Background: Outcomes of adolescents and young adults (AYA) with bone sarcomas inclusive of osteosarcoma (OGS) and Ewing’s sarcoma (ES) are impacted by various factors including inadvertent prior treatment and poor compliance. We aimed to identify prognostic factors and derive prognostic models for these patients. Methods: All AYA OGS and ES cases treated at our institute with the “OGS-12” and Ewing’s family of tumors-2001 (“EFT-2001”) protocols from 2011 to 2021, and 2013 to 2018 respectively, were prospectively analyzed. Results:. Among 606/748 (81.0%) AYA with non-metastatic osteosarcoma, significant factors included in the prognostic model were failure to complete protocol (hazard ratio (HR) 2.65, 95% confidence interval (CI) 1.65-4.26), prior treatment (HR 2.93, CI 1.4-6.1), necrosis <90% (HR 1.63, CI 1.24-2.1), joint involvement (HR 2.0, CI 1.49-2.69) and SAP> median (204 U/l) (HR 1.63, CI 1.24-2.14). Of 104/263 (39.5%) AYA ES, significant factors were failure to complete protocol (HR 2.84, CI 1.03-7.8), prior treatment (HR 6.37, CI 1.8-22.0), necrosis <100% (HR 8.73, CI 2.16-35.3), and tumor size >8cm (HR 2.64, CI 1.04-6.7). For 142/366 (38.8%) AYA with metastatic OGS, significant factors were failure to complete protocol (HR 5.29), metastases not amenable to local treatment (HR 1.96), necrosis <90% (HR 1.96), and >10 metastases (HR 2.44). For 38/82 (43.6%) AYA with metastatic extremity ES, significant factors were failure to complete protocol (HR 3.88) and metastases not amenable to local treatment (HR 10.6). Conclusion: We developed simple, effective prognostic models for AYA with bone sarcomas with wide applicability in LMIC.

B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous disease wherein cytogenetics comprises an independent prognostic factor. Cytogenetic subgroups like B-ALL with t(9;22), MLL rearrangement, hypodiploidy, and Ph-like ALL are stratified as high-risk and are treated on the high-risk regimen. However, a subset that does not fall into a specific cytogenetic risk groups, is classified as cytogenetics NOS (Not Otherwise Specified) and might receive suboptimal chemotherapy. Identifying genetic abnormalities that are susceptible to targeted therapy can help improve outcomes. Therefore, with the intent to report cytogenetic data potentially useful for targeted therapy, we report a novel JAK2 amplification in a cytogenetically complex pediatric B-ALL case with early relapse.

Background: Burkitt lymphoma (BL) is an aggressive non-Hodgkin’s lymphoma (NHL). With high-dose combination chemotherapy cure rates are excellent but associated with higher rates of infections, and morbidity. Treatment for HIV positive Burkitt lymphoma is similar to HIV negative Burkitt lymphoma along with anti-retroviral therapy. In resource constrained setting offering intensive chemotherapy sometime is difficult. There is scarcity of data regarding use of metronomic chemotherapy in aggressive lymphomas. Results: Here we present outcome and review of literature of child, diagnosed with Burkitt lymphoma and HIV who was treated with metronomic chemotherapy. After year of follow-up he is disease free.

AIMS 6 mercaptopurine (6MP) is the mainstay chemotherapy for acute lymphoblastic leukaemia (ALL) and is conventionally available as 50 mg tablets. This study aimed to evaluate the bioequivalence of a new 6MP Powder for Oral Suspension (PFOS) intended for paediatric use. Additionally, a virtual study with the obtained data was planned for determining a dose of the PFOS that matches tablet exposures and to confirm optimal drug levels in pediatrics. METHODS An open-label, randomized, two-treatment, two-period, two-sequence, single oral dose, crossover, bioequivalence study was conducted on 51 healthy subjects. A population pharmacokinetic (PopPK) model was developed using the data to perform simulations with various PFOS doses and select a bioequivalent dose. To simulate 6MP and 6 thioguanine (6TGN) exposures in pediatrics, a literature model for paediatric ALL patients, and allometrically scaled PK parameters were utilised. RESULTS The 6MP PFOS had 47% higher bioavailability compared to the reference product. Simulations using a two-compartmental PopPK model with dissolution and transit compartments showed that 40 mg of PFOS was found to be equivalent to the 50mg tablets. The simulated 6TGN concentrations in virtual paediatric patients were between 114 and 703.6 pmol/8x108 RBCs, which was within the range of values reported in paediatric ALL studies. CONCLUSION The study demonstrates that 40 mg dose of 6MP PFOS 10 mg/mL has the same extent of absorption as the 50 mg tablet which can be precisely administered in pediatrics. The study also demonstrates the role of modelling and simulation to perform virtual bioequivalence and paediatric studies.

Background Outcome and toxicity data in adolescent-adult Ewing’s Sarcoma (AA-ES) patients is sparse and merits exploration. Methods Histopathologically confirmed, non-metastatic AA- ES patients, who received standard institutional combination chemotherapy regimen (EFT-2001) comprising of ifosfamide plus etoposide and vincristine, doxorubicin, plus cyclophosphamide, lasting a total of 12 months between 2013 and 2018, were analyzed for treatment-related toxicities, event-free survival (EFS) and overall survival (OS). Results There were 235 patients (primary safety cohort, PSC) with median age of 23 (15-61) years; 159(67.7%) were males, 155 (65.9%) had skeletal primary and 114(48.5%) had extremity tumors. 196(83.4%) were treatment naïve (primary efficacy cohort, PEC) and of these 119 (60.7%) had surgery. In PEC, at a median follow up of 36.4 (IQR 20 – 55) months, estimated 5 year EFS and OS were 60.9% (95% CI 53.1% - 69.9%) and 84.5% (95% CI 77.7% - 91.9%) respectively. Of these, 158 (80.6%) complying with intended treatment, at a median follow up of 39 (IQR 26- 57) months had an estimated 5 year EFS of 63.1% (95% CI 54.8%-72.6%). In multivariable analysis good prognostic factors included, longer symptom(s) duration (HR=0.93, 95% CI 0.86-0.994), ≥ 99% necrosis (HR=0.30, 95% CI 0.11-0.77) and treatment completion (HR=0.32, 95% CI 0.14-0.74). Among PSC, grade 3-4 toxicities were febrile-neutropenia (119, 50.6%), anemia (130,55.3%), peripheral neuropathy (37,15.7%), with 3(1.3%) chemo-toxic deaths . Conclusions The outcomes of AA non-metastatic ES patients treated with EFT-2001 regimen were comparable to those reported by others, with acceptable toxicity. This regimen could be considered a standard-of-care in AA-ES.

1 Background and Objective Coronavirus disease-2019 (COVID-19) or its complications in children with cancer were not increased as compared to normal children in earlier reports. However, continuing intensive treatment during ongoing COVID-19 infection has not been studied systematically. We report a single tertiary center experience on COVID-19 in children with cancer and continuation of cancer-directed therapy in them. 2 Methods Children ≤15years on active cancer treatment detected with COVID-19 until September 15th, 2020 were prospectively followed-up. Patients were managed in accordance to well-laid guidelines. Treatment was continued for children with COVID-19 infection who were clinically stable and on intensive treatment for various childhood cancers as far as practicable. 3 Results One hundred twenty-two children (median age 8years; range 1-15years, male: female 1.7:1) with cancer were diagnosed with COVID-19. All-cause mortality rate was 7.4%(n=9) and COVID-19 related mortality rate was 4.9%(n=6). Of 118 children, 99 (83.9%), 60 (50.8%), 43 (36.4%), 26 (22.0%) and 6 (5.1%) had RT-PCR positivity at 14, 21, 28, 35 and 60 days from diagnosis of COVID-19 respectively. Scheduled risk-directed intravenous chemotherapy was delivered in 70 (90.9%) of 77 children on active systemic treatment with a median delay of 14days (range, 0-48days) and no increased toxicities. 4 Conclusions COVID-19 was not a major deterrent for the continuation of active cancer treatment despite persistent RT-PCR positivity. The long-term assessment of treatment adaptations requires further prospective follow up and real time addressal.

Introduction: Vascular endothelial growth factor (VEGF)is an angiogenic marker and implicated in carcinogenesis and prognostication of cancers. However its prognostic potential in a rare cancer-Ewing’s sarcoma merits exploration. Methods: Histopathologically confirmed consecutive ES cases registered at our institute from 2014 to 2018 were analysed. Immunohistochemical staining for VEGF was performed on tumour tissues and they were further classified based on VEGF intensity. Results: There were 105 patients including 53 non-metastatic and 52 metastatic. VEGF immunostaining in non-metastatic and metastatic cohort was negative in 20 (37.7%) and 21 (40.4%), mildly positive in 13 (24.5%) and 9 (17.3%) cases, moderately positive in 14 (26.4%) and 16 (30.8%), and was intensely positive in 6 (11.3%) and 7 (13.5%) patients, respectively. VEGF immunoexpression up to 25% was seen in 14 (13.3%) and 10 (9.5%) patients within the non-metastatic and metastatic cohort, respectively. The median EFS and OS for the entire cohort were 26.4 (95% CI 17.6-NA) and 32.5 (21.3-NA) months, respectively. Metaststatic ES patients having either VEGF immunostaining in >25% tumor cells or moderate /strong immunostaining were found to inferior EFS and OS [p= 0.017, HR-0.153; p=0.013, HR-0.109 respectively].Additionally, treatment-naïve, compliant and non-metastatic patients had superior EFS (p=0.000, 0.000, 0.020, 0.022 respectively) and OS (p=0.000, 0.000, 0.006, 0.041 respectively). Conclusion: VEGF expression and intensity were found as independent negative prognostic marker in Ewing sarcoma .This may translate to therapeutic relevance but needs validation in the subsequent, larger prospective studies.

Background Outcomes of Ewing sarcoma (ES) in low and middle income countries lags behind the rest of the world owing to multiple tumoral, logistical and socio-economic factors. The data of outcomes and toxicity in these countries is sparse, especially in the adolescent and adult (AA) population and merits exploration Procedure This was a retrospective analysis of prospectively collected data of non-metastatic AA-ES patients, who received standard institutional combination chemotherapy regimen (EFT-2001) along with surgery or definitive radiotherapy. Various cohorts were analyzed for treatment-related toxicities, event- free survival (EFS) and overall survival (OS). Results There were 235 patients (primary safety cohort, PSC) with median age of 23 years. One hundred and ninety six were treatment naïve (primary efficacy cohort, PEC) and of these 119 had surgery. In PEC, at a median follow up of 36.4 months, estimated 5 year EFS and OS were 60.9% (95% CI 53.1% - 69.9%) and 84.5% (95% CI 77.7% - 91.9%), respectively. Of these, 158 complying with intended treatment, had an estimated 5 year EFS of 63.1% (95% CI 54.8%-72.6%). In multivariate analysis, good prognostic factors included longer symptom duration, ≥ 99% necrosis and treatment completion. Among PSC, grade 3-4 toxicities were febrile-neutropenia (50.6%), anemia (55.3%), peripheral neuropathy (15.7%), with 3 (1.3%) chemo-toxic deaths. Conclusions The outcomes of AA non-metastatic ES patients treated with EFT-2001 regimen were comparable to those reported by others, with acceptable toxicity and can be considered as standard-of-care, especially in LMICs.

Background: Pediatric B-Lymphoblastic lymphoma(pB-LBL) is a rare entity, and appropriate treatment for pB-LBL is not well defined. While intensive Acute Lymphoblastic leukemia(ALL) type regimens achieve long term event free survival of 90% across western co-operative group trials, published data from Asian studies on long term outcomes in pB-LBL are scarce. We evaluated the outcomes and prognostic factors of pediatric B-LBL patients treated at our center. Methods: We retrospectively analyzed the data of pediatric B-LBL patients treated between January 2010 and December 2017 on a uniform protocol(modified BFM 90). Patients were evaluated for early response post-induction and monitored for toxicity and long term outcomes. Kaplan-Meier method was used to estimate the event free survival(EFS) and overall survival(OS). Cox regression models were performed to identify prognostic factors. Results: 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 (≥3 months) had inferior EFS(p-0.030), patients with elevated baseline Lactate Dehydrogenase(LDH) had a worse OS(p-0.037). Age, gender, site of origin, stage, and post-induction response had no bearing on outcome. Conclusions: Outcomes of pB-LBL patients treated on modified BFM 90 protocol are excellent. Higher disease burden manifested by elevated baseline LDH and delayed presentation(≥3 months) portend poorer survival.

Background: The purpose of this single-centre study was to analyse the outcomes of extracranial germ cell tumors (GCTs) in children treated on a multi-modality regimen at a single-centre. Methods: Retrospective study of children (<18 years) with a histopathologically confirmed diagnosis of extracranial GCT over a period of 10 years (January’09-December’18) treated on a uniform institution-based protocol. All completely excised teratomas and stage I gonadal tumors received no further therapy (low risk); Stage IV Ovarian, Stage III-IV extragonadal GCTs received 6 cycles of chemotherapy (high risk) and the remaining received 4 cycles of chemotherapy (intermediate risk). Results: A total of 336 kids were treated of which the analysable cohort comprised of 297with a boy-girl ratio of 1.72:1 and median age of 4 years. Gonadal GCTs(n-180) were commoner than extragonadal GCTs(n-117) with ovary as primary site in 128 children(43%) and sacrococcygeal site being the commonest extragonadal location(n-41;14%). LR, IR and HR disease were noted in 60(20.2%) patients, 125(42%)patients and 112(37.8%)patients respectively. Forty-one patients relapsed and 43 children expired (disease related-33; toxic deaths-9; unknown-1). The 5-year EFS/OS was 79.3%/84.4% respectively with gonadal site, low-risk and non-metastatic disease associated with statistically better EFS (median follow-up:52.1±37.3 months). Conclusion(s): Both cisplatin and carboplatin based regimens had comparable outcomes. The low and intermediate GCTs had an excellent outcome, thus warranting a gradual shift in the approach to these tumors by reducing therapy and decreasing late effects of therapy. In high risk GCTs however, intensifying therapies to improve outcomes must be balanced against the risk of cumulative toxicity.

Background: Even though rituximab has emerged as the standard of care for management of high risk paediatric 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 patients with BL treated in our institute. Patients and Methods: All patients diagnosed of BL between January-2015 through December-2017 were treated in a risk stratified manner with either modified MCP-842 or modified LMB protocol. Patients with poor response to MCP 842 were shifted to LMB-salvage regimen. In addition, rituximab was given for selected patients of LMB group B or C. Result: Forty-two(49.4%) of 85 analyzed patients with BL received rituximab [Median dose:1500(Range:375-1875) mg/m2]. The incidence of febrile neutropenia(p=0.02), pneumonia(p=0.005), Intensive care unit admissions(p=0.002) and toxic deaths(p=0.04) were higher amongst BL patients who received rituximab. Pneumonia was fatal in 11 of 16(69%) patients who received rituximab. The mortality was 100% for patients who developed recurrent pneumonia after completion of treatment. On multivariate analysis, rituximab continued to be significantly associated with toxic deaths, HR:11.45(95%CI: 1.87-70.07; p=0.008). The addition of rituximab to intensive chemotherapy resulted in an inferior 1-year event free survival (49.4±8.1% vs 79.3±6.5%;p=0.025) and 1-year overall survival (63.1±8.5% vs 91.8± 4.5%;p=0.007). Also, the addition of rituximab did not improve 1-year relapse free survival (78.3±7.3% vs 83.9±6.0%;p=0.817). Conclusion: The potential immunomodulatory effect of rituximab and increased susceptibility to infections in patients from LMICs being treated under resource-constrained situations has to be carefully considered while choosing this drug in the treatment BL.

Background: JMML is a pediatric haematopoietic stem cell malignancy characterised by uncontrolled proliferation of myelomonocytic and progenitor compartments and a poor outcome. We comprehensively evaluated the genomic profile of JMML that presented to our hospital for diagnosis and treatment. Procedure: We developed a 51-gene (151.5kB) low-cost targeted myeloid panel based on single-molecule molecular inversion probes. A total of 50 children with clinical and pathological features of JMML were sequenced at high coverage on an Illumina MiSeq. The presenting clinical, laboratory and follow-up data were procured from the electronic medical record system of the institution. Results: The median age of our cohort was 2 years, with a male preponderance. Among the 50 patients, 43 (86%)harboured mutations in one of the RAS/MAPK-pathway genes, most frequently in PTPN11 (14, 28%), and NRAS (14, 28%), followed by NF1(11. 22%). Interestingly, 20% (10) of children had more than one mutation, with 5 cases harbouring two RAS-pathway mutations. Monosomy 7 was detected in 32% (16) patients, and five of these did not harbour any RAS-pathway mutations. The follow-up data revealed that 37 (74%) of these children had succumbed to the disease. Children with monosomy 7 showed shorter overall survival, compared to their wildtype counterparts (p=0.02). Conclusion: Our study highlights that comprehensive genomic profiling identifies at least one mutation in almost 90% of JMML patients. Performing genomic analysis early in evaluation of JMML might help in triaging patients for allogenic stem cell transplant in resource-constrained settings.