Clinical management of NUT carcinoma (NC) in Germany: Analysis of survival, therapy response, tumor markers and tumor genome sequencing in 35 adult patients.

NUT carcinomas (NC) are very rare and highly aggressive tumors, molecularly defined by an aberrant gene fusion involving the NUTM1 gene. NCs preferentially arise intrathoracically or in the head and neck region, having a highly adverse prognosis with almost no long-term survivors. Here, we report on a cohort of 35 adult NC patients who were evaluated at University Hospital Tuebingen in an eight year time span, i.e. between 2016 and 2023. Primary objectives were overall survival (OS) and influence of primary tumor locations, fusion gene types and staging on OS. Secondary objectives were patient baseline characteristics, risk factors, tumor markers, treatment decisions and responses to therapy comparing thoracic vs non-thoracic origins. Further, data from tumor genome sequencing were analyzed. In this monocentric German cohort, 54 % of patients had thoracic tumors and 65 % harbored a BRD4-NUTM1 fusion gene. Median OS was 7.5 months, being significantly dependent on primary tumor location and nodal status. Initial misdiagnosis was a problem in 31 % of the cases. Surgery was the first treatment in most patients (46 %) and 80 % were treated with polychemotherapies, showing longer progression free survival (PFS) with ifosfamide-based than with platinum-based regimens. Patients treated with an immune checkpoint inhibitor (ICI) in addition to first-line chemotherapy tended to have longer OS. Initial LDH levels could be identified as a prognostic measure for survival prognosis. Sequencing data highlight aberrant NUTM1 fusion genes as unique tumor driver genes. This is the largest adult European cohort of this orphan tumor disease, showing epidemiologic and molecular features as well as relevant clinical data. Awareness to prevent misdiagnosis, fast contact to a specialized nation-wide center and referral to clinical studies are essential as long-term survival is rarely achieved with any of the current therapeutic regimes.

Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3.

BACKGROUND: GD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors. METHODS: The German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed. RESULTS: We identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro, significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated. CONCLUSION: Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.

NUT carcinoma in pediatric patients: Characteristics, therapeutic regimens, and outcomes of 11 cases registered with the German Registry for Rare Pediatric Tumors (STEP).

BACKGROUND AND AIMS: Nuclear protein of the testis (NUT) carcinoma (NC) is a rare and highly aggressive tumor defined by the presence of a somatic NUTM1 rearrangement, occurring mainly in adolescents and young adults. We analyzed the clinical and biological features of German pediatric patients (≤18 years) with NC. METHODS: This study describes the characteristics and outcome of 11 children with NC registered in the German Registry for Rare Pediatric Tumors (STEP). RESULTS: Eleven patients with a median age of 13.2 years (range 6.6-17.8) were analyzed. Malignant misdiagnoses were made in three patients. Thoracic/mediastinal tumors were found to be the primary in six patients, head/neck in four cases; one patient had multifocal tumor with an unknown primary. All patients presented with regional lymph node involvement, eight patients (72.7%) with distant metastases. Seven patients underwent surgery, eight radiotherapy with curative intent; polychemotherapy was administered in all patients. Novel treatment strategies including immunotherapy, targeted therapies, and virotherapy were applied in three patients. Median event-free survival and overall survival were 1.5 and 6.5 months, respectively. CONCLUSIONS: Every undifferentiated or poorly differentiated carcinoma should undergo testing for the specific rearrangement of NUTM1, in order to initiate an intense therapeutic regimen as early as possible. As in adults, only few pediatric patients with NC achieve prolonged survival. Thus, novel therapeutic strategies should be included and tested in clinical trials.

Local MRI before and after Tumor Resection in Neuroblastoma: Impact of Residual Disease on Event Free Survival.

(1) Background: The study aimed to investigate the influence of MRI-defined residual disease on local tumor control after resection of neuroblastic tumors in patients without routine adjuvant radiotherapy. (2) Methods: Patients, who underwent tumor resection between 2009 and 2019 and received a pre- and postoperative MRI, were included in this retrospective single-center study. Measurement of residual disease (RD) was performed using standardized criteria. Primary endpoint was the local or combined (local and metastatic) event free survival (EFS). (3) Results: Forty-one patients (20 female) with median age of 39 months were analyzed. Risk group analysis showed eleven low-, eight intermediate-, and twenty-two high-risk patients (LR, IR, HR). RD was found in 16 cases by MRI. A local or combined relapse or progression was found in nine patients of whom eight patients had RD (p = 0.0004). From the six patients with local or combined relapse in the HR group, five had RD (p = 0.005). Only one of 25 patients without RD had a local event. Mean EFS (month) was significantly higher if MRI showed no residual tumor (81 ± 5 vs. 43 ± 9; p = 0.0014) for the total cohort and the HR subgroup (62 ± 7 vs. 31 ± 11; p = 0.016). (4) Conclusions: In our series, evidence of residual tumor, detectable by MRI, was associated with insufficient local control, resulting in relapses or local progression in 50% of patients. Only one of the patients without residual tumor had a local relapse.

Multimodal Therapy with Consolidating Haploidentical Stem Cell Transplantation and Dinutuximab Beta for Patients with High-Risk Neuroblastoma and Central Nervous System Relapse.

Despite highly intensive multimodality treatment regimens, the prognosis of patients with high-risk neuroblastoma (HRNB) and central nervous system (CNS) relapse remains poor. We retrospectively reviewed data from 13 patients with HRNB and CNS relapse who received multimodal therapy with consolidating haploidentical stem cell transplantation (haplo-SCT) followed by dinutuximab beta ± subcutaneous interleukin-2 (scIL-2). Following individual relapse treatment, patients aged 1-21 years underwent haplo-SCT with T/B-cell-depleted grafts followed by dinutuximab beta 20 mg/m2/day × 5 days for 5-6 cycles. If a response was demonstrated after cycle 5 or 6, patients received up to nine treatment cycles. After haplo-SCT, eight patients had a complete response, four had a partial response, and one had a stable disease. All 13 patients received ≥3 cycles of immunotherapy. At the end of the follow-up, 9/13 patients (66.7%) demonstrated complete response. As of July 2023, all nine patients remain disease-free, with a median follow-up time of 5.1 years since relapse. Estimated 5-year event-free and overall survival rates were 55.5% and 65.27%, respectively. Dinutuximab beta ± scIL-2 following haplo-SCT is a promising treatment option with a generally well-tolerated safety profile for patients with HRNB and CNS relapse.

Combined Metabolic and Functional Tumor Volumes on [18F]FDG-PET/MRI in Neuroblastoma Using Voxel-Wise Analysis.

PURPOSE: The purpose of our study was to evaluate the association between the [18F]FDG standard uptake value (SUV) and the apparent diffusion coefficient (ADC) in neuroblastoma (NB) by voxel-wise analysis. METHODS: From our prospective observational PET/MRI study, a subcohort of patients diagnosed with NB with both baseline imaging and post-chemotherapy imaging was further investigated. After registration and tumor segmentation, metabolic and functional tumor volumes were calculated from the ADC and SUV values using dedicated software allowing for voxel-wise analysis. Under the mean of thresholds, each voxel was assigned to one of three virtual tissue groups: highly vital (v) (low ADC and high SUV), possibly low vital (lv) (high ADC and low SUV), and equivocal (e) with high ADC and high SUV or low ADC and low SUV. Moreover, three clusters were generated from the total tumor volumes using the method of multiple Gaussian distributions. The Pearson's correlation coefficient between the ADC and the SUV was calculated for each group. RESULTS: Out of 43 PET/MRIs in 21 patients with NB, 16 MRIs in 8 patients met the inclusion criteria (PET/MRIs before and after chemotherapy). The proportion of tumor volumes were 26%, 36%, and 38% (v, lv, e) at baseline, 0.03%, 66%, and 34% after treatment in patients with response, and 42%, 25%, and 33% with progressive disease, respectively. In all clusters, the ADC and the SUV correlated negatively. In the cluster that corresponded to highly vital tissue, the ADC and the SUV showed a moderate negative correlation before treatment (R = -0.18; p < 0.0001) and the strongest negative correlation after treatment (R = -0.45; p < 0.0001). Interestingly, only patients with progression (n = 2) under therapy had a relevant part in this cluster post-treatment. CONCLUSION: Our results indicate that voxel-wise analysis of the ADC and the SUV is feasible and can quantify the different quality of tissue in neuroblastic tumors. Monitoring ADCs as well as SUV levels can quantify tumor dynamics during therapy.

Haploidentical hematopoietic stem cell transplantation as individual treatment option in pediatric patients with very high-risk sarcomas.

Background: Prognosis of children with primary disseminated or metastatic relapsed sarcomas remains dismal despite intensification of conventional therapies including high-dose chemotherapy. Since haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is effective in the treatment of hematological malignancies by mediating a graft versus leukemia effect, we evaluated this approach in pediatric sarcomas as well. Methods: Patients with bone Ewing sarcoma or soft tissue sarcoma who received haplo-HSCT as part of clinical trials using CD3+ or TCRα/ß+ and CD19+ depletion respectively were evaluated regarding feasibility of treatment and survival. Results: We identified 15 patients with primary disseminated disease and 14 with metastatic relapse who were transplanted from a haploidentical donor to improve prognosis. Three-year event-free survival (EFS) was 18,1% and predominantly determined by disease relapse. Survival depended on response to pre-transplant therapy (3y-EFS of patients in complete or very good partial response: 36,4%). However, no patient with metastatic relapse could be rescued. Conclusion: Haplo-HSCT for consolidation after conventional therapy seems to be of interest for some, but not for the majority of patients with high-risk pediatric sarcomas. Evaluation of its future use as basis for subsequent humoral or cellular immunotherapies is necessary.

Anti-GD2 Antibody Dinutuximab Beta and Low-Dose Interleukin 2 After Haploidentical Stem-Cell Transplantation in Patients With Relapsed Neuroblastoma: A Multicenter, Phase I/II Trial.

PURPOSE: Patients with relapsed high-risk neuroblastoma (rHR-NB) have a poor prognosis. We hypothesized that graft-versus-neuroblastoma effects could be elicited by transplantation of haploidentical stem cells (haplo-SCT) exploiting cytotoxic functions of natural killer cells and their activation by the anti-GD2 antibody dinutuximab beta (DB). This phase I/II trial assessed safety, feasibility, and outcomes of immunotherapy with DB plus subcutaneous interleukin-2 (scIL2) after haplo-SCT in patients with rHR-NB. METHODS: Patients age 1-21 years underwent T-/B-cell-depleted haplo-SCT followed by DB and scIL2. The primary end point 'success of treatment' encompassed patients receiving six cycles, being alive 180 days after end of trial treatment without progressive disease, unacceptable toxicity, acute graft-versus-host-disease (GvHD) ≥grade 3, or extensive chronic GvHD. RESULTS: Seventy patients were screened, and 68 were eligible for immunotherapy. Median number of DB cycles was 6 (range, 1-9). Median number of scIL2 cycles was 3 (1-6). The primary end point was met by 37 patients (54.4%). Median observation time was 7.8 years. Five-year event-free survival (EFS) and overall survival from start of trial treatment were 43% (95% CI, 31 to 55) and 53% (95% CI, 41 to 65), respectively. Five-year EFS among patients in complete remission (CR; 52%; 95% CI, 31 to 69) or partial remission (44%; 95% CI, 27 to 60) before immunotherapy were significantly better compared with patients with nonresponse/mixed response/progressive disease (13%; 95% CI, 1 to 42; P = .026). Overall response rate in 43 patients with evidence of disease after haplo-SCT was 51% (22 patients), with 15 achieving CR (35%). Two patients developed GvHD grade 2 and 3 each. No unexpected adverse events occurred. CONCLUSION: DB therapy after haplo-SCT in patients with rHR-NB is feasible, with low risk of inducing GvHD, and results in long-term remissions likely attributable to increased antineuroblastoma activity by donor-derived effector cells.

Rare and potentially fatal - Cytogenetically cryptic TNIP1::PDGFRB and PCM1::FGFR1 fusion leading to myeloid/lymphoid neoplasms with eosinophilia in children.

Myeloid/lymphoid neoplasms with eosinophilia (MLN-eos) are rare haematological neoplasms primarily affecting adults. The heterogeneous clinical picture and the rarity of the disease, especially in children, may delay an early diagnosis. MLN-eos are characterized by constitutive tyrosine kinase (TK) activity due to gene fusions. It is thus of importance to obtain a prompt genetic diagnosis to start a specific therapy. Here, we outline the clinical, genetic, and biochemical background of TK driven MLN-eos and report two extremely rare paediatric cases of MLN-eo, the used diagnostic methods, therapy and clinical outcomes. Our results demonstrate that, standard cytogenetic and molecular methods may not be sufficient to diagnose MLN-eo due to cytogenetically cryptic aberrations. We therefore recommend performing additional evaluation with fluorescence in-situ hybridization and molecular genetic methods (array-based comparative genomic hybridization and RNA sequencing) which will lead to the correct diagnosis. Following this diagnostic route we detected a TNIP1::PDGFRB and a PCM1::FGFR1 fusion in our patients. Thus, genetic diagnosis must be precise and quick in order to initiate adequate therapies with tyrosine kinase inhibitors or HSCT.

NUT Carcinoma in Children and Adolescents: The Expert European Standard Clinical Practice Harmonized Recommendations.

BACKGROUND AND AIMS: Nuclear protein of the testis ( NUT ) carcinoma (NC) is a rare and highly aggressive tumor mainly occurring in adolescents and young adults, defined by the presence of a somatic NUTM1 rearrangement. The aim is to establish internationally harmonized consensus recommendations for the diagnosis and treatment of adolescents and young adults with NC in the framework of the European Reference Network for Paediatric Oncology. METHODS: The European Cooperative Study Group for Pediatric Rare Tumors developed recommendations according to the Consensus Conference Standard Operating procedure methodology and reviewed by external "experts." No evidence of level I to II exists. Recommendations were developed based on published prospective (level III), but more frequently retrospective series (level IV), case reports (level V), and personal expertise (level V). In addition, "strength" of recommendations were categorized by grading (grade A to E). RESULTS: Histology is mandatory for the diagnosis of NC, including immunolabeling with anti-NUT antibodies and molecular biology ( NUTM1 rearrangement) (level V; grade A). Treatment of NC usually combines aggressive approaches in multimodal regimens. Chemotherapy should be considered as first-line treatment (neoadjuvant vincristine-adriamycin-ifosfamide/cisplatin-adriamycin-ifsofamide or vincristine-doxorubicin-cyclophosphamide/ifosfamide-etoposide) for unresectable or metastatic tumor (ie, 3 courses), rapidly followed by local treatment (level IV; grade B). Referral to a specialized surgical oncology center is highly recommended (level V; grade A). In localized NC, a complete microscopic surgical resection should be attempted whenever and as soon as possible, followed by primary irradiation (60 to 70 Gy) and involved lymph nodes area (level IV; grade B). For head and neck tumors, a systematic neck dissection might be considered, even if N0 (level V; grade C). Adjuvant postirradiation chemotherapy is recommended, for a total of 9 to 12 courses (level IV; grade B). For first-line resected tumors, concomitant adjuvant chemotherapy to radiotherapy may be discussed (level IV; grade B). Targeted therapies and immunotherapeutic regimens should be delivered in the setting of prospective trials (level V; grade B). CONCLUSIONS: This project leads to a consensus strategy based on international experience with this very rare disease.

Molecular Progression of Myeloproliferative and Myelodysplastic/Myeloproliferative Neoplasms: A Study on Sequential Bone Marrow Biopsies.

Myeloproliferative neoplasms (MPN) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) both harbor the potential to undergo myelodysplastic progression or acceleration and can transform into blast-phase MPN or MDS/MPN, a form of secondary acute myeloid leukemia (AML). Although the initiating transforming events are yet to be determined, current concepts suggest a stepwise acquisition of (additional) somatic mutations-apart from the initial driver mutations-that trigger disease evolution. In this study we molecularly analyzed paired bone marrow samples of MPN and MDS/MPN patients with known progression and compared them to a control cohort of patients with stable disease course. Cases with progression displayed from the very beginning a higher number of mutations compared to stable ones, of which mutations in five (ASXL1, DNMT3A, NRAS, SRSF2 and TP53) strongly correlated with progression and/or transformation, even if only one of these genes was mutated, and this particularly applied to MPN. TET2 mutations were found to have a higher allelic frequency than the putative driver mutation in three progressing cases ("TET2-first"), whereas two stable cases displayed a TET2-positive subclone ("TET2-second"), supporting the hypothesis that not only the sum of mutations but also their order of appearance matters in the course of disease. Our data emphasize the importance of genetic testing in MPN and MDS/MPN patients in terms of risk stratification and identification of imminent disease progression.

Immunomonitoring of Stage IV Relapsed Neuroblastoma Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation and Subsequent GD2 (ch14.18/CHO) Antibody Treatment.

Haploidentical stem cell transplantation (haplo SCT) in Stage IV neuroblastoma relapsed patients has been proven efficacious, while immunotherapy utilizing the anti-GD2 antibody dinutuximab beta has become a standard treatment for neuroblastoma. The combinatorial therapy of haplo SCT and dinutuximab may potentiate the efficacy of the immunotherapy. To gain further understanding of the synergistic effects, functional immunomonitoring was assessed during the clinical trial CH14.18 1021 Antibody and IL2 After haplo SCT in Children with Relapsed Neuroblastoma (NCT02258815). Rapid immune reconstitution of the lymphoid compartment was confirmed, with clinically relevant dinutuximab serum levels found in all patients over the course of treatment. Only one patient developed human anti-chimeric antibodies (HACAs). In-patient monitoring revealed highly functional NK cell posttransplant capable of antibody-dependent cellular cytotoxicity (ADCC). Degranulation of NK cell subsets revealed a significant response increased by dinutuximab. This was irrespective of the KIR receptor-ligand constellation within the NK subsets, defined by the major KIR receptors CD158a, CD158b, and CD158e. Moreover, complement-dependent cytotoxicity (CDC) was shown to be an extremely potent effector-cell independent mechanism of tumor cell lysis, with a clear positive correlation to GD2 expression on the cancer cells as well as to the dinutuximab concentrations. The ex vivo testing of patient-derived effector cells and the sera collected during dinutuximab therapy demonstrated both high functionality of the newly established lymphoid immune compartment and provided confidence that the antibody dosing regimen was sufficient over the duration of the dinutuximab therapy (up to nine cycles in a 9-month period). During the course of the dinutuximab therapy, proinflammatory cytokines and markers (sIL2R, TNFa, IL6, and C reactive protein) were significantly elevated indicating a strong anti-GD2 immune response. No impact of FcGR polymorphism on event-free and overall survival was found. Collectively, this study has shown that in-patient functional immunomonitoring is feasible and valuable in contributing to the understanding of anti-cancer combinatorial treatments such as haplo SCT and antibody immunotherapy.

Primary lung carcinoma in children and adolescents - Clinical characteristics and outcome of 12 cases from the German registry for rare paediatric tumours (STEP).

OBJECTIVES: Primary lung carcinomas are very rare paediatric tumours with an incidence of < 2/1.000.000 per year. They are clinically and histologically heterogeneous, and there are no therapeutic guidelines for this age group. Therefore, they represent a challenge for treating physicians. This analysis was performed to expand knowledge on characteristics, treatment and prognosis of primary lung carcinoma in paediatric patients. MATERIAL AND METHODS: Between 2009 and 2019, twelve children and adolescents with lung carcinoma were identified in the prospective German registry for rare paediatric tumours (STEP). Data were analysed for histopathological entities, symptoms, diagnostics, therapy, clinical course and outcome. RESULTS: Mucoepidermoid carcinoma (MEC) was the most frequent entity (n = 7), followed by adenocarcinoma (n = 2), squamous cell carcinoma (SCC; n = 2) and adenosquamous carcinoma (n = 1). Patients presented with non-specific symptoms and often, they were initially mistreated for airway infections. Patients with MEC showed no metastases and were successfully treated with complete resection. Patients with adenocarcinoma and SCC were older than 16 years of age at diagnosis. While patients with SCC presented with distant metastases and died within one year after diagnosis, those with adenocarcinoma and adenosquamous carcinoma achieved complete remission after multimodal treatment. CONCLUSIONS: Presenting symptoms of lung carcinomas are unspecific and therefore, diagnostic evaluation and treatment are difficult. In the absence of carcinogen exposure, etiology seems to differ from adult lung carcinoma. Children diagnosed with MEC face a favourable outcome. In contrast, patients with prognostically unfavourable adenocarcinoma and SCC might benefit from molecular profiling and targeted therapies. International collaboration for the establishment of treatment protocols adjusted for distinct features of primary lung carcinoma in childhood is essential.

123Iodine-metaiodobenzylguanidine scintigraphy versus whole-body magnetic resonance imaging with diffusion-weighted imaging in children with high-risk neuroblastoma - pilot study.

BACKGROUND: The prognostic value of the International Society of Paediatric Oncology European Neuroblastoma Research Network (SIOPEN) skeletal score using 123iodine-metaiodobenzylguanidine (MIBG) has been confirmed for people with high-risk neuroblastoma. Whole-body MRI with diffusion-weighted imaging is used increasingly. OBJECTIVE: To compare the original SIOPEN score and its adaption by diffusion-weighted imaging in high-risk stage 4 neuroblastoma and to evaluate any consequences of score differences on overall survival. MATERIALS AND METHODS: This retrospective observational study included pediatric patients who underwent MIBG scintigraphy and whole-body MRI, including diffusion-weighted imaging, between 2010 and 2015. Semi-quantitative skeletal scores for each exam were calculated independently. A difference of two or more points was defined as clinically relevant and counted as M+ (more in diffusion-weighted imaging) or S+ (more in MIBG). In cases of a negative result in one of the studies, residual disease of 1 point was also rated as relevant. We tested correlation and differences on an exam basis and also grouped by different therapeutic conditions. Overall survival was used to evaluate prognostic relevance. RESULTS: Seventeen children with 25 paired examinations were evaluated. Median MIBG scintigraphy score was 0 (interquartile range [IQR] 0-4, range 0-25) vs. a median whole-body MRI score of 1 (IQR 0-5.5, range 0-35) (P=0.018). A relevant difference between whole-body MRI and MIBG scintigraphy was noted in 14 of the 25 paired examinations (M+: n=9; S+: n=5). After treatment, the median survival of cases with M+ was 14 months (IQR 4-59, range 1-74 months), while S+ cases showed a median survival of 49 months (IQR 36-52, range 36-52 months) (P=0.413). CONCLUSION: The SIOPEN scoring system is feasible for whole-body MRI but might result in slightly higher scores, probably because of MRI's superior spatial resolution. Further studies are necessary to validate any impact on prognosis.

Antiemetic Prophylaxis with Fosaprepitant and 5-HT3-Receptor Antagonists in Pediatric Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation.

BACKGROUND: High-dose myeloablative conditioning prior to autologous hematopoietic stem cell transplantation (autoHSCT) in pediatric patients is usually highly emetogenic. The antiemetic neurokinin-1 receptor antagonist fosaprepitant was safe and effective in children receiving highly emetogenic chemotherapy. Data on fosaprepitant during autoHSCT in children are currently not available. METHODS: A total of 35 consecutive pediatric patients, who received an antiemetic prophylaxis with fosaprepitant (4 mg/kg; single dose, max. 1 x 150 mg/kg BW) and ondansetron (24-hours continuous infusion; 8-32 mg/24h) or granisetron (2 x 40 µg/kg∙d-1) during highly emetogenic conditioning chemotherapy before autoHSCT were retrospectively analyzed, and their results were compared with a control group comprising 35 consecutive pediatric patients, who received granisetron or ondansetron only. The antiemetic efficacy and the safety of the two prophylaxis regimens were compared with respect to three time periods after the first chemotherapy administration (0-24h, >24-120h, >120-240h). RESULTS: Clinical adverse events and clinically relevant increases/decreases of laboratory markers were similarly low and did not significantly differ between the two study groups (p>0.05). The registered number of vomiting events was significantly higher in the control group in the time periods of 0-24h (64 vs 22 events; p<0.01), >24-120h (135 vs 78 events; p<0.0001), >120-240h (268 vs 105 events; p<0.0001), and the whole observation period 0-240h (467 vs 205 events; p<0.0001). The percentage of patients experiencing vomiting was higher in the control group during the time period of >24-120h (100% vs 74.3%) but not the other analyzed time periods (p>0.05). CONCLUSION: The fosaprepitant-based antiemetic prophylaxis was safe, well tolerated and significantly reduced vomiting in children undergoing highly emetogenic chemotherapy prior to autoHSCT. Prospective randomized trials are necessary to confirm these results.

Antiemetic prophylaxis with fosaprepitant and granisetron in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is a severe and distressing complication during allogeneic hematopoietic stem cell transplantation (alloHSCT). The antiemetic fosaprepitant has shown favorable results in pediatric and adult patients receiving chemotherapy. Data on fosaprepitant in children and adolescents undergoing alloHSCT are missing. METHODS: In this non-interventional observation study, 120 children and adolescents with a median age of 11.8 years undergoing alloHSCT after a moderately or highly emetogenic conditioning (MEC or HEC) were analyzed. They received an antiemetic prophylaxis with granisetron (2 × 40 µg/kg d-1) with or without fosaprepitant (4 mg/kg; single dose, max. 1 × 150 mg/kg BW), and were analyzed in the control (CG; n = 60) or fosaprepitant group (FG; n = 60). The efficacy and safety of the two antiemetic prophylaxis regimens were analyzed and compared with respect to the acute (0-24 h) and the delayed (> 24-120 h) CINV phase and > 120-240 h after MEC or HEC administration. RESULTS: During MEC, significantly more patients in the CG experienced vomiting during the first 0-24 h (58.6 vs. 25.0%; p = 0.0156) and during > 24-120 h (93.1% vs. 57.1%; p = 0.0020), compared with the FG. Likewise, significantly more vomiting events (269 vs. 136; p < 0.0001) were registered in the CG. During HEC, significantly more patients in the CG experienced vomiting during the first 0-24 h (32.3 vs. 9.4%; p = 0.0319) compared with the FG. Significantly more vomiting events (241 vs. 99; p < 0.0001) were registered in the CG. Laboratory and clinical adverse events were not significantly different between the two groups (p > 0.05). CONCLUSIONS: Antiemetic prophylaxis with fosaprepitant and granisetron was well tolerated, safe, and effective in pediatric patients undergoing alloHSCT. However, larger prospective trials are necessary to evaluate these findings.