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The purpose of this study was to identify key deficiencies in pediatric oncology early phase clinical trial protocols in Germany and to provide guidance for efficient trial protocol development. A systematic review of the response letters of German competent authorities (CAs) and Ethics Committees to phase I/II pediatric oncology trial submissions in the period from 2014 to 2019 was performed. Documents were requested from all five Society for Paediatric Oncology and Haematology in Germany (GPOH) phase I/II trial networks plus all nine German Innovative Therapies for Children with Consortium Cancer (ITCC) centers. A blinded dataset containing aggregated data from 33 studies was analyzed for validation. All deficiencies were reviewed, listed, and weighted using a structured matrix according to frequency, category, significance, and feasibility. In total, documents of 17 trials from 6 different sites were collected. Two hundred fifty deficiencies identified by the CAs were identified and categorized into eight categories. "Toxicity and safety" was the most prominent category (27.6%), followed by "Manufacturing and Import" (18%). The majority of deficiencies were categorized as minor and potential measures as easy to address, but an important group of major and difficult to implement deficiencies was also identified. The blinded validation dataset confirmed these findings. The majority of the EC deficiencies could be resolved by changing the wording in the patient‐facing documents. In conclusion, this study was able to detect a pattern of key deficiencies. Most of the shortcomings can be anticipated by minor changes in the protocol and increased awareness can prevent time‐consuming revisions, withdrawals, or even rejections. A corresponding guideline describing key regulatory aspects is provided. [ABSTRACT FROM AUTHOR]

Summary: Background: Epidemiology and management practices of invasive fungal diseases (IFD) after allogeneic haematopoietic stem cell transplantation (HSCT) are a subject of constant change. We investigated the contemporary incidence, diagnostics, antifungal management and outcome at a major paediatric transplant centre in Germany. Methods: The single‐centre retrospective observational study included all paediatric allogeneic HSCT patients (pts) transplanted between 2005 and 2015. Patient‐related data were assessed up to 365 days post‐transplant. The primary endpoint was the incidence of possible, probable and proven IFDs. Secondary endpoints included diagnostics and antifungal treatment; analysis of risk factors; and overall survival with the last follow‐up in January 2017. Results: A total of 221 first (196), second (21) or third (4) procedures were performed in 200 pts (median age: 9 years, range, 0.5‐22) for leukaemia/lymphoma (149) and non‐malignant disorders (72). Prophylaxis was administered in 208 HSCT procedures (94%; fluconazole, 116, mould‐active agents, 92). At least one computed tomography scan of the chest was performed in 146, and at least one galactomannan antigen assay in 60 procedures. There were 15 cases of proven (candidemia, 4; aspergillosis, 4) or probable (aspergillosis, 7) IFDs, accounting for an incidence rate of 6.8%. Overall mortality at last follow‐up was 30%; the occurrence of proven/probable IFDs was associated with a reduced survival probability (P <.001). Conclusion: Morbidity and mortality from IFDs at our institution were consistent with data reported from other centres. Utilisation of healthcare resources for prevention, diagnosis and management of IFDs was considerable. [ABSTRACT FROM AUTHOR]

This trial explored the efficacy of re-induction chemotherapy including bortezomib in paediatric relapsed/refractory acute lymphoblastic leukaemia. Patients were randomized 1:1 to bortezomib (1.3 mg/m2/dose) administered early or late to a dexamethasone and vincristine backbone. Both groups did not differ regarding peripheral blast count on day 8, the primary endpoint. After cycle 1, 8 of 25 (32%) patients achieved complete remission with incomplete blood count recovery, 7 (28%) a partial remission and 10 had treatment failure. Most common grade 3-4 toxicities were febrile neutropenia (31%) and pain (17%). Bortezomib was safely combined with vincristine. Bortezomib rarely penetrated the cerebrospinal fluid. [ABSTRACT FROM AUTHOR]

Cytomegalovirus retinitis (CMVR) may occur after allogeneic hematopoietic stem cell transplantation (HSCT). However, little is known about its incidence, strategies for ophthalmic surveillance, and timely implementation of adequate antiviral treatment in pediatric allogeneic HSCT recipients. We provide a retrospective analysis of the epidemiology and clinical features of CMVR in pediatric allogeneic HSCT patients transplanted at our center over a 16‐year period. Two patients of this cohort with leukemia are presented. Our analysis is supplemented by a systematic review on pediatric patients with leukemia and CMVR in the setting of allogeneic HSCT. The overall incidence of CMVR in our cohort was 1% (4/338) and 14.2% (3/21) in leukemic patients. In published cases, CMVR occurred at a median of 143 days after transplantation, and, in the majority of patients, was preceded by CMV detection in blood by a median of 93 days. Continued immune suppression following engraftment likely triggers CMVR. Preemptive treatment with ganciclovir as standard is usually successful. Foscarnet is used in case of resistance to ganciclovir or drug‐induced granulocytopenia. Overall, CMVR after HSCT in pediatric leukemic patients is rare, but a potentially higher vulnerability of this population for involvement of the eye warrants a standardized ophthalmological examination plan. [ABSTRACT FROM AUTHOR]