Older age, CNS leukaemic involvement and induction tumour lysis increases the risk of methotrexate (MTX)-induced neurotoxicity in childhood acute lymphoblastic leukaemia/lymphoma: Experience from a tertiary care centre in South India.

Methotrexate (MTX), although an indispensable part of contemporary treatment protocols for childhood acute lymphoblastic leukaemia (ALL)/lymphomas (LBL) in improving outcomes, can lead to serious neurotoxicity with long-term consequences. The aetiopathogenesis, predisposing factors and treatment for MTX-induced neurotoxicity are not yet well defined. The aim of our study was to detect the incidence, risk factors and to assess the overall outcomes of MTX-induced neurotoxicity among large cohort of paediatric ALL/LBL patients treated on a uniform protocol. We conducted retrospective audit of medical records of 622 consecutive children (≤14 years) diagnosed with ALL and LBL between January 2018 and December 2022 and treated on modified BFM-95 protocol at the Department of Pediatric Oncology, Regional Cancer Centre, Thiruvananthapuram. Risk factors predisposing to MTX-induced neurotoxicity were identified using binary logistic regression analysis. Forty-three children were diagnosed with MTX-induced neurotoxicity with an incidence rate of 6.9%. More than two-thirds of them had high-grade MTX-induced neurotoxicity CTCAE v5.0 with a median age of 9 years (range: 9 months to 14 years). Almost half of them developed MTX neurotoxicity during Protocol M followed by Phase-Ib consolidation (15%). Majority of these patients (84%, 36/43) were challenged again with MTX, with 11% (4/36) developing recurrence. Fifteen per cent had persistent neurological deficits at last follow-up. Univariate analysis found older age (age > 5 years) (p < 0.001), T-cell phenotype (p = 0.040), tumour lysis syndrome during induction (p < 0.001), baseline renal problems prior to MTX exposure (p < 0.001) and CNS leukaemic involvement (p < 0.003) to be significantly associated with MTX neurotoxicity. On multivariate analysis, older age (>5 years), tumour lysis during induction and CNS leukaemia retained statistical significance (p < 0.05). Methotrexate-induced neurotoxicity during paediatric acute lymphoblastic leukaemia/lymphoma therapy is a transient phenomenon in majority and re-challenge with MTX is generally safe. Older age children who develop tumour lysis during induction and CNS leukaemic involvement are at increased risk for MTX-induced neurotoxicity during ALL/LBL treatment.

A stitch in time saves nine: timely use of N-acetyl cysteine (NAC) for chemotherapy-induced veno-occlusive disease (VOD)-is it a cost-effective alternative?

Chemotherapy-induced veno-occlusive disease (VOD) is a rare liver dysfunction seen among pediatric cancer patients which could lead to severe morbidity and mortality. Defibrotide is the commonly used antidote in the management of both stem cell transplant and chemotherapy-associated VOD along with liver supportive measures. Defibrotide is costly and generally not accessible to majority of patients treated at resource poor settings. In this report, we describe the successful management of chemotherapy-induced VOD with timely administration of N-acetyl cysteine.

Drug Induced Diabetes Mellitus in Pediatric Acute Lymphoblastic Leukemia: Approach to Diagnosis and Management.

Corticosteroids and l -asparaginase used in the treatment of pediatric acute lymphoblastic leukemia (ALL) can cause drug-induced diabetes mellitus (DIDM). DIDM can lead to dyselectrolytemia, a higher risk of infections including cellulitis, bacteremia, fungemia, and a higher incidence of febrile neutropenia and may have an impact on the outcome of ALL. Literature on the management of DIDM among children with ALL is sparse and the diagnostic criteria for pediatric diabetes should be carefully applied considering the acute and transient nature of DIDM during ALL therapy. Insulin remains the standard of care for DIDM management and the choice of Insulin regimen (stand-alone Neutral Protamine Hagedorn or basal bolus) should be based on the type and dose of steroids used for ALL and the pattern of hyperglycemia. A modest glycemic control (postmeal 140 to 180 mg/dL, premeal <140 mg/dL) to prevent complications of hyperglycemia, as well as hypoglycemia, would be the general approach. This review is intended to suggest evidence-based practical guidance in the diagnosis and management of DIDM during pediatric ALL therapy.

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.

Prevalence and Clinical Outcome of FMS-Like Tyrosine Kinase Mutations Among Patients With Core Binding Factor-Acute Myeloid Leukemia: Systematic Review and Meta-Analysis.

BACKGROUND: Core binding factor acute myeloid leukemia (CBF-AML) belongs to favorable risk group in AML. However, approximately 50% of patients with CBF-AML remain incurable and their outcomes are also determined by the various co-occurring mutations. Though, FMS-like tyrosine kinase-3(FLT3) mutation in AML is associated with poor survival, the prevalence and prognostic significance of FLT3 mutations among CBF-AML is unknown. PATIENTS AND METHODS: We performed a systematic review and meta-analysis to assess the prevalence of FLT3 mutations (ITD and TKD) among patients with CBF-AML. The pooled prevalence of FLT3 mutations was estimated for patients with CBF-AML, t(8;21) and Inv(16). Pooled odds ratio was calculated to compare the prevalence of various FLT3 mutations within the 2 subsets of CBF-AML. A random effects model was adopted for analysis when heterogenicity existed (Pheterogenicity< 0.05 or I2 > 50%). Otherwise, a fixed effects model was used. RESULTS: The pooled prevalence of any FLT3 mutations among patients with CBF-AML was available from 18 studies and was 13% (95% CI: 10%-16%; I2 = 79%). Comparison of prevalence of FLT3 mutations between the 2 subgroups of CBF-AML showed that patients with t(8;21) had a higher prevalence of FLT3-ITD [pooled odds ratio(OR): 2.23 (95% CI:1.41-3.53, P < .01)] and lower prevalence of FLT3-TKD [pooled OR: 0.29 (95% CI:0.19-0.44; P < .01)] compared to patients with Inv(16). Additionally, we have discussed the prognostic significance of FLT3 mutations in CBF-AML patients. CONCLUSION: The prevalence of FLT3-TKD mutation was commoner among Inv(16) AML while FLT3-ITD mutation was commoner among t(8;21) AML. Uniform reporting of outcomes is essential to understand the prognostic significance of FLT3 mutations among CBF-AML.

Evaluating the Need for Integrated Pediatric Palliative Care Services in a Pediatric Oncology Setting: A Retrospective Audit.

OBJECTIVES: Early integrated palliative care has shown to improve the quality of life in patients with cancer. During the past decade, pediatric palliative care has become an established area of medical expertise, however due to scant information available regarding the triggers for referral and referral practice very few children receive a formal palliative care consult. MATERIALS AND METHODS: A retrospective audit of medical case records of pediatric oncology patients over a period of 1 year from September 30, 2019, to September 30, 2020, was conducted. Demographic details, diagnosis, staging, clinical parameters, reason for referral, and palliative care plan were captured in a predesigned pro forma. RESULTS: Among 126 children with cancer, 27 (21.4%) patients were referred to palliative care. Majority 21 (77%) referrals were inpatient consults. Symptom management 17 (44.7%) was the most common trigger for referral followed by referrals for psychosocial support 12 (14.4%). Children with solid tumors 16 (59%) were more often referred than hematological malignancies. Among those needing end of life care, 8 (88.8%) out of 9 families preferred home than hospital. CONCLUSION: Low incidence of palliative care referral and presence of symptoms as a trigger for palliative care referral suggests gaps in the integrated approach. The study findings prompt a review of palliative care referral criteria and referral practice in a pediatric oncology setting.

Disseminated Cryptococcosis in an Immunocompetent Child.

Disseminated cryptococcosis in children is a classic affliction associated with human immunodeficiency virus (HIV) infection or primary inherited immunodeficiency disorders (PID) with central nervous system being the most common site of dissemination. We report a rare case of disseminated cryptococcosis in an 11-year-old girl who presented with pulmonary involvement, hepatosplenomegaly, and generalized lymphadenopathy. No known inherited or acquired immune deficiencies were identified after a comprehensive laboratory work-up including genetic sequencing. She responded well to anti-fungal therapy (flucytosine and amphotericin followed by fluconazole) and is on regular follow-up.

Bilateral massive nephromegaly-A rare presentation of t-cell acute lymphoblastic leukemia.

INTRODUCTION: Renal infiltration by leukemia causing massive bilateral nephromegaly is an extremely rare presentation of T-cell acute lymphoblastic leukemia(T-ALL). CASE REPORT: 18-month-old female toddler presented with fever and progressive abdominal distension of 4-6 weeks duration. Imaging revealed bilateral massively enlarged kidneys with normal excretion. Peripheral blood counts and smear examination was unremarkable and immunophenotypic evaluation of marrow was consistent with T-ALL. Chest imaging was unremarkable. She was started on modified Indian Childhood Collaborative Leukemia Group (ICiCLe) ALL protocol. Even with the best anti-tumor lysis syndrome (TLS) prophylaxis the child required two sessions of hemodialysis. An end-induction morphological remission & end-consolidation negative minimal residual disease (MRD) could be achieved. CONCLUSION: Bilateral massive nephromegaly is an extremely rare presentation of T-ALL. This case emphasizes the unusual presentation, need for prompt remediation of TLS, and most importantly the use of early intensification with four drug anthracycline & dexamethasone-based therapy for the treatment of T-ALL in children.

Sudden blast phase in pediatric chronic myeloid leukemia-chronic phase with abnormal lymphoid blasts detected by flow cytometry at diagnosis: Can it be considered a warning sign?

BACKGROUND: Inconclusive knowledge persists regarding the course of chronic myeloid leukemia-chronic phase (CML-CP) patients with detectable abnormal blasts by flow-cytometry at diagnosis. The 2016 WHO classification is not specific regarding sub-classification of CML with <10% abnormal B-lymphoid blasts (ABLB), and suggests these patients often show rapid progression. We report the clinical course of pediatric CML-CP patients who had detectable abnormal blasts by flow-cytometry at baseline. METHODS: Retrospective audit of all pediatric CML patients between January 2013 and December 2017 were included. Their clinical presentation, demographic profile, and treatment outcomes were extracted from electronic medical records. Some of these patients got flow-cytometry done by default, though it was not a routine part of diagnostic CML marrow studies. RESULTS: Amongst 65 pediatric CML patients, flow-cytometry at initial diagnosis was available in 15 (CP-12; AP-3). Of the 12 CML-CP patients, 10 (83%) had abnormal flow-cytometric findings-5 (50%) with mixed lineage blasts (4-B/Myeloid, 1-B/T/Myeloid), and myeloid lineage blasts in the remaining 5 (50%). At a median follow-up of 26 months (range: 9-34 months), 3/5 patients with ABLB at diagnosis progressed to frank blast crisis (2 B-cell; 1 Mixed lineage). None among the five patients with diagnostic myeloid-alone aberrant blasts progressed to blast crisis. Imatinib resistant mutation was also found in 3/5 (60%) CML-CP patients with these ABLB at baseline. CONCLUSIONS: Although a retrospective study with limited sample size, presence of ABLB detected on flow-cytometry in CML-CP patients, had a noticeable early conversion to CML-BC in our cohort. Incorporation of flow-cytometry in diagnostic work-up can provide useful insight regarding the behavior of pediatric CML-CP patients and guide therapy.

High Response Rates and Promising Outcomes of Patients with Relapsed Ewing Sarcoma, Especially in Adolescents and Young Adults Treated on a Novel Hybrid Salvage Chemotherapy Regimen.

Purpose: About 30%-35% of nonmetastatic and 60%-80% of metastatic Ewing Sarcoma (ES) will relapse post-treatment and outcomes after relapse continue to be poor over last several decades. Prognostic factors affecting survival after relapse of ES are also not robustly known. We present outcomes using a novel hybrid salvage protocol of four active chemotherapeutic agents in our cohort of patients after relapse of ES. Methods: This is a retrospective analysis of all consecutive relapsed ES patients treated with curative intent over 4 years (January 2012 to December 2015). All received 12-cycles of hybrid chemotherapy regimen with surgery/radiotherapy done after first 4 cycles. Event-free survival (EFS)/overall survival (OS) estimates were analyzed by Kaplan-Meier product-limit estimator. Cox regression analysis was performed to identify prognostic factors predicting outcome in relapsed ES. Results: Salvage regimen was given to 53/108 relapsed ES patients with the rest having opted for palliation upfront. Median age of the treated patients was 19 years (range: 4-40); male:female ratio was 2.7:1. Median time to first relapse was 18.8 months (range: 2.2-91). While 41/53 patients (77%) completed salvage therapy, 6 (11.3%) progressed and 6 (11.3%) abandoned treatment. Median follow-up of the study cohort is 31 months (range: 4-81). Of the analyzable cohort (n = 47), 30 (64%) had a second relapse or progression on salvage treatment. At last follow-up, 31 patients had died (including one due to toxicity and rest due to disease) and 16 patients were alive (14 with no active disease and 2 with disease). The 4-year EFS and OS are 28% and 37%, respectively, for the entire cohort. While adolescents and young adult patients (AYA) had a better survival (p-0.041), relapsed ES patients with shorter disease-free interval (DFI) (<24 months) had a poorer survival (p-0.004). The type of relapse (local or metastatic or combined) after primary treatment did not affect outcome after salvage therapy. Conclusions: We have used a novel hybrid chemotherapy protocol using four active agents in relapsed ES, which is well tolerated and shows promising results. Older age (≥15 years) and longer DFI (>24 months) portend better survival post-relapse. In our cohort of relapsed ES, AYAs fared better than others and type of relapse after primary treatment did not affect outcome after salvage therapy.

Prognostic Value of 18F-FDG PET/CT-Metabolic Parameters at Baseline and Interim Assessment in Pediatric Anaplastic Large Cell Lymphoma.

INTRODUCTION: The event-free survival in pediatric anaplastic large cell lymphoma (ALCL) remains at 70% irrespective of the diverse chemotherapy regimens used. There is lack of valid prognostic factors identifying high-risk patients. We investigated the prognostic value of baseline metabolic parameters and interim response on F-FDG PET/CT in pediatric ALCL patients. METHODS: We retrospectively reviewed 40 pediatric ALCL patients with paired F-FDG PET/CT and treated uniformly on vinblastine-based institution protocol. The SUVmax, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis of the lymphomatous lesion were measured. Continuous PET parameters were stratified by their median values. Deauville scoring system was used to assess response to chemotherapy in the interim scan. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. RESULTS: At median follow-up of 52 months, 13 patients died and 13 had recurrence. On univariate analysis, higher whole-body MTV (WBMTV) and partial response on interim scan were statistically associated with OS. High-risk features, WBMTV, and partial response were statistically associated with DFS. On multivariate analysis combining baseline characteristics and interim response, interim response (hazard ratio, 3.56; P = 0.034) was statistically significant for OS. Multivariate analysis for DFS using only baseline characteristics revealed WBMTV as statistically significant (hazard ratio, 4.08; P = 0.035), but none of the parameters was statistically significant when baseline characteristics and interim response were evaluated together. CONCLUSIONS: Whole-body tumor burden assessment with MTV and interim response may help to identify high-risk patients who might get benefitted from intensive therapy.

Favorable outcomes and reduced toxicity with a novel vinblastine-based non-high dose methotrexate (HDMTX) regimen (modified MCP-842) in pediatric anaplastic large cell lymphoma (ALCL): experience from India.

Anaplastic large cell lymphoma (ALCL) is a rare form of non-Hodgkin lymphoma (NHL) in children. Most treatment regimens include high-dose methotrexate (HDMTX), which is logistically difficult to administer in resource-limited settings. We evaluated the outcomes of pediatric ALCL patients treated on a uniform protocol (Modified Multicentric Protocol, MCP-842 regimen) at our hospital between January 2005 and December 2016. Of the 68 patients who received treatment on the Modified MCP842 protocol, 46 patients are alive in remission, 11(16%) had disease progression, 9(13%) relapsed after achieving remission, and 5(7%) had treatment-related mortality (TRM). Seventeen of 20 relapsed/progressed patients subsequently expired. With a median follow-up of 55 months (range 2-165 months), the 4-year event-free survival (EFS) and overall survival (OS) are 63% (95% CI of 50-73%) and 70%(95% CI of 57-79%), respectively. An indigenous protocol using vinblastine (without HDMTX and steroids) is feasible in a resource-limited setting and achieves outcomes comparable to regimens incorporating HDMTX, with lower toxicity.