Children, Adolescents, And Young Adults Research Articles

Testicular germ cell tumor survival among children, adolescents, and young adults: A population-based retrospective cohort study.

10035 Background: While testicular germ cell tumor (TGCT) overall survival (OS) exceeds 90%, some patient groups, such as adolescents, have inferior event free survival (EFS) outcomes. There is a paucity of granular, population-derived data about outcomes in children, adolescents, and young adults (CAYA) with TGCT, limiting a deeper understanding of the factors that impact their survival. Methods: All male CAYA (ages 11-21 years) in Ontario, Canada diagnosed with TGCT between 1992-2021 were identified using provincial cancer registries. Detailed disease and treatment characteristics were chart abstracted for ~2/3 of the cohort and determined through health administrative databases for the remainder. We assessed 5-year OS and EFS (first of death, recurrence/progression, or subsequent malignant neoplasm [SMN]) using Kaplan-Meier analysis and the log rank test. Follow-up started at TGCT diagnosis, except for survival after SMN or recurrence, where follow-up started at event date. Results: 748 TGCT patients were identified; 521 were chart abstracted and thus had EFS data available. Median age at diagnosis was 19 years (interquartile range:18-21) and 83.6% had non-seminoma histology. OS and EFS ± standard error (SE) were (94.7 ± 0.8 %, n=748) and (76.4 ± 1.9%, n=521), respectively. Among patients with chart abstracted data, OS and EFS differed by cancer extent at diagnosis and were lowest among CAYA with non-lung organ metastases (Table). Patients who underwent retroperitoneal lymph node dissection (RPLND) for initial treatment (91/521) had higher survival than those who did not (OS 96.6 ± 1.9% vs 93.7 ± 1.2%, p=0.04; EFS 87.6 ± 3.5 % vs 74.1 ± 2.1 %, p=0.0008), particularly CAYA with lung-only organ metastases. OS post SMN (n=28) was 77.3 ± 8.2%, with lower OS after non-TGCT SMN (50.8 ± 14.4%, n=13) than second primary TGCT (100 ± 0%, n=15), p=0.002. OS after recurrence/progression (n=116) was superior in the 59 who did not receive chemotherapy at initial diagnosis (89.7 ± 4%) compared to the 57 who had initial chemotherapy (65.9 ± 6.4%; p=0.0001). Conclusions: CAYA with TGCT have low EFS, consistent with previous studies. The extent of metastasis is a significant predictor. Efforts are needed to improve the survival outcomes of young TGCT patients with organ metastasis at diagnosis, and those who recur or develop a non-TGCT SMN. [Table: see text]

The role of immune checkpoint blockade in children, adolescents, and young adults: A systematic review and meta-analysis.

10057 Background: Immune checkpoint blockade (ICB) has changed the treatment landscape for many types of adult cancer. However, while certain subsets of cancer in children, adolescents, and young adults (CAYA) are ICB-responsive, ICBs are less routinely used in clinical practice, thus clinical experience lags behind that of adults. Therefore, we performed a systematic review and meta-analysis to evaluate the safety and efficacy of ICB in the CAYA population. Methods: PubMed, Cochrane and Embase libraries were systematically searched for clinical trials evaluating ICB therapies for cancer in CAYA patients. We excluded reviews, case reports, observational studies, retrospective studies, studies with overlapping populations, trials with no outcomes of interest, and studies enrolling the adult populations (>40 years). We pooled the prevalence of treatment-related adverse events (TRAE), objective response rate (ORR), stable disease (SD), and their corresponding 95% confidence intervals (95% CI). For ORR and TRAE endpoints, we performed a subgroup analysis of each drug (PD-1, PD-L1 and CTLA-4) and each tumor type. A comparative analysis of the reported median overall survival (OS) and progression-free survival (PFS) was also completed. Statistical analysis was performed using R software version 4.3.1 and heterogeneity was evaluated through I2 statistics. Results: From 3,753 initial studies, 15 clinical trials were included, comprising 797 patients with median age ranging from 6.5 to 16.0 years (1-30 years) and multiple types of hematologic and solid malignancies. An all-grade TRAE rate of 66% was found (95% CI 60-71), while the proportion of grade 3/4 TRAE was 19% (95% CI 13-27). In the tumor type subgroup analysis for all-grade TRAE and grade 3/4 TRAE, solid tumors had the highest rates; 92% (95% CI 41-99) and 50% (95% CI 14-42), respectively. Central nervous system tumors had all-grade and grade 3/4 TRAE rates of 61% (95% CI 53-68) and 21% (95% CI 12-33), respectively. Fatigue, anemia, and nausea were the most frequently reported TRAE. The ORR was 13% (95% CI 5-27) (82 of 531 patients). For drug class and tumor type subgroup analysis, PD-1 inhibitors and lymphoma presented the highest proportion of ORR, with 25% (95% CI 8-56) and 59% (95% CI 23-87), respectively. SD was noted in 21% (95% CI 14-30) of patients (97 of 467 patients). Median OS, available for 300 patients, ranged from 4.4 to 23.7 months, while median PFS, available for 299 patients, ranged from 1.2 to 6.2 months. Conclusions: This study suggests that ICB is well tolerated in CAYA patients with different cancer types. As previously reported in the literature, certain subsets of CAYA cancer are ICB-responsive. This pooled safety data supports the continued investigation of ICB in CAYA patients most likely to benefit from ICB therapy, including advancing ICB into combination strategies.

Access for adolescents and young adults with hard-to-cure cancer to PROFYLE: The pan-Canadian precision oncology pipeline.

10012 Background: Cancer is the most common cause of disease-related death in children, adolescents and young adults (CAYA). Approximately, 1.5% of patients with cancer in Canada are adolescents and young adults (AYAs) (age 15-29). AYAs often present with advanced disease and limited access to clinical trials including genomic testing. The PRecision Oncology For Young peopLE (PROFYLE) national, collaborative program, was created to provide equitable access to molecular profiling to identify novel targeted treatment options for CAYA with hard-to-cure cancers. The AYA node of PROFYLE aims to enhance the inclusion of AYAs across Canada at pediatric and adult centers while raising awareness of improving cancer outcomes of this underserved population. Methods: Building upon 3 pre-existing regional precision oncology programs, PROFYLE was implemented as the first pan-Canadian precision oncology pipeline. The PROFYLE study is multi-centred, non-randomized, interventional, and qualitative. Inclusion criteria: ≤29y; treatment at a Canadian center; diagnosis of a hard-to-cure cancer. It includes genomic and transcriptomic sequencing of paired germline and cancer fresh/frozen samples. Actionable findings, potential targeted therapy options including available clinical trials, clarification of diagnosis, and genetic counseling recommendations are provided to the clinical care team. Results: To date, > 1,200 CAYA are included from all provinces. Of these, 33% were AYAs. Cancer diagnoses included: 47% sarcoma, 15% leukemia/lymphoma, 13% CNS tumor, 25% other. Of the AYAs enrolled, 53% had ≥1 significant tumour profiling finding (48% specific mutations/fusions; 6% DNA repair defect signature, hypermutation, microsatellite instability, chromosomal instability; 3% predictors of therapeutic resistance; 5% outliers in gene expression). 71% had potentially useful findings (15% diagnostic; 9% prognostic; 59% therapeutic; 2% etiologic; 15% cancer predisposition; 2% secondary germline; 0.5% pharmacogenetic). 23% had a pathogenic/likely pathogenic germline variant. 60% had ≥1 potentially actionable somatic alteration. 64% of clinicians indicated that molecular findings impacted clinical management (12% diagnostic; 6% prognostic, 60% therapeutic; 16% germline genetic). 24% indicated a change in treatment planning in response to these findings. Conclusions: The goal of developing a national precision oncology pipeline that provides equitable access to molecular profiling in a clinically relevant timeframe has been realized through the establishment of PROFYLE. Findings demonstrate that the sequencing platform provided medically informative results in the majority of enrolled AYAs. The success of PROFYLE underscores the importance of the continuing efforts to increase the access to this precision oncology initiative for all AYAs with cancer in Canada.

COVID-19 infection in children, adolescents, and young adults with Down syndrome and hematologic malignancies.

Children, adolescents, and young adults (CAYAs) with Down syndrome (DS) and hematologic malignancies are particularly vulnerable to infections and related complications. There are limited data regarding COVID-19 infections in this group. We aimed to understand the clinical course of COVID-19 in this population. This observational study leverages the de-identified clinical and sociodemographic data captured by the Pediatric Oncology COVID-19 Case Report Registry (POCC) regarding CAYAs with cancer and COVID-19. We evaluated CAYAs (≤21years at COVID-19 infection) with hematologic malignancies and COVID-19 reported from April 1, 2020 to May 2, 2023, comparing those with and without DS. Using multivariable logistic regression, we examined rates of hospitalization, intensive care unit (ICU) admission, respiratory support, and changes in cancer-directed therapy. Among 1408 CAYAs with hematologic malignancies, 55 had DS (CAYA-DS). CAYA-DS had higher rates of hospitalization, ICU admission, and respiratory support (p<.001) than CAYAs without DS. Similarly, multivariable analyses found higher odds of hospitalization (odds ratio [OR]=2.8, 95% confidence interval [CI]: 1.5-5.1), ICU admission (OR=4.2, 95% CI: 1.9-9.1), and need for respiratory support (OR=4.2, 95% CI: 2.0-8.8) among CAYA-DS. Modifications to cancer-directed therapy were more common among CAYA-DS when related to neutropenia (p=.001), but not when unrelated to neutropenia (p=.88); CAYA-DS did not have higher odds of changes to cancer-directed therapy (OR=1.20, 95% CI: 0.7-2.1). We identify CAYA-DS with hematologic malignancies as a vulnerable subpopulation at greater risk for severe COVID-19 infection. This can inform conversations with patients and families regarding therapeutic and preventive measures, as well as the risks and benefits of modifying chemotherapy in the setting of COVID-19.

The Australian New Zealand Consortium in Children, Adolescents, and Young Adults Oncofertility action plan.

International and national oncofertility networks, including the US-led Oncofertility Consortium, FertiProtekt, and the Danish Network, have played pivotal roles in advancing the discipline of oncofertility over the last decade. Many other countries lack a shared approach to pediatric oncofertility health service delivery. This study aims to describe baseline oncofertility practices at Australian New Zealand Children's Haematology/Oncology Group centers in 2019-2021, describe binational priorities for care, and propose a 5-year action plan for best practice to be implemented by the newly formed Australian New Zealand Consortium in Children, Adolescents, and Young Adults (CAYA) Oncofertility (ANZCO).

Characteristics and outcomes of children, adolescents and young adults with relapsed/refractory non-hodgkin lymphoma undergoing autologous stem cell transplant

BackgroundThere is paucity of data regarding outcomes of children, adolescents and young adults (CAYA) patients with non-Hodgkin lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT).MethodsPatients aged 0–39 years undergoing first ASCT for NHL at MD Anderson Cancer Center between 2000 and 2020 were analyzed.ResultsTwo hundred twenty-one patients were included in the analysis, 129 (58%) were male and the median age was 32 (range 6–39) years. The most common histological subtypes were diffuse large B cell lymphoma (DLBCL) (44%), T-NHL (19%) and primary mediastinal B-Cell lymphoma (PMBCL) (19%). Younger patients (age ≤ 25) had lower incidence of DLBCL and higher incidence of PMBCL and T-NHL compared to older patients (age > 25) (P = 0.02). None of the younger patients had double hit (DH)/double expressor (DE) DLBCL, compared to 14 patients in the older age group (18%, P = 0.07). Considering the three main aggressive NHL subtypes (DLBCL, PMBCL and T-NHL), younger patients had numerically better 15-year post-transplant progression free survival (PFS) (67% vs. 54%) and overall survival (OS) (71% vs. 62%) compared to older patients, yet these differences did not reach statistical significance (P = 0.19 and P = 0.24, respectively). In multivariate analysis, not achieving a CR prior to ASCT was independently predictive of worse PFS [partial remission (PR) (HR, 3.9); stable disease (SD) (HR, 18.0), P = 0.03] and of worse OS [PR (HR, 4.2), SD (HR, 6.5) and progressive disease (HR, 4.7), P < 0.0001]. DH/DE status was an independent adverse predictor of PFS in multivariate analysis (HR 5.8, p = 0.03).Ten patients (4.5%) (all aged > 25 years) developed second primary malignancies (SPM), at a median of 34.4 (range, 1.0–196.6) months after ASCT, and SPM was the cause of death in five (50%) of them.ConclusionsCAYA NHL patients aged ≤ 25 years who received ASCT presented a distinct NHL histology as compared to older CAYA patients, and none in this younger age group had DH/DE DLBCL. We observed a trend towards improved PFS and OS in younger patients. Disease status at ASCT was predictive of both PFS and OS. DH/DE status was an adverse predictor of PFS.

Multicenter Pilot Trial of Intrathecal Liposomal Cytarabine Combined with FAB Chemoimmunotherapy with Reduced Doxorubicin in CAYA with Mature De-Novo B-NHL

Background: Children, adolescents, and young adults (C-AYA) with newly diagnosed advanced Mature B Non-Hodgkin Lymphoma (MB-NHL), specifically Burkitt Lymphoma (BL) and Diffuse Large B Cell Lymphoma (DLBCL), have achieved ≥ 90% overall survival with multi-agent chemotherapy and intrathecal chemotherapy (IT) without central nervous system (CNS) radiation (Cairo et al., Blood 2007; Goldman/Cairo et al., BJH 2014; Frazier/Cairo, et al., BJH 2014; Minard-Colin, et al., NEJM 2020). Standard therapy includes short but intensive courses of multiagent chemotherapy including CNS-penetrating high dose methotrexate and cytarabine for CNS penetration as well as vincristine, prednisone, doxorubicin, and cyclophosphamide with or without etoposide. Patients also receive 9, 10 and 13 IT doses of intrathecal chemotherapy when treated according to FAB Group B, FAB Group C (CNS -) and FAB Group C (CNS +) protocols, respectively. While this approach has effectively eliminated need for CNS radiation for disease control, the need for sedation of patients during these procedures results in the need for repeated episodes of patient fasting, increased healthcare costs, and most importantly, general anesthesia is associated with long-term late effects in cognitive development (Banerjee et al., JAMA Oncol, 2019). Liposomal cytarabine (LC) is a formulation of cytarabine encapsulated in spherical multivesicular, biodegradable particles known as DepoCyt® which has a maximum-tolerated intrathecal dose of 35 mg in patients between the ages of 3 and 21 years (Bomgaars et al., JCO, 2004). This liposomal formulation has a half-life of 100-263 hours compared with only 3.4 hours of standard cytarabine. As an s-phase specific agent, prolonged exposure may increase its efficacy in controlling CNS disease while decreasing the total number of intraventricular doses required for treatment. Objective: To determine the safety and efficacy of reduction of IT therapy and substitution of LC within modified FAB group B and C backbones of systemic immunochemotherapy. Methods: LC was incorporated into the multiagent chemotherapy regimen in a unique manner to mitigate the risk of possible CNS toxicity. A total of 2 doses of LC were administered as part of the prophylaxis IT therapy for Group B and CNS negative group C patients. A total of 4 doses of LC were administered as part of the treatment of Group C CNS + patients (Table 1). The LC was given only in phases of therapy in which no systemic cytarabine was administered. When Methotrexate was given, the LC was only given after clearance. Dexamethasone replaced prednisone for all patients to mitigate potential CNS toxicities from LC. Results: This trial enrolled 33 patients with newly diagnosed MB-NHL (25 Group B, 8 Group C with 7 CNS+). Median age was 12 (Range 3-25). Males comprised 64% of patients and 52% had Burkitt Lymphoma/Leukemia. The CNS was involved in 21% of patients, and a total of 78 doses of LC was given. Twenty-six patients received 2 prophylactic doses (25 Group B and 1 Group C CNS negative). Six of seven CNS + patients received all 4 planned doses of LC. The median days from the start of the induction cycles until LC administration (post methotrexate clearance) was 3 days. Of the 33 patients, only 1 (3%) had a transient Grade 3 adverse event (facial nerve palsy). With dexamethasone prophylaxis, there were minimal adverse events and no toxic deaths reported. There were no other serious adverse events, such as seizure, headaches, nausea, vomiting, fever, somnolence, confusion, or asthenia that have been previously reported. The 2-year EFS and OS of LC when added to an FAB backbone for MB-NHL, was 94.5% and 97.2%, respectively (Figure 1). Conclusions: By utilizing dexamethasone prophylaxis and waiting for systemic methotrexate clearance, we were able to demonstrate that IT LC in C-AYAs with MB-NHL who received FAB chemoimmunotherapy with HD MTX was feasible, safe, and did not compromise event free and overall survival. We were also able to reduce the total number of IT injections without apparent compromise to CNS prophylaxis and treatment.

Fertility preservation before and after cancer treatment in children, adolescents, and young adults.

Fertility is a top concern for many survivors of cancer diagnosed as children, adolescents and young adults (CAYA). Fertility preservation (FP) treatments are effective, evidence-based interventions to support their family building goals. Fertility discussions are a part of quality oncology care throughout the cancer care continuum. For nearly 2 decades, clinical guidelines recommend counseling patients about the possibility of infertility promptly at diagnosis and offering FP options and referrals as indicated. Multiple guidelines now recommend post-treatment counseling. Infertility risks differ by cancer treatments and age, rendering risk stratification a central part of FP care. To support FP decision-making, online tools for female risk estimation are available. At diagnosis, females can engage in mature oocyte/embryo cryopreservation, ovarian tissue cryopreservation, ovarian suppression with GnRH agonists, in vitro oocyte maturation, and/or conservative management for gynecologic cancers. Post-treatment, several populations may consider undergoing oocyte/embryo cryopreservation. Male survivors' standard of care FP treatments center on sperm cryopreservation before cancer treatment and do not have the same post-treatment indication for additional gamete cryopreservation. In practice, FP care requires systemized processes to routinely screen for FP needs, bridge oncology referrals to fertility, offer timely fertility consultations and access to FP treatments, and support financial navigation. Sixteen US states passed laws requiring health insurers to provide insurance benefits for FP treatments, but variation among the laws and downstream implementation are barriers to accessing FP treatments. To preserve the reproductive futures of CAYA survivors, research is needed to improve risk stratification, FP options, and delivery of FP care.

PATH-09. THE IMPACT OF MISMATCH REPAIR DEFICIENCY ON GLIOMAS IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS; A MULTI-CENTRIC, COLLABORATIVE STUDY LED BY THE IRRDC AND GLIOMA TASKFORCE

Abstract BACKGROUND Primary mismatch repair deficiency (pMMRD) is a pan-cancer mechanism caused by somatic mutations or inherited as part of Lynch Syndrome (LS) or constitutional mismatch repair deficiency (CMMRD). PMMRD results in universal hypermutation and microsatellite instability leading to chemoradiation resistance but sensitivity to immunotherapy. The prevalence of pMMRD in gliomas of children, adolescents, and young adults (CAYA), and the impact of germline inheritance is unknown. METHODS We harnessed functional genomic tools across population-based (Toronto), and multiple institutional (SJ, CBTN) cancer databases (n=1276) to determine the prevalence, subgroups, and impact of germline mutations in pMMRD gliomas. RESULTS Data from Toronto, SJ and CBTN reveals prevalence of 10%, 5% and 5% in pediatric high-grade gliomas (HGG). Molecularly, pMMRD is absent in gliomas harboring pediatric-type fusions, BRAF-V600E, and histone mutations, but enriched in HGG harboring IDH and TP53 mutations. In AYA (n=660), pMMRD was detected in 5% of IDH-WT and IDH-mutant high-grade astrocytomas, but notably absent in all oligodendrogliomas and other low-grade gliomas. Across this entire CAYA dataset, all except one pMMRD gliomas harbored germline MMR mutations (97%). Strikingly, LS predominated over CMMRD with significant difference in age of glioma onset (LS: 29-years versus CMMRD: 11-years; p&amp;lt; 0.001, IRRDC dataset). Survival analysis (Kaplan-Meier) confirmed the poor overall survival (OS) for pMMRD and other pediatric subtypes of HGG (3-year OS &amp;lt; 25%). In contrast, IDH-mutant pMMRD HGG have significantly worse OS than IDH-mutant non-pMMRD counterparts. Remarkably, immunotherapy significantly improves survival not only in children, but also for AYA patients with refractory pMMRD HGG (3-year OS &amp;gt; 50%). CONCLUSION This large study demonstrates that pMMRD drives a significant proportion of HGG across CAYA with an alarming impact of germline predisposition. Specifically, unrecognized AYA LS patients with MMRD HGG. These findings support universal screening for MMRD in HGG to identify patients for surveillance and immunotherapy.

PATH-07. GENOMIC AND IMMUNE ANALYSIS OF PRIMARY REPLICATION-REPAIR DEFICIENT (RRD) GLIOMAS REVEALS THREE SUBGROUPS WITH DISTINCT DRIVERS AND RESPONSE TO IMMUNOTHERAPY: AN IRRDC REPORT.

Abstract BACKGROUND Replication-repair deficiency (RRD) caused by germline/somatic defects in mismatch repair (MMRD) and/or polymerase-proofreading genes (PPD) drives 5-10% of high-grade gliomas in children, adolescents, and young adults (CAYA). Despite harbouring high mutation-burden (TMB), the basis of their heterogenous responses to immune-checkpoint inhibitors (ICI) is unknown. METHODS We performed multi-omic and immune analyses on human RRD-glioma specimens and developed murine models to investigate their differential responses to ICI. RESULTS RRD-gliomas in 202 CAYA-patients uniformly harbored high genomic microsatellite-instability and hypermutation (median TMB: 302-mutations/megabase), with specific MMRD mutational signatures contributing to frequent mutations in TP53 (88%), ATRX (83%), RAS/MAPK (77%) and IDH1/2 (17%). Strikingly, common pediatric mutations (K27M, G34R/V and BRAF;p.V600E) unrelated to MMRD signatures were absent, and a unique methylation profile distinct from non-RRD gliomas was observed. Molecularly, RRD-gliomas segregated into three genomic subgroups: RRD1 (MMRD+PPD; 56%), RRD2 (MMRD-only; 27%), and RRD3 (MMRD+IDH1/2; 17%). RRD1 included glioblastomas that developed early in germline CMMRD patients across the cerebral hemispheres and posterior-fossa, harbored extreme TMB (median: 420-mutations/megabase), balanced copy-number profiles, and immunogenic PPD signatures. RRD3 predominated in Lynch syndrome, presented in older children, were located in the forebrain, harbored lower TMB (median: 31-mutations/megabase) and demonstrated specific chromosomal gains/losses. Enrichment for immune-resistant JAK-STAT signalling in the RRD2/RRD3 transcriptome, and presence of high CD8+ T-cells in RRD1-glioma microenvironment, correlated with significantly improved 24-month post-ICI survival of 75% in RRD1 versus 43% and 33% for RRD2/3, respectively (p &amp;lt; 0.0001). Genetically engineered mouse models recapitulated the immuno-genomic phenotype and ICI-responses of the human RRD-subgroups, allowing successful preclinical testing of combinatorial checkpoint-inhibition strategies. Significant temporal and spatial heterogeneity linked to genomic instability and post-therapy immune-escape were observed. CONCLUSION Our data emphasizes an immediate need to distinguish RRD-glioma subgroups in clinical practice and translate our preclinical discoveries to subgroup-specific ICI-based combinatorial clinical trials.

Treatment of Refractory Adenovirus (ADV) Infections Using Adv-Specific Cytotoxic T-Lymphocytes (CTLs) in Children, Adolescents and Young Adults (CAYA) Post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT), Solid Organ Transplantation (SOT), or with Primary Immunodeficiency (PID)

Background: AlloHSCT induces long-term, cure in CAYA with malignant and non-malignant disorders, including those with primary immunodeficiencies (PID). However, post-transplant complications secondary to immunosuppression and slow or delayed immune reconstitution remains a cause of morbidity and mortality amongst AlloHSCT recipients (Satwani/Cairo, BBMT, 2009). Major complications include refractory viral infections, most importantly adenovirus (ADV), which is secondary to absent or decreased adenovirus specific T-cell immunity which occurs due to delayed immune reconstitution and/or continued immunosuppression (George/Cairo, BJH, 2012). The use of virus-specific (vs) CTLs in immunocompromised patients offer an opportunity to restore temporary virus specific immunity. From the Viral Cytotoxic T-Lymphocyte Consortium (VIRCTLC), we present safety and efficacy results on immune compromised, AlloHSCT, or SOT patients treated with familial ADV specific CTLs. Objective: Determine the safety and efficacy of familial ADV specific CTLs for the treatment of refractory systemic ADV infections. Design/Methods: Patient were deemed eligible if they had a history of AlloHSCT, SOT, or PID and had evidence of ADV infections refractory to anti-viral agents. Refractory ADV infection was defined by increasing serum RT-PCR DNA (by 1 log) after 7 days or persistent quantitative RT-PCR DNA copies after 14 days of appropriate anti-viral therapy, and/or known resistance/intolerance to anti-viral agents. Related donors were required to be matched ≥3 HLA (A, B, or DRB1) loci and have an adequate T-cell response to viral specific MACS ADV PepTivators®. We chose a direct selection method to facilitate more rapid generation of cellular products in a point of care setting (and with 14 hrs eligibility determination). Peripheral blood mononuclear cells were collected from eligible family donors using non-mobilized apheresis. vsCTLs were isolated using the CliniMACS ® Prodigy following stimulation with viral specific MACS® GMP PepTivator® AdV5 Hexon, generously provided by Miltenyi Biotec®. ADV specific CTLs were enriched using a Cytokine Capture System (CCS). CD4+ and CD8+ vsCTLs were quantified by flow cytometry (Feuchtinger et al, Blood, 2010). The target cell dose was 0.5x10 4 CD3+ cells/kg (recipient weight) for haploidentical related donors and 2.5x10 4 CD3+ cells/kg for matched related donors. Repeated doses were permitted every 2 weeks to a maximum of doses in the absence of a complete response (CR) and adverse events. The following were used to define response: CR - undetected ADV PCR, partial response (PR) - at least one log decrease from baseline, progressive disease (PD) - at least one log increase from baseline, and patients with stable disease. Results: Fifteen patients were enrolled: 10 females and 5 males; aged 1-19 years. All patients were post-AlloHSCT. All vsCTL donors were haploidentical: 8 were the original HSCT donors and 7 were third party donors (5 maternal, 2 paternal). The mean number of ADV CTL infusions was 3.7 (range: 1-16). One patient with underlying aplastic anemia had progressive disease complicated by increased adenoviral load despite 5 infusions of vsCTLs. Patient received FDA approval for additional CTLs, totaling 16 doses. Thirteen patients achieved CR as defined and 2 achieved PR. The overall response (OR) was 100% and the CR was 88%. The average time to OR was 33 days (range 6-112 days) and time to CR was 34 days (range 6-112 days). Day 100 and 365 overall survival (OS) post-HSCT was 86.1% (CI95: 49.4-95.7) and 70.5% (CI95: 38.9-87.8), respectively (Figure 1). For patients who achieved CR, the Day 100 OS post AlloHSCT was 83.9% (CI95: 55.0-94.3) and Day 365 post AlloHSCT was 74.6% (CI95: 39.8-91.1). Day 100 and 365 probability of ADV related mortality was 0% (Figure 2). One patient developed acute grade 2 skin GVHD possibly related to infusion, which resolved. Conclusion: Our preliminary data demonstrate that haploidentical ADV specific CTLs manufactured by direct selections using the CCS with the CliniMACS® Prodigy and ADV specific peptivators are safe, well-tolerated, and efficacious in patients with refractory/persistent ADV infections after AlloHSCT. Manufacturing is rapid, reproducible, and effective. Accrual is ongoing. This research is supported by FDA RO1006301A1.

Patient-reported outcome measures in children, adolescents, and young adults with palliative care needs—a scoping review

BackgroundMeasuring outcomes facilitates evaluation of palliative services for children, adolescents, and young adults (CAYAs) with life-limiting and/or life-threatening (LL/LT) conditions. Implementation of patient-reported, proxy-reported, or patient-centered outcome measures (hereafter PROMs) is recommended to ensure palliative services. The purpose of this scoping review was to provide an overview of PROMs relevant for CAYAs living with LL/LT conditions eligible for pediatric palliative care (PPC).MethodsArksey and O’Malley’s 6-stage scoping review framework was used to guide the review. The identified citations had to report on PROMs in any context including CAYAs with LL/LT conditions up to 25 years of age. A systematic search of Medline, EMBASE, CINAHL, APA PsycInfo, Health and Psychosocial Instruments, and AMED took place in January 2021 and was updated in June 2022. Citations were screened independently by pairs of researchers. The scoping review protocol was registered, and peer-review published.ResultsOf 3690 identified citations, 98 reports were included, of which the majority were from Western countries and about PROMs in CAYAs living with cancer or organ failure. A total of 80 PROMs were identified, assessing a range of phenomena, where quality of life and symptoms (especially pain) during the stage of ongoing care were the most frequent. There were only a few reports about outcome measures at time of diagnosis or in end-of-life care. CAYAs self-reported on the PROMs or collaborated with their parents in about half of the reports, while the remaining had proxies answering on behalf of the CAYAs. In the identified reports, PROMs were used to characterize a sample through cross-sectional or longitudinal research, and less often to assess effects of interventions.ConclusionThe identified PROMs in the CAYA population eligible for PPC is characterized by studies in high-income countries during ongoing care, primarily in patients with cancer or organ failure. More research is needed in patients living with other LL/LT conditions, and during different stages of the disease course, especially at time of diagnosis, during transition to adulthood, and in end-of-life care. This scoping review of PROMs relevant for young patients eligible for PPC may inform future research about patient-/proxy-reported or patient-centered outcome measures in PPC.Trial registrationReview registration: (https://osf.io/yfch2/) and published protocol (Holmen et al. Syst Rev. 10:237, 2021).

Long Term Clinical Outcome and Quality of Life of Children, Adolescents and Young Adults Treated with Pencil Beam Scanning Proton Therapy for Rhabdomyosarcoma

To assess the long-term clinical outcomes of children, adolescents and young adults (CAYAs) with rhabdomyosarcoma (RMS) treated with pencil beam scanning proton therapy (pbsPT). One hundred twenty-one RMS (embryonal, n = 102; 84.3%) patients treated between January 2000 and December 2020 were included in this analysis. The median age was 4.7 years (range, 0.1-35.3). All patients received systemic chemotherapy according to prospective protocols. The median total dose delivered was 54 Gy (RBE) (range, 41.4-74.0). After a median follow-up time of 85.5 month (range,3.4-240.0), we observed 23 local/regional and 12 distant failures. The estimated 5-year local control (LC) and overall survival (OS) was 81.5% and 80%, respectively. For the subgroups of parameningeal (PM), orbital, urogenital and H&N non-PM the 5-year LC was 74.7%, 92%, 100% and 66.7%. The corresponding figures for OS were 68.8%, 100%, 100%, and 66.7, respectively. The 5-year non-ocular Grade 3 toxicity free survival was 78.9%. At the start of pbsPT children and their caregivers reported QoL significantly worse than the norm group. QoL improved however over the follow up period to normal values in nearly all domains. Median of PEDQOL PROXY reported QoL in Normgroup (children: 4- 18 yrs) and RMS patients (n = 27-42 answers per domain): CONCLUSION: Excellent clinical outcome was observed for CAYAs with RMS treated with pbsPT. Two thirds of treatment failures were local. High-grade late non-ocular toxicity was manageable. QoL improved towards normal scores in nearly all domains after therapy.

Lymph node metastases in young patients with gastrointestinal stromal tumor: A nationwide analysis.

Children, adolescents, and young adults (CAYA) (age ≤39 years) with GIST have high rates of LNM, but their clinical relevance is undefined. This study analyzed the impact of LNM on overall survival (OS) for CAYA with GIST. The National Cancer Database was queried for patients with resected GIST and pathologic nodal staging data from 2004-2019. Factors associated with LNM were identified. Survival was assessed stratified by presence of LNM. Of 4420 patients with GIST, 238 were CAYA (5.4%). When compared to older adults, CAYA more often had small intestine primaries (51.8% vs. 36.6%, p < 0.0001), T4 tumors (30.7% vs. 24.5%, p = 0.0275) and pN1 disease (11.3% vs. 4.7%, p < 0.0001). Within a multivariable Cox proportional hazards regression model adjusting for age, comorbid disease, mitotic rate, tumor size, and primary site, LNM were associated with increased hazard of death for older adults (hazard ratio [HR]: 1.83; confidence interval [CI]: 1.35-2.42; p < 0.0001), but not CAYA (HR: 3.38; CI: 0.50-14.08; p = 0.13). For CAYA, only high mitotic rate predicted mortality (HR: 4.68; CI: 1.41-18.37: p = 0.02). LNM are more commonly identified among CAYA with resected GIST who undergo lymph node evaluations, but do not appear to impact OS as observed in older adults. High mitotic rate remains a predictor of poor outcomes for CAYA with GIST.

HGG-27. THE IMPACT OF MISMATCH REPAIR DEFICIENCY ON GLIOMAS IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS; A REPORT FROM THE IRRDC AND THE GLIOMA TASK FORCE

Abstract Mismatch repair deficiency (MMRD) is a pan-cancer mechanism resulting in universal hypermutation. MMRD-gliomas are resistant to chemoradiation but respond to immunotherapy. MMRD can occur somatically or be inherited as part of Lynch Syndrome (LS) or Constitutional Mismatch Repair Deficiency (CMMRD). However, the prevalence of MMRD in gliomas of children, adolescents, and young adults (CAYA), and impact of germline inheritance is unknown. We utilized functional genomic tools on population-based and validation cohorts from 3 large databases (Toronto, St-Jude and CBTN) to determine the prevalence, subgroup, and impact of germline mutations on MMRD-gliomas. Ongoing data on 998 pediatric-gliomas from Toronto reveals that MMRD is extremely rare in pediatric low-grade gliomas (PLGG) but common in pediatric high-grade gliomas (PHGG) (9%, p&amp;lt;0.0001). Similarly, data from St-Jude and CBTN (n=374) reveals that MMRD exists only in PHGG (8%). In both cohorts, MMRD-PHGG are enriched for RAS/MAPK, IDH, and TP53 mutations while pediatric-type fusions, BRAF-V600E and histone mutations are absent. In AYA-HGG (n=884), the most common groups include glioblastomas without chromosome-7/10 alterations (9%) and IDH1-astrocytomas, while MMRD is not present in IDH-oligodendrogliomas. All but 1 CAYA-MMRD-gliomas harbored germline MMR mutations. Data from the IRRDC on 174 patients reveal that LS is more common than CMMRD in gliomas, with the median age of onset 11 and 29 years in CMMRD and LS, respectively (p&amp;lt;0.001). Furthermore, CMMRD gliomas are commonly caused by germline PMS2 and MSH6 mutations, enriched for secondary polymerase mutations (60%, p&amp;lt;0.001), and exhibit ultra-hypermutation. In contrast, LS-gliomas are caused by MSH2 and MLH1 mutations, and enriched for IDH1 mutations (32%, p&amp;lt;0.025) with a lower mutational burden. Our data reveals high prevalence of MMRD in CAYA-HGG with alarming impact of germline predisposition. Specifically, unrecognized LS patients with AYA MMRD-HGG. These findings support universal screening for MMRD in HGG to identify patients for immunotherapy and surveillance.

HGG-26. GENOMIC AND IMMUNE ANALYSIS OF PRIMARY REPLICATION-REPAIR DEFICIENT (RRD) GLIOMAS REVEALS THREE SUBGROUPS WITH DISTINCT DRIVERS AND RESPONSE TO IMMUNOTHERAPY: AN IRRDC REPORT

Abstract BACKGROUND Replication-repair deficiency (RRD) caused by germline/somatic defects in mismatch repair (MMRD) and/or polymerase-proofreading genes (PPD) drives 5-10% of gliomas in children, adolescents, and young adults (CAYA). Although RRD-gliomas harbour high mutation-burden (TMB), the basis of their heterogenous biology, clinical behavior, and response to immune-checkpoint inhibitors (ICI) is unknown. METHODS We analyzed the genome (whole exome, low-coverage genome), methylome, transcriptome (bulk, single-nuclei), and the immune-microenvironment of RRD-gliomas in a large cohort of IRRDC patients and correlated these with clinical outcomes and response to ICI. RESULTS Gliomas in 202 CAYA-patients uniformly harbored hypermutation and genomic microsatellite-instability. Median TMB was 297-mutations/megabase, with frequent mutations in TP53 (90%), ATRX (85%), RAS/MAPK (80%) and IDH1/2 (15%). MMRD (but not PPD) mutational signatures contributed to the enrichment of driver mutations in POLE, IDH1, and TP53 while common pediatric mutations (K27M, G34R/V and BRAF;p.V600E) not driven by MMRD signatures were absent. Paired analyses suggested acquisition of novel variants driven by the mutational signatures that also impacted the immune microenvironment. Multi-omic analyses classified RRD-gliomas into three subgroups: RRD1 (MMRD+PPD; 60%), RRD2 (MMRD-only; 23%), and RRD3 (MMRD+IDH1/2; 16%). All RRD1-gliomas were glioblastomas with earlier age of onset, enrichment in CMMRD, arose at diverse locations including the posterior-fossa, classified in proximity to methylation-RTK1-subclass, exhibited balanced copy number profiles, harbored the highest TMB (median: 409-mutations/megabase), and immunogenic PPD signatures. Conversely, RRD3-gliomas were frequent in Lynch syndrome, presented at an older age, with predominant localization in the forebrain, more complex genomic instability, clustered in proximity to IDH1-gliomas, and harbored lower TMB (median: 33-mutations/megabase). RRD1-gliomas revealed the highest immune infiltrates with significantly improved median post-ICI survival of 52-months versus &amp;lt;12-months for RRD2/3 (p&amp;lt;0.0001). CONCLUSIONS The distinct genomic subgroups of RRD-gliomas can explain their diverse clinical outcomes, highlighting the need for developing subgroup-specific, immune-directed treatment approaches for these patients.

QUALITY OF LIFE IN PEDIATRIC HIGH‐RISK HODGKIN LYMPHOMA TREATED WITH BRENTUXIMAB‐BASED INTENSIVE CHEMOTHERAPY—COMPARISON TO HISTORICAL TREATMENT COHORT AND HEALTHY PEERS

Introduction: Hodgkin lymphoma (HL) in children, adolescents, and young adults (CAYA) is highly curable. Patient experiences during cancer treatment vary substantially and may influence later quality of life (QOL). We sought to: (1) describe patient-reported QOL during treatment for high-risk classical HL in CAYA with HLHR13, a brentuximab-incorporating chemotherapy regimen with response-adapted radiotherapy (r-aRT); (2) compare QOL among patients treated on HLHR13, high-risk HL patients treated with Stanford V chemotherapy and r-aRT (HOD99), and healthy CAYA. Methods: Eligible patients were ≤18 (HLHR13) or ≤21 years old (HOD99) upon diagnosis of Stage IIB, IIIB, or IV HL. For HLHR13 and HOD99, QOL was assessed with PedsQL 4.0 Generic Core Scales and PedsQL 3.0 Cancer Module. HLHR13 consisted of 2 “AEPA” cycles (brentuximab, etoposide, prednisone, and doxorubicin) and 4 “CAPDac” cycles (cyclophosphamide, brentuximab, prednisone, and dacarbazine) with r-aRT (25.5 vs. 0 Gy). HLHR13 chemotherapy lasted 20 weeks including 6 rest weeks. HOD99 consisted of 12 weeks of Stanford V (bleomycin, doxorubicin, mechlorethamine, prednisone, vinblastine, and vincristine) with r-aRT (25.5 vs. 15 Gy). Despite differing regimen durations, QOL assessments were compared at timepoints considered equivalent. HLHR13 incorporated 2-year off-therapy long-term follow up QOL assessments. Patient demographics and QOL scores were summarized by descriptive statistics. We used Wilcoxon rank-sum tests to compare PedsQL 3.0 scores in HLHR13 patients vs. HOD99 patients and pooled two sample t-tests to compare patient and healthy CAYA PedsQL 4.0 scores. Raw p-values were corrected for multiple comparisons. Results: At study entry, HLHR13 patients’ (n = 63) QOL was significantly worse than healthy CAYA and consistent with HOD99 patients’ (n = 78) QOL as measured by PedsQL 4.0 Generic Core Scales. HLHR13 patients’ QOL gradually improved. Compared to HOD99 patients, HLHR13 patients had better cancer-specific QOL scores (PedsQL 3.0 Cancer Module) during treatment, particularly for nausea, worry, cognitive problems and treatment anxiety. Two years off therapy, HLHR13 patients (n = 39) reported better QOL in social and emotional domains than did healthy CAYA. Conclusions: Among similar groups of CAYA with HL, HLHR13 treatment was associated with higher patient-reported cancer-specific QOL than was HOD99 despite longer treatment duration and more intensive administration schedule. PedsQL 3.0 Cancer Module distinguished cancer-specific experience differences between HLHR13 and HOD99. Mechlorethamine in HOD99 may have produced excess nausea. Two years after treatment, HLHR13-treated CAYA reported better social and emotional QOL than healthy peers. Observed excellent QOL could reflect positive psychosocial impacts of living beyond lymphoma or a biased group of CAYA continuing in survivorship care. Keywords: chemotherapy, late effects in lymphoma survivors, Hodgkin lymphoma The research was funded by: St. Jude Children's Research Hospital and Seagen Inc Conflicts of interests pertinent to the abstract: M. P. Link Research funding: Seagen, Inc J. E. Flerlage Research funding: Seagen, IncSS

Response-adapted therapy (tx) with nivolumab plus brentuximab vedotin (nivo + BV) without autologous hematopoietic cell transplantation (auto-HCT) in children, adolescents, and young adults (CAYA) with low-risk relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL): CheckMate 744.

7515 Background: Outcomes are poor for patients (pts) with cHL who develop R/R disease after first-line (1L) chemotherapy ± radiotherapy (RT). Salvage tx that attain high event-free survival (EFS) rates and minimize late toxicity by omitting high-dose chemotherapy (HDCT)/auto-HCT are needed. CheckMate 744 (NCT02927769) is the first multicenter phase 2 study evaluating a risk-stratified, response-adapted salvage tx with nivo + BV in CAYA with R/R cHL. In the standard-risk cohort, complete molecular response (CMR) rate before consolidation with HDCT/auto-HCT was 94% (Harker-Murray et al. Blood 2022). With highly active salvage tx, pts in low-risk cohort could achieve high EFS without HDCT/auto-HCT; we report data from this cohort. Methods: Pts were aged 5–30 y and had ≤ 3 cycles (C) of 1L anthracycline-based systemic tx. Risk stratification was described in Harker-Murray et al. Pts received 4C of nivo + BV induction. Pts with CMR received additional 2C nivo + BV before involved-site radiation therapy (ISRT) consolidation (dose, 30–30.6 Gy). Pts with suboptimal response received 2C BV + bendamustine intensification; pts with CMR proceeded to ISRT consolidation. Primary endpoints: CMR rate (Lugano 2014) any time before ISRT and 3-y EFS rate, both per blinded independent central review (BICR). For CMR and overall response rate (ORR), a 90% confidence interval (CI) was used per statistical plan. Results: Among 28 pts treated with nivo + BV, median (range) age was 17 (6–27) y; 64% of pts were aged &lt; 18 y. Most (64%) pts had stage II disease at relapse; 82% had relapse ≥ 12 mo after 1L tx, 2 pts had prior RT. Median (range) follow-up was 31.9 (2.2–55.3) mo. CMR, ORR, 3-y EFS and PFS rates are shown in Table. Median duration of response was not reached; 87% of pts had sustained response at 36 mo’ follow-up. Efficacy outcomes were comparable in the pediatric population (CMR per BICR before ISRT, 88.9%; 3-y EFS rate, 78.3%). During induction, 22 (78.6%) pts had treatment-related adverse events (TRAEs; grade 3/4, 25.0% pts; hematologic, &lt; 10% pts; immune-mediated, 21.4%). Serious AEs leading to discontinuation included rash, pyrexia, and acute kidney injury (1 pt each). Conclusions: The findings demonstrate that most CAYA with low-risk R/R cHL can be salvaged with chemoimmunotherapy with a favorable toxicity profile, and do not require HDCT/auto-HCT. Clinical trial information: NCT02927769 . [Table: see text]

Ensuring access to innovative therapies for children, adolescents, and young adults across Canada: The single patient study experience.

Innovative therapeutic approaches are needed to alleviate the burden of life-limiting, rare, and chronic conditions affecting children, adolescents, and young adults (CAYA). This includes a need for improved access to both clinical research and to non-approved or off-label therapies, together with, ultimately, more therapies achieving regulatory approval in Canada. The single patient study (SPS), also known as an open label individual patient (OLIP) study, was introduced by Health Canada to open access to non-marketed drugs where a clinical trial is not readily available, but the drug is considered too investigational to be managed on a standard Special Access Program. SPS is designed for patients who have a serious or life-threatening condition and have exhausted available treatment options. Our report summarizes this relatively new development in the Canadian regulatory environment and highlights the opportunities and challenges as identified by regulators, pharmaceutical representatives, academic researchers, and patient/parent advocates.

Safety and efficacy of post-haematopoietic cell transplantation maintenance therapy with blinatumomab for relapsed/refractory CD19-positive B-cell acute lymphoblastic leukaemia: protocol for a phase I–II, multicentre, non-blinded, non-controlled trial (JPLSG SCT-ALL-BLIN21)

IntroductionRelapsed and refractory B-cell acute lymphoblastic leukaemia (R/R-B-ALL) is linked to a significant relapse rate after allogeneic haematopoietic cell transplantation (allo-HCT) in children, adolescents and young adults (CAYA). No standard...