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2. No difference in survival after HLA mismatched versus HLA matched allogeneic stem cell transplantation in Ewing sarcoma patients with advanced disease

Author

Thiel, U., Schober, S. J., Ranft, A., Gassmann, H., Jabar, S., Gall, K., von Lüttichau, I., Wawer, A., Koscielniak, E., Diaz, M. A., Ussowicz, M., Kazantsev, I., Afanasyev, B., Merker, M., Klingebiel, T., Prete, A., Gruhn, B., Bader, P., Jürgens, H., Dirksen, U., Handgretinger, R., Burdach, S., and Lang, P.

Published
2021
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3. Antiemetic Prophylaxis with Fosaprepitant and 5-HT3-Receptor Antagonists in Pediatric Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation

Author

Cabanillas Stanchi KM, Willier S, Vek J, Schlegel P, Queudeville M, Rieflin N, Klaus V, Gansel M, Rupprecht JV, Flaadt T, Binder V, Feuchtinger T, Lang P, Handgretinger R, and Döring M

Subjects
fosaprepitant, 5-ht3-antagonists, pediatric, antiemetic prophylaxis, chemotherapy induced nausea and vomiting, autologous hematopoietic stem cell transplantation, Therapeutics. Pharmacology, RM1-950
Abstract

Karin Melanie Cabanillas Stanchi,1,* Semjon Willier,2,* Julia Vek,1 Patrick Schlegel,1 Manon Queudeville,1 Nora Rieflin,1 Veronika Klaus,1 Melanie Gansel,1 Joachim Vincent Rupprecht,1 Tim Flaadt,1 Vera Binder,2 Tobias Feuchtinger,2 Peter Lang,1 Rupert Handgretinger,1 Michaela Döring1 1Department of General Pediatrics, Hematology/Oncology, University Children‘s Hospital Tübingen, Tübingen, Germany; 2Department of Pediatric Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Dr. Von Hauner Children’s Hospital, University Hospital, LMU, Munich, Germany*These authors contributed equally to this workCorrespondence: Michaela DöringDepartment I – General Pediatrics, Hematology/Oncology, University Hospital Tübingen - Children’s Hospital, Hoppe-Seyler-Str. 1, Tübingen 72076, GermanyTel +49-7071-2981355Fax +49-7071-295203Email michaela.doering@med.uni-tuebingen.deBackground: 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.Keywords: fosaprepitant, 5-HT3-antagonists, pediatric, antiemetic prophylaxis, chemotherapy-induced nausea and vomiting, autologous hematopoietic stem cell transplantation

Published
2020

5. Knochenmark

Author

Sykora, K.-W., Welte, K., Niemeyer, C., Handgretinger, R., Matthes-Martin, S., Lang, P., Strahm, B., Kratz, C., Niemeyer, Charlotte, editor, and Eggert, Angelika, editor

Published
2018
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6. Efficacy, Safety And Feasibility Of Antiemetic Prophylaxis With Fosaprepitant, Granisetron And Dexamethasone In Pediatric Patients With Hemato-Oncological Malignancies

Author

Cabanillas Stanchi KM, Ebinger M, Hartmann U, Queudeville M, Feucht J, Ost M, Koch MS, Malaval C, Mezger M, Schober S, Weber S, Michaelis S, Lange V, Lang P, Handgretinger R, and Döring M

Subjects
Fosaprepitant, aprepitant, granisetron, pediatric, antiemetic prophylaxis, chemotherapy, CINV, chemotherapy induced nausea and vomiting, chemotherapy induced vomiting, CIV, 5-HT¬3R-antagonist, NK1R-antagonists, dexamethasone, Therapeutics. Pharmacology, RM1-950
Abstract

Karin Melanie Cabanillas Stanchi,1,* Martin Ebinger,1,* Ulrike Hartmann,2 Manon Queudeville,1 Judith Feucht,1 Michael Ost,1 Marie-Sarah Koch,1 Carmen Malaval,1 Markus Mezger,1 Sarah Schober,1 Simone Weber,1 Sebastian Michaelis,1 Veit Lange,1 Peter Lang,1 Rupert Handgretinger,1 Michaela Döring1 1Department of General Pediatrics, Hematology/Oncology, University Children‘s Hospital Tübingen, Tübingen 72076, Germany; 2University Pharmacy, Eberhard-Karls-University of Tübingen, Tübingen 72076, Germany*These authors contributed equally to this workCorrespondence: Michaela DöringUniversity Hospital Tübingen - Children’s Hospital, Department I – General Pediatrics, Hematology/Oncology, Hoppe-Seyler-Str. 1, Tübingen 72076, GermanyTel +49-(0)7071-2981355Fax +49-(0)7071-295203Email michaela.doering@med.uni-tuebingen.deBackground: Chemotherapy-induced nausea and vomiting (CINV) are a major burden for patients undergoing emetogenic chemotherapy. International guidelines recommend an antiemetic prophylaxis with corticosteroids, 5-HT3R-antagonists and NK1R-antagonists. The NK1R-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

Published
2019

8. Correction to: No difference in survival after HLA mismatched versus HLA matched allogeneic stem cell transplantation in Ewing sarcoma patients with advanced disease

Author

Thiel, U., Schober, S. J., Ranft, A., Gassmann, H., Jabar, S., Gall, K., von Lüttichau, I., Wawer, A., Koscielniak, E., Diaz, M. A., Ussowicz, M., Kazantsev, I., Afanasyev, B., Merker, M., Klingebiel, T., Prete, A., Gruhn, B., Bader, P., Jürgens, H., Dirksen, U., Handgretinger, R., Burdach, S., and Lang, P.

Published
2021
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9. Haematopoietic stem cell transplantation for severe autoimmune diseases in children: A review of current literature, registry activity and future directions on behalf of the autoimmune diseases and paediatric diseases working parties of the European Society for Blood and Marrow Transplantation

Author

Achini-Gutzwiller, F, Snowden, J, Corbacioglu, S, Greco, R, Alexander, T, Badoglio, M, Labopin, M, Abinun, M, Apte, S, Arnold, R, Domenech, A, Brierley, C, Burman, J, Castilla-Llorente, C, Cooper, N, Daghia, G, Daikeler, T, del Papa, N, de Vries-Bouwstra, J, Farge, D, Finke, J, Hagglund, H, Hawkey, C, Henes, J, Hiepe, F, Jessop, H, Kiely, D, Kazmi, M, Kirgizov, K, Kramer, E, Mancardi, G, Marjanovic, Z, Martin, R, Martin, T, Ma, D, Moore, J, Miller, P, Muraro, P, Oliveira, M, Polushin, A, Onida, F, Simoes, B, Puyade, M, Resnick, I, Ricart, E, Rovira, M, Saccardi, R, Saif, M, Sakellari, I, Sharrack, B, Snarski, E, Scherer, H, Sossa, C, Withers, B, Wulffraat, N, Zaccara, E, Amrolia, P, Ansari, M, Balduzzi, A, Dalassier, A, Dalle, J, Diaz, C, Feuchtinger, T, Locatelli, F, Lucchini, G, Galimard, J, Vincent, M, Handgretinger, R, Kleinschmidt, K, Lawitschka, A, Martinez, A, Peters, C, Rocha, V, Ruggeri, A, Sedlacek, P, Svec, P, Toporski, J, Yesilipek, A, Achini-Gutzwiller F. R., Snowden J. A., Corbacioglu S., Greco R., Alexander T., Snowden J., Badoglio M., Labopin M., Abinun M., Apte S., Arnold R., Domenech A., Brierley C., Burman J., Castilla-Llorente C., Cooper N., Daghia G., Daikeler T., del Papa N., de Vries-Bouwstra J., Farge D., Finke J., Hagglund H., Hawkey C., Henes J., Hiepe F., Jessop H., Kiely D., Kazmi M., Kirgizov K., Kramer E., Mancardi G., Marjanovic Z., Martin R., Martin T., Ma D., Moore J., Miller P., Muraro P., Oliveira M. -C., Polushin A., Onida F., Simoes B., Puyade M., Resnick I., Ricart E., Rovira M., Saccardi R., Saif M., Sakellari I., Sharrack B., Snarski E., Scherer H. U., Sossa C., Withers B., Wulffraat N., Zaccara E., Amrolia P., Ansari M., Balduzzi A., Dalassier A., Dalle J. -H., Diaz C. H., Feuchtinger T., Locatelli F., Lucchini G., Galimard J. -E., Vincent M. G., Handgretinger R., Kleinschmidt K., Lawitschka A., Martinez A. P., Peters C., Rocha V., Ruggeri A., Sedlacek P., Svec P., Toporski J., Yesilipek A., Achini-Gutzwiller, F, Snowden, J, Corbacioglu, S, Greco, R, Alexander, T, Badoglio, M, Labopin, M, Abinun, M, Apte, S, Arnold, R, Domenech, A, Brierley, C, Burman, J, Castilla-Llorente, C, Cooper, N, Daghia, G, Daikeler, T, del Papa, N, de Vries-Bouwstra, J, Farge, D, Finke, J, Hagglund, H, Hawkey, C, Henes, J, Hiepe, F, Jessop, H, Kiely, D, Kazmi, M, Kirgizov, K, Kramer, E, Mancardi, G, Marjanovic, Z, Martin, R, Martin, T, Ma, D, Moore, J, Miller, P, Muraro, P, Oliveira, M, Polushin, A, Onida, F, Simoes, B, Puyade, M, Resnick, I, Ricart, E, Rovira, M, Saccardi, R, Saif, M, Sakellari, I, Sharrack, B, Snarski, E, Scherer, H, Sossa, C, Withers, B, Wulffraat, N, Zaccara, E, Amrolia, P, Ansari, M, Balduzzi, A, Dalassier, A, Dalle, J, Diaz, C, Feuchtinger, T, Locatelli, F, Lucchini, G, Galimard, J, Vincent, M, Handgretinger, R, Kleinschmidt, K, Lawitschka, A, Martinez, A, Peters, C, Rocha, V, Ruggeri, A, Sedlacek, P, Svec, P, Toporski, J, Yesilipek, A, Achini-Gutzwiller F. R., Snowden J. A., Corbacioglu S., Greco R., Alexander T., Snowden J., Badoglio M., Labopin M., Abinun M., Apte S., Arnold R., Domenech A., Brierley C., Burman J., Castilla-Llorente C., Cooper N., Daghia G., Daikeler T., del Papa N., de Vries-Bouwstra J., Farge D., Finke J., Hagglund H., Hawkey C., Henes J., Hiepe F., Jessop H., Kiely D., Kazmi M., Kirgizov K., Kramer E., Mancardi G., Marjanovic Z., Martin R., Martin T., Ma D., Moore J., Miller P., Muraro P., Oliveira M. -C., Polushin A., Onida F., Simoes B., Puyade M., Resnick I., Ricart E., Rovira M., Saccardi R., Saif M., Sakellari I., Sharrack B., Snarski E., Scherer H. U., Sossa C., Withers B., Wulffraat N., Zaccara E., Amrolia P., Ansari M., Balduzzi A., Dalassier A., Dalle J. -H., Diaz C. H., Feuchtinger T., Locatelli F., Lucchini G., Galimard J. -E., Vincent M. G., Handgretinger R., Kleinschmidt K., Lawitschka A., Martinez A. P., Peters C., Rocha V., Ruggeri A., Sedlacek P., Svec P., Toporski J., and Yesilipek A.

Abstract

Although modern clinical management strategies have improved the outcome of paediatric patients with severe autoimmune and inflammatory diseases over recent decades, a proportion will experience ongoing or recurrent/relapsing disease activity despite multiple therapies often leading to irreversible organ damage, and compromised quality of life, growth/development and long-term survival. Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) have been used successfully to induce disease control and often apparent cure of severe treatment-refractory autoimmune diseases (ADs) in children. However, transplant-related outcomes are disease-dependent and long-term outcome data are limited in respect to efficacy and safety. Moreover, balancing risks of HSCT against AD prognosis with continually evolving non-transplant options is challenging. This review appraises published literature on HSCT strategies and outcomes in individual paediatric ADs. We also provide a summary of the European Society for Blood and Marrow Transplantation (EBMT) Registry, where 343 HSCT procedures (176 autologous and 167 allogeneic) have been reported in 326 children (<18 years) for a range of AD indications. HSCT is a promising treatment modality, with potential long-term disease control or cure, but therapy-related morbidity and mortality need to be reduced. Further research is warranted to establish the position of HSCT in paediatric ADs via registries and prospective clinical studies to support evidence-based interspeciality guidelines and recommendations.

Published
2022

10. Immunotargeting relapsed or refractory precursor B-cell acute lymphoblastic leukemia – role of blinatumomab

Author

Queudeville M, Handgretinger R, and Ebinger M

Subjects
R/R precursor B-cell ALL, blinatumomab, T-cell, immunotherapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Manon Queudeville, Rupert Handgretinger, Martin Ebinger Department of Pediatric Hematology and Oncology, University Children’s Hospital, University of Tübingen, Tübingen, Germany Abstract: Patients with refractory or relapsed (R/R) acute lymphoblastic leukemia (ALL) have a dismal prognosis of around 5% long-term survival when treated with cytotoxic chemotherapy and allogenic stem cell transplantation. T-cell immunobased strategies open up new therapeutic perspectives. Blinatumomab is the first of a new class of antibody constructs that was labeled bispecific T-cell engager (BiTE): it consists of two single chain variable fragment connected with a flexible linker, one side binding CD3, the other CD19. The tight binding and the close proximity to the CD19-positive B-cells and leukemic cells leads to non-major histocompatibility complex-restricted T-cell activation, polyclonal T-cell expansion and direct target cell killing. Applied by continuous infusion, blinatumomab achieves morphological complete response rates ranging from 39% to 69% in R/R ALL patients (compared to 25% after second-line chemotherapy) with prolonged overall survival (blinatumomab median overall survival, 7.7 months vs chemotherapy, 4.0 months). In comparison to conventional cytotoxic second-line protocols blinatumomab has a favorable safety profile. The main adverse event is related to the mode of action of blinatumomab: the induction of a cytokine-release syndrome that can be managed by interruption and/or the application of steroids or tocilizumab. Another typical complication is the occurrence of neurological side effects, such as seizures and encephalopathy. This neurotoxicity is reversible after application of steroids and/or withdrawal of blinatumomab. Blinatumomab has proven to be a powerful therapeutic option in R/R ALL patients both adult and pediatric because of its efficacy and limited toxicity. Keywords: R/R precursor B-cell ALL, blinatumomab, T-cell, immunotherapy

Published
2017

11. Low leukemia burden improves blinatumomab efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia

Author

Queudeville, M., Stein, A. S., Locatelli, Franco, Ebinger, M., Handgretinger, R., Gokbuget, N., Gore, L., Zeng, Y., Gokani, P., Zugmaier, G., Kantarjian, H. M., Locatelli F. (ORCID:0000-0002-7976-3654), Queudeville, M., Stein, A. S., Locatelli, Franco, Ebinger, M., Handgretinger, R., Gokbuget, N., Gore, L., Zeng, Y., Gokani, P., Zugmaier, G., Kantarjian, H. M., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Background: A lower baseline bone marrow blast percentage (bBMB%) is associated with better outcomes in patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving blinatumomab. The objective of this analysis was to investigate the association between bBMB% and treatment outcomes in relapsed/refractory (R/R) B-ALL. Methods: Data from five trials of blinatumomab for R/R B-ALL were pooled for analyses. Patients were placed in one of three groups: group 1, ≥50% bBMBs; group 2, ≥25% to <50% bBMBs; group 3, ≥5% to <25% bBMBs. Response and survival outcomes were compared between groups. Results: Data from 683 patients (166 pediatric, 517 adult) were analyzed. Collectively, patients in groups 2 and 3 had significantly higher odds of achieving a complete remission (CR) (odds ratio [OR], 3.50 [95% confidence interval (CI), 2.23–5.48] and 3.93 [95% CI, 2.50–6.18], respectively; p <.001) and minimal/measurable residual disease response (OR, 2.61 and 3.37, respectively; p <.001) when compared with group 1 (reference). Groups 2 and 3 had a 37% and 46% reduction in the risk of death (hazard ratio [HR], 0.63 and 0.54, respectively; p <.001) and a 41% and 43% reduction in the risk of an event (relapse or death) (HR, 0.59 and 0.57, respectively; p <.001) compared with group 1. No significant differences in response or survival outcomes were observed between groups 2 and 3. Seven of nine patients whose bBMB% was lowered to <50% with dexamethasone achieved CR with blinatumomab. Conclusion: Any bBMB% <50% was associated with improved efficacy following blinatumomab treatment for R/R B-ALL.

Published
2023

12. Haematopoietic stem cell transplantation for severe autoimmune diseases in children : a review of current literature, registry activity and future directions on behalf of the autoimmune diseases and paediatric diseases working parties of the European Society for Blood and Marrow Transplantation

Author

Achini‐Gutzwiller, FR, Snowden, JA, Corbacioglu, S, Greco, R, Alexander, T, Snowden, J, Badoglio, M, Labopin, M, Abinun, M, Apte, S, Arnold, R, Domenech, A, Brierley, C, Burman, J, Castilla‐Llorente, C, Cooper, N, Daghia, G, Daikeler, T, del Papa, N, de Vries‐Bouwstra, J, Farge, D, Finke, J, Hagglund, H, Hawkey, C, Henes, J, Hiepe, F, Jessop, H, Kiely, D, Kazmi, M, Kirgizov, K, Kramer, E, Mancardi, G, Marjanovic, Z, Martin, R, Martin, T, Ma, D, Moore, J, Miller, P, Muraro, P, Oliveira, M, Polushin, A, Onida, F, Simoes, B, Puyade, M, Resnick, I, Ricart, E, Rovira, M, Saccardi, R, Saif, M, Sakellari, I, Sharrack, B, Snarski, E, Scherer, HU, Sossa, C, Withers, B, Wulffraat, N, Zaccara, E, Amrolia, P, Ansari, M, Balduzzi, A, Dalassier, A, Dalle, J, Diaz, CH, Feuchtinger, T, Locatelli, F, Lucchini, G, Galimard, J, Vincent, MG, Handgretinger, R, Kleinschmidt, K, Lawitschka, A, Martinez, AP, Peters, C, Rocha, V, Ruggeri, A, Sedlacek, P, Svec, P, Toporski, J, Yesilipek, A, Achini-Gutzwiller, F, Snowden, J, Corbacioglu, S, Greco, R, Alexander, T, Badoglio, M, Labopin, M, Abinun, M, Apte, S, Arnold, R, Domenech, A, Brierley, C, Burman, J, Castilla-Llorente, C, Cooper, N, Daghia, G, Daikeler, T, del Papa, N, de Vries-Bouwstra, J, Farge, D, Finke, J, Hagglund, H, Hawkey, C, Henes, J, Hiepe, F, Jessop, H, Kiely, D, Kazmi, M, Kirgizov, K, Kramer, E, Mancardi, G, Marjanovic, Z, Martin, R, Martin, T, Ma, D, Moore, J, Miller, P, Muraro, P, Oliveira, M, Polushin, A, Onida, F, Simoes, B, Puyade, M, Resnick, I, Ricart, E, Rovira, M, Saccardi, R, Saif, M, Sakellari, I, Sharrack, B, Snarski, E, Scherer, H, Sossa, C, Withers, B, Wulffraat, N, Zaccara, E, Amrolia, P, Ansari, M, Balduzzi, A, Dalassier, A, Dalle, J, Diaz, C, Feuchtinger, T, Locatelli, F, Lucchini, G, Galimard, J, Vincent, M, Handgretinger, R, Kleinschmidt, K, Lawitschka, A, Martinez, A, Peters, C, Rocha, V, Ruggeri, A, Sedlacek, P, Svec, P, Toporski, J, and Yesilipek, A

Subjects
autoimmune diseases, haematopoietic stem cell transplantation, paediatric, ddc:610, paediatric, surgical procedures, operative, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, haematopoietic stem cell transplantation, 610 Medizin, autoimmune diseases, autoimmune disease, Hematology
Abstract

Although modern clinical management strategies have improved the outcome of paediatric patients with severe autoimmune and inflammatory diseases over recent decades, a proportion will experience ongoing or recurrent/relapsing disease activity despite multiple therapies often leading to irreversible organ damage, and compromised quality of life, growth/development and long-term survival. Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) have been used successfully to induce disease control and often apparent cure of severe treatment-refractory autoimmune diseases (ADs) in children. However, transplant-related outcomes are disease-dependent and long-term outcome data are limited in respect to efficacy and safety. Moreover, balancing risks of HSCT against AD prognosis with continually evolving non-transplant options is challenging. This review appraises published literature on HSCT strategies and outcomes in individual paediatric ADs. We also provide a summary of the European Society for Blood and Marrow Transplantation (EBMT) Registry, where 343 HSCT procedures (176 autologous and 167 allogeneic) have been reported in 326 children (

Published
2022

14. The role of haematopoietic stem cell transplantation for sickle cell disease in the era of targeted disease-modifying therapies and gene editing

Author

de la Fuente, J, Gluckman, E, Makani, J, Telfer, P, Faulkner, L, Corbacioglu, S, Amrolia, P, Ansari, M, Balduzzi, A, Dalassier, A, Dalle, J, Hereda Diaz, C, Feuchtinger, T, Locatelli, F, Lucchini, G, Galimard, J, Gonzalez Vincent, M, Handgretinger, R, Kleinschmidt, K, Lawitschka, A, Perez Martinez, A, Peters, C, Rocha, V, Ruggeri, A, Sedlacek, P, Svec, P, Toporski, J, Yesilipek, A, de la Fuente J., Gluckman E., Makani J., Telfer P., Faulkner L., Corbacioglu S., Amrolia P., Ansari M., Balduzzi A., Dalassier A., Dalle J. -H., Hereda Diaz C., Feuchtinger T., Locatelli F., Lucchini G., Galimard J. -E., Gonzalez Vincent M., Handgretinger R., Kleinschmidt K., Lawitschka A., Perez Martinez A., Peters C., Rocha V., Ruggeri A., Sedlacek P., Svec P., Toporski J., Yesilipek A., de la Fuente, J, Gluckman, E, Makani, J, Telfer, P, Faulkner, L, Corbacioglu, S, Amrolia, P, Ansari, M, Balduzzi, A, Dalassier, A, Dalle, J, Hereda Diaz, C, Feuchtinger, T, Locatelli, F, Lucchini, G, Galimard, J, Gonzalez Vincent, M, Handgretinger, R, Kleinschmidt, K, Lawitschka, A, Perez Martinez, A, Peters, C, Rocha, V, Ruggeri, A, Sedlacek, P, Svec, P, Toporski, J, Yesilipek, A, de la Fuente J., Gluckman E., Makani J., Telfer P., Faulkner L., Corbacioglu S., Amrolia P., Ansari M., Balduzzi A., Dalassier A., Dalle J. -H., Hereda Diaz C., Feuchtinger T., Locatelli F., Lucchini G., Galimard J. -E., Gonzalez Vincent M., Handgretinger R., Kleinschmidt K., Lawitschka A., Perez Martinez A., Peters C., Rocha V., Ruggeri A., Sedlacek P., Svec P., Toporski J., and Yesilipek A.

Abstract

Sickle cell disease is one of the most common, life-threatening, non-communicable diseases in the world and a major public health problem. Following the implementation of simple preventive and therapeutic modalities, infant mortality has almost been abolished in high-income countries, but only a small amount of progress has been made in improving survival in adulthood. Progressive end-organ damage, partly related to a systemic vasculopathy, is increasingly recognised. With the availability of a variety of novel disease-modifying drugs, gene addition and gene editing strategies, matched sibling donor haematopoietic stem cell transplantation (HSCT) in children (offering an overall survival rate of 95% and an event-free survival rate of 92%), and encouraging outcomes after alternative donor HSCT, the new challenge is to risk stratify patients, revise transplantation indications, and define the best therapeutic approach for each patient. The ultimate challenge will be to enable these advances in low-income and middle-income countries, where disease prevalence is highest and where innovative strategies are most needed.

Published
2020

16. Blinatumomab in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia: RIALTO expanded access study final analysis

Author

Locatelli, Franco, Zugmaier, G., Mergen, N., Bader, P., Jeha, S., Schlegel, P. -G., Bourquin, J. -P., Handgretinger, R., Brethon, B., Rossig, C., Kormany, W. N., Viswagnachar, P., Chen-Santel, C., Locatelli F. (ORCID:0000-0002-7976-3654), Locatelli, Franco, Zugmaier, G., Mergen, N., Bader, P., Jeha, S., Schlegel, P. -G., Bourquin, J. -P., Handgretinger, R., Brethon, B., Rossig, C., Kormany, W. N., Viswagnachar, P., Chen-Santel, C., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

The safety and efficacy of blinatumomab, a CD3/CD19-directed bispecific molecule, were examined in an open-label, single-arm, expanded access study (RIALTO). Children (.28 days and, 18 years) with CD191 relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) received up to 5 cycles of blinatumomab by continuous infusion (cycle: 4 weeks on/2 weeks off). The primary end point was incidence of adverse events. Secondary end points included complete response (CR) and measurable residual disease (MRD) response within the first 2 cycles and relapse-free survival (RFS), overall survival (OS), and allogeneic hematopoietic stem cell transplant (alloHSCT) after treatment. At final data cutoff (10 January 2020), 110 patients were enrolled (median age, 8.5 years; 88% had ≥5% baseline blasts). A low incidence of grade 3 or 4 cytokine release syndrome (n = 2; 1.8%) and neurologic events (n = 4; 3.6%) was reported; no blinatumomab-related fatal adverse events were recorded. The probability of response was not affected by the presence of cytogenetic/molecular abnormalities. Median OS was 14.6 months (95% confidence interval [CI]: 11.0-not estimable) and was significantly better for MRD responders vs MRD nonresponders (not estimable vs 9.3; hazard ratio, 0.18; 95% CI: 0.08-0.39). Of patients achieving CR after 2 cycles, 73.5% (95% CI: 61.4%- 83.5%) proceeded to alloHSCT. One-year OS probability was higher for patients who received alloHSCT vs without alloHSCT after blinatumomab (87% vs 29%). These findings support the use of blinatumomab as a safe and efficacious treatment of pediatric R/R B-ALL. This trial was registered at www.clinicaltrials.gov as #NCT02187354.

Published
2022

17. Haematopoietic stem cell transplantation for severe autoimmune diseases in children: A review of current literature, registry activity and future directions on behalf of the autoimmune diseases and paediatric diseases working parties of the European Society for Blood and Marrow Transplantation

Author

Achini-Gutzwiller, F. R., Snowden, J. A., Corbacioglu, S., Greco, R., Alexander, T., Snowden, J., Badoglio, M., Labopin, M., Abinun, M., Apte, S., Arnold, R., Domenech, A., Brierley, C., Burman, J., Castilla-Llorente, C., Cooper, N., Daghia, G., Daikeler, T., del Papa, N., de Vries-Bouwstra, J., Farge, D., Finke, J., Hagglund, H., Hawkey, C., Henes, J., Hiepe, F., Jessop, H., Kiely, D., Kazmi, M., Kirgizov, K., Kramer, E., Mancardi, G., Marjanovic, Z., Martin, R., Martin, T., Ma, D., Moore, J., Miller, P., Muraro, P., Oliveira, M. -C., Polushin, A., Onida, F., Simoes, B., Puyade, M., Resnick, I., Ricart, E., Rovira, M., Saccardi, R., Saif, M., Sakellari, I., Sharrack, B., Snarski, E., Scherer, H. U., Sossa, C., Withers, B., Wulffraat, N., Zaccara, E., Amrolia, P., Ansari, M., Balduzzi, A., Dalassier, A., Dalle, J. -H., Diaz, C. H., Feuchtinger, T., Locatelli, Franco, Lucchini, G., Galimard, J. -E., Vincent, M. G., Handgretinger, R., Kleinschmidt, K., Lawitschka, A., Martinez, A. P., Peters, C., Rocha, V., Ruggeri, A., Sedlacek, P., Svec, P., Toporski, J., Yesilipek, A., Locatelli F. (ORCID:0000-0002-7976-3654), Achini-Gutzwiller, F. R., Snowden, J. A., Corbacioglu, S., Greco, R., Alexander, T., Snowden, J., Badoglio, M., Labopin, M., Abinun, M., Apte, S., Arnold, R., Domenech, A., Brierley, C., Burman, J., Castilla-Llorente, C., Cooper, N., Daghia, G., Daikeler, T., del Papa, N., de Vries-Bouwstra, J., Farge, D., Finke, J., Hagglund, H., Hawkey, C., Henes, J., Hiepe, F., Jessop, H., Kiely, D., Kazmi, M., Kirgizov, K., Kramer, E., Mancardi, G., Marjanovic, Z., Martin, R., Martin, T., Ma, D., Moore, J., Miller, P., Muraro, P., Oliveira, M. -C., Polushin, A., Onida, F., Simoes, B., Puyade, M., Resnick, I., Ricart, E., Rovira, M., Saccardi, R., Saif, M., Sakellari, I., Sharrack, B., Snarski, E., Scherer, H. U., Sossa, C., Withers, B., Wulffraat, N., Zaccara, E., Amrolia, P., Ansari, M., Balduzzi, A., Dalassier, A., Dalle, J. -H., Diaz, C. H., Feuchtinger, T., Locatelli, Franco, Lucchini, G., Galimard, J. -E., Vincent, M. G., Handgretinger, R., Kleinschmidt, K., Lawitschka, A., Martinez, A. P., Peters, C., Rocha, V., Ruggeri, A., Sedlacek, P., Svec, P., Toporski, J., Yesilipek, A., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Although modern clinical management strategies have improved the outcome of paediatric patients with severe autoimmune and inflammatory diseases over recent decades, a proportion will experience ongoing or recurrent/relapsing disease activity despite multiple therapies often leading to irreversible organ damage, and compromised quality of life, growth/development and long-term survival. Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) have been used successfully to induce disease control and often apparent cure of severe treatment-refractory autoimmune diseases (ADs) in children. However, transplant-related outcomes are disease-dependent and long-term outcome data are limited in respect to efficacy and safety. Moreover, balancing risks of HSCT against AD prognosis with continually evolving non-transplant options is challenging. This review appraises published literature on HSCT strategies and outcomes in individual paediatric ADs. We also provide a summary of the European Society for Blood and Marrow Transplantation (EBMT) Registry, where 343 HSCT procedures (176 autologous and 167 allogeneic) have been reported in 326 children (<18 years) for a range of AD indications. HSCT is a promising treatment modality, with potential long-term disease control or cure, but therapy-related morbidity and mortality need to be reduced. Further research is warranted to establish the position of HSCT in paediatric ADs via registries and prospective clinical studies to support evidence-based interspeciality guidelines and recommendations.

Published
2022

18. Positive Selection of Hematopoietic Progenitor Cells for Autologous and Allogeneic Transplantation in Pediatric Patients with Solid Tumors and Leukemia

Author

Koehl, U., Gunkel, M., Grüttner, H. P., Sörensen, J., Esser, R., Kotchetkov, R., Keyser, M., Tonn, T., Schumm, M., Handgretinger, R., Gröschel, B., Vogel, J. U., Cinatl, J., Jr, Niegemann, E., Ebener, U., Seifried, E., Kornhuber, B., Schwabe, D., Berdel, W. E., editor, Büchner, Th., editor, Kienast, J., editor, Van De Loo, J., editor, Jürgens, H., editor, Ritter, J., editor, and Vormoor, J., editor

Published
2000
Full Text
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30. Allo-SCT using BU, CY and melphalan for children with AML in second CR

Author

Beier, R, Albert, M H, Bader, P, Borkhardt, A, Creutzig, U, Eyrich, M, Ehlert, K, Gruhn, B, Greil, J, Handgretinger, R, Holter, W, Klingebiel, T, Kremens, B, Lang, P, Mauz-Körholz, C, Meisel, R, Müller, I, Peters, C, Reinhardt, D, Sedlacek, P, Schulz, A, Schuster, F R, Schrauder, A, Strahm, B, Sykora, K W, Wössmann, W, Zimmermann, M, and Sauer, M G

Published
2013
Full Text
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37. Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III

Author

Bakhtiar, S., Salzmann-Manrique, E., Blok, H.J., Eikema, D.J., Hazelaar, S., Ayas, M., Toren, A., Goldstein, G., Moshous, D., Locatelli, F., Merli, P., Michel, G., Ozturk, G., Schulz, A., Heilmann, C., Ifversen, M., Wynn, R.F., Aleinikova, O., Bertrand, Y., Tbakhi, A., Veys, P., Karakukcu, M., Kupesiz, A., Ghavamzadeh, A., Handgretinger, R., Unal, E., Perez-Martinez, A., Gokce, M., Porta, F., Aksu, T., Karasu, G., Badell, I., Ljungman, P., Skorobogatova, E., Yesilipek, A., Zuckerman, T., Bredius, R.R.G., Stepensky, P., Shadur, B., Slatter, M., Gennery, A.R., Albert, M.H., Bader, P., Lankester, A., Pediat Dis Working Party, and Inborn Errors Working Party EBMT

Subjects
surgical procedures, operative
Abstract

Type I and III leukocyte adhesion deficiencies (LADs) are primary immunodeficiency disorders resulting in early death due to infections and additional bleeding tendency in LAD-III. The curative treatment of LAD-I and LAD-III is allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this retrospective multicenter study, data were collected using the European Society for Blood and Marrow Transplantation registry; we analyzed data from 84 LAD patients from 33 centers, all receiving an allo-HSCT from 2007 to 2017. The 3-year overall survival estimate (95% confidence interval [CI]) was 83% (74-92) for the entire cohort: 84% (75-94) and 75% (50-100) for LAD-I and LAD-III, respectively. We observed cumulative incidences (95% CI) of graft failure (GF) at 3 years of 17% (9%-26%) and grade II to IV acute graft-versus-host disease (aGVHD) at 100 days of 24% (15%-34%). The estimate (95% CI) at 3 years for GF- and GVHD-II to IV-free survival as event-free survival (EFS) was 56% (46-69) for the entire cohort; 58% (46-72) and 56% (23-88) for LAD-I and LAD-III, respectively. Grade II to IV acute GVHD was a relevant risk factor for death (hazard ratio 3.6; 95% CI 1.4-9.1; P = .006). Patients' age at transplant >= 13 months, transplantation from a nonsibling donor, and any serological cytomegalovirus mismatch in donor-recipient pairs were significantly associated with severe acute GVHD and inferior EFS. The choice of busulfan- or treosulfan-based conditioning, type of GVHD prophylaxis, and serotherapy did not impact overall survival, EFS, or aGVHD. An intrinsic inflammatory component of LAD may contribute to inflammatory complications during allo-HSCT, thus providing the rationale for considering anti-inflammatory therapy pretreatment.

Published
2021

38. Author Correction: Blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia: results of the RIALTO trial, an expanded access study (Blood Cancer Journal, (2020), 10, 7, (77), 10.1038/s41408-020-00342-x)

Author

Locatelli, Franco, Zugmaier, G., Mergen, N., Bader, P., Jeha, S., Schlegel, P. -G., Bourquin, J. -P., Handgretinger, R., Brethon, B., Rossig, C., and Chen-Santel, C.

Subjects
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, blinatumomab
Published
2021

40. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia

Author

Frangoul, H. Altshuler, D. Cappellini, M.D. Chen, Y.-S. Domm, J. Eustace, B.K. Foell, J. De La Fuente, J. Grupp, S. Handgretinger, R. Ho, T.W. Kattamis, A. Kernytsky, A. Lekstrom-Himes, J. Li, A.M. Locatelli, F. Mapara, M.Y. De Montalembert, M. Rondelli, D. Sharma, A. Sheth, S. Soni, S. Steinberg, M.H. Wall, D. Yen, A. Corbacioglu, S.

Subjects
hemic and lymphatic diseases
Abstract

Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are the most common inherited hematologic disorders, affecting approximately 60,000 and 300,000 patients worldwide, respectively. Current therapies, including red blood cell (RBC) transfusion and iron chelation in TDT and transfusion, pain management, and hydroxyurea in SCD, help to manage the disorders but do not address the underlying cause. Drug therapies, such as crizanlizumab and luspatercept, have also helped to reduce the need for transfusion in TDT patients and the incidence of vaso-occlusive episodes in SCD patients. Allogeneic bone marrow transplantationmay be a curative option, but finding an appropriate donor is difficult. An association has been observed between elevated levels of fetal hemoglobin and improved morbidity and mortality in these patients. Downregulating BCL11A, a transcription factor that blocks fetal hemoglobin in erythroid cells, may help to increase fetal hemoglobin levels and improve outcomes. Using the CRISPR-Cas9 gene-editing technique, CTX001, an investigational drug, was infused in 2 patients. This article describes the results of infusing CTX001 in 1 patient with TDT and another with SCD. © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Published
2021

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