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The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T-cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first- or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplantation and be definitive therapy versus those in whom it provides a more effective bridge to haematopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully humanised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prioritisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary mediastinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this population. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials. CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell therapies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success. The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies. Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regulatory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially important as these are very expensive therapies. The model for drug development for cell therapy in paediatric oncology could also involve a ‘later stage handoff’ to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies.

As cancer immunotherapies continue to expand across all areas of oncology, it is imperative to establish a standardized approach for defining and capturing clinically important toxicities, such as cytokine release syndrome (CRS). In this paper, we provide considerations for categorizing the variety of adverse events that may accompany CRS and for recognizing that presentations of CRS may differ among various immunotherapies (e.g., monoclonal antibodies, CAR T cell therapies and T cell engagers, which can include bispecific antibodies and other constructs). The goals of this paper are to ensure accurate and consistent identification of CRS in patients receiving immunotherapies in clinical studies to aid in reporting; enable more precise evaluation of the therapeutic risk-benefit profile and cross-study analyses; support evidence-based monitoring and management of important toxicities related to cancer immunotherapies; and improve patient care and outcomes. These efforts will become more important as the number and variety of molecular targets for immunotherapies broaden and as therapies with novel mechanisms continue to be developed.

Purpose To assess the computed tomography (CT) portion of a positron emission tomography (PET)/CT, at lower dose without breath holding, as compared to diagnostic chest CT (dCTC), performed at regular dose with breath holding, and question the necessity of both for patient care in pediatric oncology. Materials and Methods This retrospective study included 46 pediatric patients with histologically proven malignant tumors that had a total of 119 scans. Results A total of 29 discrepancies were found between dCTC and PET/CT reports. Conclusion In the evaluation of metastatic thoracic disease in pediatric oncology patients, the non-breath holding CT portion of PET/CT has sensitivity and specificity that approaches dCTC.

Background Autologous or allogeneic hematopoietic stem cell transplant (SCT) is often considered in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) but there are limited data on the use of SCT for the treatment of NHL in the pediatric setting. Procedure To evaluate the role of SCT for children with NHL, we reviewed 36 consecutive pediatric patients with NHL who underwent an allogeneic (n = 21) or autologous (n = 15) SCT at our institution between 1982 and 2004. Pathologic classification included: lymphoblastic lymphoma (n = 12), Burkitt lymphoma (BL) (n = 5), diffuse large B-cell lymphoma (n = 4), anaplastic large cell lymphoma (ALCL) (n = 13), peripheral T cell lymphoma (n = 1), and undifferentiated NHL (n = 1). Donor source for allogeneic-SCT recipients was an HLA-matched related donor (n = 15), a matched unrelated donor (n = 4), or a mismatched donor (related n = 1; unrelated n = 1). Twenty-eight patients (78%) had chemotherapy responsive disease at the time of transplant (either CR or PR). Results Overall survival (OS) and disease-free survival (DFS) were 55% and 53% with a median follow-up of 9.75 years. Outcomes were similar in patients receiving autologous and allogeneic-SCT (DFS 53% in both groups). Patients with ALCL had a DFS of 76.9%. In contrast, of five patients transplanted for BL, none survived. DFS among patients with chemotherapy sensitive disease was 61%, compared with 25% among patients with relapsed/refractory disease (P = 0.019). Conclusions Allogeneic and autologous SCT offer the prospect of durable, disease-free survival for a significant proportion of pediatric patients with relapsed or refractory NHL. Survival is superior among patients with chemotherapy sensitive disease. Pediatr Blood Cancer 2013;60:2018–2024. © 2013 Wiley Periodicals, Inc.

We report a case of hepatoblastoma in a 10-year-old girl with mosaic-type trisomy 18. A comprehensive literature review reveals only 2 cases involving mosaic trisomy 18 patients. Our patient underwent an abbreviated chemotherapy course before complete surgical resection. Her hepatoblastoma did not contain cells with trisomy 18. The conservative management approach resulted in a successful outcome; she remains disease free >2 years after surgery. Along with presenting a literature review, this report demonstrates a favorable outcome in a mosaic trisomy 18 child with hepatoblastoma where tumor cells lacked a trisomy 18 karyotype.

CMI responses, combined with quantification of CMV DNA (DNAemia), may identify transplantation recipients at risk for invasive disease. PBMC were collected in pediatric transplantation candidates at one, three, and six months post-transplant in 10 subjects (six renal, three cardiac, one stem cell) and at single time points in eight HC and 14 children greater than one yr post-transplant (LTTx). Cells were stimulated with anti-CD3mAb or CMV pp65 peptide pools and responses assessed by IFNG enzyme-linked immunosorbent spot assay and cytokine secretion. IFNG responses to anti-CD3mAb were significantly lower pretransplant relative to HC and were further decreased at one and three months post-transplant, but recovered to levels comparable to HC by six months. Responses to pp65 among CMV-seropositive recipients followed a similar pattern but recovered by three months. CMV-seropositive LTTx and HC showed a Th1 cytokine response to pp65 stimulation. Three LTTx subjects developed CMV DNAemia; two demonstrated decreased responses to anti-CD3mAB (and pp65 in the CMV seropositive subject) at the onset of DNAemia, which recovered as DNAemia resolved. Monitoring CMI in children is feasible and may provide an adjunct biomarker to predict CMV progression and recovery.

Background.Because tuberculosis (TB) in children implies recent infection, children serve as sentinels for disease transmission within a community. Despite the significance of diagnosing tuberculosis in children, most cases are diagnosed on clinical evidence rather than laboratory findings.Methods.W

Autologous or allogeneic hematopoietic stem cell transplant (SCT) is often considered in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) but there are limited data on the use of SCT for the treatment of NHL in the pediatric setting.To evaluate the role of SCT for children with NHL, we reviewed 36 consecutive pediatric patients with NHL who underwent an allogeneic (n = 21) or autologous (n = 15) SCT at our institution between 1982 and 2004. Pathologic classification included: lymphoblastic lymphoma (n = 12), Burkitt lymphoma (BL) (n = 5), diffuse large B-cell lymphoma (n = 4), anaplastic large cell lymphoma (ALCL) (n = 13), peripheral T cell lymphoma (n = 1), and undifferentiated NHL (n = 1). Donor source for allogeneic-SCT recipients was an HLA-matched related donor (n = 15), a matched unrelated donor (n = 4), or a mismatched donor (related n = 1; unrelated n = 1). Twenty-eight patients (78%) had chemotherapy responsive disease at the time of transplant (either CR or PR).Overall survival (OS) and disease-free survival (DFS) were 55% and 53% with a median follow-up of 9.75 years. Outcomes were similar in patients receiving autologous and allogeneic-SCT (DFS 53% in both groups). Patients with ALCL had a DFS of 76.9%. In contrast, of five patients transplanted for BL, none survived. DFS among patients with chemotherapy sensitive disease was 61%, compared with 25% among patients with relapsed/refractory disease (P = 0.019).Allogeneic and autologous SCT offer the prospect of durable, disease-free survival for a significant proportion of pediatric patients with relapsed or refractory NHL. Survival is superior among patients with chemotherapy sensitive disease.

CMI responses, combined with quantification of CMV DNA (DNAemia), may identify transplantation recipients at risk for invasive disease. PBMC were collected in pediatric transplantation candidates at one, three, and six months post-transplant in 10 subjects (six renal, three cardiac, one stem cell) and at single time points in eight HC and 14 children greater than one yr post-transplant (LTTx). Cells were stimulated with anti-CD3mAb or CMV pp65 peptide pools and responses assessed by IFNG enzyme-linked immunosorbent spot assay and cytokine secretion. IFNG responses to anti-CD3mAb were significantly lower pretransplant relative to HC and were further decreased at one and three months post-transplant, but recovered to levels comparable to HC by six months. Responses to pp65 among CMV-seropositive recipients followed a similar pattern but recovered by three months. CMV-seropositive LTTx and HC showed a Th1 cytokine response to pp65 stimulation. Three LTTx subjects developed CMV DNAemia; two demonstrated decreased responses to anti-CD3mAB (and pp65 in the CMV seropositive subject) at the onset of DNAemia, which recovered as DNAemia resolved. Monitoring CMI in children is feasible and may provide an adjunct biomarker to predict CMV progression and recovery.

Osteosarcoma at the molecular level is among the most complex pediatric ­malignancies. Despite its relatively high incidence in the pediatric patient population many aspects of this disease continue to defy understanding. Osteosarcoma is the most common primary malignant bone tumor in children and adolescents (Arndt and Crist 1999). Approximately 400 children and adolescents are diagnosed each year in the United States (Meyers and Gorlick 1997). In the adolescent age range, it is the second most common malignancy, following only lymphoma in incidence. Osteosarcoma continues to be diagnosed solely based upon its histologic appearance. Despite having tremendously variable appearance, characterized descriptively by its histologic subtype, the presence of a malignant spindle cell which produces osteoid is the basis for diagnosing osteosarcoma. Molecular analyses of gene copy number, translocations, and gene expression do not contribute to making the diagnosis.

Thirty six patients (pts) with NHL, aged 3.5–20.9 years (median 14.7 years) received an allo-SCT (n=21) or auto-SCT (n=15) at our institution between 12/82 and 12/04. Pathologic NHL classification included: lymphoblastic (n=12), Burkitt’s (n=5), Large Cell (n=17) including ki-1 + (n=11), peripheral NHL (n=1), and undifferentiated NHL (n=1). Disease status at SCT was: first remission (CR1) (n=1), CR2 (n=15), CR3 (n=5), partial remission (n=7), relapse (Rel) or refractory (Ref) (n=8). Cytoreductive regimens were total body irradiation (TBI)-based for all but 3 pts in each of the allo-SCT and auto-SCT group. For the allo-SCT pts, donors were: matched related (n=15), mismatched related (n=1), and unrelated (n=5); graft-versus-host disease (GvHD) prophylaxis included T-cell depletion (TCD) (n=10) or post-BMT immunosuppression (n=11). Only one pt received a non-myeloablative allo-SCT. With one pt in the allo-SCT group lost to follow-up, 35 of 36 pts in the entire cohort were evaluable. The median follow up of the entire group was 21.5 months; it was 34 months and 20 months respectively for the allo-SCT and the auto-SCT groups. The overall survival (OS) and disease-free survival (DFS) were 56% and 54%, respectively. Ten of the 11 pts with ki-1 positive NHL are alive, disease-free after either allo-SCT (n=4) or auto-SCT (n=7) with a median follow-up of 26 months. The DFS for those patients transplanted in CR was 60% compared to 49% for those transplanted in either PR or Rel/Ref disease. Of the eight pts transplanted with progressive disease, 2 are alive, disease-free at 110 and 115 months; both pts post allo-SCT. For the allo-SCT group, the DFS was 52%. Seven pts relapsed, 4 of whom had Rel/Ref disease at the time of SCT. Four pts died of SCT-related complications. Five pts developed Grade II–IV aGvHD. For the auto-SCT group, the DFS was 53%. Two pts relapsed, and 2 pts died of toxicity. In summary, both allo-SCT and auto-SCT offer the prospect of durable disease-free survival for a significant proportion of pediatric patients with NHL after a first relapse or disease progression. In particular, those pts with ki-1-positive NHL had the most favorable outcome. As expected, pts transplanted in minimal residual disease achieved superior DFS. Results N CR/PR Rel/Ref Relapse TRM DFS Allo-SCT 21 11/4 6 33% 20% 52% Auto-SCT 15 10/3 2 13% 13% 53%