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Increasing numbers of patients surviving malignant bone tumors around the knee joint have led to an increasing importance to investigate long-term results. This study assessed the long-term results of rotationplasty after resection of malignant bone tumors regarding functional outcome and quality of life to allow better comparison with other treatment options in bone cancer treatment.60 participants who underwent rotationplasty due to bone cancer took part in this multicentric questionnaire-based study. The long-term functional outcome was measured by the Musculoskeletal tumor society score (MSTS) and the Tegner activity level scale. The health-related quality of life (HRQL) was assessed by using the Short Form Health Survey (SF-36).Patients treated with rotationplasty (median follow-up of 22 years, range 10-47 years) regained a high level of activity (median MSTS score of 24). Even a return to high level sports was possible (mean Tegner activity level scale of 4). Duration of follow-up did not influence the functional outcome. HRQL scores were comparable to the general German population. Concerns of psychological problems due to the unusual appearance of the rotated foot have not been confirmed.Rotationplasty can be a good alternative to endoprosthetic replacement or amputation, either as primary surgery or as a salvage procedure. Especially for growing children and very active patients rotationplasty should be considered.Durch die steigenden Überlebensraten von Patienten, die maligne Knochentumore im Bereich des Kniegelenks überleben, wird es immer wichtiger, die Langzeitergebnisse dieser Patienten zu untersuchen. In dieser Studie wurden die Langzeitergebnisse der Borggreve-Umkehrplastik nach Resektion maligner Knochentumore im Hinblick auf das funktionelle Ergebnis und die Lebensqualität untersucht, um einen besseren Vergleich mit anderen Behandlungsoptionen in der Knochenkrebsbehandlung zu ermöglichen.60 Teilnehmer, die sich aufgrund eines Knochentumors einer Borggreve-Umkehrplastik unterzogen, nahmen an dieser multizentrischen Studie teil. Das langfristige funktionelle Ergebnis wurde mit dem Musculoskeletal Tumor Society Score (MSTS) und der Tegner-Aktivitätsskala erfasst. Die gesundheitsbezogene Lebensqualität (HRQL) wurde mit Hilfe des Short Form Health Surveys (SF-36) ermittelt.Die befragten Patienten (mediane Nachbeobachtungszeit von 22 Jahren, Spanne 10–47 Jahre) erlangten ein hohes Aktivitätsniveau zurück (medianer MSTS-Score von 24). Selbst eine Rückkehr zum Leistungssport war möglich (mittlere Tegner-Aktivitätsskala von 4). Die Dauer der Nachbeobachtung hatte keinen Einfluss auf das funktionelle Ergebnis. In Bezug auf die gesundheitsbezogene Lebenszufriedenheit (HRQL) zeigten sich vergleichbare Ergebnisse zur allgemeinen deutschen Bevölkerung. Die Befürchtungen von psychologischen Problemen aufgrund des ungewöhnlichen Aussehens des gedrehten Fußes haben sich nicht bestätigt.Die Borggreve-Umkehrplastik kann eine gute Alternative zum endoprothetischen Ersatz oder zur Amputation sein, nicht nur als Primäreingriff, sondern auch als Sekundäreingriff nach Versagen des endoprothetischen Ersatzes. Insbesondere bei Kindern im Wachstumsalter und bei sehr aktiven Patienten sollte die Borggreveplastik in Betracht gezogen werden.

Chimeric antigen receptor (CAR) T cell therapy is a potent new treatment option for relapsed or refractory hematologic malignancies. As the monitoring of CAR T cell kinetics can provide insights into the activity of the therapy, appropriate CAR T cell detection methods are essential. Here, we report on the comprehensive validation of a flow cytometric assay for peripheral blood CD19 CAR T cell detection. Further, a retrospective analysis (n = 30) of CAR T cell and B cell levels over time has been performed, and CAR T cell phenotypes have been characterized. Serial dilution experiments demonstrated precise and linear quantification down to 0.05% of T cells or 22 CAR T cell events. The calculated detection limit at 13 events was confirmed with CAR T cell negative control samples. Inter-method comparison with real-time PCR showed appreciable correlation. Stability testing revealed diminished CAR T cell values already one day after sample collection. While we found long-term CAR T cell detectability and B cell aplasia in most patients (12/17), some patients (5/17) experienced B cell recovery. In three of these patients the coexistence of CAR T cells and regenerating B cells was observed. Repeat CAR T cell infusions led to detectable but limited re-expansions. Comparison of CAR T cell subsets with their counterparts among all T cells showed a significantly higher percentage of effector memory T cells and a significantly lower percentage of naïve T cells and T EMRA cells among CAR T cells. In conclusion, flow cytometric CAR T cell detection is a reliable method to monitor CAR T cells if measurements start without delay and sufficient T cell counts are given.

Simple Summary Currently, patients with high-risk neuroblastoma are uniformly treated with maximum therapy. This study investigated a high-risk subgroup characterized by the presence of the amplified MYCN oncogene in the tumor regardless of the stage. In contrast to the corresponding high-risk subgroup consisting of patients with metastases and age at diagnosis over 18 months, the investigated subgroup had generally a superior survival chance. However, the detection of mutations of specific genes in the tumor tissue (RAS and p53 pathway including ALK) had a strong, negative impact. These genes should be therefore also investigated in the future. Complete surgical removal of the primary tumor proved to be beneficial for high-risk neuroblastoma patients assigned to the high-risk category solely by MYCN amplification. Abstract Background: To identify variables predicting outcome in neuroblastoma patients assigned to the high-risk group solely by the presence of MYCN oncogene amplification (MNA). Methods: Clinical characteristics, genomic information, and outcome of 190 patients solely assigned to high-risk neuroblastoma by MNA were analyzed and compared to 205 patients with stage 4 neuroblastoma aged ≥18 months with MNA (control group). Results: Event-free survival (EFS) and overall survival (OS) at 10 years were 47% (95%-CI 39–54%) and 56% (95%-CI 49–63%), respectively, which was significantly better than EFS and OS of the control group (EFS 25%, 95%-CI 18–31%, p < 0.001; OS 32% 95%-CI 25–39%, p < 0.001). The presence of RAS-/p53-pathway gene alterations was associated with impaired 10-year EFS and OS (19% vs. 55%, and 19% vs. 67%, respectively; both p < 0.001). In time-dependent multivariable analyses, alterations of RAS-/p53-pathway genes and the extent of the best primary tumor resection were the only independent prognostic variables for OS (p < 0.001 and p = 0.011, respectively). Conclusions: Neuroblastoma patients attributed to high risk solely by MYCN amplification have generally a more favorable outcome. Mutations of genes of the RAS and/or p53 pathways and incomplete resection are the main risk factors predicting poor outcome.

In the present study, we show that concomitant inhibition of Hedgehog (HH) signaling by the glioma-associated oncogene homolog1 (GLI1)-targeting agent GANT61 and the antiapoptotic BCL-2 protein family member MCL-1 by A-1210477 synergistically induces cell death in HH-driven cancers, i.e. rhabdomyosarcoma (RMS) and medulloblastoma (MB) cells. Combined genetic and pharmacological inhibition emphasized that co-treatment of GANT61 and A-1210477 indeed relies on inhibition of GLI1 (by GANT61) and MCL-1 (by A-1210477). Mechanistic studies revealed that A-1210477 triggers the release of BIM from MCL-1 and its shuttling to BCL-xL and BCL-2. Indeed, BIM proved to be required for GANT61/A-1210477-induced cell death, as genetic silencing of BIM using siRNA significantly rescues cell death upon GANT61/A-1210477 co-treatment. Similarly, genetic silencing of NOXA results in a significant reduction of GANT61/A-1210477-mediated cell death. Also, overexpression of MCL-1 or BCL-2 significantly protects RMS cells from GANT61/A-1210477-triggered cell death. Addition of the pan-caspase inhibitor zVAD.fmk significantly decreases GANT61/A-1210477-stimulated cell demise, indicating apoptotic cell death. In conclusion, GANT61 and A-1210477 synergize to engage mitochondrial apoptosis. These findings provide the rationale for further evaluation of dual inhibition of HH signaling and MCL-1 in HH-driven cancers.

Prognosis of refractory childhood cancers despite multimodal treatment strategies remains poor. Here, we report a single center experience encountered in 18 patients with refractory solid malignancies treated with adoptive cellular immunotherapy (ACI) from haploidentical or matched donors following hematopoietic stem cell transplantation. While seven patients were in partial and six in complete remission (CR), five patients suffered from relapsed diseases at the time of ACI. 1.5-year probabilities of overall survival (OS) and progression-free survival (PFS) were 19.5% and 16.1% for all patients. Patients in CR showed estimated 1.5-year OS and PFS of 50.1% and 42.7%, respectively. CR was induced or rather sustained in ten children, with two still being alive 9.6 and 9.3 years after ACI. Naive, central and effector memory T-cells correlated with responses. However, the majority of patients relapsed. Cumulative incidence of relapse was 79.8% at 1.5 years. Acute graft versus host disease (aGVHD) occurred in nine of 18 patients (50%) with aGVHD grade I–II observed in six (33%) and aGVHD grade III seen in three (17%) patients, manageable in all cases. Altogether, study results indicate that donor-derived ACI at its current state offers palliation but no clear curative benefit for refractory childhood cancers and warrants further improvement.

Well-established donor lymphocyte infusion (DLI) and novel cytokine-induced killer (CIK) cell therapy for the treatment of relapsing hematologic malignancies after allogeneic hematopoietic stem cell transplantation (HSCT) were compared with respect to feasibility, safety, and efficacy. Altogether, a total of 221 infusions were given to 91 patients (DLI, n = 55; CIK, n = 36). T cell recovery was significantly improved after CIK cell therapy (P.0001). Although patients with CIK cell treatment showed a significantly worse prognosis at the time of HSCT (risk score, 1.7 versus 2.1; P.0001), DLI and CIK cell therapy induced complete remission (CR) in 29% and 53% patients, respectively, whereas relapse occurred in 71% and 47%. In both groups, all patients with overt hematologic relapse at the time of immunotherapy (DLI, n = 11; CIK, n = 8) succumbed to their disease, while 36% and 68% patients with DLI or CIK cell therapy applied due to molecular relapse or active disease at the time of transplantation achieved CR. The 6-month overall survival rate in the latter patients was 57% and 77%, respectively, with a median follow-up of 27.9 months (range, .9 to 149.2 months). The 6-month cumulative incidence of relapse was 55% and 22% in patients who received DLI and CIK cell therapy, respectively (P = .012). Acute graft-versus-host disease developed in 35% of the patients who received DLI and in 25% of those who received CIK. No transfusion-related deaths occurred. These data, while underscoring the therapeutic value of conventional DLI, suggest the improved safety and to a certain extent efficacy of CIK cell therapy for patients at high risk for post-transplantation relapse of various hematologic malignancies.

Background Autologous stem cell transplantation remains an integral treatment tool for certain childhood malignancies. In children, a central venous catheter is typically necessary to provide adequate flow rates for preparative apheresis. In this study, the feasibility and efficiency of collecting CD34+ cells via an indwelling Hickman catheter, preimplanted for chemotherapy, instead of placing an additional temporary central venous catheter was evaluated. Study design and methods Forty-eight pediatric leukaphereses for autologous hematopoietic stem cell transplantation using Spectra Optia MNC, Version 3.0 were reviewed. We compared preimplanted Hickman catheters with a temporary Shaldon catheter, inserted for apheresis. Apheresis was considered successful if a dose of 2 × 106 CD34+ peripheral blood stem cells/kg BW was achieved. Results In 43 (89.6%) of the 48 patients, a Hickman catheter was used for leukapheresis. Only 5 patients (10.4%) received a temporary Shaldon catheter. In both groups, apheresis was performed without apparent adverse reactions. The dose of collected CD34+ peripheral blood stem cells was 12.7 × 106 (range, 2.3-70.7 × 106 ) cells/kg BW in the Hickman group and 16.2 × 106 (range, 3.8-48.4 × 106 ) cells/kg BW in the Shaldon group, showing no statistically significant difference (p = 0.58). In both groups, the primary endpoint of a minimal CD34+ cell concentration of 2 × 106 cells/kg BW was achieved at a maximum of two leukapheresis sessions. Apheresis efficacy was further confirmed by the collection efficiency of 40.2% in the Hickman group and 27.8% in the Shaldon group (p = 0.32). Conclusion These data indicate the reliable feasibility and efficacy of mobilized apheresis via an indwelling Hickman catheter. In light of this, the routine insertion of a dialysis catheter for the purpose of leukapheresis should be critically reconsidered.

10033 Background: Low dose maintenance therapy as consolidation after multimodal standard therapy has been shown to improve survival in patients with sarcoma. It is however unclear which drugs and how long would be optimal. We investigated whether adding oral maintenance chemotherapy after standard multimodal therapy (ST) in patients with localized RMS and RMS-like sarcoma defined as high and very-high risk (HR and VHR), according to CWS stratification, would improve survival. Methods: Patients (pts) age > 6 months < 21 years, with 1. embryonal RMS N0, incompletely resected, (Group II or III), tumor size > 5cm and/or ≥10 years, in unfavorable primary sites and all N1 (HR RMS Group), 2. alveolar RMS N0/N1 (VHR RMS Group) 3.Unidfferentiated sarcoma (UDS), extraskeletal Ewing sarcoma (EES) and primary non resectable (Group III) synovial sarcoma (SS) (HR RMS-like Group) in complete remission after ST including 9 cycles of ifosfamide, vincristine and actinomycin D +/- doxorubicin, surgery and/or radiotherapy were eligible for randomization to stop treatment (S-arm) or receive maintenance chemotherapy (M-arm) with eight 10-days courses consisting of trofosfamide (2x 75mg/m²/day) and idarubicine (1 x 5mg/m²/day 1,4,7,10) alternating with trofosfamide and etoposide (2x 25mg/m²/day). The study was designed with 80% power and a two-sided alpha level of 5% to detect an increase in 3 yr EFS from 60 to 75%. Randomisation was stratified according to risk groups. To reduce possible imbalances in the number of treatment assignments, a permuted block design was used. The initial calculated sample size was 145 pts in each group (recruitment period six years). Due to the lower than planned recruitement rate, the accrual was extended to 10 years and sample size recalculated to 98 pts in each group. Results: Between 1.7.2009 and 30.6.2019, 441 pts were eligible at diagnosis and 337 at the end of ST. 195 pts were randomized: 99 were assigned to the S-arm and 96 to M-arm. The distribution of the following clinical features:age, gender, tumor size, IRS-Group, T-Status, N-Status, histology and localisation showed no significant difference between the treatment groups. In the intent to treat population, with a median follow up of 4.9 years (IQR 3.0-5.7) in surviving pts, 3yr EFS and OS in M-arm vs S-arm were respectively: EFS 66.2% (95% IC 57.1-76.79) vs 75.0% (95% IC 66.8-84.3) (p 0.07) and OS 81.9% (95% IC 74.2-90.4) vs 84.6 (95% IC 77.5-92.4) (p 0.15). Toxicity grade 3 (no grade 4) in the M-arm was: hematological in 51 %, febrile infection 5%, sensory neuropathy in 1% pts. Conclusions: The addition of maintenance therapy with trofosfamide, etoposide and idarubicine after ST does not improve EFS and OS in patients with high risk RMS and RMS-like sarcomas. Clinical trial information: 2007-0001478-10.

Acute lymphatic leukemia is the most common malignant disease in children. Despite a good prognosis, new therapeutic concepts are needed for patients with refractory and relapsed disease.The importance of chimeric antigen receptor (CAR) T‑cell therapy for patients with refractory and post-stem cell transplantation.Overview of studies in childhood; presentation of extraction, use, side effects and prognostic factors.In 30 patients with a leukemia burden of5% at the time of lymphocytic chemotherapy, the probability of event-free survival after 12 months was 0.70; in patients with a leukemia burden of5%, the probability of event-free survival was only 0.23.Further improvements in vector design will help to improve the effectiveness of this treatment. It will become important to isolate factors that will make it possible to identify patients who will respond to this therapy in the long term.HINTERGRUND: Die akute lymphatische Leukämie (ALL) ist im Kindesalter die häufigste maligne Erkrankung. Trotz guter Prognose bedarf es neuer Therapiekonzepte für Patienten mit refraktärer und rezidivierter Erkrankung.Stellenwert der CAR-T-Zell-Therapie (CAR chimärer Antigenrezeptor) für Patienten mit refraktärer ALL und nach Stammzelltransplantation MATERIAL UND METHODEN: Übersicht über Studien im Kindesalter; Darstellung von Gewinnung, Einsatz, Nebenwirkungen und Prognosefaktoren ERGEBNISSE: Bei 30 Patienten, die mit CAR-T Zellen behandelt wurden und zum Zeitpunkt der lymphozytendepletierenden Chemotherapie eine Leukämielast5 % aufwiesen, betrug die Wahrscheinlichkeit des ereignisfreien Überlebens nach 12 Monaten 0,70; bei Patienten mit einer Leukämielast5 % nur 0,23.Weitere Verbesserungen im Vektordesign werden dazu beitragen, die Effektivität der CAR-T-Zell-Therapie zu verbessern. Wichtig wird die Identifizierung von Faktoren sein, mit denen sich Patienten bestimmen lassen, die auf diese Therapie langfristig ansprechen.

Simple Summary In this study, we apply the ERBB2-chimeric antigen receptor (CAR)-modified natural killer (NK) cell line NK-92 (NK-92/5.28.z), a well-defined, good manufacturing practice (GMP)-compliant, third-party, off-the-shelf immune effector cell product as a novel immunotherapeutic approach for the treatment of high-risk rhabdomyosarcomas. Our preclinical in vitro data show enormous potential to improve immunotherapy of ERBB2-positive high-risk rhabdomyosarcoma a still incurable, rapidly lethal disease, assigning to NK-92/5.28.z cells rather than to unmodified parental NK-92 cells a multifarious role as ERBB2-specific CAR-targeted killers and modulators of endogenous adaptive immunity of the host, justifying the further evaluation of this approach in in vivo mouse xenograft models as a prerequisite for a possible future phase I/II clinical trial in defined subsets of high-risk rhabdomyosarcoma patients. Abstract The dismal prognosis of pediatric and young adult patients with high-risk rhabdomyosarcoma (RMS) underscores the need for novel treatment options for this patient group. In previous studies, the tumor-associated surface antigen ERBB2 (HER2/neu) was identified as targetable in high-risk RMS. As a proof of concept, in this study, a novel treatment approach against RMS tumors using a genetically modified natural killer (NK)-92 cell line (NK-92/5.28.z) as an off-the-shelf ERBB2-chimeric antigen receptor (CAR)-engineered cell product was preclinically explored. In cytotoxicity assays, NK-92/5.28.z cells specifically recognized and efficiently eliminated RMS cell suspensions, tumor cell monolayers, and 3D tumor spheroids via the ERBB2-CAR even at effector-to-target ratios as low as 1:1. In contrast to unmodified parental NK-92 cells, which failed to lyse RMS cells, NK-92/5.28.z cells proliferated and became further activated through contact with ERBB2-positive tumor cells. Furthermore, high amounts of effector molecules, such as proinflammatory and antitumoral cytokines, were found in cocultures of NK-92/5.28.z cells with tumor cells. Taken together, our data suggest the enormous potential of this approach for improving the immunotherapy of treatment-resistant tumors, revealing the dual role of NK-92/5.28.z cells as CAR-targeted killers and modulators of endogenous adaptive immunity even in the inhibitory tumor microenvironment of high-risk RMS.

Introduction The survival of children with stage 4(M) neuroblastoma without MYCN amplification and below the age of 18 months is considered better than the still dismal outcome of older high-risk neuroblastoma patients. This study analyzes the impact of clinical and molecular characteristics on the long-term outcome. Patients and methods Clinical presentation, survival, and recurrence patterns of patients enrolled onto trials NB90, NB97, and NB2004 were retrospectively analyzed. Gene expression signatures based on RNA microarrays (TH10) were investigated if tumor material was available. Results Between 1990 and 2015, 177 patients with stage 4(M) MYCN nonamplified neuroblastoma aged less than 18 months at diagnosis were eligible. After a median follow-up of 9.7 years (IQR 5.0, 13.4), the proportions of 10-year event-free survival (EFS) and overall survival (OS) were 73% (95% confidence interval [CI] 67-79%) and 86% (95% CI 80-92%), respectively. Of the 27 neuroblastoma recurrences, 44% occurred in more than one site. Four additional patients presented histologically mature ganglioneuroma at recurrence. Six patients developed a secondary malignancy. The secondary 5-year EFS and OS of the 27 patients with neuroblastoma recurrence were 44% and 59%, respectively. TH10 gene expression signature was not prognostically predictive in the investigated subcohort. Conclusion The outcome of patients with stage 4(M) neuroblastoma aged less than 18 months is favorable when treated with high-risk or otherwise intensive therapy. The development of secondary malignancies and the potential of maturation to ganglioneuroma call for a controlled stepwise reduction of treatment intensity.

Background Rhabdomyosarcoma (RMS) of the female genitourinary tract (FGU-RMS) located at the vagina or uterus is one of the most favorable RMS sites. Little is known about treatment and outcome in infants and relapsed disease (RD). Methods Characteristics, treatment, and outcome of 71 children with FGU-RMS registered within five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry (1981-2019) were evaluated. Results FGU-RMS was diagnosed in 67 patients with localized disease (LD) at a median age of 2.89 years (0.09-18.08). Multimodal treatment consisted of chemotherapy (CHT) (n = 66), secondary surgery (n = 32), and radiotherapy (n = 11). Age at diagnosis ≤12 months was the only significant negative prognostic factor influencing the event-free survival (EFS). Ten-year EFS and overall survival (OS) for infants ≤12 months were 50% and 81%, respectively. In contrast, children with LD >1 year and ≤10 years had a 10-year EFS and OS of 78% and 94% (P = .038), and >10 years of 82% and 88%, respectively (P = .53). Metastatic disease was observed in four patients of which three are alive. RD occurred in five of 12 infants ≤1 year and 10/55 children at a median of 1.38 years (0.53-2.97) after initial diagnosis. Treatment of patients with RD consisted of multimodal treatment (n = 13) or resection only (n = 2). Nine patients (60%) were alive in clinical remission at a median of 7.02 years (1.23-16.72) after diagnosis of RD. Conclusion Infants with FGU-RMS have a higher relapse rate than older children with FGU-RMS, but prognosis is fair.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration-–time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.

Haematologica : journal of the European Hematology Association 106(5), 1390-1400 (2021). doi:10.3324/haematol.2019.244780, Published by Ferrata Storti Foundation, Pavia

Background We have analyzed the outcome of patients with localized extraskeletal Ewing sarcoma (EES) treated in three consecutive Cooperative Weichteilsarkomstudiengruppe (CWS) soft tissue sarcoma (STS) studies: CWS-91, CWS-96, and CWS-2002P. Methods Patients were treated in CWS-91 with four- (vincristine, dactinomycin, doxorubicin, and ifosfamide [VAIA] or cyclophosphamide [VACA II]) or five-drug (+etoposide [EVAIA]) cycles, in CWS-96 they were randomly assigned to receive VAIA or CEVAIE (+carboplatin and etoposide), and in CWS-2002P with VAIA III plus optional maintenance therapy (MT) with cyclophosphamide and vinblastine. Local therapy consisted of resection and/or radiotherapy (RT). Results Two hundred forty-three patients fulfilled the eligibility criteria. The 5-year event-free survival (EFS) and overall survival (OS) were 63% (95% confidence interval [CI] 57-69) and 73% (95% CI 67-79), respectively. The 5-year EFS by study was 64% (95% CI 54-74) in CWS-91, 57% (95% CI 48-66) in CWS-96, and 79% (95% CI 67-91) in CWS-2002P (n.s.). The 5-year OS was 72% (95% CI 62-82) in CWS-91, 70% (95% CI 61-79) in CWS-96, and 86% (95% CI 76-96) in CWS-2002P (n.s.). In CWS-96, 5-year EFS and OS in the VAIA arm versus the CEVAIE were 65% (95% CI 52-81) versus 55% (95% CI 39-76) log-rank p = .13, and 85% (95% CI 75-96) versus 61% (95% CI 45-82), log-rank p = .09. Conclusion Our analysis provides interesting information on the treatment and specificities of EES, which can be useful for a better understanding of this rare entity and should be considered in the development of future clinical trials for Ewing sarcoma defined as FET-ETS fusion positive tumors.

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications., This work was funded by Deutsche Krebshilfe grant 70112499, the NCT Heidelberg and an Illumina Medical Research Grant. Part of this work was funded by the National Institute of Health Research (to S.B. and Z.J.) and to UCLH Biomedical research centre (BRC399/NS/RB/101410). Human tissues were obtained from University College London NHS Foundation Trust as part of the UK Brain Archive Information Network (BRAIN UK, Ref: 18/004) which is funded by the Medical Research Council and Brain Tumour Research UK. The methylation profiling at NYU is supported by a grant from the Friedberg Charitable Foundation (to M.Sn.). M.Mi. would like to thank the Luxembourg National Research Fond (FNR) for the support (FNR PEARL P16/BM/11192868 grant). Open Access funding enabled and organized by Projekt DEAL.

Importance: Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Objective: To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant. Design, Setting, and Participants: In this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow

ZusammenfassungArzneimittel für neuartige Therapien (ATMP) wie somatische Gentherapie und Zelltherapie besitzen ein hohes therapeutisches Potenzial für Krankheiten, die sehr früh im Leben beginnen, und die bisher nicht behandelbar waren. Sie werden oft in einem sehr frühen Entwicklungsstadium zugelassen, wenn an wenigen Betroffenen die Wirksamkeit gezeigt wurde und sich ein bisher nie dagewesener Therapieerfolg auftut, vor allem, wenn die Therapie vor Eintritt von Organschäden greift. Dadurch ergeben sich für Pädiater neue arzneimittelrechtliche und ethische Fragen.Um die neuen Behandlungsmöglichkeiten adäquat einzusetzen, muss die Diagnose früher als bisher gestellt werden, oder neue Screeningmethoden müssen zur Verfügung stehen. Denkbar ist, dass das Neugeborenenscreening in zeitkritische Krankheiten in den ersten 72 h nach Geburt und ein genetisches Screening (z. B. in der 4. bis 5. Lebenswoche) aufgeteilt wird.ATMP sind bei ihrer Zulassung noch nicht in ausreichender Anzahl angewendet worden, sodass die notwendigen Erkenntnisse für Wirksamkeit und Sicherheit noch nicht vorliegen (Nutzen-Risiko-Verhältnis). Deswegen werden sie unter strengen Auflagen in spezialisierten Behandlungszentren nach Qualitätskriterien eingesetzt, die der Gemeinsame Bundesausschuss (G-BA) nach Beratung mit den Fachgesellschaften festlegt. Der Aufwand der Therapie und der Dokumentation des Verlaufes in Registern ist erheblich und muss entsprechend vergütet werden.Der Wert eines ATMP wird erst mit seiner breiteren Anwendung nach der Zulassung klar, ähnlich wie die Sicherheit eines Arzneimittels nicht mit der Zulassung vollumfänglich bekannt ist. Für die Pädiatrie ergeben sich neue Herausforderungen und Chancen.

NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities. Whereas they are quite rare in most solid tumors they are present at much higher frequencies in certain rare tumors such as infantile fibrosarcoma, congenital mesoblastic nephroma, secretory breast, or salivary gland carcinoma. NTRK gene fusions or TRK fusion proteins are considered strong oncogenic drivers. If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity. So far only larotrectinib is approved in the European Union. Both drugs have been shown to be effective and well tolerated in phase I and phase II studies. The low prevalence of TRK fusion-positive cancers poses challenges for diagnostic and clinical work-flows. On one hand, patients with NTRK gene fusions should be identified; on the other hand, epidemiological, histological, and resource-related aspects have to be taken into account. Based on these premises, we suggest a diagnostic algorithm for TRK fusion cancers and present current data on TRK inhibitors.NTRK-Genfusionen sind seltene genetische Alterationen, die tumorentitätenübergreifend vorkommen können. Während sie in den meisten soliden Tumoren nur sehr niederfrequent vorkommen, lassen sie sich in bestimmten Tumoren wie dem infantilen Fibrosarkom, dem kongenitalen mesoblastischen Nephrom und dem sekretorischen Mamma- oder Speicheldrüsenkarzinom jedoch häufig nachweisen. NTRK-Genfusionen bzw. TRK-Fusionsproteine gelten als starke onkogene Treiber. Bei Nachweis von NTRK-Genfusionen können TRK-Inhibitoren unabhängig von der Tumorentität eingesetzt werden. Vertreter sind Entrectinib und Larotrectinib. Bislang ist nur Larotrectinib in der Europäischen Union zugelassen. Für beide wurden Wirksamkeit und Verträglichkeit in Phase-I- und Phase-II-Studien gezeigt. Die Seltenheit der TRK-Fusionstumoren stellt diagnostische und klinische Prozesse vor große Herausforderungen: Einerseits sollen alle Patienten mit TRK-Fusionstumoren identifiziert werden, andererseits sind epidemiologische und histologische Aspekte sowie Ressourcen zu berücksichtigen. Basierend auf diesen Punkten möchten wir einen Diagnosealgorithmus für TRK-Fusionstumoren vorschlagen, außerdem stellen wir aktuelle Daten zu den TRK-Inhibitoren vor.

The treatment of children and adolescents with soft tissue sarcoma (STS) consists of a multimodality approach involving surgery, chemotherapy and radiotherapy. The optimal timing and intensity of these three treatment modalities must be planned with regard to the prognostic factors and considering possible late effects of treatment.

Systemic viral diseases frequently occur in allogeneic hematopoietic stem cell transplantation, but data in children receiving chemotherapy for acute leukemia are scarce. We therefore collected and analyzed the published data on symptomatic infection from cytomegalovirus, herpes simplex virus, varicella zoster virus, parvovirus B19, or adenovirus in pediatric acute leukemia. Reports on 68 children were identified, of whom 16 patients have died from the infection. Further studies have to (1) evaluate the true incidence of these infections in pediatric acute leukemia, (2) their impact on outcome, and (3) whether a subpopulation of patients could benefit from screening and prophylactic strategies.

Cancer in children and adolescents under the age of 18 is rare; in 2017, approximately 2220 new cases in Germany were reported to the German Childhood Cancer Registry. The aim of the GPOH has always been to treat as many affected patients as possible in a standardized way, preferably in prospective, controlled studies. The Joint Federal Committee has also laid down this requirement in the paediatric oncology guideline. In a survey among the study chairs of the GPOH, it was determined how the number of clinical trials has changed following the amended drug legislation. In 2002, 33 therapy optimization studies (TOS) of the GPOH were open. Overall, TOS decreased from 33 in 2002 to 2 in 2017. The number of drug trials has increased to 16 by 2017 (almost 1100 patients registered). At the time, the number of clinical registries has increased to 28 with a total of more than 1800 registered patents. This observation shows that the clinical registers have taken on a new significance in paediatric oncology. Three examples are used to examine what contributions registries can make in relation to studies on the treatment of patients and to scientific progress. In summary, the experience gained so far from the examples discussed illustrates that studies and registries mutually represent a meaningful and necessary addition to the study group structure in paediatric oncology.Krebserkrankungen bei Kindern und Jugendlichen unter 18 Jahren sind selten; im Jahr 2017 wurden ca. 2220 Neuerkrankungen in Deutschland an das Deutsche Kinderkrebsregister gemeldet. Ziel der GPOH war es immer, möglichst alle betroffenen Patienten standardisiert, am besten in prospektiven, kontrollierten Studien, zu behandeln. Diese Vorgabe hat auch der Gemeinsame Bundesausschuss in der Kinderonkologierichtlinie festgeschrieben. In einer Umfrage unter den Studienleitern der GPOH wurde ermittelt, wie sich nach der geänderten Arzneimittelgesetzgebung, die Zahl der klinischen Studien verändert hat. Im Jahr 2002 waren 33 Therapieoptimierungs-studien (TOS) der GPOH geöffnet. Insgesamt ist ein Rückgang der TOS von 33 im Jahre 2002 auf 2 im Jahre 2017 zu verzeichnen. Die Zahl der Arzneimittelstudien hat sich bis zum Jahr 2017 auf 16 erhöht (knapp 1100 erfasste Patienten). Zeitgleich hat sich die Zahl der klinischen Register auf 28 erhöht mit insgesamt mehr als 1800 dort erfassten Patienten. Diese Beobachtung zeigt, dass die klinischen Register eine neue Bedeutung in der pädiatrischen Onkologie bekommen haben. An 3 Beispielen wird dargelegt, welche Beiträge Register im Verhältnis zu Studien zur Behandlung der Patienten und zum wissenschaftlichen Fortschritt leisten können. Zusammengefasst verdeutlichen die bisherigen Erfahrungen aus den diskutierten Beispielen, dass Studien und Register wechselseitig eine sinnvolle und notwendige Ergänzung der Studiengruppenstruktur in der Kinderonkologie darstellen.

Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2–18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective “real-world-practice” study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.

Recently, new advances were made regarding the depletion of CD45RAWithin this project we investigated CD45RA-depletion from G-CSF mobilized PBSC by two different purification strategies according to GMP, specifically direct depletion of CD45RAWith log -3.9 and - 3.8 the depletion quality of CD45RACD45RA-depletion from G-CSF mobilized PBSC is feasible as one- and two-step approach and results in sufficient reduction of CD45RA

ZusammenfassungKrebserkrankungen bei Kindern und Jugendlichen unter 18 Jahren sind selten; im Jahr 2017 wurden ca. 2220 Neuerkrankungen in Deutschland an das Deutsche Kinderkrebsregister gemeldet. Ziel der GPOH war es immer, möglichst alle betroffenen Patienten standardisiert, am besten in prospektiven, kontrollierten Studien, zu behandeln. Diese Vorgabe hat auch der Gemeinsame Bundesausschuss in der Kinderonkologierichtlinie festgeschrieben. In einer Umfrage unter den Studienleitern der GPOH wurde ermittelt, wie sich nach der geänderten Arzneimittelgesetzgebung, die Zahl der klinischen Studien verändert hat. Im Jahr 2002 waren 33 Therapieoptimierungs-studien (TOS) der GPOH geöffnet. Insgesamt ist ein Rückgang der TOS von 33 im Jahre 2002 auf 2 im Jahre 2017 zu verzeichnen. Die Zahl der Arzneimittelstudien hat sich bis zum Jahr 2017 auf 16 erhöht (knapp 1100 erfasste Patienten). Zeitgleich hat sich die Zahl der klinischen Register auf 28 erhöht mit insgesamt mehr als 1800 dort erfassten Patienten. Diese Beobachtung zeigt, dass die klinischen Register eine neue Bedeutung in der pädiatrischen Onkologie bekommen haben. An 3 Beispielen wird dargelegt, welche Beiträge Register im Verhältnis zu Studien zur Behandlung der Patienten und zum wissenschaftlichen Fortschritt leisten können. Zusammengefasst verdeutlichen die bisherigen Erfahrungen aus den diskutierten Beispielen, dass Studien und Register wechselseitig eine sinnvolle und notwendige Ergänzung der Studiengruppenstruktur in der Kinderonkologie darstellen.

AML SCT-BFM 2007 was the first hematopoietic stem cell transplantation (HCT) trial in Germany to comply with the European Clinical Trials Directive, and aimed to standardize pediatric HCT for acute myeloid leukemia (AML) across centers in Germany, Austria, and the Czech Republic. Children with high-risk features and a good early response achieving a complete first remission (CR-1) and those in CR-2 after a first relapse were stratified to receive HCT from a matched donor after myeloablative conditioning consisting of busulfan, cyclophosphamide, and melphalan. Four-year EFS and OS were 61 and 70%. Cumulative incidence of relapse (CIR) was 22%. TRM was 15% and correlated with age reaching 9% (SE 3%) in children younger than 12 years and 31% (SE 9%) in older children and adolescents. Children with poorly responding primary disease or relapse were allocated to receive early HCT after a cytoreductive regimen with fludarabine, amsacrine, and cytarabine, followed by reduced intensity conditioning and prophylactic donor lymphocyte infusions. Four-year EFS and OS were 49 and 53%. CIR was 38% and TRM 11%. For patients with primary poor response disease, early use of RIC HCT followed by prophylactic DLI can induce long-term remissions in more than 50% (EFS 46% (SE 9%)).

Allogeneic hematopoietic stem cell transplantation (alloHSCT) has become a well-established treatment option for many patients suffering from malignant and non-malignant diseases. In the past decade, high-resolution HLA-typing, remission surveillance, pre-emptive immune intervention, and standardisation in supportive care measures have substantially improved transplant outcomes. This retrospective study evaluated transplant procedures in 162 paediatric patients with acute lymphoblastic leukaemia (n = 124) or acute myeloid leukaemia (n = 38) who received their first alloHSCT in our institution over an 11-year period. We observed a significant reduction in risk of non-relapse mortality (NRM) over time (HR = 0.34, 95% CI 0.12-0.98; P = 0.05), the 4-year NRM estimate decreased from 20% in 2005-2008 to 7% in 2012-2016 (P = 0.02) and an increase in survival after relapse. There was no significant difference in patients who received a graft from a sibling, haplo, or an unrelated donor with regard to their overall survival (P = 0.45), event-free survival (P = 0.61), and non-relapse mortality (P = 0.19). Our data suggest that a specific transplant infrastructure with a highly experienced team in an accredited transplant centre likely contributes to better transplant outcomes for acute leukaemia patients in complete remission regardless of donor type.

BACKGROUND Endothelial cell malignancies are extremely rare in childhood. New identification of genetic abnormalities (WWTR1:CAMTA1 translocation) helps to recognize potential therapeutic targets. Little is known about treatment and outcome of these patients. METHODS Clinical course, treatment, and outcome in patients with endothelial cell malignancies treated within the Cooperative Weichteilsarkom Studiengruppe (CWS) trials CWS-91, -96, -2002P, and the Soft-Tissue Sarcoma Registry (SoTiSaR) were analyzed (1991-2019). RESULTS Patients had angiosarcoma (AS) (n = 12), malignant epithelioid hemangioendothelioma (EHE) (n = 16), and kaposiform hemangioendothelioma (KHE) (n = 13). The median age was 5.39 years (range, 0.8-17.34); 33 patients had localized disease (LD), and 8 patients had metastatic disease. Therapy consisted of chemotherapy (CHT) (AS n = 8, EHE n = 9, KHE n = 5), interferon or new agent therapy (EHE n = 5, 2 KHE n = 2), microscopically or macroscopically complete resection (AS n = 3, EHE n = 6, KHE n = 3), and radiotherapy (AS n = 6, EHE n = 2, KHE n = 1). Two patients (KHE) had watch-and-wait strategy resulting in stable disease. Complete remission (CR) was achieved in AS (10/12; 83%), EHE (10/16; 63%), and KHE (5/13; 38%). The five-year EFS and OS for patients with AS was 64% (± 29 CI 95%) and 80% (± 25, CI 95%), with EHE 62% (± 24, CI 95%) and 78% (± 23, CI 95%), with KHE 33% (± 34, CI 95%) and 92% (± 15, CI 95%), respectively. Complete resection was a significant prognostic factor for AS, LD for EHE. CONCLUSIONS Endothelial cell malignancies in childhood have a fair outcome with multimodal treatment. New treatment options are needed for metastic disease.

Survival in children with relapsed/refractory a cute myeloid leukemia is unsatisfactory. Treatment consists of one course of fludarabine, cytarabine and liposomal daunorubicin, followed by fludarabine and cytarabine and stem-cell transplantation. Study ITCC 020/I-BFM 2009-02 aimed to identify the recommended phase II dose of clofarabine replacing fludarabine in the abovementioned combination regimen (3+3 design). Escalating dose levels of clofarabine (20-40 mg/m²/day x 5 days) and liposomal daunorubicin (40-80 mg/m²/day) were administered with cytarabine (2 g/m²/day x 5 days). Liposomal DNR was given on day 1, 3 and 5 only. The cohort at the recommended phase II dose was expanded to make a preliminary assessment of anti-leukemic activity. Thirty-four children were enrolled: refractory 1st (n=11), early 1st (n=15), ≥2ⁿd relapse (n=8). Dose level 3 (30 mg/m² clofarabine; 60 mg/m² liposomal daunorubicin) appeared to be safe only in patients without subclinical fungal infections. Infectious complications were dose-limiting. The recommended phase II dose was 40 mg/m² clofarabine with 60 mg/m² liposomal daunorubicin. Side-effects mainly consisted of infections. The overall response rate was 68% in 31 response evaluable patients, and 80% at the recommended phase II dose (n=10); 22 patients proceeded to stem cell transplantation. The 2-year probability of event-free survival (pEFS) was 26.5±7.6 and probability of survival (pOS) 32.4±8.0%. In the 21 responding patients, the 2-year pEFS was 42.9±10.8 and pOS 47.6±10.9%. Clofarabine expo-sure in plasma was not significantly different from that in single-agent studies. In conclusion, clofarabine was well tolerated and showed high response rates in relapsed/refractory pediatric acute myeloid leukemia. Patients with (sub)clinical fungal infections should be treated with caution. Clofarabine has been taken forward in the Berlin-Frankfurt-Münster study for newly diagnosed acute myeloid leukemia. The Study ITCC-020 was registered as EUDRA-CT 2009-009457-13; Dutch Trial Registry number 1880. CA extern

In the present study, we show that pharmacological repression by the Hedgehog (Hh) pathway inhibitor (HPI) GANT61 induces expression of the proapoptotic protein Noxa in TP53-mutated embryonal pediatric tumor cells driven by Hh signaling (i.e. rhabdomyosarcoma (RMS) and medulloblastoma (MB)). Similarly, genetic silencing of Gli1 by siRNA causes increased Noxa mRNA and protein levels, while overexpression of Gli1 results in decreased Noxa expression. Furthermore, TAp73 mRNA and protein levels are increased upon Gli1 knockdown, while Gli1 overexpression reduces TAp73 mRNA and protein levels. However, knockdown of TAp73 fails to block Noxa induction in GANT61-treated cells, suggesting that Noxa is not primarily regulated by TAp73. Interestingly, mRNA levels of the transcription factor EGR1 correlate with those of Noxa and TAp73. Silencing of EGR1 results in decreased Noxa and TAp73 mRNA levels, indicating that EGR1 is involved in regulating transcriptional activity of Noxa and TAp73. These findings suggest that Gli1 represses Noxa and TAp73, possibly via EGR1. These findings could be exploited for the treatment of Hh-driven tumors, e.g. for their sensitization to chemotherapeutic agents.

Undifferentiated solid tumors with small blue round cell histology and expression of CD99 mostly resemble Ewing sarcoma. However, they also may include other tumors such as mesenchymal chondrosarcoma, synovial sarcoma, or small cell osteosarcoma. Definitive classification usually requires detection of entity-specific mutations. While this approach identifies the majority of Ewing sarcomas, a subset of lesions remains unclassified and, therefore, has been termed "Ewing-like sarcomas" or small blue round cell tumors not otherwise specified. We developed an approach for further characterization of small blue round cell tumors not otherwise specified using an array-based DNA-methylation profiling approach. Data were analyzed by unsupervised clustering and t-distributed stochastic neighbor embedding analysis and compared with a reference methylation data set of 460 well-characterized prototypical sarcomas encompassing 18 subtypes. Verification was performed by additional FISH analyses, RNA sequencing from formalin-fixed paraffin-embedded material or immunohistochemical marker analyses. In a cohort of more than 1,000 tumors assumed to represent Ewing sarcomas, 30 failed to exhibit the typical EWS translocation. These tumors were subjected to methylation profiling and could be assigned to Ewing sarcoma in 14 (47%), to small blue round cell tumors with CIC alteration in 6 (20%), to small blue round cell tumors with BCOR alteration in 4 (13%), to synovial sarcoma and to malignant rhabdoid tumor in 2 cases each. One single case each was allotted to mesenchymal chondrosarcoma and adamantinoma. 12/14 tumors classified as Ewing sarcoma could be verified by demonstrating either a canonical EWS translocation evading initial testing, by identifying rare breakpoints or fusion partners. The methylation-based assignment of the remaining small blue round cell tumors not otherwise specified also could be verified by entity-specific molecular alterations in 13/16 cases. In conclusion, array-based DNA-methylation analysis of undifferentiated tumors with small blue round cell histology is a powerful tool for precisely classifying this diagnostically challenging tumor group.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. In 7% of the cases it is localized at the chest wall or intrathoracically. The aim of this study was to analyze the multimodal treatment concepts and outcomes of children suffering from intrathoracic and chest wall RMS treated within three different Cooperative Soft Tissue Sarcoma (CWS) trials and one registry (Soft Tissue Sarcoma Registry, SoTiSaR). Data of 51 patients with thoracic RMS enrolled in three different CWS trials (CWS-86, -91, -2002P) and one registry (SoTiSaR) were analyzed retrospectively. Surgery and its influence on outcome were assessed. Median follow-up was 37.5 months (0.9–152.5). Median age of the patients was 8.8 years (range 0–19 years). The 5-year overall survival rate (OS) was 57% (95%-CI 49–65) and the 5-year event–free survival rate (EFS) was 45% (38–52). Thirty-five patients had tumors located at the chest wall (EFS: 51%, 43–59), and 16 patients had intrathoracic tumors (EFS: 26%, 13–39). Seventeen patients with tumors ≤ 5 cm had a better outcome (EFS: 64%, 52–76) compared to patients with tumors larger than 5 cm (EFS: 36%, 27–45). Radiotherapy (RT) significantly improved the survival of patients with alveolar RMS compared to patients with embryonal histology (EFS: 66%, 52–80 vs. 32%, 21–43 p = 0.02). Complete tumor excision during delayed surgery was the main prognostic factor for survival (p = 0.045). Thoracic RMS is a rare tumor entity. Completeness of tumor resection significantly improved survival of the patients.

Zusammenfassung Hintergrund Fertilitätsprotektive Massnahmen vor gonadotoxischen Therapien spielen aufgrund steigender Überlebensraten bei Krebs- und Autoimmunerkrankungen im reproduktiven Alter eine zunehmende Rolle. Obwohl die Fertilität von Kindern und Jugendlichen durch gonadotoxische Therapien relevant eingeschränkt sein kann, wird die Möglichkeit fertilitätsprotektiver Massnahmen bisher zu wenig berücksichtigt. Methoden Selektive Literaturrecherche auf der Basis klinisch- wissenschaftlicher Erfahrung der Autoren und Darstellung der möglichen fertilitätsprotektiven Massnahmen inklusive deren Indikationen, Durchführung, Risiken und Wirksamkeit. Ergebnisse Indiziert sind die Massnahmen bei allen Mädchen und Jungen mit einem hohen Risiko einer Gonadenschädigung. Die Komplexität der Techniken erfordert eine besondere Expertise in der Beratung und Durchführung, die in Deutschland für Mädchen insbesondere in den Zentren des Netzwerks FertiPROTEKT (www.fertiprotekt.com) gegeben ist. Bei Mädchen kommt überwiegend die Kryokonservierung von Ovargewebe in Betracht. Bei postpubertären Mädchen ist auch die Kryokonservierung von Oozyten potenziell möglich. Bei postpubertären Knaben können Spermien konserviert werden. Das Einfrieren von Hodengewebe gilt v. a. bei präpubertären Knaben derzeit als experimentell. Die Erfolgsraten sind noch schwer zu beziffern, diskutiert werden Geburtenraten von ca. 50%. Die Krankenkassen erstatten diese Massnahmen nicht. Schlussfolgerung Auch bei Kindern und Jugendlichen sollten bei stark gonadotoxischen Therapien fertilitätsprotektive Massnahmen erwogen werden und eine entsprechende Beratung durch geschulte Ärzte erfolgen.

Alveolar rhabdomyosarcoma commonly arises in the extremities and is characterized by aggressive biology and high frequency of metastases. Whole-body imaging is increasingly employed in pediatric oncology but not recommended as standard in the staging of soft-tissue sarcomas. After observing patients with a large symptomatic alveolar rhabdomyosarcoma lesion and a smaller silent lesion in the more distal part of an extremity we sought to estimate the frequency of this constellation. We retrospectively evaluated the data of prospectively registered paediatric patients (age

Background: Children with high-risk 1st relapse B-ALL after frontline chemotherapy have a poor prognosis and are candidates for allogeneic hematopoietic stem cell transplant (alloHSCT) after achieving complete remission (CR). We previously reported that treatment with blinatumomab, a CD3/CD19-directed BiTE ® (bispecific T-cell engager) molecule, resulted in superior efficacy in event-free survival (EFS) and minimal residual disease (MRD) remission vs intensive multidrug chemotherapy as the 3rd consolidation block before alloHSCT in children with high-risk 1st relapse B-ALL in a phase 3 RCT (JAMA 2021;325:843-54).Here we provide FU of EFS, overall survival (OS), and safety as of Sep 2020, ie, beyond the July 2019 primary analysis. Methods: In this phase 3 RCT (Amgen NCT02393859), children >28 days and Results: Enrollment was terminated based on the interim analysis for benefit of blinatumomab (7/17/19 primary analysis). The following results reflect an updated analysis as of 9/14/20. Between Nov 2015-Aug 2019, 111 patients were randomized; 54 (49%) received blinatumomab and 57 (51%) received chemotherapy at 47 centers in 13 countries. Baseline characteristics were comparable in both arms (Table 1). After a median FU of 31 months, EFS was significantly superior with blinatumomab vs chemotherapy [63% vs 37%, stratified log-rank p CAR-T cell treatment after investigational therapy was reported for some patients; blinatumomab arm: 2/54 and chemotherapy arm: 9/57 patients (Table 2). Both blinatumomab arm patients had CD19+ disease after blinatumomab treatment, with OS of 22.1 and 12.8 months, and 1/2 alive at last FU. Of the 5 patients in the chemotherapy arm who later received blinatumomab, 3 had CD19+ disease after chemotherapy and 2 did not have CD19 expression data available; OS for these 5 patients ranged from 11.1-22.9 months with 2/5 alive at last FU. There were also 3 patients in the chemotherapy arm (but no exposure to blinatumomab) with CD19+ relapse who received CAR-T at relapse; OS for these patients ranged from 18.8-28.0 months and 2/3 were alive at last FU; a fourth patient with CD19-negative relapse who received chemotherapy only at relapse had OS of 24.8 months. Summary/Conclusion: In children with high-risk 1st relapse B-ALL, treatment with 1 cycle of blinatumomab vs chemotherapy before alloHSCT resulted in significantly superior EFS and improved OS. The incidence of CD19-negative relapse after blinatumomab was low. No evidence of a negative impact of blinatumomab followed by CAR-T cell therapy was noted in this small subset of patients. Figure 1 Figure 1. Disclosures Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Zugmaier: Amgen: Current Employment; Micromet/Amgen: Patents & Royalties: Patents 20190300609 and 20130323247 licensed; receives royalties of family members of international applications published as WO2010/052014; WO2010/052013; WO2011/051307; WO2012/055961; WO 2012/062596; WO2014/122251; and WO2015/181683; Amgen: Current equity holder in publicly-traded company. Rizzari: Sobi: Other: personal fees; Shire: Other: Grants and personal fees; Medac: Other: Grants and personal fees; Jazz Pharmaceuticals: Other: Personal fees; Amgen: Other: Personal fees. Morris: Amgen: Current Employment. Gruhn: AmgenGmbh: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel costs; Bellicum Pharma Gmbh: Membership on an entity's Board of Directors or advisory committees, Other: travel costs; EUSA Pharma Gmbh: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Other: travel costs; Novartis Pharma Inc.: Honoraria, Other: travel costs; pfizer: Honoraria; servier: Honoraria, Other: travel costs; Neovii Biotech GmbH: Other: travel costs; medac GmbH: Other: travel costs. Zeng: Amgen: Current Employment. Pilankar: Iqvia: Current Employment, Other: Iqvia provides support for Amgen. Kormany: Amgen: Current Employment. Moericke: Amgen: Other: Grants; Shire: Other: Personal fees. Peters: Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants. Saha: Amgen: Other: Personal fees. von Stackelberg: Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Miltenyi: Consultancy, Honoraria.

Background: To identify variables predicting outcome in neuroblastoma patients assigned to the high-risk group solely by the presence of MYCN oncogene amplification (MNA). Methods: Clinical characteristics, genomic information, and outcome of 190 patients solely assigned to high-risk neuroblastoma by MNA were analyzed and compared to 205 patients with stage 4 neuroblastoma aged ≥18 months with MNA (control group). Results: Event-free survival (EFS) and overall survival (OS) at 10 years were 47% (95%-CI 39–54%) and 56% (95%-CI 49–63%), respectively, which was significantly better than EFS and OS of the control group (EFS 25%, 95%-CI 18–31%, p &lt, 0.001, OS 32% 95%-CI 25–39%, p &lt, 0.001). The presence of RAS-/p53-pathway gene alterations was associated with impaired 10-year EFS and OS (19% vs. 55%, and 19% vs. 67%, respectively, both p &lt, 0.001). In time-dependent multivariable analyses, alterations of RAS-/p53-pathway genes and the extent of the best primary tumor resection were the only independent prognostic variables for OS (p &lt, 0.001 and p = 0.011, respectively). Conclusions: Neuroblastoma patients attributed to high risk solely by MYCN amplification have generally a more favorable outcome. Mutations of genes of the RAS and/or p53 pathways and incomplete resection are the main risk factors predicting poor outcome.

Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.

// Michael Merker 1 , Verena Pfirrmann 1 , Sarah Oelsner 1, 2 , Simone Fulda 3, 4, 5 , Thomas Klingebiel 1 , Winfried S. Wels 2 , Peter Bader 1 and Eva Rettinger 1 1 Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt, Germany 2 Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany 3 Institute for Experimental Cancer Research in Pediatrics, Goethe University, Frankfurt, Germany 4 German Cancer Consortium (DKTK), Heidelberg, Germany 5 German Cancer Research Center (DKFZ), Heidelberg, Germany Correspondence to: Michael Merker, email: michael.merker@kgu.de Keywords: soft tissue sarcoma, cell therapy, cytokine-induced killer cells, chimeric antigen receptor, pediatric cancer Received: April 04, 2017 Accepted: June 29, 2017 Published: August 02, 2017 ABSTRACT Pediatric patients with recurrent, refractory or advanced soft tissue sarcoma (STS) who are simultaneously showing signs of cumulative treatment toxicity are in need of novel therapies. In this preclinical analysis, we identified ErbB2 as a targetable antigen on STS cells and used cytokine-induced killer (CIK) cells transduced with the lentiviral 2 nd -generation chimeric antigen receptor (CAR) vector pS-5.28.z-IEW to target ErbB2-positive tumors. Solely CIK cell subsets with the CD3 + T cell phenotype showed up to 85% cell surface expression of the respective CAR. A comparison of wildtype (WT), mock-vector and ErbB2-CAR-CIK cells showed, that engineered cells exhibited diminished in vitro expansion, retained WT CIK cell phenotype with higher percentages of differentiated effector memory/effector cells. Activating natural killer (NK) cell receptor NKG2D-restricted target cell recognition and killing of WT and ErbB2-CAR-CIK cells was maintained against ErbB2-negative tumors, while ErbB2-CAR-CIK cells demonstrated significantly increased cytotoxicity against ErbB2-positive targets, including primary tumors. ErbB2-CAR- but not WT CIK cells proliferated, infiltrated and efficiently lysed tumor cell monolayers as well as 3D tumor spheroids. Here, we demonstrate a potential cell therapeutic approach using ErbB2-CAR-CIK cells for the recognition and elimination of tumor cells expressing ErbB2, which we identified as a targetable antigen on high-risk STS cells.

The prognosis in children with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia (T-ALL) or lymphoblastic lymphoma (T-LBL) is poor. Nelarabine (Ara-G) has successfully been used as salvage therapy in these children, but has been associated with significant, even fatal, neurotoxicities. We retrospectively analysed 52 patients with r/r T-ALL/T-LBL aged ≤19 years who were treated with Ara-G alone (n = 25) or in combination with cyclophosphamide and etoposide (n = 27). The majority of patients (45/52) received 1-2 cycles of Ara-G. Seventeen patients (32·7%) had refractory disease, 28 (53·8%) were in first relapse and 7 (13·5%) were in second relapse. A response to Ara-G was achieved in 20 patients and 15 (28·8%) were in remission at last follow-up. Twelve patients (23·1%) had neurotoxic adverse effects (neuro-AE) of any grade, of whom 7 (13·5%) developed neurotoxicity ≥ grade III. The most frequent neuro-AEs were peripheral motor neuropathy (19·2%), peripheral sensory neuropathy (11·5%) and seizures (9·6%). Three patients died of central neuro-AE after 1-2 cycles of combination therapy. Patients with neurotoxicity were significantly older (median 15·17 years) than those without (10·34 years, P = 0·017). No differences were observed between mono- and combination therapy concerning outcome and neuro-AE. The incidence of neuro-AE was not associated with concurrent intrathecal therapy or prior central nervous system irradiation.

Background and objectives This study aims at examining the potential survival benefits of primary versus secondary surgery in the management of children diagnosed with pleuropulmonary blastoma (PPB) type II/III. Patients and methods Disease characteristics, treatment, and survival of 29 children with localized PPB type II/III, treated in six prospective Cooperative Weichteilsarkom Studiengruppe (CWS) trials, were reviewed retrospectively. Results Five year event free survival (EFS) and overall survival (OS) of children treated according to CWS protocols was 72%. Patients with tumors ≤10 cm had a 5 year OS of 91% versus 57% in patients with tumors >10 cm (P = 0.025). Five year OS of patients with macroscopically incomplete upfront resections was 44% as opposed to 68% in patients with delayed/secondary microscopically or macroscopically complete resection after an initial biopsy (P = 0.476). Ten patients died of disease, one patient died of second malignancy. Tumor size and complete tumor resection at any time were significant prognostic factors (P = 0.025/0.003) for EFS. EFS for microscopically complete, microscopically incomplete, and macroscopically incomplete resection at any time was 91%, 90%, and 25%, respectively (P = 0.01). Conclusions Primary or secondary microscopically/macroscopically complete tumor resections in combination with chemotherapy correlates with long term survival in children with PPB. J. Surg. Oncol. 2017;115:164-172. © 2017 Wiley Periodicals, Inc.

Monitoring of minimal residual disease (MRD) or chimerism may help guide pre-emptive immunotherapy (IT) with a view to preventing relapse in childhood acute lymphoblastic leukemia (ALL) after transplantation. Patients with ALL who consecutively underwent transplantation in Frankfurt/Main, Germany between January 1, 2005 and July 1, 2014 were included in this retrospective study. Chimerism monitoring was performed in all, and MRD assessment was performed in 58 of 89 patients. IT was guided in 19 of 24 patients with mixed chimerism (MC) and MRD and by MRD only in another 4 patients with complete chimerism (CC). The 3-year probabilities of event-free survival (EFS) were .69 ± .06 for the cohort without IT and .69 ± .10 for IT patients. Incidences of relapse (CIR) and treatment-related mortality (CITRM) were equally distributed between both cohorts (without IT: 3-year CIR, .21 ± .05, 3-year CITRM, .10 ± .04; IT patients: 3-year CIR, .18 ± .09, 3-year CITRM .13 ± .07). Accordingly, 3-year EFS and 3-year CIR were similar in CC and MC patients with IT, whereas MC patients without IT experienced relapse. IT was neither associated with an enhanced immune recovery nor an increased risk for acute graft-versus-host disease. Relapse prevention by IT in patients at risk may lead to the same favorable outcome as found in CC and MRD-negative-patients. This underlines the importance of excellent MRD and chimerism monitoring after transplantation as the basis for IT to improve survival in childhood ALL.

AML SCT-BFM 2007 was the first hematopoietic stem cell transplantation (HCT) trial in Germany to comply with the European Clinical Trials Directive, and aimed to standardize pediatric HCT for acute myeloid leukemia (AML) across centers in Germany, Austria, and the Czech Republic. Children with high-risk features and a good early response achieving a complete first remission (CR-1) and those in CR-2 after a first relapse were stratified to receive HCT from a matched donor after myeloablative conditioning consisting of busulfan, cyclophosphamide, and melphalan. Four-year EFS and OS were 61 and 70%. Cumulative incidence of relapse (CIR) was 22%. TRM was 15% and correlated with age reaching 9% (SE 3%) in children younger than 12 years and 31% (SE 9%) in older children and adolescents. Children with poorly responding primary disease or relapse were allocated to receive early HCT after a cytoreductive regimen with fludarabine, amsacrine, and cytarabine, followed by reduced intensity conditioning and prophylactic donor lymphocyte infusions. Four-year EFS and OS were 49 and 53%. CIR was 38% and TRM 11%. For patients with primary poor response disease, early use of RIC HCT followed by prophylactic DLI can induce long-term remissions in more than 50% (EFS 46% (SE 9%)).