Epilepsia Partialis Continua as a Sequelae of Measles Infection in Children With Hematolymphoid Malignancies.

PURPOSE: To share our clinical experience with the diagnosis and management of children with hematolymphoid malignancies presenting with epilepsia partialis continua (EPC) as a sequelae of measles infection. MATERIALS AND METHODS: In December 2022, a series of children in our hemato-oncology unit presented with focal status epilepticus with no conclusive evidence pointing toward any underlying etiology. One such child had a typical measles rash a few weeks before the onset of this focal status epilepticus. After a series of cases with a similar presentation, a clinical pattern suspicious for measles became evident. cerebrospinal fluid polymerase chain reaction was positive for measles virus with measles immunoglobin M detected in the serum. This led to the diagnosis of measles inclusion-body encephalitis in a series of children who presented with EPC over a period of 3 months. EPC is a rare manifestation of measles that is seen only in immunocompromised patients. RESULTS: Among the 18 children reported in this series, only 10 had a history of rashes. The rash was mostly transient and elicited only on retrospective history taking. Five of the 18 children who did not lose consciousness during the prolonged seizure episode survived the disease but had residual neurologic sequelae. Among the 18 children, two were unimmunized and immunization status could not be confirmed in three other children. CONCLUSION: This case series highlights the threats posed by measles infection in children with cancer who are immunosuppressed because of the underlying disease and ongoing chemotherapy. Loss of herd immunity because of declining measles immunization rates secondary to vaccine hesitancy and COVID-19 lockdown pose a greater risk of measles infection and its complications for patients with deficient immune systems.

Challenges in Management of Pediatric Chronic Myeloid Leukemia (pCML) in the Low-Middle Income Countries (LMICs): Insights from an International CML Foundation (iCMLf) Multi-National Survey.

Despite being a rare disease, high-income countries (HICs) have formulated guidelines for management of pediatric CML (pCML). We conducted a survey amongst 24 physicians from 22 Low-Middle Income Countries (LMICs) to gather information regarding their practice and experience in treating children with pCML. Rarity of pCML, lack of adequate expertise, and setting-adapted guidelines along with limitations in diagnostic infrastructure as well as challenges in accessing tyrosine kinase inhibitors (TKIs) were identified as major barriers in optimum management of patients. For the first time in literature, our findings provide valuable insights into the multifaceted challenges faced in managing pCML in LMICs.

Treatment and follow-up of children with chronic myeloid leukaemia in chronic phase (CML-CP) in the tyrosine kinase inhibitor (TKI) era-Two decades of experience from the Tata Memorial Hospital paediatric CML (pCML) cohort.

Tyrosine kinase inhibitors (TKIs) have drastically improved the outcomes of pCML (paediatric CML) but data on long-term off-target toxicities of TKIs in children are scarce. In this single-centre, retrospective cum prospective study of pCML in chronic phase, we report our experience of treating 173 children with imatinib and following them for long-term toxicities. Mean (SD) time to attain CHR, CCyR and MMR were 3.05 (2.1), 10.6 (8.4) and 43.4 (31.8) months respectively. DMR was not attained in 59 (34%) patients at last follow-up. Ten patients were switched to second-generation TKIs (2G-TKIs; nilotinib = 1/dasatinib = 9) due to poor/loss in response, of which seven had kinase domain mutations. Three patients progressed to the blastic phase. At a median follow-up of 84 (3-261) months, the 5-year EFS and OS for the entire cohort were 96.9% (95% CI: 93.4-100) and 98.7% (95% CI: 96.9-100) respectively. Screening for long-term toxicities revealed low bone density and hypovitaminosis D in 70% and 80% respectively. Other late effects included short stature (27%), delayed puberty (15%), poor sperm quality (43%) and miscellaneous endocrinopathies (8%). Children younger than 5 years at diagnosis were more susceptible to growth and endocrine toxicities (p = 0.009). Regular monitoring for long-term toxicities, timely intervention and trial of discontinuation whenever feasible are likely to improve the long-term outlook of pCML.

Intracranial disease in pediatric Hodgkin lymphoma-case report and review of literature.

Central nervous system (CNS) involvement in Hodgkin lymphoma (HL) is an extremely rare presentation with dismal outcomes according to reported literature. An 8-year-old girl presented to us with complaints of on-off fever, right cervical swelling and bilateral ptosis. Positron emission tomography (PET) showed intracranial extra-axial soft tissue masses in right infero-lateral temporal lobe, sella and bilateral parasellar region along with cervical, mediastinal, axillary, abdominal and inguino-pelvic nodes, liver lesions and extensive marrow lesions involving the axial and appendicular skeleton. Histopathology of the cervical lymph node revealed a diagnosis of classical Hodgkin lymphoma. Child received 2 cycles of OEPA and 4 cycles of COPP followed by radiotherapy to bulky cervical lymph nodes and intracranial lesion. The child has been disease-free for 44 months with no neurological sequalae. Intracranial spread is rare in Hodgkin lymphoma and is associated with inferior outcomes. Due to its rarity, there are no specific treatment guidelines for this entity. The choice of ideal chemotherapeutic agents and role of whole-brain radiotherapy needs further evaluation.

Clinico-radiological profile, management and follow-up of methotrexate induced neurotoxicity in children with acute lymphoblastic leukemia.

Methotrexate-induced neurotoxicity is a well-defined side-effect of high-dose and intrathecal methotrexate with characteristic clinico-radiological findings and transient nature. Our experience in managing this entity in children with acute lymphoblastic leukemia(ALL) is reported here. All children with de novo ALLregistered from January 2016 through December 2021 who developed methotrexate-induced neurotoxicity were included. Of children with ALL treated during the study period, thirty-three experienced methotrexate induced neurotoxicity with an incidence of 1.25%. Stroke-like symptoms(36.36%; 12/33) were the most common clinical manifestation followed by seizures(30.3%, 10/33). Twenty-three patients had radiological features consistent with methotrexate-induced leukoencephalopathy. With emerging evidence, thirty-one patients were re-challenged with methotrexate (IV/IT), of whom 4 patients had recurrence of symptoms. No long-term neurological sequalae were noted in our cohort, despite rechallenging. Therefore in our study, methotrexate induced neurotoxicity is a self-limiting toxicity and methotrexate can be re-challenged safely without compromising theintensity of CNS-directed therapy.

Treating relapsed B cell-precursor ALL in children with a setting-adapted mitoxantrone-based intensive chemotherapy protocol (TMH rALL-18 PROTOCOL) - experience from Tata Memorial Hospital, India.

The outlook of relapsed ALL in low- and middle-income countries (LMICs) is dismal due to high treatment-related toxicities and inadequate resources. We report our experience of using a locally adapted mitoxantrone-based protocol for non-high risk (HR) relapsed B-ALL (rALL). A retrospective cum prospective study of standard and intermediate risk (SR and IR) rALL patients treated on TMH rALL-18 protocol (adapted from COG/UKALLR3/Int-Re-ALL protocols) between November 2018 and January 2021 was analyzed. The protocol comprising of 7 blocks of multi-agent chemotherapy including mitoxantrone in induction followed by local irradiation and maintenance, underwent serial modifications based on our experience with initial patients. Eighty-two patients (SR rALL, 3; IR rALL, 79) were treated on TMH rALL-18 protocol. Of 321 grade 3/4 reported toxicities, around 43% (138 toxicities) were noted during induction. Induction chemotherapy was outpatient-based; however, 68 patients (82.9%) required supportive care admissions. Twelve out of 19 patients with gram negative bacilli sepsis (included 7 MDRO) died during reinduction. Five remission deaths were seen during block 3 after which cytarabine was dose reduced (3 g to 2 g/m2). Post-reinduction minimal residual disease was negative in 54 (80.6%) out of 67 evaluable patients. At a median follow-up of 24 months (95% CI 22-27), the estimated 2-year event-free and overall survival of the entire cohort was 58% (95% CI 48.1-69.9) and 60.3% (95% CI 50.5-72). Until the time, targeted therapies are freely accessible in LMICs, strengthening supportive care as well as local adaptation of protocols that strike a fine balance between efficacy and tolerability are mandated.

Clinical features, predictors and outcome of posterior reversible encephalopathy syndrome (PRES) in children with hematolymphoid malignancies.

BACKGROUND AND AIM: Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological syndrome characterized by a neurotoxic state with vasogenic edema. We studied the clinical profile, predisposing factors, imaging features, and outcome of PRES in children receiving treatment for hematolymphoid malignancies. METHODS: Retrospective analysis of the clinical data and radiological features of patients with PRES diagnosed between June 2014 and December 2019. RESULTS: Fifty-two patients (boy: girl = 3:1) were diagnosed with PRES during the study period with a median age of 11 (range:1-15) years. Primary diagnoses were acute leukemias (n = 42), non-Hodgkin lymphoma (n = 8), Hodgkin lymphoma (n = 1), and Langerhan's cell histiocytosis (n = 1). Most common presenting symptoms were seizures (n = 52), altered sensorium (n = 42), headache (n = 39), and visual disturbances (n = 8). Hypertension at time of diagnosis was noted in 50 (96%) patients. Classic hyper-intense lesions on FLAIR and diffusion weighed (DW) images were noted in parieto-occipital region in 39 patients (75%). Central PRES involving basal ganglia was seen in 3 (6%) patients. A subsequent neuro-imaging was done in 18 patients (MRI: 13; CT: 5) at a median interval of 16.2 weeks. Neurological sequelae were observed in 10 (19%) patients, whereas 1 succumbed due to PRES. CONCLUSIONS: PRES is an important clinico-radiological syndrome in patients undergoing chemotherapy for hematological malignancies. High index of suspicion, early diffusion-weighted images on MRI in children with classic symptoms help in early diagnosis. A small minority of patients may develop long-term sequelae.

Clinical outcomes and prognostic factors in children with B-cell lymphoblastic lymphoma (LBL) treated according to on modified BFM-90 protocol: Experience from a Tertiary cancer care center in India.

Pediatric B-cell lymphoblastic lymphoma (LBL) is a rare entity, and appropriate treatment for pediatric B-cell LBL is not well defined. While intensive ALL type regimens achieve long term survival of 90% across Western co-operative group trials, published data from Asian studies on long term outcomes are scarce. We retrospectively analyzed the data of pediatric B-cell LBL patients treated between January 2010 and December 2017 on a uniform protocol (modified BFM 90). Kaplan-Meier method was used to estimate the survival and Cox regression models to identify prognostic factors. Of 21 patients who received treatment on the modified BFM-90 protocol, 17(81%) were alive in remission, 3(14%) had relapse, and 1(4%) had treatment-related mortality (TRM) while in remission. Two of 3 relapsed patients subsequently expired. With a median follow-up of 66 months (range 6-114), 5-year event free survival (EFS) and overall survival (OS) were 80% (95% CI:71-89%) and 91% (95% CI:85-97%), respectively. While delayed presentation from symptom onset (p=0.030), and partial response at early (D35) interim assessment (p=0.025) had inferior EFS, patients with elevated baseline LDH had a worse OS (p=0.037). Outcomes of pediatric B-cell LBL patients treated on a modified BFM-90 protocol at a single center in India were excellent. In our study, higher disease burden manifested by elevated baseline LDH and delayed presentation (≥3months) and partial interim response portend poorer survival.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.2005725.

Clinicopathologic Profile and Treatment Outcomes of Children With Diffuse Large B-cell Lymphomas: Experience From a Tertiary Cancer Center in India.

Clinicopathologic profile and outcome of 15 children (15 years or above) with diffuse large B-cell lymphoma treated with MCP-842 protocol are reported. Eleven of 15 presented with advanced (stage-III/IV) disease. Post-2 cycles of chemotherapy, complete metabolic and morphologic response was documented in 10 (66%) and rest 5 (33%) with partial response achieved complete metabolic remission by end of treatment. At a median follow-up of 44 months (range: 16 to 79 mo), the 3-year event-free survival and overall-survival were 77.1%±11.7% and 85.7%±9.4%, respectively. Though majority of our patients had advanced disease, outcome on MCP-842 protocol was satisfactory.

Psychological distress in primary caregivers of children with cancer during COVID-19 pandemic-A single tertiary care center experience.

OBJECTIVE: Families of children with cancer undergoing treatment during COVID-19 pandemic represent a vulnerable population for psychological distress and early identification and remedial measures are imperative for wellbeing of both the children and the caregivers. This article reports the results of assessment of psychological distress in primary caregivers of children with cancer undergoing treatment at a tertiary care center. METHODS: Primary caregivers of children with cancer (≤15 years) taking treatment at our institute during the period of July 2020 to August 2020 were prospectively evaluated for psychological distress using Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) tools over a telephonic call. There were 2 cohorts, A and B (50 participants each) depending on whether child was diagnosed with COVID-19 or not respectively during the study period. RESULTS: The assessment tool, PHQ-9 showed a score of ≥10 in 13% (n = 13) participants (95%CI:7.1%-21.2%) in the entire cohort and in 16% (n = 8, 95%CI:5.8%-26.2%) and 10% (n = 5, 95%CI:1.7%-18.3%) participants in cohort A and cohort B respectively. GAD-7 showed a score of ≥8 in 18% (n = 18) participants (95%CI:11.0%-27.0%) in the entire cohort and in 20% (n = 10, 95%CI:8.9%-31.1%) and 16% (n = 8, 95%CI:5.8%-26.2%) participants in cohort A and cohort B respectively. All participants were assessed, and supportive psychotherapeutic interventions administered over telephonic call. CONCLUSIONS: Primary caregivers should be assessed and followed up for psychological distress irrespective of other co-existing factors. Robust support systems built over time could help withstand the exceptional strain of a major surge during a pandemic.

A novel case of intrachromosomal amplification and insertion of RUNX1 on derivative chromosome 2 in pediatric AML.

Intrachromosomal amplification of RUNX1 gene on chromosome 21 (iAMP21) is a rare occurrence in acute myeloid leukemia (AML). Herein, we describe a case of AML with amplification of RUNX1 and its insertion on chromosome 2 detected by conventional karyotyping and confirmed by metaphase FISH. A six-year-old female was diagnosed as acute myeloid leukemia with monocytic differentiation. The patient's bone marrow revealed 74% blasts which were MPO negative. Conventional karyotyping revealed a complex karyotype, with rearrangements in chromosomes 1, 2, 7, 8 and hsr(21). FISH on interphase cells with LSI RUNX1-RUNX1T1 dual colour dual fusion translocation probe showed 6-7 copies of RUNX1 signal. Metaphase FISH with LSI RUNX1-RUNX1T1 probe confirmed amplification of RUNX1 and insertion of amplified RUNX1 sequences on long arm of chromosome 2. Induction chemotherapy was initiated, however, the patient died within one month of diagnosis suggesting poor outcome associated with this novel finding. Insertion of amplified RUNX1 on another chromosome has not yet been reported so far.

Imatinib-induced retroperitoneal fibrosis in a child with chronic myeloid leukemia: a case report.

A 12 year old boy with chronic myeloid leukemia (CML) presenting with bilateral pitting pedal edema and abdominal distension after about 41 months of imatinib therapy and was diagnosed to have retroperitoneal fibrosis (RPF) based on imaging and biopsy findings. He was found to have bilateral hydroureteronephrosis needing double-J stenting to the more severely affected right ureter. Imatinib was briefly interrupted and restarted later due to rising transcript levels and unavailability of other alternatives at that time which was later substituted by dasatinib once generic versions became available. Child remains asymptomatic after 18 months of DJ stenting. RPF is a rare complication of imatinib this being the second case reported in the literature.

COVID-19 in cancer patients on active systemic therapy - Outcomes from LMIC scenario with an emphasis on need for active treatment.

BACKGROUND: There is limited data on outcomes in cancer patients with coronavirus disease 2019 (COVID-19) from lower middle-income countries (LMICs). PATIENTS AND METHODS: This was an observational study, conducted between 12 April and 10 June 2020 at Tata Memorial centre, Mumbai, in cancer patients undergoing systemic therapy with laboratory confirmed COVID-19. The objectives were to evaluate cumulative 30-day all-cause mortality, COVID-19 attributable mortality, factors predicting mortality, and time to viral negativity after initial diagnosis. RESULTS: Of the 24 660 footfalls and 7043 patients evaluated, 230 patients on active systemic therapy with a median age of 42 (1-75) years were included. COVID-19 infection severity, as per WHO criteria, was mild, moderate, and severe in 195 (85%), 11 (5%), and 24 (11%) patients, respectively. Twenty-three patients (10%) expired during follow-up, with COVID-19 attributable mortality seen in 15 patients (6.5%). There were no mortalities in the pediatric cohort of 31 (14%) patients. Advanced stage cancer being treated with palliative intent vs others [30-day mortality 24%% vs 5%, odds ratio (OR) 5.6, 95% CI 2.28-13.78, P < .001], uncontrolled cancer status vs controlled cancer (30-day mortality37.5%% vs 4%%, OR 14, 95% CI 4.46-44.16, P < .001) and severe COVID-19 vs mild COVID-19 (30-day mortality 71% vs 3%, OR 92.29, 95% CI 26.43-322.21, P < .001) were significantly associated with mortality. The median time to SARS-CoV-2 RT-PCR negativity was 17 days [interquartile range (IQR)17-28) in the cohort. CONCLUSIONS: The mortality rates in cancer patients with COVID-19 who are receiving systemic anti-cancer therapy in LMICSs are marginally higher than that reported in unselected COVID-19 cohorts with prolonged time to viral negativity in a substantial number of patients. The pediatric cancer patients tended to have favorable outcomes.

Increased toxicities in children with Burkitt lymphoma treated with rituximab: Experience from a tertiary cancer center in India.

BACKGROUND: Even though rituximab has emerged as standard of care for the management of high-risk pediatric Burkitt lymphoma (BL), its safety in children from the low-middle-income countries (LMICs) remains to be proven. We herein report our experience of using rituximab in children with BL. METHODS: All patients diagnosed with BL between January 2015 and December 2017 were treated in a risk-stratified manner with either the modified MCP-842 or modified LMB protocol. Patients with poor response to MCP-842 were switched to the LMB-salvage regimen. In addition, rituximab was given to selected high-risk patients. RESULT: Forty-two (49.4%) of 85 patients with BL received rituximab. The incidence of febrile neutropenia (90.5% vs 67.4%; P = 0.02), pneumonia (38.1% vs 11.6%; P = 0.005), intensive care unit admissions (54.5% vs 17.6%; P = 0.002), and toxic deaths (26.2% vs 9.3%; P = 0.04) was higher among BL patients who received rituximab. Pneumonia was fatal in 11 of 16 (69%) patients who received rituximab. On multivariate analysis, rituximab continued to be significantly associated with toxic deaths ( OR: 11.45 [95% CI: 1.87-70.07; P = 0.008]). The addition of rituximab to intensive chemotherapy resulted in an inferior one-year event-free survival (49.4% ± 8.1% vs 79.3% ± 6.5%; P = 0.025) and one-year overall survival (63.1% ± 8.5% vs 91.8% ± 4.5%; P = 0.007) with no improvement in one-year relapse-free survival (78.3% ± 7.3% vs 83.9% ± 6.0%; P = 0.817). CONCLUSION: Rituximab was associated with increased toxicities and toxic deaths in our patients. The potential immunomodulatory effect of rituximab and increased susceptibility to infections in patients from LMICs have to be carefully considered while choosing this drug in the treatment of BL in resource-constrained settings.

Defibrotide treatment but not prophylaxis is useful in hepatic sinusoidal obstruction syndrome in children undergoing autologous stem cell transplant following high-dose chemotherapy: A single-center experience from the Royal Marsden Hospital, UK.

BACKGROUND: Hepatic sinusoidal obstruction syndrome (SOS) is a serious complication of autologous stem cell transplant (ASCT) in children with historically high mortality rates. Defibrotide has shown proven benefit in its treatment and may have a modest role in prevention. We report our experience with SOS in children undergoing autologous transplant. METHODS: Case records of 82 consecutive patients undergoing ASCT following high-dose chemotherapy between 2010 and 2017 were reviewed. Defibrotide was used for treatment of all with SOS and prophylactically in patients receiving busulfan-based conditioning until 2014. RESULTS: Fourteen of the 82 children (17%) were diagnosed with SOS. The incidence was higher in those receiving busulfan-based conditioning (13/42 vs 1/40, P = 0.008). Mean (±SD) time to diagnosis of SOS was 19 (±5.6) days following stem cell rescue. Bilirubin levels and ultrasound were normal in 7/14 and 3/14 patients. Coagulopathy was noted in 10/14; one child developed multiorgan involvement. Nine children had mild SOS, whereas two and three had moderate and severe SOS, respectively. Intensive care was required for four of five non-mild cases. Patients with SOS had significantly delayed platelet recovery, higher transfusion requirement, and longer hospital stay. Unavailability of defibrotide prophylaxis for 17/42 receiving busulfan did not change the incidence of SOS (7/25 with defibrotide vs 6 /17 without defibrotide, P = 0.74). There was no significant difference in the severity of SOS between these groups. CONCLUSION: Hepatic SOS was more commonly seen in children receiving busulfan-based conditioning. Stopping the use of prophylactic defibrotide did not increase incidence or severity of SOS. Overall outcome was excellent with supportive care and timely treatment with defibrotide.

Machine learning derived genomics driven prognostication for acute myeloid leukemia with RUNX1-RUNX1T1.

Panel based next generation sequencing was performed on a discovery cohort of AML with RUNX1-RUNX1T1. Supervised machine learning identified NRAS mutation and absence of mutations in ASXL2, RAD21, KIT and FLT3 genes as well as a low mutation to be associated with favorable outcome. Based on this data patients were classified into favorable and poor genetic risk classes. Patients classified as poor genetic risk had a significantly lower overall survival (OS) and relapse free survival (RFS). We could validate these findings independently on a validation cohort (n = 61). Patients in the poor genetic risk group were more likely to harbor measurable residual disease. Poor genetic risk emerged as an independent risk factor predictive of inferior outcome. Using an unbiased computational approach based we provide evidence for gene panel-based testing in AML with RUNX1-RUNX1T1 and a framework for integration of genomic markers toward clinical decision making in this heterogeneous disease entity.

Assessment of tumor Epstein-Barr Virus status and its impact on outcomes in intermediate and high-risk childhood classic Hodgkin Lymphoma treated at a tertiary cancer center in India.

Indian studies on EBV in childhood classic Hodgkin Lymphoma (cHL) have mainly analyzed the epidemiology of EBV-positive [EBV(+)HL] or negative HL [EBV(-)HL], with limited data on outcomes. We studied a large cohort of children with intermediate and high-Risk cHL for tumor EBV status and its impact on outcomes retrospectively. Of evaluable 189 patients, 84.7% had EBV(+)HL. Positive status was significantly associated with age ≤ 10 years (p < .001), males (p = .015), non-Nodular Sclerosis (NS) histology (p = .004) and inversely with bulky-mediastinal disease (p < .001). At a median follow-up of 29-months (range1-75), 3-year Event-Free Survival (EFS) for EBV(+)HL and EBV(-)HL was 93.6%(95%CI:89.8%-97.5%), 81.1%(95%CI:67.2%-97.9%), (p = .048) and Overall Survival (OS) was 94.9%(95%CI:91.6%-98.4%), 84.6%(95%CI:71.5%-100%), (p = .075) respectively. Three-year EFS was better in males (HR-0.267,95%CI:0.078-0.916, p = .036) in EBV(+)HL and in patients with serum-albumin > 3g/dL (HR-0.117,95%CI:0.019-0.705, p = .019) in EBV(-)HL. EBV is associated with most of intermediate and high-risk childhood cHL, occurs in younger male patients with non-NS histology, with reduced incidence of bulky-mediastinal disease and favorable survival in childhood cHL.

Managing peritoneal involvement in children and young people with rhabdomyosarcoma: A single-center experience from the United Kingdom.

We describe our experience in managing nine children and adolescents with rhabdomyosarcoma (RMS) and peritoneal involvement. The radiological pattern of peritoneal involvement was diverse from only ascites to solid peritoneal mass/omental caking. Treatment included systemic chemotherapy in all, surgery in three, and radiotherapy in eight. Two patients with presumed nonmalignant ascites, no solid peritoneal metastasis, nonalveolar histology, near-complete resection of residual disease, and radiotherapy survived long term. One patient has just completed treatment, and the remaining six relapsed/progressed at the time of reporting. Five of six patients died after a median of 5 (3-7) months from relapse despite second-line chemotherapy.