Response assessment by positron emission tomography-computed tomography as compared with contrast-enhanced computed tomography in childhood Hodgkin lymphoma can reduce the need for radiotherapy in low- and middle-income countries.

INTRODUCTION: The InPOG-HL-15-01, a multicentric prospective study, used a risk-stratified and response-based approach with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) backbone to treat children and adolescents with newly diagnosed Hodgkin lymphoma (HL) and reduce the use of radiation therapy (RT). Children/adolescents with bulky disease or inadequate response at early response assessment (ERA) after two cycles of chemotherapy were assigned to receive RT. For ERA, positron emission tomography computed tomography (PET-CT) was recommended but not mandatory in view of limited access. This study aimed to compare the impact of using contrast-enhanced computed tomography (CECT) and PET-CT on treatment decisions and outcomes. METHODOLOGY: 396 patients were enrolled and 382 had an ERA at the assigned time point. Satisfactory response was defined as Deauville score 3 or less for patients undergoing PET-CT and complete response (CR)/very good partial response (VGPR) for patients undergoing CECT. Outcomes of interest incorporate 5 year event-free survival (EFS), EFS including abandonment (EFSa), and overall survival (OS). RESULTS: At ERA, satisfactory response was documented in 277 out of 382 (72.5%) participants and this was significantly higher in PET-CT (151 out of 186, 81.2%) as compared with CECT-based assessments (126 out of 196, 64.3%) respectively (p value < .001). Amongst the 203 patients with nonbulky disease (wherein the indication for RT was entirely dependent on ERA), 96 out of 114 (84.2%) and 61 out of 89 (68.5%) patients achieved a satisfactory response according to the PET-CT and CECT (p value = .008) respectively and hence a lesser proportion of patients in the PET-CT arm received RT. Despite a lower usage of RT the 5 year OS of both groups, ERA based on CECT (91.8%) versus PET-CT (94.1%) was comparable (p value = .391) and so was the 5 year EFS (86.7 vs. 85.5%, p value = .724). CONCLUSION: Use of PET-CT as the modality for ERA is more likely to indicate a satisfactory response as compared with CECT and thereby decreases the need for RT in response-based treatment algorithm for HL-afflicted children. The reduction in the application of RT did not impact the overall outcome and plausibly would lower the risk of delayed toxic effects.

Generic romiplostim for children with persistent or chronic immune thrombocytopenia: Experience from a tertiary care centre in North India.

Thrombopoietin receptor agonists are important therapeutic option in children with immune thrombocytopenia (ITP). We evaluated the response, efficacy, safety of a generic form of romiplostim manufactured in India for treating children with persistent/chronic ITP at our centre. Study of 45 children with persistent/chronic ITP was conducted of which 5 discontinued and 40 were included between 2019-2020. Patients received romiplostim for 20 weeks, at a dose of 5 mcg/kg/week. Platelet count at week 1, 3, 20 and 26 was assessed. Predesigned algorithm was used for dose adjustment. After 20 weeks, patients who had platelet count of 50 × 109/L or above were tapered off medication and monitored till 26 weeks. Median platelet count at enrolment was 11 x 109/L (IQR 23 X 109/L). 13/40 children had received >/= three lines of prior ITP therapy. Platelet response (platelet count rise to more than 50×109/L without rescue medications) observed in 26 (65%) patients at week 20. Rescue medication was used in 12/40 children. Sustained platelet response after tapering and stopping romiplostim observed in 22/40 children. No adverse events were considered serious or led to discontinuation of treatment. Our data demonstrated generic romiplostim is well tolerated and efficacious in children with persistent/chronic ITP.

Hodgkin Lymphoma in Children Under 5 Years: Do They Behave Differently?

The median age of presentation for Hodgkin lymphoma (HL) is lower in developing countries with a higher proportion under 5 years of age possibly attributable to the high prevalence of Epstein-Barr virus-driven disease. It is unclear whether the clinical presentation and outcomes of this cohort are different with concern regarding late effects being most pronounced in this age group. We report the outcome of children under 5 years of age enrolled in the InPOG-HL-15-01, the first multicentric collaborative study for newly diagnosed children and adolescents with HL from India. Thirty-five (9%) of the study population was younger than 5 years with a striking male preponderance of 34:1. They were less likely to have bulky disease, mediastinal or splenic involvement. The outcomes appear to be at least as favorable as in the older patient group. Efforts need to be made to evolve treatment strategies that spare this very young cohort from potential late effects.

Outcome and prognostic factors in childhood B non-Hodgkin lymphoma from India: Report by the Indian Pediatric Oncology Group (InPOG-NHL-16-01 study).

The literature on B-non-Hodgkin lymphoma (NHL) in India is restricted to individual hospital data. The study aimed to evaluate the epidemiology and outcome of B-NHL in our country. One hundred and ninety-one patients of B-NHL from 10 centers diagnosed between 2013 and 2016 were analyzed retrospectively. B/T lymphoblastic lymphoma and patients with inadequate data were excluded. The median age was 88 months (IQR: 56, 144) with an M:F ratio of 5.6:1. Undernourishment and stunting were seen in 36.5% and 22%. Primary site was abdomen in 66.5%. Hypoalbuminemia was noted in 82/170 (48.2%). Histological subtypes: Burkitt lymphoma (BL): 69.6%, Burkitt-like: 10.4%, and diffuse large B cell lymphoma (DLBCL): 13.6%, unclassified and others (6.4%). Stage distribution: I/II, 33 (17.3%), III, 114 (59.7%), and IV, 44 (23%). One-eighty-six patients took treatment. Protocols used were LMB and BFM in 160/186 (86%). At a median follow-up of 21.34 (IQR: 4.34, 36.57) months, the disease-free-survival (DFS) was 74.4% and event-free-survival (EFS) was 60.7%. Treatment-related mortality (TRM), relapse/progression and abandonment were 14.3%, 14.5%, and 8.4%, respectively. Bone marrow positivity, stage IV disease, and lactate dehydrogenase (LDH) > 2,000 U/l predicted inferior EFS. Stage IV disease, LDH > 2,000 U/l, bone marrow positivity, tumor lysis syndrome and low albumin predicted TRM; LDH retained significance on multivariate analysis for EFS and TRM [OR: 4.54, 95% CI: 1.14-20, p 0.03; OR 20, 95%CI: 1.69-250, p 0.017]. BL was the main histological subtype. High TRM and relapse/progression are hampering survival. An LDH > 2,000 U/l was adversely prognostic. These data demonstrate a need to develop a national protocol that balances toxicity and potential for cure.

Unique Challenges Faced by a Child with Standard Risk Leukemia in Post-COVID Era: A Case Report.

Children with malignancies are facing new challenges in post-COVID-19 era. We report an interesting case of a child on treatment for acute lymphoblastic leukemia having a very protracted course of illness with complications not often seen with standard therapy. It intends to make pediatric oncologists and intensive care specialists wary of potential newer complications. How to cite this article: Bhayana S, Kalra M, Sachdeva P, Sachdev A, Sachdeva A. Unique Challenges Faced by a Child with Standard Risk Leukemia in Post-COVID Era: A Case Report. Indian J Crit Care Med 2022;26(6):733-735.

Treating early-stage Hodgkin lymphoma in resource-limited settings: InPOG-HL-15-01 experience.

BACKGROUND: Hodgkin lymphoma (HL) in childhood is an eminently curable disease. Excellent outcomes can be achieved even in resource-limited settings and increasingly, the focus is on limiting long-term toxicity. Contemporary treatment incorporates a risk-stratified, response-adapted approach using multiagent chemotherapy with or without low-dose radiotherapy (RT). Many developing countries continue to use ABVD (adriamycin, bleomycin, vinblastin, and dacarbazine)-based regimen owing to limited acute toxicity, cost, and ease of delivery. We report outcomes of children with early-stage HL using limited cycles of ABVD-based treatment in the first prospective multicentric collaborative study from India InPOG-HL-15-01. METHODS: Children <18 years with biopsy-proven HL were enrolled. Patients with stages I and IIA with or without bulky disease were classified as having early-stage disease. Patients were planned to receive four cycles of ABVD subject to satisfactory early response assessment (ERA) scheduled after two cycles of chemotherapy. RT was limited to patients with bulky disease or those with suboptimal ERA. RESULTS: Four hundred ten patients were enrolled over 30 months from 27 centers. One hundred thirty-four were classified as having early-stage disease. Fifty-three (40%) of these had bulky disease. One hundred ten (83%) of this cohort achieved complete or very good partial ERA. Fifty-four (40%) received RT. At a median of 52 months since diagnosis, 5-year event-free survival (EFS) and overall survival (OS) is 94% and 95.5%, respectively. Treatment-related mortality and abandonment were <1%. CONCLUSION: Limited cycles of ABVD with RT to selected patients is a very effective option for patients with early-stage disease in resource-limited settings.

Stuttering Priapism in a Teenage Boy: Lesson to be Learnt.

Untreated priapism can lead to ischemic damage of the penis and impotence. This case report describes a 14-year-old boy who presented with a history of priapism for 2 months, which was undiagnosed, ridiculed, and ignored even by medical practitioners. The underlying etiology was later identified to be chronic myeloid leukemia. Despite the usage of multimodal treatment, it took 7 days for control of priapism. The young boy is now left with an erectile dysfunction. The case highlights that priapism in children is a medical emergency needing aggressive evaluation and treatment.

Safe administration of high-dose methotrexate with minimal drug level monitoring: Experience from a center in north India.

BACKGROUND: High-dose methotrexate (HDMTX) is recommended to be administered with serial monitoring of methotrexate (MTX) levels, which may not be universally feasible in resource-limited settings. In this study, we evaluated the overall experience of administration of HDMTX at our center by monitoring a single drug level at 54 h from the start of MTX infusion. METHODS: This retrospective study was performed at a tertiary level hospital in north India, over a 5-year period (2011-2015). All patients <18 years of age with newly diagnosed acute lymphoblastic leukemia (ALL) and T-non-Hodgkin lymphoma (T-NHL) were enrolled in the study. Details of HDMTX and all significant toxicities requiring prolonged or repeat hospitalization were retrieved from the medical records. All eligible patients received HDMTX as per the recommendations followed by at least three doses of leucovorin rescue, before drug levels were sent at 54 h. Subsequent leucovorin doses were adjusted accordingly. RESULTS: The records of 598 cycles of HDMTX in 184 patients were reviewed. A total of 531 of 598 cycles (88.7%) were managed with monitoring only a single plasma drug level at 54 h from the beginning of infusion. Delayed MTX clearance was seen in 260 of 598 cycles (43.5%). Only three episodes (0.5%) were associated with significant toxicity. There were no deaths. CONCLUSIONS: The strategy of monitoring MTX concentration at 54 h was safe in our cohort. Although recommended, dynamic monitoring of plasma drug levels may not always predict toxicity.

A health care labyrinth: perspectives of caregivers on the journey to accessing timely cancer diagnosis and treatment for children in India.

BACKGROUND: Cure rates for children with cancer in India lag behind that of high-income countries. Various disease, treatment and socio-economic related factors contribute to this gap including barriers in timely access of diagnostic and therapeutic care. This study investigated barriers to accessing care from symptom onset to beginning of treatment, from perspectives of caregivers of children with cancer in India. METHODS: Semi-structured in-depth interviews were conducted with caregivers of children (< 18 years) diagnosed with cancer in seven tertiary care hospitals across New Delhi and Hyderabad. Purposive sampling to saturation was used to ensure adequate representation of the child's gender, age, cancer type, geographical location and socioeconomic status. Interviews were audio recorded after obtaining informed consent. Thematic content analysis was conducted and organised using NVivo 11. RESULTS: Thirty-nine caregivers were interviewed, where three key themes emerged from the narratives: time intervals to definitive diagnosis and treatment, the importance of social supportive care and the overall accumulative impacts of the journey. There were two phases encapsulating the experiences of the family: referral pathways taken to reach the hospital and after reaching the hospital. Most caregivers, especially those from distant geographical areas had variable and inconsistent referral pathways partly due to poor availability of specialist doctors and diagnostic facilities outside major cities, influence from family or friends, and long travel times. Upon reaching the hospital, families mostly from public hospitals faced challenges navigating the hospital facilities, finding accommodation, and comprehending the diagnosis and treatment pathway. Throughout both phases, financial constraint was a recurring issue amongst low-income families. The caregiver's knowledge and awareness of the disease and health system, religious and social factors were also common barriers. CONCLUSION: This qualitative study highlights and explores some of the barriers to childhood cancer care in India. Our findings show that referral pathways are intrinsically linked to the treatment experience and there should be better recognition of the financial and emotional challenges faced by the family that occur prior to definitive diagnosis and treatment. This information would help inform various stakeholders and contribute to improved interventions addressing these barriers.

A comparison of ketamine + midazolam to propofol for procedural sedation for lumbar puncture in pediatric oncology by nonanesthesiologists-a randomized comparative trial.

BACKGROUND: Both ketamine-midazolam and propofol are frequently used in pediatric oncology units for procedural sedation. However, there are no prospective, randomized comparative trials (RCT) comparing the two groups when the procedure is performed by nonanesthesiologists. OBJECTIVE: To compare ketamine + midazolam (group A) and propofol (group B) as sedative agents for intrathecal chemotherapy with regard to efficacy, side effects, time to induction, time to recovery, and smoothness of recovery. METHODS: A partially-blinded RCT was conducted between August 2015 and March 2017 after gaining institutional ethics committee approval. Children aged 1-12 years requiring intravenous sedation for intrathecal chemotherapy were included. Patients were allocated to two treatment arms using computer-generated randomization tables, after obtaining written consent. The initial doses used were: ketamine 2 mg/kg, midazolam 0.2 mg/kg, and propofol 2.5 mg/kg, as per standard recommendations. The patient, parents, and person analyzing the data were blinded. Time to sedation, dose required, depth of sedation, vital parameters, time and smoothness of recovery, and emergence phenomena were documented. RESULTS: We enrolled 152 patients (76 each in group A and B). Nine patients had a failure of sedation (all in group B). Mean time to sedation and recovery was shorter in group B (P < 0.001). Transient drop in saturation was more frequent in group B, without statistical significance (P = 0.174). Mean depth of sedation was greater in group A (P < 0.001). Emergence symptoms were more frequently experienced in group A (P < 0.001). CONCLUSIONS: Ketamine-midazolam combination is safer and more effective. Propofol is faster in onset and recovery, and has smoother emergence with poor efficacy at recommended initial doses.

Refractory LCH With Secondary Intracranial PNET: A Case Report and Review of Literature.

The occurrence of second malignant neoplasms in patients with Langerhans cell histiocytosis is infrequent but has been reported. Here we report the case of a child with refractory Langerhans cell histiocytosis who was treated with cladribine and later developed a secondary intracranial primitive neuroectodermal tumor. The possible association of cladribine with second neoplasm is further discussed.

Confirmation of Bevacizumab Activity, and Maintenance of Efficacy in Retreatment After Subsequent Relapse, in Pediatric Low-grade Glioma.

BACKGROUND: Management of low-grade gliomas (LGG) can be a challenge, particularly when not resectable and refractory or recurrent following standard treatments. We undertook a retrospective analysis of 2 institutions' experiences treating children for refractory or progressive LGG with bevacizumab-based therapy (BBT). PROCEDURE: Inclusion criteria were patients younger than 18 years of age who had previously failed one or more lines of therapy. Treatment was intravenous bevacizumab 10 mg/kg and intravenous irinotecan 125 to 150 mg/m2 every 2 weeks. RESULTS: Sixteen children (median age of 8.6 y), 5 with neurofibromatosis type 1 and 8 with disseminated disease were treated between 2009 and 2013. Median duration of treatment was 12 months (range, 3 to 45 mo). Seven patients (44%) showed clinical improvement (3 patients within a month) and 8 patients (50%) remained clinically stable during BBT. Imaging studies showed 3 (19%) had a partial response, 11 (69%) stable disease, and 2 (12%) had progressive disease. Four patients had progressive disease after stopping BBT (median duration of 5 mo). Three of these 4 were able to be retreated with BBT and all achieved an objective response. Treatment was well tolerated with no grade 3 or 4 toxicities related to bevacizumab. Irinotecan was discontinued in 4 patients because of grade 2-3 toxicities. CONCLUSIONS: We conclude that BBT is well tolerated and led to disease control in patients with refractory or recurrent cases of LGG. Retreatment with BBT led to disease control in most of these cases. Larger, prospective studies are warranted to confirm these results.

Assessment of the phenotypic severity of hemophilia A: using rotational thromboelastometry (ROTEM) and APTT-clot waveform analysis.

BACKGROUND: Hemophilia A (HA) is an X-linked inherited bleeding disorder caused by reduced factor VIII (FVIII) levels. Approximately 10-15% of patients with severe HA (SHA) do not present with the anticipated bleeding pattern. Here, we assessed the phenotypic severity of hemophilia A using rotational thromboelastometry (ROTEM) and activated partial thromboplastin time-clot waveform analysis (APTT-CWA). METHODS: Patients diagnosed with hemophilia A were enrolled. Clinical phenotype assignment was performed according to the published literature, and patients were classified into four phenotypic subgroups. The whole blood sample was first run on ROTEM in INTEM mode using platelet-poor plasma, APTT was run, and the APTT-CWA graph was simultaneously recorded. RESULTS: A total of 66 patients were recruited for this study. Statistically significant differences were observed between the four phenotypically categorized groups using ROTEM and APTT-CWA. On comparing patients with mild/moderate-to-severe phenotypes (Group II) with SHA without inhibitors (Group IV), no significant difference was found for all parameters of ROTEM or APTT-CWA. The MCF, MA30, MAXV, and Alpha angle values using ROTEM were found to be the lowest in patients with SHA with inhibitors, which helped differentiate them from those with SHA without inhibitors. However, these two groups could not be differentiated using the APTT-CWA parameters. CONCLUSION: ROTEM can be used to distinguish patients with SHA with inhibitors from those with SHA without inhibitors using a combination of parameters with high sensitivity and specificity. However, APTT-CWA cannot be used to differentiate these patient groups.

Empirical Antitubercular Treatment for Lymphadenopathy: Are We Missing Lymphoma?

OBJECTIVE: To evaluate the proportion of patients who received empirical treatment with antitubercular therapy (ATT) prior to the diagnosis of Hodgkin lymphoma (HL) in the first multicentric, prospective study on HL from India, and to assess its impact on extent of disease at diagnosis and outcomes. METHODS: Children < 18 y with biopsy proven HL were enrolled in InPOG-HL-15-01. Along with other clinical and epidemiological data, history of prior treatment with ATT was documented. All patients received treatment as per a risk-stratified, response-adapted strategy. RESULTS: Out of 396, 115 (29%) children had received ATT prior to establishing a definitive diagnosis of HL. This cohort presented with advanced-stage disease (p = 0.001) and B symptoms (p = 0.001) in a higher proportion of cases. Consequently, those children were more likely to receive 6 rather than 4 cycles of chemotherapy (p = 0.001). They were more likely to have infradiaphragmatic involvement (p = 0.001). Overall survival and event-free survival were not different. CONCLUSION: Empirical treatment with ATT in children presenting with lymphadenopathy continues to be practiced widely in India. The delay in diagnosis may contribute to children presenting with advanced-stage disease warranting more intensive treatment for successful outcomes.

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.