Pediatric Treatment Protocols Research Articles

Do children with Osteosarcoma benefit from Pulmonary Metastasectomy? - A Systematic Review Of Published Studies and 'Real world' Outcomes.

To critically examine the evidence-base for survival benefit of Pulmonary metastasectomy (PM) for Osteosarcoma (OS) in the paediatric population. PM for OS is recommended as standard of care in both paediatric and adult treatment protocols. Recent results from the PulMiCC trial demonstrate no survival benefit from Pulmonary Metastasectomy (PM) in Colorectal Cancer in adults. A systematic review was undertaken according to PRISMA guidelines. Medline, Embase and 2 clinical trials registers were searched for ALL STUDIES detailing paediatric OS patients (<18y) undergoing PM with a comparison cohort group that did not receive PM. Eleven studies met inclusion criteria dating from 1984 - 2017. All studies were retrospective and none directly compared PM versus No PM in paediatric patients as its main objective(s). Three-year survival rates ranged from 0-54% for PM and 0-16% for no PM. No PM patients were usually those with unresectable disease and/or considered to have a poor prognosis. All studies were at high risk of bias and there was marked heterogeneity in the patient selection. There is a weak evidence-base (Level IV) for a survival benefit of PM for OS in paediatric patients likely due to selection bias of 'favourable cases'. The included studies many of which detailed outdated treatment protocols were not designed in their reporting to specifically address the questions directly. A randomised controlled trial - whilst ethically challenging in a paediatric population - incorporating modern OS chemotherapy protocols is needed to crucially address any 'survival benefit'.

Deciphering Childhood Rosacea: A Comprehensive Review.

Childhood rosacea is a lesser known, yet significant, skin condition presenting diagnostic and treatment challenges. Although often underdiagnosed due to unclear diagnostic criteria, it manifests similarly to adult rosacea, with features such as papulopustular, telangiectasia, granulomatous, idiopathic facial aseptic granuloma, and ocular rosacea. The complex pathophysiology involves genetic, immunological, and environmental factors. Distinguishing childhood rosacea from conditions like acne, steroid rosacea, sarcoidosis, and lupus vulgaris is crucial but complicated by the lack of established criteria. Treatment strategies, mainly extrapolated from adult management protocols, include topical therapies, systemic medications, and laser treatments, adapted for pediatric patients. Special attention is given to ocular rosacea, often preceding skin manifestations, necessitating multidisciplinary care. The review underscores the urgent need for clear diagnostic guidelines, increased awareness, and tailored pediatric treatment protocols to improve patient outcomes and mitigate the condition's evolution into adulthood.

Improved MRD Negativity Rates in Adverse Genomic Risk B-ALL Patients with Chemotherapy / Blinatumomab Induction: Experience from the Australasian Leukaemia Lymphoma Group (ALLG) ALL06/09 Studies

Introduction: Despite the benefits conferred by pediatric treatment protocols, outcomes in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL) remain inferior to children. Poor outcomes in AYA ALL have been associated with reduced tolerability of intensive cytotoxics and higher incidence of adverse risk disease. Our earlier ALLG ALL06 study demonstrated intensive pediatric induction/consolidation could be delivered in a similar time frame as in children suggesting tolerability was not a major contributor to poor outcome in AYA ALL. ALL06 established post consolidation (TP2=d79) minimal residual disease (MRD) positivity (MRD+) and high BMI was predictive of inferior disease free- and overall survival (OS). In order to improve TP2 MRD negativity (MRD-) in B-cell disease, the ALLG ALL09 study substituted standard consolidation for blinatumomab (blin) in phase I and II of a BFM-style protocol . We present the impact of blin on outcomes in genomic cohorts from ALL09 and compare these to similar cohorts from ALL06 treated with standard chemotherapy. Methods: Between Sep 2020 and Apr 2022, 55 patientswere enrolled to ALL09. Of these, 45 had appropriate samples for genomic analyses and 39/45 had an MRD marker identified. These 39 patients formed the genomic cohort presented below. Genomic subtyping was performed using whole transcriptome sequencing, MLPA, karyotype and FISH analyses, and disease was classified into genomic adverse (AR) vs standard (SR) risk based on contemporary literature classifiers. Bone marrow MRD was assessed using ASO-PCR for IGH and TCR rearrangements, at d33 post induction (TP1), and TP2 post blin consolidation. Differences in TP2 MRD were assessed, with estimated 3 yr relapse free survival (RFS) and OS calculated using the Kaplan-Meier method. Results: In the ALL09 cohort, median follow up was 629 days with 3 yr RFS 84.5% and OS 87.1%. In the genomic cohort, median follow up was 602 days with 3 yr RFS 88.8% and OS 93.2%, respectively. These compared favorably to 3 yr RFS and OS (both 67.5%) in the B-cell genomic cohort from ALL06. Between ALL09 and ALL06 there were similar proportions of AR patients (73% and 62.5%, respectively). In ALL09, the most frequent subtypes were PAX5alt (18%) and PAX5 p.P80R (11%) versus KMT2Ar and DUX4r (both 17.5%) in ALL06. In ALL09, Ph-like disease represented 13% vs 12.5% in ALL06. In the ALL09 genomic cohort, the MRD+ rate reduced between TP1 and TP2 (p&amp;lt; 0.001), with the reduction in the rate of positivity being more pronounced in the AR cohort (AR MRD+ TP1=85% vs AR TP2=39%; p&amp;lt; 0.001). In contrast, in ALL06 MRD+ in the AR cohort reduced by only 28% between TP1 and TP2 (p &amp;gt;0.05). This suggests a positive impact of blin consolidation in AR patients in ALL09. Despite improved AR MRD+ rates overall, not all genomic subtypes in ALL09 followed this trend (Table 1). To date, there are 5 relapses in the ALL09 cohort, 4 from the genomic cohort. Of these, 1 was hypodiploid and strikingly the remaining 3 patients harbored a TCF3 rearrangement ( TCF3r). All 4 relapses were significantly associated with MRD+ at TP2 (RFS: MRD-, 100% (n=14) vs MRD+, 71% (n=25); p= 0.013), and all were observed in the AR genomic group. Of interest, the fifth case, outside of the genomic cohort, was classified as PAX5alt. In ALL09, high-risk (HR) patients proceeded to intensive HR block chemotherapy with the aim of eliminating MRD prior to allogeneic transplant (SCT). In the genomics cohort 15 patients proceeded to HR therapy, n=12 were considered AR. Sustained MRD+ through HR blocks 1 and 2 was noted in patients harboring PAX5 p.P80R (3/3), KMT2Ar (2/2) and TCF3r (2/3). Of the 9 patients who proceeded to SCT, 3 had PAX5 p.P80R 1 had PAX5alt, 2 were KMT2Ar and there was 1 each of DUX4r, hypodiploid and TCF3r. The 3 patients who remained MRD+ in the SR cohort had PAX5 p.P80R and all 3 proceeded to SCT. Conclusion: This is the first report of the impact of blin consolidation on genomic subsets of de novo AYA ALL. Our study suggests blin sensitivity as assessed by TP2 MRD response may be genomic subtype dependent, with TCF3r associated with sustained MRD+, leading to eventual relapse (3/3 patients). In addition, the PAX5 p.P80R subset was also associated with sustained high levels of TP2 MRD+ (3/4 with an MRD marker) and SCT (3/5 patients). These results may assist with identification of AYA ALL subsets that could benefit from alternative approaches as blin becomes increasingly incorporated into front-line protocols.

Long-Term Outcomes of T-Cell Acute Lymphoblastic Leukemia and Risk Factors for Survival in a Multicenter Registry Study from Brazil

Introduction T-cell acute lymphoblastic leukemia (T-ALL) constitutes around 25% of all newly diagnosed cases of acute lymphoblastic leukemia (ALL) in adults. While most pediatric treatment protocols categorize patients (pts) based on their phenotype, this approach is seldom applied to adults. Nevertheless, there is a scarcity of reported cohorts specifically focusing on adult T-ALL. Often, these cases are studied alongside B-cell cases, despite their notable biological differences, or grouped with T-cell lymphoblastic lymphoma, which exhibits a more favorable prognosis compared to T-ALL. The objective of this study is to present outcomes and identify prognostic factors for survival of adults newly diagnosed with T-ALL, utilizing data from a real-world multicenter registry study conducted in Latin America. Methods This registry encompassed four different academic centers in Brazil. The study included pts aged 15 years and above newly diagnosed with T-ALL between January 2009 and June 2022. Clinical data were collected from medical records after ethical approval. Overall (OS) and event-free (EFS) survivals were calculated by Kaplan-Meier method, with Cox regression multivariate analysis (MVA) for finding risk factors and competing risk analysis for relapse. Results A total of 97 pts were included, with a median age of 27 years (range, 15 - 82). Thymic T-ALL accounted for 51% of the cases. Mediastinal bulky was found in 48% and positivity of initial cerebrospinal fluid (CSF) evaluation was 12.5% (by morphology or flow cytometry). Baseline features of this cohort are summarized in table 1. Most pts (88%) were treated with pediatric-inspired regimens (asparaginase [ASP]-based), mostly adapted GMALL (43%) and adapted BFM (22%). Native E. coli ASP was used in 76% and pegylated ASP (PEG-ASP) was used in remaining cases. During presentation or treatment, 15% of the subjects experienced thrombosis of any site, with most cases being associated with the use of ASP (64%) and diagnosed during induction (64%). Following the frontline regimen, 77.3% of pts achieved complete response (CR). Overall, 11.3% of pts died during the induction phase, while 8% were primary refractory. Univariate analysis for CR showed correlation with age (p=0.002), bulky size (p=0.016), and use of ASP (p=0.009). Median follow-up period was 6 years. Overall, allogeneic stem cell transplant (alloHSCT) was performed in 18 pts, being 11/18 in first CR. Five-year OS and 5y EFS were 43.7% (95% confidence interval [CI]: 34.4-55.5) and 36.4% (95% CI 27.9-47.5), respectively. Over the follow-up, 5-year relapse rate and non-relapse mortality (NRM) were 35.6% and 27.9%, respectively. Among pts who underwent alloHSCT, 5y OS was 64%. In the univariate analysis, older age (HR 1.02 [1.01-1.04], p&amp;lt;0.01) was associated with lower OS. Conversely, thymic T-ALL (HR 0.54 [0.3-0.96], p=0.03) and use of ASP (HR 0.35 [0.17-0.716], p&amp;lt;0.01) were associated with higher OS. Initial white blood cell count was not statistically associated with OS. Subsequently, we performed a subgroup analysis focusing on the adult and young adult population (AYA, age between 15-45 years). In this subgroup (n=85), 89% were treated with pediatric-inspired regimens and 5y OS was 46.5%. In the univariate analysis, thrombosis (HR 2.21 [1.09-4.48], p=0.02) was associated with lower OS, while thymic T-ALL (HR 0.48 [0.24-0.93], p=0.03) and the use of ASP (HR 0.317 [0.13-0.75], p&amp;lt;0.01) were associated with higher OS. In the MVA for AYA, thymic T-ALL (HR 0.50 [0.25-0.98], p=0.04) and thrombosis (HR 2.23 [0.97-5.13], p=0.054) remained associated with OS, while older age was not (HR 1.004 [0.96 - 1.04], p=0.81) (Figure 1). Conclusions Reported outcomes of T-ALL in this registry from Latin America are comparable to older reports from large groups worldwide. Currently, European groups have reported OS rates surpassing 70% for adults with T-ALL.However, in our setting, even in the AYA population, OS was disappointing. This could be attributed to increased NRM due to treatment toxicity and limited access to HSCT, which may have contributed to these findings. As previously reported, thymic T-ALL remains a lower-risk subtype. Additionally, thrombosis has emerged as an independent risk factor for OS in the AYA population, which is a novel finding that warrants further research. To the best of our knowledge, this is the first study specifically focusing on adult T-ALL from Latin America.

Abstract 3924: Cooperation between mutant IL7R and TLX3 generates mixed myeloid lymphoid leukemia from thymocyte progenitors

Abstract Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Despite the current pediatric treatment protocols have resulted in 5-year overall survival rates of up to 90%, treatments have substantial side effects. Therefore, it is important to identify more specific therapeutic targets and develop more effective and less toxic drugs and drug combinations. We have shown that overexpression of TLX3 in association with mutant IL7R (mutIL7R) is sufficient to generate aggressive leukemia from transduced CD4-CD8- (DN) thymocyte progenitors. To better understand mutIL7R/TLX3-mouse leukemia, we combined single cell RNA sequencing (scRNAseq), Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq), DNA Next Generation Sequencing (NGS) Chromatin Immunoprecipitation Sequencing (ChIP-Seq) and flow cytometry to explore the cooperation of mutIL7R and TLX3 in orchestrating leukemogenesis. We found that mutIL-7R+TLX3 induced murine mixed T/myeloid leukemia. Myeloid cell clones (CD11b+) expressed identical TCR rearrangements as the T cell clones (CD8+), indicating that mutant IL-7R+TLX3 generated mixed leukemia from T cell progenitors. Moreover, the passaged leukemia lost the T-cell phenotype and acquired a pro-B-like phenotype, suggesting preferential expansion of pro-B cells (CD19+, B220+ IgM-), which were not detected in the founder leukemia presumably due to its low frequency. We next sought to determine whether the oncogene combination is sufficient to drive a similar immunophenotype profile in vitro. We showed that ectopic expression of mutIL7R and TLX3 in DN primary thymocytes growing on OP9-DL4 pushed the cells to myeloid (CD11b+, Gr1+) and B-cell (B220) phenotype over a time course of 4, 8 and 20 days, while T-cell development was blocked, suggesting that TLX3 expression prevented differentiation into CD4+/CD8+ T-cells. To better understand the genes regulated by TLX3 on driving a mixed phenotype leukemia we performed ChiP-seq of D1 cell line ectopically expressing mutIL7R and TLX3. We identified RUNX as a possible key mediator of the mixed-phenotype-leukemia induced by TLX3 in combination with mutIL7R. Additionally, scRNAseq showed upregulation of PU.1 in mice leukemia, suggesting PU.1 as a potential therapeutic target. To assess whether targeted therapy could successfully treat mutIL7R/TLX3-mouse leukemia, we treated mice that had been injected with the thymocytes transduced with mutIL-7R+TLX3 genes. We found that PU.1 inhibition reduced spleen weights, indicating decreasing of leukemia engraftment. Taken together, we generated a high-resolution dataset with detailed information about the transcriptional landscape and immunophenotype of leukemia generated by mutIL-7R+TLX3, a combination that is observed in patient samples, and suggests new therapeutic drug strategies. Citation Format: Gisele Rodrigues. Cooperation between mutant IL7R and TLX3 generates mixed myeloid lymphoid leukemia from thymocyte progenitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3924.

High-Dose Methotrexate: Nursing Considerations for Administration and Supportive Care.

High-dose methotrexate (HDMTX) is the backbone of many pediatric and adult oncology treatment protocols. It requires appropriate monitoring and supportive care because delayed elimination of MTX can lead to serious toxicities. No reviews specifically addressing nursing management regarding standard treatment protocols and delayed MTX elimination exist. This article provides an overview of HDMTX treatment and nursing considerations, including toxicities, components of supportive care management, and strategies to manage administration and delayed elimination of MTX. A review of published literature and guidelines was performed to evaluate nursing considerations for patients receiving HDMTX. Using existing and novel tools, nurses can closely monitor patients and provide supportive care to mitigate HDMTX toxicity. Early identification of delayed MTX elimination and subsequent treatment with glucarpidase, if appropriate, has been associated with shorter length of hospital stay and decreased incidence of grade 4 toxicities and mortality.

Cooperation between Mutant IL7R and TLX3 Generates Mixed Myeloid/Lymphoid Leukemia from Thymocyte Progenitors

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Despite current pediatric treatment protocols that have resulted in 5-year overall survival rates up to 90%, treatments have substantial side effects. Therefore, it is important to identify more specific therapeutic targets and develop more effective and less toxic drugs and drug combinations. We have shown that overexpression of TLX3 in association with mutant IL7R (mutIL7R) is sufficient to generate aggressive leukemia from transduced CD4-CD8- (DN) thymocyte progenitors. To better understand mutIL7R/TLX3-mouse leukemia, we combined single cell RNA sequencing (scRNAseq), Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq), DNA Next Generation Sequencing (NGS) and flow cytometry to explore the cooperation of mutIL7R and TLX3 in orchestrating leukemogenesis. We found that mutIL-7R+TLX3 induced murine mixed T/myeloid leukemia. Myeloid cell clones (CD11b+) expressed identical TCR rearrangements with T cell clones (CD8+), indicating that mutant IL-7R+TLX3 generates mixed leukemia from T cell progenitors. Moreover, the passaged leukemia lost the T-cell phenotype and acquired a pro-B-like phenotype, suggesting preferential expansion of pro-B cells (CD19+, B220+ IgM-), which were not detected in the founder leukemia presumably due to its low frequency. We next sought to determine whether the oncogene combination is sufficient to drive a similar immunophenotype profile in vitro. We showed that ectopic expression of mutIL7R and TLX3 in DN primary thymocytes pushed the cells to myeloid (CD11b+, Gr1+) and B-cell (B220) phenotype over a time course of 4, 8 and 20 days, while T-cell development was blocked, suggesting that TLX3 expression prevented differentiation into CD4+/CD8+ T-cells. To further characterize the mixed T/myeloid leukemia at the molecular level, we compared the leukemia expressed genes to a TLX-bound genes public dataset. We found that 42 TLX3 target genes are expressed in mutIL7R+TLX3 leukemia. Interaction network analysis suggested significant Myc stimulation. We then confirmed Myc upregulation at the protein level in a thymocyte cell line, indicating that mutIL7R alone induces Myc but requires TLX-3 cooperation to induce maximal Myc expression levels. Taken together, we generated a high-resolution dataset with detailed information about the transcriptional landscape and immunophenotype of leukemia generated by mutIL-7R+TLX3, a combination that is observed in patient samples, and suggests new therapeutic drug strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patterns of Treatment Gaps and Opportunities for Advancement of Pediatric Radiation Therapy Services in Tertiary Care University Hospital in Pakistan - A Retrospective Audit

<h3>Objectives</h3> The aim of this study was to review pattern of treatment gap for pediatric patients treated with radiation therapy at our university hospital and identify the reasons for treatment interruptions. <h3>Methods</h3> Hospital database was reviewed for individual treated with radiation therapy(RT) on pediatric treatment protocol or age between 0-18years from January 2009-March 2021 with or without general anesthesia(GA). Patients were identified who had treatment gap of one or more days during RT delivery. Data for demographic details, diagnosis, region of treatment, duration of gap and reason for treatment interruption were recorded and analyzed. <h3>Results</h3> Out of 511 patients treated from January,2009-March,2021, there were 178 events of treatment gap recorded in 118 patients. The mean age of patients was 8.2years [± 4.95, (1-19years)] and 71(60%) them were male. Eighty one patients (75%) were referred from another institute for radiotherapy. All cases were discussed in tumor board and RT plans were peer-reviewed. Most of these patients were treated for sarcomas 57%(67 patients), CNS 15%(16 patients), lymphomas 14%(16 patients) and renal tumors 10%(12%) patients. Duration of treatment gap was 1-2days in 40(34%) patients, 2-7days in 42(36%) patients and ≥8days in 36(30%) patients. Major reasons included in-patient admission due to fever, neutropenia or diarrhea in 53 patients, machine breakdown in 29 patients, refusal of anesthesia fitness due to chest congestion in 24 patients, patients' social reason in 14 and RT re-planning in 10 patients. Out of 118 patients, 45(38%) were being treated under GA and 73(62%) without GA. 24 of 45 patients treated under GA had treatment interruption because of being unfit for GA before RT. Patients treated under GA also had longer duration of interruption, 36% having 3-7days gap and 42% having total gap of ≥8days. <h3>Conclusion</h3> These finding domonstrate potenial areas of improvement through active monitorying and supportive care during treatment and equipment maintenance to avoid interruptions, hence to achieve optimal local control with radiotherapy. Special attention is required for general anesthesia and corrdination with pediatric oncologist.

A Retrospective Analysis of Rituximab Treatment for B Cell Depletion in Different Pediatric Indications.

Background: Rituximab (RTX) is used in cancer therapy as well as in the treatment of autoimmune diseases and alloimmune responses after transplantation. It depletes the disease-causing B cells by binding to the CD (cluster of differentiation) 20 antigen. We evaluate different pediatric treatment protocols (via fixed treatment schedule, B cell- or symptom-controlled) and their therapeutic effects.Methods: Demographic information, clinical and laboratory characteristics, and special laboratory values such as immunoglobulin G (IgG), CD19 positive B cells and Epstein-Barr viral load were retrospectively analyzed in children treated with RTX between 2008 and 2016.Results: Seventy-six patients aged 1 to 19 (median 13) years were treated with 259 RTX infusions. The spectrum of diseases was very heterogeneous. RTX led to a complete depletion of the B cells. The reconstitution time varied between patients and was dependent on the application schedule (median 11.8 months). Fourteen out of 27 (52%) patients developed hypogammaglobulinaemia. The risk of IgG deficiency was 2.6 times higher in children under 4 years of age than in olderones. In the last group IgG deficiency developed in only 38% of the cases (n = 8). Recurrent and severe infections were observed each in 11/72 (15%) patients. Treatment-related reactions occurred in 24/76 (32%) cases; however, treatment had to be discontinued in only 1 case. In 16/25 (76%), the Epstein-Barr viral load dropped below the detection limit after the first RTX infusion.Conclusion: RTX is an effective and well-tolerated drug for the treatment of oncological diseases as well as autoimmune and alloimmune conditions in children. B cell depletion and reconstitution varies both intra- und interindividually, suggesting that symptom-oriented and B cell-controlled therapy may be favorable. Treatment-related reactions, IgG deficiency and infections must be taken into account.

Barriers and Proposed Solutions to a Successful Implementation of Pediatric Sepsis Protocols.

The implementation of managed protocols contributes to a systematized approach to the patient and continuous evaluation of results, focusing on improving clinical practice, early diagnosis, treatment, and outcomes. Advantages to the adoption of a pediatric sepsis recognition and treatment protocol include: a reduction in time to start fluid and antibiotic administration, decreased kidney dysfunction and organ dysfunction, reduction in length of stay, and even a decrease on mortality. Barriers are: absence of a written protocol, parental knowledge, early diagnosis by healthcare professionals, venous access, availability of antimicrobials and vasoactive drugs, conditions of work, engagement of healthcare professionals. There are challenges in low-middle-income countries (LMIC). The causes of sepsis and resources differ from high-income countries. Viral agent such as dengue, malaria are common in LMIC and initial approach differ from bacterial infections. Some authors found increased or no impact in mortality or increased length of stay associated with the implementation of the SCC sepsis bundle which reinforces the importance of adapting it to most frequent diseases, disposable resources, and characteristics of healthcare professionals. Conclusions: (1) be simple; (2) be precise; (3) education; (5) improve communication; (5) work as a team; (6) share and celebrate results.

The Application of Minimal Residual Disease in Hemato-Oncology: A Review of Its Current Utility in Trials, Regulatory Decisions and Clinical Practice

The concept of minimal residual disease (MRD) has become common across multiple hematological malignancies. However, there is considerable variation in the application of this concept to research activities and clinical practice across different diseases. We sought to investigate the current status of MRD testing in research, its standing with regulators, and its application in clinical practice, and interpreted the differences identified in light of the differentiating characteristics of each disease. Seven malignancies were considered: acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM).The technology used to detect MRD, or its near equivalents of major or deep molecular response (MMR) in CML, is under constant development; current techniques are based on polymerase chain reaction for all indications considered (including next-generation sequencing) or flow cytometry for four indications (ALL, AML, CML, and MM), with a role for imaging also proposed in MM.A review of the published literature (via PubMed) for each of the diseases identified multi-study meta-analyses describing the prognostic significance of MRD in ALL, CML, and MM; evidence of this relationship was based on analysis of individual studies for the other four diseases.In the context of the prognostic significance of MRD status, MMR is well established as an outcome in clinical trials in CML and is emerging as a trial outcome measure in other indications. A review of registered active Phase 2 and 3 clinical trials (via clinicaltrials.gov) found that MRD (or an equivalent such as molecular response) was listed as an outcome measure in 21% of trials in ALL, 17% in CLL, and 12% in MRD; this was more common in Phase 3 trials (15/40, 16/51, and 14/73 trials, respectively). MRD was listed as an outcome measure in 6% of trials in AML, 2% in DLBCL, and 6% in FL. Furthermore, the European Medicines Agency formally accepted MRD as an intermediate endpoint in CLL (effective from 2016), while MMR was recommended as a primary endpoint in CML in 2013; consultation is ongoing regarding acceptance of MRD in MM. The US Food and Drug Administration has led a number of workshops on the use of MRD in four indications (MM, CLL, AML, and ALL).Aside from academic interest and clinical development programs, the use of MRD testing to guide treatment is recommended in US and European clinical guidelines for ALL, CML, and the acute promyelocytic variant of AML, and in US guidelines for CLL; US guidelines for MM recommend assessment of MRD but do not suggest that the result should inform the course of treatment. For other malignancies, prognostic implications and utility in trial settings are acknowledged, but MRD testing is not recommended in practice.The role of MRD in a range of hematological malignancies appears to be evolving rapidly. MMR in CML has been important in trials and in clinical practice for a number of years, but has recently been followed by MRD in CLL, while MRD testing in MM is on the horizon. MRD evaluation is now an integral part of both adult and pediatric treatment protocols. The biological basis of each disease (targets for detection, location of disease), interacting with the available technology, treatments, and treatment intent, may have contributed to different speeds of uptake. Given the growing body of research on detection technologies and its role in other malignancies, we expect MRD testing to become increasingly widespread and its role to shift from prognosis to a key factor in determining treatment pathways. DisclosuresNo relevant conflicts of interest to declare.

Factors impacting enrollment on NCI-COG Pediatric MATCH trial treatment protocols.

10007 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients age 1 to 21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on the genetic alterations detected in their tumor. Treatment arm assignments and enrollment decisions have now been made for 1000 study participants: we report here match and enrollment data and factors affecting treatment protocol enrollment. Methods: Patients enrolled in the Pediatric MATCH screening protocol were assigned to an open treatment protocol if an actionable mutation (aMOI) was detected by tumor DNA and RNA-based cancer gene panel sequencing. After a match, treatment protocol enrollment must occur within 8-12 weeks. Patient demographic data, reasons for not enrolling on treatment protocol (if applicable), and prior history of molecular testing were reported by study sites. The Fisher exact test was used to compare protocol enrollment rates between groups. Results: Results were analyzed for the first 1000 patients with testing completed (enrolled between July 2017 and October 2020). At least one tumor aMOI was detected in 310 (31%) patients and treatment protocol slots were available for 284 patients (28%). A total of 131 patients (46% of those matched) enrolled on a treatment arm. No difference in treatment protocol match or enrollment rate was observed for gender, race, or ethnicity. Both treatment protocol match rate (105/275, 38% vs 86/394, 22%) and enrollment rate (56/275, 20% vs 33/394, 8%) were significantly more frequent in patients with a reported history of prior molecular testing (p&lt;0.0001). The most common reasons provided for not enrolling on a treatment protocol were: patient receiving other treatment (32% of responses), poor clinical status (16%), lack of measurable disease (11%), or ineligible diagnosis for that treatment arm (10%). Ineligibility due to history of excluded prior targeted therapy (6%) or inability to swallow capsules (4%) was less frequent. Conclusions: The rate of Pediatric MATCH treatment protocol enrollment has exceeded pre-study projections, due to more frequent actionable mutation detection and treatment assignment than anticipated (28% observed, 10% projected). This may in part reflect an increased number of targetable events in recurrent or refractory pediatric cancers. Correlative studies analyzing pre-treatment tumors from MATCH study patients are underway and will address this hypothesis. Prior history of molecular testing was associated with higher match and enrollment rate and poor clinical status was a common reason for not enrolling on a treatment protocol, suggesting that early molecular screening of children with solid malignancies may facilitate enrollment to biomarker-selected trials of targeted therapies. Clinical trial information: NCT03155620.

The implementation of a national paediatric oncology protocol for neuroblastoma in South Africa.

PurposeThe aim of the World Health Organization-International Paediatric Oncology Society is to improve childhood cancer survival in low- and middle-income countries to 60% by 2030. This can be achieved using standardised evidence-based national treatment protocols for common childhood cancers. The aim of the study was to describe the development and implementation of the SACCSG NB-2017 neuroblastoma (NB) treatment protocol as part of the treatment harmonisation process of the South African Children’s Cancer Study Group.MethodsThe Consolidated Framework for Implementation Research was used to identify factors that could influence the implementation of the national NB protocol as a health care intervention. The evaluation was done according to five interactive domains for implementation: intervention characteristics, inner setting, outer setting, individual or team characteristics and the implementation process.ResultsThe protocol was developed over 26 months by 26 physicians involved in childhood cancer management. The process included an organisational phase, a resource identification phase, a development phase and a research ethics approval phase. Challenges included nationalised inertia, variable research ethical approval procedures with delays and uncoordinated clinical trial implementation.ConclusionThe implementation of the national NB protocol demonstrated the complexity of the implementation of a national childhood cancer treatment protocol. However, standardised paediatric cancer treatment protocols based on local expertise and resources in limited settings are feasible.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10552-021-01424-2.

Diagnosis, Prevention, Treatment and Surveillance of Anthracycline-Induced Cardiovascular Toxicity in Pediatric Cancer Survivors

Advances in pediatric cancer therapies have dramatically improved the likelihood of survival. As survivors are aging, however, we are now understanding that treatment carries a significant risk of cardiovascular toxicity, which can develop immediately, or even many years after completing therapy. Anthracycline derivates are some of the most commonly used agents in pediatric oncology treatment protocols, which have a dose-dependent correlation with the development of cardiac toxicity. As we learn more about the mechanisms of toxicity, we are developing prevention strategies, including improvements in surveillance, to improve early diagnosis of heart disease. Current survivorship surveillance protocols often include screening echocardiograms to evaluate systolic function by measuring the ejection fraction or fractional shortening. However, these measurements alone are not enough to capture early myocardial changes. The use of additional imaging biomarkers, serum biomarkers, electrocardiograms, as well as cholesterol and blood pressure screening, are key to the early detection of cardiomyopathy and cardiovascular disease. Medical treatment strategies are the same as those used for heart failure from other causes, but earlier recognition and implementation can lead to improved long term outcomes.

EPID-03. COMPARISON OF SURVIVAL IN ADULT AND PEDIATRIC PATIENTS WITH MEDULLOBLASTOMA: A 2018 SEER BASED ANALYSIS

Medulloblastoma (MB) is the most common high-grade primary brain malignancy in children and accounts for 1% of adult brain tumors. Previous studies have compared survival in pediatric and adult MB from the National Cancer Institute Surveillance Epidemiology and End Results (SEER) database finding no difference. However, diagnostic subgroup analyses are limited. We examined survival in children (age 0–19) and adults (20–79) coded as MB in the 2018 SEER database (2000–2016), using Kaplan Meier analysis, log-rank test and Cox proportional hazard ratios (HR) with 95% confidence intervals (CI).). MB in SEER-18 is defined as ICD-O-3 histology codes 9470–9474 (n=1,728). ICD 9473, supratentorial PNET (sPNET, n=97) is biologically distinct so was analyzed separately. 5-year survival for MB, excluding sPNET, was similar in children (n = 1,091, 75.3%) and adults (n= 488, 79.1%) (HR=0.97, CI: 0.79 – 1.17, p=0.50). Subtype analyses showed no survival difference comparing adults and children with desmoplastic nodular MB (n=222, p=0.09), large cell MB (n=73, p=0.46), or MB NOS (n=1330, p=0.10). In contrast, children with sPNET had improved survival (n=65, 72.3%) compared to adults (n=29, 51.7%) (HR = 2.0, CI: 1.10 – 3.92; p=0.02,). In conclusion, 2018 SEER data for MB continue to show no survival difference between adults and children, suggesting adult patients could appropriately be entered on pediatric MB treatment protocols. Further analyses of the 2018 data are ongoing adjusting for sex, race, and treatment. Comparison of adults and children with MB and sPNET will be re-evaluated using the new 2016 World Health Organization classification.

Outcome Among Adolescents and Young Adults with Mature B-Cell Non Hodgkin Lymphoma at Pediatric Versus Adult Centers: A Population-Based Study Using the IMPACT Cohort

Background: Disparities in survival between adolescents and young adults (AYA) treated for acute lymphoblastic leukemia in pediatric versus adult centers are well documented. Whether similar disparities exist among AYA with mature B-cell non-Hodgkin lymphoma (B-NHL) is unknown, despite substantial differences between pediatric and adult treatment protocols. We compared outcomes among AYA with B-NHL by locus of care (LOC; pediatric versus adult) using a population-based clinical AYA database. We also assessed whether socioeconomic status or geographic area impacted outcome in this population. Methods: The IMPACT cohort comprises all Ontario, Canada AYA aged 15-21 years diagnosed with one of six common cancers (including NHL) between 1992-2012. Detailed demographic, disease (histology, stage), treatment, and outcome data were collected through chart abstraction and validated by content experts. Postal code at diagnosis allowed determination of neighbourhood income quintile and rural residence. Linkage to population-based health administrative data identified additional events (second cancers, relapse, death). Event-free (EFS) and overall survival (OS) were determined using Kaplan-Meier methods. The impact of LOC on EFS and OS was determined using multivariable Cox proportional hazard models, adjusted for demographics and disease-related variables. Results: Among 176 AYA with B-NHL, 62 (35.2%) received therapy at a pediatric center. Pediatric center AYA were more likely to have Burkitt lymphoma (BL) than diffuse large B-cell lymphoma (DLBCL) as compared to adult center AYA [26/62 (41.9%) vs. 21/114 (18.4%); p&amp;lt;0.001], and more likely to have advanced stage (i.e. Stage III/IV) disease [38/62 (61.3%) vs. 46/114 (40.4%); p=0.006]. The 5-year EFS and OS (with standard errors) for the whole cohort were 72.2%±3.4% and 76.1%±3.2%. Both EFS and OS were superior among pediatric center patients (EFS 82.2%±4.9% vs. 66.7%±4.4%; p=0.02), (OS 85.5%±4.5% vs. 71.1%±4.3%; p=0.03). When stratified by histology (BL vs. DLBCL), the EFS and OS were similar. However, the superior outcome of pediatric center AYA retained statistical significance only among those with DLBCL (Table 1). Adjusted for histology (BL vs. DLBCL), stage, and time period of diagnosis, adult center AYA had inferior EFS [hazard ratio (HR) 2.4, 95% confidence interval (95CI) 1.1-4.9, p=0.02] and OS (HR 2.5, CI 1.1-5.7, p=0.03). Neither neighbourhood income quintile nor rural residence was associated with EFS or OS. Conclusions: In this population-based cohort, AYA with B-NHL treated at pediatric centers experienced substantially superior EFS and OS compared to those treated at adult centers, even accounting for disease characteristics. In subgroup analyses, this difference retained statistical significance among patients with DLBCL but not among patients with BL, though the latter analyses were limited by small sample sizes. Future analyses will analyze whether patterns of treatment failure and late effects vary by locus of care. Further confirmatory studies are warranted, as are studies to determine the relative contribution of pediatric protocols versus other components of care. Our results nonetheless suggest that similar to AYA with acute lymphoblastic leukemia, AYA with B-NHL may benefit from being treated in pediatric centers with pediatric protocols. Disclosures Baxter: Servier: Membership on an entity's Board of Directors or advisory committees.

Pediatric acute lymphoblastic leukemia treatment protocols improvement: emphasis on minimal residual disease

Treatment of acute lymphoblastic leukemia (ALL) in children during the last 50 years has changed significantly, which has increased the survival of patients from 10–15 % in the early 60s to 80–85 % by the mid-2000s. Such results have been achieved through the development of new polychemotherapy regimens, the introduction of neuroleukemia prophylaxis, the strengthening of standard chemotherapy by increasing the dose and / or frequency of chemotherapeutic drugs administration, and the definition of criteria for patient stratification into prognostic risks groups and the development of principles of risk-adopted therapy.However, inspite of the overall success of pediatric acute lymphoblastic leukemia therapy, some variants of acute lymphoblastic leukemia associated with poor prognosis, especially acute lymphoblastic leukemia with BCR-ABL1 and MLL rearrangements. Besides the prolonged persistence of minimal residual disease is also an unfavorable prognostic factor requiring therapy intensification.In the current issue we present the main steps in the evolution of programmed chemotherapy of children with acute lymphoblastic leukemia. Great attention was paid for modern risk-stratifying criteria with an emphasis on minimal residual disease.

Uncommon cytogenetic abnormalities identifying high-risk acute myeloid leukemia in children.

Pediatric acute myeloid leukemia (AML) represents an aggressive disease and is the leading cause of childhood leukemic mortality. The genomic landscape of pediatric AML has been recently mapped and redefined thanks to large-scale sequencing efforts. Today, understanding how to incorporate the growing list of genetic lesions into a risk stratification algorithm for pediatric AML is increasingly challenging given the uncertainty regarding the prognostic impact of rare lesions. Here we review some uncommon cytogenetic lesions to be considered for inclusion in the high-risk groups of the next pediatric AML treatment protocols. We describe their main clinical characteristics, biological background and outcome. We also provide some suggestions for the management of these rare but challenging patients and some novel targeted therapeutic options.

High Frequency of Fusion Gene Transcript Resulting From t(10;11)(p12;q23) Translocation in Pediatric Acute Myeloid Leukemia in Poland

11q23/MLL rearrangements are frequently detected in pediatric acute myeloid leukemia. The analysis of their clinical significance is difficult because of the multitude of translocation fusion partners and their low frequency. The presence of t(10;11)(p12;q23) translocation was previously identified in pediatric acute myelogenous leukemia (AML). It is considered as the second most common translocation detected in pediatric 11q23/MLL-rearranged (present KMT2A) AML, after t(9;11)(p22;q23). The presence of the above translocation was previously identified as an unfavorable prognostic factor. Since June 2015, the Polish Pediatric Leukemia/Lymphoma Study Group has applied the therapeutic protocol requiring extensive diagnostics of genetic changes in pediatric AML. Until November 2019, molecular genetic studies were performed in 195 children with diagnosed AML to identify carriers of fusion gene transcripts for 28 most common chromosomal translocations in acute leukemia. The fusion gene transcript for translocation t(10;11)(p12;q23) involving MLL gene was detected with unexpectedly high frequency (8.9%) in our research. It was the highest frequency of all detected MLL rearrangements, as well as other detected fusion gene transcripts from chromosomal aberrations characteristic for AML. It seems that chromosomal aberration between chromosomes 10 and 11 can be relatively frequent in some populations. Paying attention to this fact and ensuring proper genetic diagnosis seem to be important for appropriate allocation of patients to risk groups of pediatric AML treatment protocols.

Development of mNavigator: Digital Health Application to Facilitate Compliance With Standardized Pediatric Cancer Treatment Protocols in Tanzania

PURPOSE Use of standardized treatment protocols has been demonstrated to improve outcomes for pediatric patients with cancer. Yet it is challenging to implement standardized treatment protocols in low- and middle-income countries as a result of infrastructure and resource constraints, as well as poor health provider compliance with treatment protocols. At Bugando Medical Centre (BMC) in Tanzania, health provider compliance with standardized paper-based treatment protocols is low at 22%. One-year overall survival rates among pediatric patients with cancer at BMC are 40% and almost one third of patients abandon treatment. We posit that improving protocol compliance in this setting may decrease treatment abandonment and improve survival rates. Use of digital case management systems has been shown to improve compliance with treatment protocols because of the ability to incorporate such features as decision-support algorithms, prompts and alerts, and checklists. The digital health application mNavigator was designed to facilitate health provider compliance with standardized pediatric cancer treatment protocols in Tanzania. METHODS mNavigator was developed by adapting an open-source digital case management platform called CommCare. The three stages of mNavigator development were as follows: workflow mapping and form development; form programming in CommCare; and quality assurance using mock and deidentified patient records to identify errors in information flow or outputs, assess preliminary usability, and determine areas for improvement. Standardized treatment protocols for Burkitt lymphoma and retinoblastoma were initially incorporated into mNavigator. The mNavigator prototype underwent usability testing at BMC before implementation in routine clinical practice. RESULTS Preliminary system usability, acceptance, and satisfaction evaluation demonstrated high usability response scores (&gt; 80%). Perceived benefits of the mNavigator system included a user-friendly interface, improved record keeping, and assistance with patient tracking using standardized treatment protocols. Suggestions for improvement centered on the incorporation of other standardized treatment protocols (eg, Wilms tumor), improving interoperability with existing electronic recordkeeping systems, and making similar systems available for other clinical departments. CONCLUSION To our knowledge, mNavigator is the first digital health case management system specifically developed to improve health provider compliance with pediatric cancer treatment protocols in a low-resource setting. With high usability and acceptability, mNavigator has been implemented in routine clinical practice. Implementation and patient outcomes evaluations are ongoing and will inform the scale-up for use in other low- and middle-income countries.