Paul G Schlegel’s research while affiliated with University of Wuerzburg and other places

Therapeutic options of advanced pediatric adrenocortical carcinoma (pACC) are limited, and achieving valuable risk stratification remains challenging. We refined the value of prognostic factors, with an emphasis on resection status. Retrospective, international data from 106 patients with advanced pACC from various collaborating centers of the international pACC working groups ENSAT-PACT, IC-PACT, and/ or from individual international collaboration diagnosed were collected. 106 patients aged 0.1 to 18.1 (median 7.6) years were diagnosed with pACC with 42 tumor stage III and 64 stage IV, respectively. 80% (85/106) of the tumors were hormone-producing with a mean Ki67 index for both stage groups of 29%. Patient survival was 45% (48/106) with mean follow-up of 17.7 months. Higher age, tumor stage IV, and increased Ki67 index worsened the prognosis on overall survival. Resection status had an essential impact on survival as the patients with R0 resection (n=32) had a better overall survival (71% for stage III patients; 80% for stage IV patients) than patients with R1 (n=24) (45% for stage III; 69% for stage IV), R2 (n=33) (17% for stage III; 15% for stage IV), and Rx (n=7) (0% for stage III; 17% for stage IV). Of the 10 patients with tumor spillage only few (57% of stage III; 0% of stage IV patients) survived. The resection status has an significant impact on overall survival in pACC. Therefore, tumor surgery should only be undertaken by experienced surgeons proficient in adrenalectomy and oncology, ideally within specialized pediatric oncological centers with an multi-disciplinary team setting.

Inflammation-based scores have been demonstrated to be independent prognostic factors in predicting outcomes in adult ACC. We aimed to investigate the prognostic role of these scores in pACC patients. An international, multicenter analysis was conducted on a pediatric cohort from 21 ACC centers. Pretreatment inflammation-based scoring parameters, including neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and serum albumin, as well as clinical parameters, were analyzed. Primary endpoint was 10-year overall survival (OS). 129 pediatric patients (50.4% females, mean age 87 months) across all tumor stages with a median follow-up of 36 months were included. 107/108 patients underwent primary surgery and 62/106 received systemic treatment at the time of diagnosis. Of 102 patients, 27 died from disease. In the univariable analysis, NLR ≥ 5 (HR 8.0, 95% CI 3.4-19.1), MLR ≥ 0.28 (HR 4.2, 95% CI 1.7-10.4), PLR ≥ 190 (HR 4.5, 95% CI 2.0-10.4), and dNLR ≥ 1.44 (HR 5.9, 95% CI 2.3-15.5), as well as clinical parameters age ≥ 4 years (HR 5.5; 95% CI 1.9-15.8), tumor stage IV (HR 5.7, 95% CI 2.7-11.9), and incomplete resection status (HR 8.0, 95% CI 3.6-17.7) were significantly associated with reduced 10-year OS. After multivariable adjustment only tumor stage IV (HR 336.7, 95% CI = 5.8-19518.1) and MLR ≥ 0.28 (HR 247.1, 95% CI=3.1-19907.5) were significantly associated with an unfavorable outcome. Inflammation-based scores tend to have prognostic value in pACC and could serve as prognostic tools after further validation in future studies with sufficient case number.

Background: CAR-T cell treatment became standard therapy for relapsed or refractory hematologic malignancies, such as non-hodgkins lymphoma and multiple myeloma. Owing to the rapidly progressing field of CAR-T cell therapy and the lack of generally accepted treatment guidelines, we hypothesized significant differences between centers in prevention, diagnosis and management of short- and long-term complications. Methods: To capture the current CAR-T cell management among German centers to determine the medical need and specific areas for future clinical research the DAG-HSZT (Deutsche Arbeitsgemeinschaft für Hämatopoetische Stammzelltransplantation und Zelluläre Therapie ; German Working Group for Hematopoietic Stem Cell Transplantation and Cellular Therapy) performed a survey among 26 German CAR-T cell centers. Results: We received answers from 17 centers (65%). The survey documents the relevance of evidence in the CAR-T cell field with a homogeneity of practice in areas with existing clinical evidence. In contrast, in areas with no – or low quality - clinical evidence, we identified significant variety in management in between the centers: management of cytokine release syndrome (CRS), immune effector cell related neurotoxicity syndrome (ICANS), IgG substitution, autologous stem cell back-up’s, anti-infective prophylaxis and vaccinations. Conclusion: The results indicate the urgent need for better harmonization of supportive care in CAR-T cell therapies including clinical research to improve clinical outcome.

BACKGROUND Success of allogeneic hematopoietic cell transplantation (alloHCT) is sharped by alloreactivity, i.e. the ability of donor T-cells to recognize particular recipient motifs as non-self and get activated. Donor T-cells recognizing recipient tissue can cause harmful graft-versus-host disease (GvHD) while activity against leukemic blasts can protect against relapse (GvL). In HLA-matched alloHCT, alloreacticity is driven by subtle nonpathogenic variants in natural proteins, socalled minor histocompatibility antigens (miHAgs), however, not all variants are immunogenic. METHODS To analyze the impact of mHAgs-differences on alloHCT outcomes, we selected a purely pediatric cohort of 102 HLA-matched allo HCTs transplanted between 2003 and 2017. Panel sequencing of 46 validated miHAgs was performed using Ilumina MiSeq, only variants in the graft-versus-host direction were considered. RESULTS In a logistic regression model for the whole cohort acute GvHD incidence was significantly dependent on the proportion of miHAg mismatches (all genes) with an 95%-CI 1.0263-1.1998, p=.01 and an odds ratio of 1.1066. From all variants tested, only mismatches in TRIM42 were significant as a predictor with a FDR <.05. Furthermore, proportion of mismatches was a predictor of all-cause mortality. Risk of relapse was evaluated by regression analysis for competing risks: proportion of miHAg mismatches failed to be predictive for relapse ( p=.37). However, looking at patients with acute lymphobastic leukemia (ALL) only (n=36), mismatches in hematopoiesis-restricted genes protected from relapse (95%-CI 1.0016-1.0712, p=.04, hazard ratio 1.0358). CONCLUSION Thus, in children GvHD and mortality seem to be related to the overall number of miHAg-differences whereas variants in hematopoiesis-restriced genes protect from ALL relapse. These data implicate that selection of TCRs with a specificity for hematopoietic miHAgs could be a way to improve GvL effect without increasing the risk of GvhD.

Introduction: CAR-T cell treatment became standard therapy for relapsed or refractory hematologic malignancies, such as lymphoma and multiple myeloma. Owing to the rapidly progressing field of CAR-T cell therapy and the lack of generally accepted treatment guidelines, we hypothesized that there are significant differences between centers in prevention, diagnosis and management of short- and long-term complications. Our aim was to capture the current CAR-T cell management among German centers to determine the medical need and specific areas for future clinical research. Methods: The DAG-HSZT (Deutsche Arbeitsgemeinschaft für Hämatopoetische Stammzelltransplantation und Zelluläre Therapie) performed a survey among 26 German CAR-T cell centers to document the management of CAR-T cell therapy. We designed questions as well as answer choices (O.P. and D.W) and discussed / edited them together with the co-authors P.D., M.S, W.B.. The DAG-HSZT (Deutsche Arbeitsgemeinschaft für Hämatopoetische Stammzelltransplantation und Zelluläre Therapie e. V.; German Working Group for Hematopoietic Stem Cell Transplantation and Cellular Therapy) then designed an online survey and distributed the survey among the PIs from all 26 German CAR-T cell centers. Results: We received answers from 17 centers (65%). The survey impressively documents the relevance of evidence in the CAR-T cell field. We found a large homogeneity of practice in areas with existing clinical evidence. In contrast, in areas with no – or low quality clinical evidence – we observed significant variety in management in between the centers: CAR-T cell logistics, management of cytokine release syndrome (CRS), immune effector cell related neurotoxicity syndrome (ICANS), IgG substitution, autologous stem cell back-ups, anti-infective prophylaxis, and vaccinations. Conclusions: We have identified a better harmonization of supportive care in CAR-T cell therapies as a medical need to be addressed in future clinical research bearing the potential to improve clinical outcome.

Histopathological differentiation in pediatric adrenocortical carcinoma (pACC) is difficult and clinical prediction and stratification scores are not evaluated yet. Therefore, this review aims to summarize current evidence on the value and accuracy of the two commonly used scoring systems (Weiss/AFIP) pACC. On this base, one might be able to evaluate if patients may benefit from a unique scoring system. For this we performed a systematic review of the published literature and included 128 patients in our analysis. The majority (72%) of the pACCs had a good clinical course. The follow up time ranged from 0-420 months with a mean age of 5.6 years at diagnosis. Patients with a good clinical course were younger (mean 4.8y) than patients with a poor outcome (mean 7.6y). Comparing the two scoring systems, the specificity of the Weiss score was very low (25%), whereas the sensitivity was 100%. According to the AFIP score, specificity (77%) was higher than Weiss score, whereas the sensitivity of the AFIP score was minimal lower with 92%. Age differences were recognizable as the specificity was lower in infants <4y (20%) than in older children (32%). In contrast, the specificity of the AFIP score was higher in infants <4 y (82%) than in older age groups (76%). Summarizing our results we could show, that the Weiss score is not a suitable tool for the prediction of malignancy in pACC in comparison with the AFIP score, but further efforts may seek to ensure early and accurate stratification through augmented scoring.

Hematopoietic stem cell transplantation (HSCT) from haploidentical donors is a viable option for patients lacking HLA-matched donors. Here we report the results of a prospective multicenter phase I/II trial of transplantation of TCRαβ and CD19-depleted peripheral blood stem cells from haploidentical family donors after a reduced-intensity conditioning with fludarabine, thiotepa, and melphalan. Thirty pediatric and 30 adult patients with acute leukemia ( n = 43), myelodysplastic or myeloproliferative syndrome ( n = 6), multiple myeloma ( n = 1), solid tumors ( n = 6), and non-malignant disorders ( n = 4) were enrolled. TCR αβ/CD19-depleted grafts prepared decentrally at six manufacturing sites contained a median of 12.1 × 10 ⁶ CD34 ⁺ cells/kg and 14.2 × 10 ³ TCRαβ ⁺ T-cells/kg. None of the patients developed grade lll/IV acute graft-versus-host disease (GVHD) and only six patients (10%) had grade II acute GVHD. With a median follow-up of 733 days 36/60 patients are alive. The cumulative incidence of non-relapse mortality at day 100, 1 and 2 years after HSCT was 5%, 15%, and 17% for all patients, respectively. Estimated probabilities of overall and disease-free survival at 2 years were 63% and 50%, respectively. Based on these promising results in a high-risk patient cohort, haploidentical HSCT using TCRαβ/CD19-depleted grafts represents a viable treatment option.