88%), FANCJ (2.44%), FANCE (1.22%), FANCF (1.22%), FANCI (1.22%), FANCN (1.22%), FANCC (1.22%), FANCD1 (0.61%) and FANCB (0.61%)]. A total of 56 novel variants were identified in our cohort, including a hotspot variant: a deletion of exon 27 in the FANCA gene and a nonsense variant at c.787 C>T in the FANCG gene. Our comprehensive molecular findings can aid in the stratification of molecular investigation in the diagnosis and management of FA patients.

Assessing the current knowledge, attitude and behaviour of adolescents and young adults living with haemophilia.

INTRODUCTION: There is significant incidence of Haemophilia in India, with second largest number of persons with Haemophilia A. 20,778 patients registered with Haemophilia Foundation of India in 2018. Research in India includes diagnostic studies, complications and co-morbidities, prenatal diagnosis, inhibitor development and gene therapy. Limited is known about quality of life of these patients. Since Haemophilia leads to the loss of 'normal lifestyle' in young people resulting in emotional distress and depression, it is important to analyse Knowledge, Attitude and Behaviour of persons with Haemophilia. AIM: The aim of the study is to focus on exploring the status of Haemophilia and knowledge, attitude, behaviour of adolescents and youths with haemophilia with the objectives to study 1) the current medical status of haemophilia amongst target population; 2) the knowledge, attitude and behaviour of patients with haemophilia towards their condition. METHODS: Respondents in the age group of 15-30 years, who were registered with the Hemophilia Treatment Centers of Government Hospitals/Hemophilia Societies, were interviewed. Data were collected using a structured questionnaire. The study was conducted in two different states and with respondents of two different age groups. FINDINGS: Most respondents suffered from severe haemophilia and co-morbidities such as anxiety, stress, chronic pain and head-ache. All of them felt that haemophilia interferes in leading a normal life and perceive a grim future. CONCLUSION: Young people in India need technical, financial and psychological support to prevent complications related to haemophilia. While most of them take responsibility for their health, more behavioural changes need to be inducted to improve quality of life.

Taking on a pandemic's challenge: Emergent solutions from a single Hemophlia treatment center in North India.

INTRODUCTION: The global pandemic caused by SARS-COV-2 infection has raised several unique concerns in the bleeding disorders community. Although the risk of COVID-19 infection is not increased in patients with inherited bleeding disorders, the indirect effects of this infection are many. METHODS: A cross sectional survey was conducted among patients registered to our centre with inherited bleeding disorders. A web-based based questionnaire was developed and shared with patients and families. RESULTS: 120 patients/ families answered the questionnaire completely. During the period of lockdown, many had bleeds that were left untreated due to either difficulty in travel or unavailability of treatment. The time to treatment ranged from 8 h to 15 days in those who had a bleed. 36 % faced financial difficulties and 40 % families reported losing their job or source of income during this period. DISCUSSION: Few solutions that emerged while treating patients during this period and recommendations are discussed. Even though haemophilia has been included under the essential health services and states mandated to continue treatment for these patients despite the global crisis, patients still face challenges in terms of transport and finance.

Convalescent plasma to aid in recovery of COVID-19 pneumonia in a child with acute lymphoblastic leukemia.

The natural history of COVID-19 infection in children is still evolving as the pandemic unfolds. Few cases of severe and often fatal COVID-19 have been reported although the infection is mild in the large majority. Children with cancers are recognised as a high risk group for all infections. Since there aren't any definite treatment guidelines established in children with severe COVID, treatment is guided by adult recommendations which too are often not evidence based. We report the case of a 4-year-old girl with severe COVID-19 associated pneumonia who presented to us as febrile neutropenia. The use of convalescent plasma along with steroids and IVIG showed dramatic results in this child and she recovered without the need for any specific treatment. This is highlighted as one of the earliest cases that is reporting the use of convalescent plasma in a child; the first ever in a child with underlying malignancy.

IgA-mediated autoimmune hemolytic anemia in an infant.

Autoimmune Hemolytic anemia (AIHA) a relatively uncommon form of hemolytic anemia in children, occurs due to the premature destruction of red blood cells caused by presence of autoantibodies directed against antigens on RBCs. Warm reactive AIHA is the most common form due to IgG isotype of immunoglobulin class binding to autologous RBCs at 370C and confirmed with a positive DAT screening. We present a case of DAT-negative primary warm AIHA in an infant due to IgA antibody. A 10 month old male infant presented with dark colored urine and irritability for past two months, with associated history of fever, diarrhea and vomiting. He had received one red cell transfusion 10 days prior. On physical examination he had pallor with tachycardia without splenomegaly. On investigation his hemoglobin was 5.8 g/dl, WBC 25.9 × 103/mm3 and normal platelets counts. Peripheral blood smear had spherocytes and biochemical values showed high bilirubin and LDH. Immunohematological work up revelaed polyspecific DAT was negative but monospecific DAT screening showed strong (4+) positivity for IgA and a weak IgG positivity. The patient was diagnosed as IgA-mediated Warm AIHA and was started on prednisolone at 2 mg/kg/day following which hemoglobin improved over the next 2 months. After 2 weeks, prednisolone was tapered and stopped by the end of 3 months. Patients with clinical and laboratory evidence of acute hemolysis, an additional screening for IgA antibody may be done even in cases where poly-specific DAT is negative. Early detection helps in avoiding further investigations and provide efficient management.

Aplastic Anemia: Non-COVID Casualties in the COVID-19 Era.

With the emergence of COVID-19 pandemic, health care for many non-COVID illnesses has inadvertently slid back. For most patients with life-threatening illnesses, the directive from the Ministry of Health and Family Welfare to continue the treatment for essential health services has come as a relief. However, for certain life-threatening illnesses such as aplastic anemia, the situation has been grim. We discuss the poor outcome of 2 children followed up at our center for aplastic anemia and analyze the reasons for the same.

Trisomy chromosome 6 as a sole cytogenetic abnormality in acute myeloid leukemia.

Identification of cytogenetic abnormalities plays an important role in the diagnosis and prognosis of leukemias. Isolated trisomy 6 is a rare abnormality, the prognostic significance of which is not well established. We report one case of acute myeloid leukemia (AML-M5 variant) with trisomy 6 as the sole cytogenetic abnormality. Previously, trisomy 6 has been reported in aplastic anemia, myelodysplastic syndrome, and AML, usually associated with hypocellular marrow. However, our patient had a very short history and hypercellular marrow infiltrated with blasts. We report this case due to the rarity of the condition. More studies are required to ascertain the role of trisomy 6 in the development of leukemia as well as in prognosis.

X-linked hyper IgM syndrome: clinical, immunological and molecular features in patients from India.

BACKGROUND: X-linked hyper-IgM (XHIM) is a primary immunodeficiency disorder characterized by recurrent infections, low serum IgG and IgA and normal or elevated IgM. It results from mutations in the CD40 ligand (CD40L) gene. Confirmation of diagnosis with identification of underlying molecular defect is important for the initiation of appropriate therapeutic interventions, including immunoglobulin replacement, antibiotics and bone marrow transplantation. METHODS: To investigate the molecular basis of XHIM, we evaluated 7 patients with suspected XHIM and abnormal CD40L expression on activated CD4(+) T lymphocytes. The entire coding region and intronic splice sites of the CD40L gene were sequenced from the genomic DNA of the patients. RESULTS: 7 mutations; 3 nonsense (c.172delA, c.A229T, c.C478T), 1 missense (c.A506G) and 3 splice sites [c.346+2(T→C), c.289-1(G→C), c.346+1(G→T)] were identified, out of which 5 were novel. CONCLUSION: A wide heterogeneity in the nature of mutations has been observed in Indian XHIM patients in the present study. Identification of mutations in this rare disorder will help in genetic diagnosis in affected families which could be further useful in prenatal diagnosis.

Disseminated myeloid sarcomas-a rare presentation of acute myeloid leukemia.

Acute Myeloid Leukemias (AML) may present rarely as anatomical distortions at extramedullary sites, termed as Myeloid Sarcomas (MS). Though MS can involve different sites, concomitant involvement of multiple sites is very rare. Here, we describe an adolescent girl who presented with disseminated MS at multiple sites. Such a presentation of AML has not been described before. The delay in presentation of the patient to a proper medical center is also to be noted here.

A Comparative Analysis of the Bleeding Profile and Quality of Life Among Women With Hemophilia Genotype Compared to Other Bleeding Disorders.

Introduction Women with bleeding disorders continue to be underdiagnosed as well as undertreated. Women with bleeding disorders include those with genotype for hemophilia (traditionally named hemophilia carriers), von Willebrand disease (VWD), platelet function disorders, and rare bleeding disorders. Among these women, the carriers of hemophilia are usually considered asymptomatic. The present study compares the bleeding profile and quality of life (QOL) of women and girls with hemophilia and compares it to those diagnosed with VWD and rare bleeding disorders. Methods The present study is part of a prospective observational study (August 2023-July 2028) done on women and girls >12 years in two groups. Group 1 was mothers, sisters, or daughters of patients with hemophilia A who were proven carriers. Group 2 was girls and women registered at our center as following bleeding symptoms and diagnosed as either suffering from VWD or rare bleeding disorders. The bleeding profile was assessed by 1:1 interview using the International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT). Health-related QOL (HRQOL) was assessed using the EuroQOL five dimension (EQ5D5L) questionnaire. Results The baseline data collected in the first six months of this prospective study is being presented here. At the time of submission, the center caters to 970 patients with hemophilia and inherited bleeding disorders. Eighty girls (post pubertal) and women with either obligate carrier status for hemophilia (n=68) or a previously diagnosed bleeding disorder (10 VWD, one afibrinogenemia, one factor VII deficiency) were enrolled. The median age of Group 1 was 35 years (25-70 years), whereas that of Group 2 was 15.5 years (13-23 years). In Group 1 (women and girls with hemophilia (WGH)), 58 and 10 were carriers of hemophilia A and B, respectively. Additionally, 83% of WGH had more than one family member with bleeding disorder, whereas 75% of Group 2 had a positive family history. The number of family members with the same disorder ranged from 0-4. Among 68 hemophilia carrier women, 20 reported bleeding symptoms (29.4%), of which 18 reported menorrhagia, one antepartum hemorrhage, and one post-partum hemorrhage and two had joint/muscle bleeds and one each had ENT and gastrointestinal bleeding. Three of them were admitted for treatment of excessive bleeding and treated with plasma/red cells. Three women reported gynecological procedures for excessive bleeding, one was on treatment for ovarian cysts, and four received packed red cells after delivery. The BAT score above 6 was reported only in 10% of WGH. Eighteen patients had undergone a surgical procedure in their life, and three of these women required a transfusion during surgery. Only one woman reported similar complaints in her daughter. The comparative analysis of HRQOL showed a significantly worse score for Group 1 in EQ5D5L domains for pain and anxiety/depression compared to that of Group 2. Conclusions A significant proportion of previously asymptomatic women with hemophilia carrier status were recognized to have significant bleeding tendencies. The QOL of these carriers is comparable to girls with VWD and rare bleeding disorders and requires special attention.

Freedom From Bleeds With Low-Dose Emicizumab Prophylaxis in Inhibitor-Positive Hemophilia A.

Background: The real-world data on outcome of hemophilia A patients with inhibitors (HAI) is sparse, especially from developing countries. In a setting of inequitable healthcare opportunities for hemophilia patients, especially those with inhibitors, low-dose practices of emicizumab are emerging. In the present article, we describe our experience of managing HAI patients on low-dose emicizumab over a period of 56 months (from December 2019 to August 2024). Methods: The present study reports the response of patients with inhibitor-positive severe hemophilia A (HAI) and a high annual bleed rate to two-dose schedules of emicizumab prophylaxis. All patients with HAI were previously managed with on-demand bypassing agents (BPAs) before being shifted to emicizumab. Seven patients were treated on standard dose of 3 mg/kg weekly for 4 weeks followed by once in 2 weeks, whereas 25 patients were started on low dose of 3 mg/kg once in 4 weeks with or without loading as per clinical decision. Bleed frequency, joint involvement, trough drug level and hemophilia joint health score (HJHS) were documented serially till in September 2023 (median of 16.4 months of follow-up). After September 2023, all patients were shifted to low dose of 3 mg/kg once in 4 weeks, following which 18 more patients were added, and this regimen has continued to date. Results: Thirty-two patients were initiated on emicizumab prophylaxis between December 2019 and December 2022. The median duration of follow-up of this cohort was 16.4 months (7.7 - 27.3 months). There was a significant reduction in bleed rate and improvement in HJHS in both arms after initiation of emicizumab. During a cumulative follow-up period of 562.8 months involving the 32 patients, only one patient experienced a bleed that required treatment. At 12 months post-initiation, the median baseline HJHS improved from 9 to 0 in children who received full dose and from 12 to 4 in those who received low dose. The mean emicizumab trough level observed in September 2023 in both groups were 29.92 ± 2.53 µg/mL and 12.6 ± 3.79 µg/mL, respectively. No significant difference was noted either in treated bleeds or HJHS score between patients who received standard or low-dose emicizumab. In view of clinical equivalence, the standard-dose patients were also shifted to low dose, and 18 more patients were subsequently added to this arm since September 2023. The last date of follow-up for this analysis was 31 Aug 2024. The cost of treatment on low-dose emicizumab in India compared to on-demand BPAs modeled on a child weighing 10 kg is analyzed. Conclusions: Emicizumab prophylaxis even in lower doses is effective in preventing bleeds and improving joint outcome in HAI with pre-existing high bleed rate and arthropathy. This opens up an avenue for providing equity in healthcare delivery for HAI in low- and middle-income countries (LMICs) such as India.

Expert Opinions on the Management of Hemophilia A in India: The Role of Emicizumab.

Hemophilia A (HA) is a genetic disorder of hemostasis associated with a deficiency or reduced activity of clotting factor VIII (FVIII). This disorder remains unacceptably underdiagnosed in India. Early diagnosis and appropriate management of HA can substantially prevent morbidity and mortality. Currently, HA is managed with regular replacement therapy using standard or extended half-life FVIII concentrates or non-factor drug products. The challenges associated with FVIII concentrates include plateauing of drug effect, issues with its administration and adherence to treatment, breakthrough bleeds, and the development of inhibiting antibodies against administered clotting factors. Emicizumab is a bispecific antibody, launched in India in April 2019, for managing patients with HA. To investigate the role of emicizumab in Indian patients with HA, opinions were sought from 13 eminent hematologists and experts from India on the effectiveness of emicizumab in preventing all bleeds, spontaneous bleeds, perioperative bleeds, and intracranial hemorrhage; resolving target joints; and reducing the rate of hospitalizations and fatality associated with HA in children and adults, with or without inhibitors. The benefits of emicizumab over traditional FVIII concentrates include the subcutaneous route of delivery, less frequent dosing, and a lack of inhibitor development, in addition to providing sustained hemostasis without in-depth monitoring. It is a safe and effective management option for all HA patients, especially for patients with certain archetypes, such as those with inhibitors, those with high annualized bleed rates, those living far away from hemophilia care centers, pediatric patients and infants with intravenous access challenges, and those with a history of life-threatening bleeding events.

Correction: Expert Opinions on the Management of Hemophilia A in India: The Role of Emicizumab.

[This corrects the article DOI: 10.7759/cureus.58941.].

Intestinal mucormycosis: a rare entity in pediatric oncology.

Mucormycosis is increasingly emerging as an important cause of invasive fungal infection in immunocompromised patients. Intestinal mucormycosis is extremely rare, difficult to diagnose, and has dismal prognosis. We report two children with acute lymphoblastic leukemia and intestinal mucormycosis. Despite surgery and appropriate antifungal therapy, only one survived. Literature review showed only 10 other childhood cancer cases with intestinal mucormycosis. All had abdominal pain preceding gut perforation. All except one had leukemia and majority were in induction phase of therapy. Only 5 of these 12 children survived. Other than appropriate antifungal therapy, early surgery and rising neutrophils aid in recovery.