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Background: Chemotherapy-induced nausea and vomiting (CINV) are a major burden for patients undergoing emetogenic chemotherapy. International guidelines recommend an antiemetic prophylaxis with corticosteroids, 5-HT 3 R-antagonists and NK 1 R-antagonists. The NK 1 R-antagonist fosaprepitant has shown favorable results in pediatric and adult patients. There is little pediatric experience with fosaprepitant. Methods: This non-interventional observation study analyzed 303 chemotherapy courses administered to 83 pediatric patients with a median age of 9 years (2-17 years), who received antiemetic prophylaxis either with fosaprepitant and granisetron with or without dexamethasone (fosaprepitant group/FG; n=41), or granisetron with or without dexamethasone (control group/CG; n=42), during moderately (CINV risk 30-90%) or highly (CINV risk>90%) emetogenic chemotherapy. The two groups' results were compared with respect to the safety and efficacy of the antiemetic prophylaxis during the acute (0-24hrs after chemotherapy), delayed (>24-120hrs after chemotherapy) and both CINV phases. Laboratory and clinical adverse events were compared between the two cohorts. Results: Adverse events were not significantly different in the two groups (p>0.05). Significantly fewer vomiting events occurred during antiemetic prophylaxis with fosaprepitant in the acute (23 vs 142 events; p<0.0001) and the delayed (71 vs 255 events; p<0.0001) CINV phase. In the control group, the percentage of chemotherapy courses with vomiting was significantly higher during the acute (24%/FG vs 45%/CG; p<0.0001) and delayed CINV phase (28%/FG vs 47%/CG; p=0.0004). Dimenhydrinate (rescue medication) was administered significantly more often in the CG, compared to the FG (114/FG vs 320/CG doses; p<0.0001). Likewise, in the control group, dimenhydrinate was administered in significantly more (p<0.0001) chemotherapy courses during the acute and delayed CINV phases (79 of 150; 52.7%), compared to the fosaprepitant group (45 of 153; 29.4%). Conclusion: Antiemetic prophylaxis with fosaprepitant and granisetron with or without dexamethasone was well tolerated, safe and effective in pediatric patients. However, larger prospective trials are needed to evaluate these findings.

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1. Background Chemotherapy-induced nausea and vomiting (CINV) is a feared and burdensome complication after emetogenic chemotherapy (EC), especially in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Antiemetic prophylaxis (AEP) is thus a substantial factor in the transplantation management. Guidelines recommend a comprehensive AEP with NK1R-antagonists (neurokinin-1 receptor), 5-HT3R-antagonists (5-hydroxytryptamine-3 receptor), and corticosteroids. The water-soluble aprepitant derivative fosaprepitant (NK1R-antagonist) was shown to be highly effective in adult patients with moderately to highly EC when combined with granisetron (5-HT3R-antagonist). There is very little experience with fosaprepitant in pediatric patients. 2. Patients and Methods In this single-center retrospective study, 80 pediatric patients during allogeneic HSCT who received AEP either with intravenous fosaprepitant and granisetron (fosaprepitant group; FG) or a standard prophylaxis regimen with granisetron two times per day(historical control group; CG) were analyzed for safety and efficacy of the prophylaxis regimen. Efficacy of the two AEP regimen was evaluated comparing the vomiting frequency, percentages of patients vomiting and the need for rescue medication (dimenhydrinate) during the acute (<24h) and the delayed (24-120h) CINV phase in both groups. Safety was evaluated comparing drug-related clinical and laboratory-chemical side-effects (exanthema, gastrointestinal symptoms, sweating, liver and kidney parameters, and electrolytes). Exclusion criteria were vomiting or receiving antiemetic medication within 48 hours before the start of antiemetic prophylaxis. 3. Results A total of 80 pediatric patients with a median age of 9 years (range 2-17 years) who underwent allogeneic HSCT between 2015 and 2018 were consecutively enrolled and analyzed. Patients were transplanted for the treatment of acute leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), ALL-relapse, AML-relapse; total: 36.5% of the patients), myelodysplastic syndromes (4.8% of the patients) solid tumors and lymphoma (neuroblastoma, brain tumor, non-Hodgkin's lymphoma, Hodgkin's lymphoma; 44.9% of the patients), and non-malignant hematopoietic diseases (thalassemia major, sickle cell anemia; 13.8% of the patients). The patients received allogeneic grafts from matched unrelated donors (48.4%), matched family donors (16.2%) and mismatched family donors (35.5%). Distribution of the patient characteristics was not significantly different in both study groups (p>0.05). The patients of the FG (n=40; HSCT between 2017 and 2018) received a single dose of fosaprepitant (3.5-4 mg per kg bodyweight (mg/kg); maximum 150 mg; intravenous (IV) infusion) directly before starting the myeloablative conditioning and as PRN (pro re nata) medication every five days after HSCT (same dosage; IV infusion), as well as granisetron (2x20 µg/kg per day; starting on the first day of the conditioning; max. 3 mg; IV infusion <30 min.). The patients of the historical CG (n=40; patients transplanted between 2013 and 2014) received granisetron only at the same dosages. Discontinuation of the antiemetic medication was not necessary for any of the patients (CG and FG). Clinical side-effects and laboratory-chemical changes were not significantly different in both study groups (p>0.05). When compared to the patients of the CG, significantly less patients of the FG experienced vomiting in both, the acute (p<0.001) and the delayed CINV phase (p<0.0001); accordingly, significantly less vomiting events (p<0.0001) were observed during both CINV phases in the FG. Furthermore, the FG received significantly fewer doses of dimenhydrinate in comparison to the CG (p<0.001). 4. Conclusions The prophylaxis regimen with fosaprepitant in combination with granisetron was safe and more effective in comparison to the standard prophylaxis regimen with granisetron only in pediatric patients undergoing allogeneic HSCT with a myeloablative conditioning. However, larger prospective trials are needed to evaluate these findings. 5. Keywords Chemotherapy-induced nausea and vomiting; antiemetic prophylaxis; fosaprepitant; pediatric patients 6. Acknowledgments This study was supported by the Stefan-Morsch-Stiftung, Birkenfeld, Germany. Disclosures Schlegel: Miltenyi Biotec: Patents & Royalties, Research Funding. Seitz:Miltenyi Biotec: Patents & Royalties, Research Funding. Lang:Miltenyi Biotec: Patents & Royalties, Research Funding. Handgretinger:Miltenyi Biotec: Patents & Royalties: Co-patent holder of TcR alpha/beta depletion technologies, Research Funding.