The Outcome of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Experience from a Referral Center in South India.

Although improved survival in children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL) has been demonstrated in trials, the outcome appears to be inferior in low- and middle-income countries (LMIC). Methods A file review of children aged ≤ 15 years diagnosed with Ph-ALL from 2010 to 2019 was performed. Minimal residual disease (MRD) was assessed by flow-cytometry. Real-time polymerase chain reaction (qRT-PCR) was used to quantify the BCR::ABL1 transcripts during treatment. Results The mean age of the 20 patients in the study was 91 months. Of 19 patients in whom the BCR::ABL1 transcript was confirmed, 10(50%) had P210, 7(35%) had P190, and two showed dual expression. The mean dose of imatinib that was administered was 294 ± 41 mg/m2/day. qRT-PCR for BCR::ABL1 was < 0.01% in all patients who were in remission or had a late relapse and was ≥ 0.01% in patients who had an early relapse. Two patients underwent HSCT. The 3-year event-free survival (EFS) was 35.0 ± 10.7%. Patients with a good prednisolone response (GPR) and a negative end-of-induction MRD demonstrated a superior EFS to those who lacked either or both (80.0 ± 17.9% vs. 16.7 ± 15.2%, P = 0.034). Conclusion The 3-year EFS of 20 children with Ph-ALL treated with chemotherapy and TKI was < 50%. An unusually high proportion of patients with p210 transcript expression; sub-optimal TKI dosing and lesser intensity of chemotherapy, due to the concern of high treatment-related mortality in LMIC are possible reasons for the poor outcome. Conventional treatment response parameters such as GPR and MRD predict outcomes in Ph-ALL. qRT-PCR for BCR::ABL1 may have a role in predicting early relapse. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-023-01684-9.

What happens to children with acute lymphoblastic leukemia in low- and middle-income countries after relapse? A single-center experience from India.

Managing a child with acute lymphoblastic leukemia (ALL) after relapse is arduous in low- and middle-income countries. A file review of children aged ≤15 years diagnosed with relapsed ALL from 2010 to 2019 was performed. Classification of relapse followed the Berlin-Frankfurt-Münster (BFM) scheme. The majority of patients were treated with a modified ALL-REZ-BFM protocol. Of 764 children treated for ALL in the study period, 163 (21.3%) relapsed. The median age at relapse was 101 months (range: 8-297). The immunophenotype was B-ALL and T-ALL in 140 (86%) and 23 (14%) patients. The site of relapse was extramedullary, combined, and medullary in 46 (28%), 45 (28%), and 72 (44%) patients. Very early, early, and late relapses were observed in 57 (35%), 66 (40%), and 40 (25%) patients. The proportions of extramedullary and medullary sites were greater among patients with early and late relapses, respectively (p = 0.039). Eighty-four (52%) patients were treated with palliative intent. The 2-year event-free survival (EFS) of patients treated with curative intent was 36.3 ± 6.3%. The 2-year EFS for very early/early and late relapses were 18.2 ± 6.2% and 67.6 ± 10.4% (p < 0.001). The 2-year EFS did not differ between extramedullary, combined, and medullary relapses. Treatment-related mortality occurred in 14 (20%) patients. More than 50% of the patients with relapse were treated with the intent of palliation. Extramedullary relapses were more likely to be early and did not have a better outcome than medullary relapses. Children with late relapse had a fair chance of survival with chemotherapy.

The Nutritional Trajectory of Children with Acute Lymphoblastic Leukemia: A 10-Year Follow up Study from a Referral Center in South India.

OBJECTIVE: Survivors of childhood acute lymphoblastic leukemia (ALL) are vulnerable to late adverse events such as obesity and an associated metabolic syndrome. METHODS: Children treated for ALL from 2002 to 2012 were included. BMI was calculated at diagnosis, end of treatment, and 5, 8, and 10-years from diagnosis. BMI-centiles were used to categorize the patients: underweight (<5th-percentile), normal (5th-85th percentile), overweight (85th-95th percentile), and obese (≥95th centile). RESULTS: The study included 179 children with ALL (median age: 59-months). The proportions of patients who were underweight, normal, overweight/obese, were 37%, 56% and 7%, respectively, at diagnosis; and 15%, 51% and 34%, respectively, at 5-years from diagnosis. The median (IQR) BMI Z-score at diagnosis was -1.12(-2.40, -0.26). The median (IQR) BMI z-score of the cohort was higher after 5 [0.22(-0.83,1.24), P < 0.001] and 10-years of diagnosis [0.30(-0.69,0.99), P < 0.001], respectively. The proportion of overweight/obese individuals was higher after 5 (34%, P < 0.001) and 10 (26%, P = 0.001) years. There was a significant correlation between the baseline BMI Z-score and that observed after 5-years (ρ = 0.49, P < 0.001), and 10-years (ρ = 0.55, P < 0.001). CONCLUSION: At 10-years of follow-up, >25% of children with ALL were overweight/obese. The BMI Z-score at the time of diagnosis continued to correlate with the Z-score after 10-years.

Vanishing Bile Duct Syndrome Secondary to Hodgkin Lymphoma in a Child.

Vanishing bile duct syndrome (VBDS) is a condition resulting from progressive destruction and loss of intrahepatic bile ducts leading to cholestasis, biliary cirrhosis, and liver failure. It occurs secondary to various pathologic conditions like autoimmune diseases, graft versus host disease, drug reactions, and as a paraneoplastic syndrome in malignancies. We here described a 9-year-old girl who presented with cervical lymphadenopathy and jaundice. This child was diagnosed as a case of Hodgkin lymphoma. All other causes of cholestasis were ruled out by appropriate investigations (particularly autoimmune, metabolic, infections, and drug-induced possibilities). On liver biopsy, her diagnosis was established as VBDS. In view of hepatic dysfunction, alternative chemotherapy with dexamethasone, high-dose cytarabine, and cisplatin (DHAP) was given, and she was started on hepatoprotective measures with ursodeoxycholic acid. Hepatic function gradually improved after the initiation of chemotherapy. VBDS is considered a dismal paraneoplastic syndrome with a high-case fatality. This case report highlights the importance of early recognition and initiation of appropriate full-dose chemotherapy as the only way to achieve complete resolution of VBDS.

The Unique Balancing Act of Managing Children With Cancer and COVID-19 Infection: A Single Center Experience From South India.

Children with cancer are vulnerable to severe infections. Balancing the intensive treatment of cancer, with the potential risk of coronavirus disease-2019 (COVID-19) related morbidity and mortality is a unique challenge. Children with cancer testing positive for severe acute respiratory syndrome coronavirus 2 virus by reverse-transcription polymerase chain reaction at our center were studied. Thirty-seven children tested positive for COVID-19 during the study period. The severity of the illness was mild, moderate, severe, and critical in 10 (27%), 13 (35%), 12 (32%), and 2 (5%) patients, respectively. Of the 14 patients with a severe/critical illness, 2 had oncological emergencies, 4 had dengue co-infection, and 1 had an inguinal bacterial abscess. All patients were discharged in a stable condition. Modification of the treatment protocol was performed in 11 (33%) of 33 patients who were on active treatment for cancer. There was a median delay of 32.5 days to administer the next cycle of chemotherapy in patients who acquired COVID-19 during cancer treatment. Six of 7 patients who were retested after 14 days remained positive by reverse-transcription polymerase chain reaction. Children with cancer with COVID-19 recover with good supportive care. Curative chemotherapy can be administered safely with appropriate modifications in children with cancer with COVID-19.

Postchemotherapy tumor volume as a prognostic indicator in Wilms tumor: A single-center experience from South India.

BACKGROUND: Optimal risk stratification is the key to minimizing relapse and toxicity in children with Wilms tumor (WT). The study evaluated poor tumor volume response to chemotherapy as a risk factor that predicts relapse. PROCEDURE: Children with WT who were treated between 2005 and 2020 at the center were analyzed. Tumor volumes at the time of diagnosis and after preoperative chemotherapy were calculated from cross-sectional imaging. The International Society of Paediatric Oncology (SIOP)-WT-2001 protocol was used for treatment. The area under a receiver operating characteristic curve was estimated to ascertain the ability of tumor volume to predict relapse. RESULTS: Ninety-five patients with a median age of 40 months were included. A postchemotherapy tumor volume cutoff of 270 ml was ascertained to have the best predictive value for relapse. Patients with a tumor volume of <270 ml following preoperative chemotherapy had a better 3-year event-free survival (EFS) than those with a tumor volume of ≥270 ml (89.8% ± 4.0% vs. 57.4% ± 12.5%, p = .001). The data demonstrated that a tumor volume of ≥270 ml after chemotherapy was associated with an increased risk of relapse (hazard ratio [HR]: 5.3, p = .006). The EFS in patients with an epithelial or stromal type of histopathology was not affected by the tumor volume response (p = .437). Conversely, patients with other types of intermediate-risk histopathology who had a poor tumor volume response had an inferior survival (3-year EFS 51.4% ± 18.7%, p = .001). CONCLUSION: A postchemotherapy tumor volume cutoff of ≥270 ml emerged as a strong predictor of relapse in a low- and middle-income country (LMIC) center study of WT treated with the SIOP protocol.

Successful Treatment of Late Isolated Bone Metastasis in a Patient with Bilateral Retinoblastoma Using an Unconventional Method.

Though survival in bilateral retinoblastoma (RB) has improved due to advancement in diagnostics and treatment modalities, children require long-term follow-ups for recurrence and second malignancies. We report a case of bilateral RB in a 7-month-old baby who was treated with chemotherapy, transpupillary thermotherapy, and periocular carboplatin for both eyes following which there was complete regression of tumour. Six and a half years after treatment, the child presented with metastatic recurrence of tumour in the left ulna. He was treated successfully with chemotherapy, extracorporeal radiation and reimplantation therapy. A less aggressive treatment approach for isolated bone relapse may be considered in selected cases.

Complete Peripheral Blast Clearance is Superior to the Conventional Cut-Off of 1000/µL in Predicting Relapse in Pediatric Pre-B Acute Lymphoblastic Leukemia.

Risk-stratification has contributed to a dramatic improvement in survival in pediatric acute lymphoblastic leukemia (ALL). This study evaluated the utility of prephase response and day 15 bone marrow when a minimal residual disease (MRD) assessment was available. A file review of children aged ≤ 15 years diagnosed with precursor-B ALL from 2014 to 2019 was performed. The protocol used for risk stratification and treatment was based on a UKALL-2003 backbone. All patients received one week of prephase therapy comprised of intravenous dexamethasone in the first 48 h followed by oral prednisolone. The median age of the 255 patients in the study was 5 years. Following the prephase, the peripheral blood absolute blast count was 0 and ≥ 1000/µL blasts in 141 (56%) and 29 (11%), respectively. Ten of 199 (5%) patients with an evaluable day 15 bone marrow had M3 status. At the end of induction, 30 (12%), 127 (50%) and 98 (38%) patients belonged to the standard-risk, intermediate-risk and high-risk (HR) groups, respectively. An M3 day15 bone marrow was the sole reason for escalation in three (3%) of the patients in the HR group. A lack of complete clearance of peripheral blood blasts post-prephase [HR: 2.45 (1.04-5.75), p = 0.040] and a positive MRD [HR: 3.00 (1.28-7.02), p = 0.011] independently predicted risk of relapse. Complete blast clearance is superior to the traditional cut-off of 1000/µL in predicting relapse. The role of a day 15 bone marrow morphology is diminished when an end of induction MRD is available.

A single assessment of methotrexate levels at 42 hours permits safe administration and early discharge in children with lymphoblastic lymphoma and leukemia receiving high-dose methotrexate.

High-dose methotrexate (HDMTX) is an important component of treatment in pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Optimal rescue therapy is essential for the safe administration of HDMTX. A cost-effective strategy that does not compromise safety is necessary for low- and middle-income countries. Consecutive admissions for HDMTX in children with ALL and LL over 12 months were analyzed. The dose of HDMTX was 3 g/m2 in B-ALL and B-LL and 5 g/m2 in T-ALL and T-LL. A methotrexate level was measured at 42 hours of starting HDMTX infusion (T42-MTX). Three doses of folinic acid at T42, T48, and T54 and alkalinized hydration till T54 were administered if T42-MTX <1 µM. A total of 282 cycles of HDMTX that were administered in 71 patients were analyzed. T42-MTX was <1 µM in 266 (94.3%) cycles. T42-MTX was ≥1 µM in 12% and 3% of cycles of HDMTX administered at a dose of 5 g/m2 and 3 g/m2, respectively (p = .074). The median duration of hospitalization for HDM was three days and did not differ with the dose of HDMTX administered (p = .427). Mucositis, delayed recovery of blood counts, and hospitalization for reversible toxicity occurred after 21 (7.4%), 28 (9.9%), and 19 (6.7%) cycles of HDMTX, respectively. Mucositis was greater following the administration of 5 g/m2 of HDMTX. A single T42-MTX measurement permits the safe administration of HDMTX and an expedited discharge from the hospital within three days in more than 90% of children with ALL/LL.

An Unusual Presentation of Hemorrhagic Disease in an Infant: A Probable Case of Abetalipoproteinemia.

We report a probable case of abetalipoproteinemia in an infant who presented with unusual symptoms of late-onset vitamin K deficiency. Abetalipoproteinemia is a rare autosomal recessive disease caused by mutation of the microsomal triglyceride transfer protein gene, resulting in the absence of microsomal triglyceride transfer protein function in the small bowel. It is characterized by the absence of plasma apolipoprotein B-containing lipoproteins, fat malabsorption, hypocholesterolemia, retinitis pigmentosa, progressive neuropathy, myopathy, and acanthocytosis. A biopsy of the small intestine characteristically shows marked lipid accumulation in the villi of enterocytes. Large supplements of fat-soluble vitamins A, D, E, and K have been shown to limit neurologic and ocular manifestations. Dietary fat intake is limited to medium-chain triglycerides.

Effect of imatinib on growth in children with chronic myeloid leukemia.

Imatinib is a preferred drug for pediatric Chronic Myeloid Leukemia (CML). Long-term use has inhibitory effects on other tyrosine kinase pathways causing off-target complications such as growth impairment. Our aim was to evaluate impact of long-term use on longitudinal growth in children with CML in Kerala. We hypothesized that the impact would be lesser compared to Northern India as Kerala has the lowest rates of underweight and stunting, with a high literacy rate and per capita income. Children ≤14 years of age, diagnosed with CML and received imatinib for at least 1 year were included. Girls >9 years of age and boys >11 years were considered pubertal. Height Z scores were derived using WHO AnthroPlus. Paired t test compared difference of Z scores in prepubertal and postpubertal age groups. Height Z scores were compared with mid-parental height and sibling height Z scores. Thirty-six children were included (M = 21; F = 15). Median duration of imatinib exposure was 84 months. Decrease in longitudinal growth affected children in both prepubertal and postpubertal age groups. Decrease in height Z scores was more in prepubertal age group when imatinib therapy was initiated (p = .0018). Of 10 patients currently above 19 years (of whom 8 were in pubertal age and 2 in prepubertal age at start of imatinib) none are stunted. Patient's height Z scores was lesser compared to sibling height Z scores (p = .027). Children on continuous imatinib showed a significant stunting when treatment was initiated during prepubertal age. There is a catch-up of growth as the final height reached is within normal limits of WHO reference values.

Palonosetron is a Better Choice Compared With Ondansetron for the Prevention of Chemotherapy-induced Nausea and Vomiting (CINV) in a Resource-limited Pediatric Oncology Center: Results From a Randomized Control Trial.

Palonosetron (PG) is a newer, safe, and effective long-acting 5-HT3 antagonist commonly used in adults, but data in children are limited. A randomized controlled trial was carried out among children with cancer during their first cycle of moderate or highly emetogenic chemotherapy to receive either PG or ondansetron (OG) with the aim of comparing their efficacy, safety, and cost-effectiveness. In total, 200 children (mean age, 8 y, male:female=1.8:1) were recruited, 100 in each arm. Complete response, defined as no vomiting, in acute (<24 h), delayed (24 to 120 h), and overall phases (0 to 120 h) was observed in 88%, 88%, and 81% of cases, respectively, for PG versus 84%, 79%, and 72%, respectively, for OG (P=0.42, 0.09 and 0.21, respectively). Complete protection rates, defined as no nausea and vomiting in children above 6 years of age, in acute, delayed, and overall phases were 84%, 81%, and 73%, respectively, for PG versus 79%, 67%, and 60%, respectively, for OG (P=0.44, 0.06 and 0.10, respectively). Overall, the efficacy and safety of PG in the prevention of chemotherapy-induced nausea and vomiting was comparable with OG, but PG was a more cost-effective and suitable choice for busy centers in resource-limited countries.

Utility of QuantiFERON®-TB gold In-Tube test compared with tuberculin skin test in diagnosing tuberculosis in Indian children with malnutrition.

This prospective cohort study was conducted to compare the accuracy of QuantiFERON®-TB (QFT) Gold In-Tube test and tuberculin skin test (TST) in diagnosing tuberculosis (TB) in predominantly bacille Calmette-Guerin-vaccinated children with a high incidence of malnutrition. The sensitivity of the QFT versus the TST was 69.6% versus 52.9% for WHO-defined TB, with specificity of 86% versus 78.3%, respectively. The concordance of the TST and QFT was 79% overall (κ = 0.430), 62.5% in those with WHO-defined TB and 85.7% in those without TB. Majority of the QFT+/TST - discordance was seen in children with TB, whereas majority of the TST+/QFT - discordance was seen in those without TB. The TST was more likely to be negative in children with moderate-to-severe malnutrition (P = 0.003) compared to the QFT, which was more likely to be positive in younger children. The significantly better performance of the QFT in malnourished children and those at younger ages supports its use for TB diagnosis in these subpopulations.

Undifferentiated thymic carcinoma with intracranial metastasis in a two-year-old.

Thymic carcinoma with central nervous system involvement is very rare in children. A 27-month-old girl presented with a unilateral squint, vomiting, and behavioral changes. Imaging studies showed a silent anterior mediastinal mass and a large metastatic mass at the base of the skull. Biopsy of the anterior mediastinal mass confirmed an undifferentiated tumor consistent with thymic carcinoma. The child died within 3 months of the onset of symptoms, due to progression of the disease. These lethal tumors of unknown histogeneses and etiology are aggressive in nature, resistant to therapy, and have a rapidly fatal course.

Hydroa vacciniforme-like lymphoma: a case report from India.

We report a 14-year-old Indian boy who presented with a history of weight loss, fever, facial edema, and a relapsing papulovesicular eruption on the face and limbs for 1 year. Histopathology of the skin showed dense lymphoid infiltrate from dermis to subcutaneous fat. Immunohistochemistry of this lymphoid infiltrate was CD3, CD8, CD56, CD57, Granzyme B, TIA, and Epstein Barr virus LMP1. The histopathology and immunohistochemistry were consistent with the diagnosis of hydroa vacciniforme-like T-cell lymphoma. The child responded remarkably to oral steroids but relapsed on tapering doses. CHOP (Cyclophosphamide, Adriamycin, Vincristine, and Prednisolone) chemotherapy was initiated in view of systemic involvement to which he showed some response, however, the disease relapsed again. He then had a rapidly progressive disease and ultimately succumbed to his illness. This is the first case of hydroa vacciniforme-like T-cell lymphoma being reported from this subcontinent.

Steroid-responsive anemia in patients of Ghosal hematodiaphyseal dysplasia: simple to diagnose and easy to treat.

Ghosal hematodiaphyseal dysplasia (GHDD) is a recently recognized cause of steroid-responsive anemia. We would like to report 3 cases of GHDD who presented in early childhood with moderate to severe anemia, splenomegaly, and a hypocellular marrow with increased reticulin. They were easily diagnosed with long-bone x-rays showing diaphyseal and metaphyseal widening and loss of diaphyseal constriction. All cases dramatically responded to oral steroid and no longer needed blood transfusion. They required steroid at low doses for long term (up to 5 y). GHDD is easy to diagnose with long-bone radiography and consistently responds to steroid. It should therefore be considered as a differential diagnosis of unusual anemia in early childhood, especially in children from the Middle East or the Indian subcontinent.