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1. Outcomes of allogeneic haematopoietic cell transplantation for myelofibrosis in children and adolescents: the retrospective study of the EBMT Paediatric Diseases WP

Author

Wachowiak, J, Galimard, J, Dalissier, A, Rihani, R, Alsaedi, H, Wynn, R, Dalle, J, Peffault de Latour, R, Sedlacek, P, Balduzzi, A, Schroeder, T, Bodova, I, Gonzalez Vicent, M, Gruhn, B, Hamladji, R, Krivan, G, Patrick, K, Sobkowiak-Sobierajska, A, Stepensky, P, Unal, A, Amrolia, P, Perez Martinez, A, Rialland, F, Aljurf, M, Isgro, A, Toren, A, Bierings, M, Corbacioglu, S, Kalwak, K, Wachowiak J., Galimard J. -E., Dalissier A., Rihani R., AlSaedi H., Wynn R. F., Dalle J. -H., Peffault de Latour R., Sedlacek P., Balduzzi A., Schroeder T., Bodova I., Gonzalez Vicent M., Gruhn B., Hamladji R. -M., Krivan G., Patrick K., Sobkowiak-Sobierajska A., Stepensky P., Unal A., Amrolia P., Perez Martinez A., Rialland F., Aljurf M., Isgro A., Toren A., Bierings M., Corbacioglu S., Kalwak K., Wachowiak, J, Galimard, J, Dalissier, A, Rihani, R, Alsaedi, H, Wynn, R, Dalle, J, Peffault de Latour, R, Sedlacek, P, Balduzzi, A, Schroeder, T, Bodova, I, Gonzalez Vicent, M, Gruhn, B, Hamladji, R, Krivan, G, Patrick, K, Sobkowiak-Sobierajska, A, Stepensky, P, Unal, A, Amrolia, P, Perez Martinez, A, Rialland, F, Aljurf, M, Isgro, A, Toren, A, Bierings, M, Corbacioglu, S, Kalwak, K, Wachowiak J., Galimard J. -E., Dalissier A., Rihani R., AlSaedi H., Wynn R. F., Dalle J. -H., Peffault de Latour R., Sedlacek P., Balduzzi A., Schroeder T., Bodova I., Gonzalez Vicent M., Gruhn B., Hamladji R. -M., Krivan G., Patrick K., Sobkowiak-Sobierajska A., Stepensky P., Unal A., Amrolia P., Perez Martinez A., Rialland F., Aljurf M., Isgro A., Toren A., Bierings M., Corbacioglu S., and Kalwak K.

Abstract

This retrospective study evaluated 35 children (median age 5.2 years; range 0.4–18) with myelofibrosis (MF), including 33 with primary myelofibrosis and 2 with secondary myelofibrosis transplanted from matched sibling donor (MSD) (n = 17) or non-MSD (n = 18) between 2000 and 2022. Conditioning was usually chemotherapy-based (n = 33) and myeloablative (n = 32). Fifteen patients received bone marrow (BM), 14 haematopoietic cells (HC) from peripheral blood (PB), and 6 from cord blood (CB). Day +100 acute GvHD II–IV incidence was significantly lower after MSD-haematopoietic cell transplantation (MSD-HCT) than after non-MSD-HCT [18.8% (4.3–41.1) vs 58.8% (31–78.6); p = 0.01]. Six-year non-relapse mortality (NRM) was 18% (7.1–32.8), relapse incidence was 15.9% (5.6–30.9), progression-free survival (PFS) was 66.1% (47–79.7), GvHD-free relapse-free survival was 50% (30.6–66.7), and overall survival (OS) was 71.1% (51.4–84). Six-year PFS and OS were significantly higher after BM transplantation compared to HCT from other sources [85.1% (52.3–96.1) vs 50.8% (26.3–71), p = 0.03, and 90.9% (50.8–98.7) vs 54% (28.1–74.2), p = 0.01, respectively], whereas NRM was significantly lower [0% vs 32% (12.3–53.9); p = 0.02]. This first multicentre study on outcomes of allogeneic HCT in children with myelofibrosis proves feasibility and curative effect of transplantation in these children, suggests that bone marrow transplantation is associated with better outcomes, and indicates the need for further studies.

Published
2024

2. A Multi-center, Open-Label, Single-Arm Trial to Evaluate the Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency (Jan, 10.1007/s10875-021-01181-6, 2022)

Author

Santamaria, M, Neth, O, Douglass, JA, Krivan, G, Kobbe, R, Bernatowska, E, Grigoriadou, S, Bethune, C, Chandra, A, Horneff, G, Borte, M, Sonnenschein, A, Kralickova, P, Ramon, SS, Langguth, DD, Gonzalez-Granado, LI, Alsina, L, Querolt, M, Griffin, R, Hames, C, Mondou, E, Price, J, Sanz, A, Lin, J, Santamaria, M, Neth, O, Douglass, JA, Krivan, G, Kobbe, R, Bernatowska, E, Grigoriadou, S, Bethune, C, Chandra, A, Horneff, G, Borte, M, Sonnenschein, A, Kralickova, P, Ramon, SS, Langguth, DD, Gonzalez-Granado, LI, Alsina, L, Querolt, M, Griffin, R, Hames, C, Mondou, E, Price, J, Sanz, A, and Lin, J

Published
2022

3. A Multi-Center, Open-Label, Single-Arm Trial to Evaluate the Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency

Author

Santamaria, M, Neth, O, Douglass, JA, Krivan, G, Kobbe, R, Bernatowska, E, Grigoriadou, S, Bethune, C, Chandra, A, Horneff, G, Borte, M, Sonnenschein, A, Kralickova, P, Ramon, SS, Langguth, D, Gonzalez-Granado, LI, Alsina, L, Querolt, M, Griffin, R, Hames, C, Mondou, E, Price, J, Sanz, A, Lin, J, Santamaria, M, Neth, O, Douglass, JA, Krivan, G, Kobbe, R, Bernatowska, E, Grigoriadou, S, Bethune, C, Chandra, A, Horneff, G, Borte, M, Sonnenschein, A, Kralickova, P, Ramon, SS, Langguth, D, Gonzalez-Granado, LI, Alsina, L, Querolt, M, Griffin, R, Hames, C, Mondou, E, Price, J, Sanz, A, and Lin, J

Abstract

PURPOSE: The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI). METHODS: Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject's previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured. RESULTS: Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate. CONCLUSIONS: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI.

Published
2022

4. Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients

Author

Geier, CB, Ellison, M, Cruz, R, Pawar, S, Leiss-Piller, A, Zmajkovicova, K, McNulty, SM, Yilmaz, M, Evans, MO, Gordon, S, Ujhazi, B, Wiest, I, Abolhassani, H, Aghamohammadi, A, Barmettler, S, Bhar, S, Bondarenko, A, Bolyard, AA, Buchbinder, D, Cada, M, Cavieres, M, Connelly, JA, Dale, DC, Deordieva, E, Dorsey, MJ, Drysdale, SB, Ehl, S, Elfeky, R, Fioredda, F, Firkin, F, Forster-Waldl, E, Geng, B, Goda, V, Gonzalez-Granado, L, Grunebaum, E, Grzesk, E, Henrickson, SE, Hilfanova, A, Hiwatari, M, Imai, C, Ip, W, Jyonouchi, S, Kanegane, H, Kawahara, Y, Khojah, AM, Kim, VH-D, Kojic, M, Koltan, S, Krivan, G, Langguth, D, Lau, Y-L, Leung, D, Miano, M, Mersyanova, I, Mousallem, T, Muskat, M, Naoum, FA, Noronha, SA, Ouederni, M, Ozono, S, Richmond, GW, Sakovich, I, Salzer, U, Schuetz, C, Seeborg, FO, Sharapova, SO, Sockel, K, Volokha, A, von Bonin, M, Warnatz, K, Wegehaupt, O, Weinberg, GA, Wong, K-J, Worth, A, Yu, H, Zharankova, Y, Zhao, X, Devlin, L, Badarau, A, Csomos, K, Keszei, M, Pereira, J, Taveras, AG, Beaussant-Cohen, SL, Ong, M-S, Shcherbina, A, Walter, JE, Geier, CB, Ellison, M, Cruz, R, Pawar, S, Leiss-Piller, A, Zmajkovicova, K, McNulty, SM, Yilmaz, M, Evans, MO, Gordon, S, Ujhazi, B, Wiest, I, Abolhassani, H, Aghamohammadi, A, Barmettler, S, Bhar, S, Bondarenko, A, Bolyard, AA, Buchbinder, D, Cada, M, Cavieres, M, Connelly, JA, Dale, DC, Deordieva, E, Dorsey, MJ, Drysdale, SB, Ehl, S, Elfeky, R, Fioredda, F, Firkin, F, Forster-Waldl, E, Geng, B, Goda, V, Gonzalez-Granado, L, Grunebaum, E, Grzesk, E, Henrickson, SE, Hilfanova, A, Hiwatari, M, Imai, C, Ip, W, Jyonouchi, S, Kanegane, H, Kawahara, Y, Khojah, AM, Kim, VH-D, Kojic, M, Koltan, S, Krivan, G, Langguth, D, Lau, Y-L, Leung, D, Miano, M, Mersyanova, I, Mousallem, T, Muskat, M, Naoum, FA, Noronha, SA, Ouederni, M, Ozono, S, Richmond, GW, Sakovich, I, Salzer, U, Schuetz, C, Seeborg, FO, Sharapova, SO, Sockel, K, Volokha, A, von Bonin, M, Warnatz, K, Wegehaupt, O, Weinberg, GA, Wong, K-J, Worth, A, Yu, H, Zharankova, Y, Zhao, X, Devlin, L, Badarau, A, Csomos, K, Keszei, M, Pereira, J, Taveras, AG, Beaussant-Cohen, SL, Ong, M-S, Shcherbina, A, and Walter, JE

Abstract

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.

Published
2022

5. Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study

Author

Albert, M. H., Sirait, T., Eikema, D. -J., Bakunina, K., Wehr, C., Suarez, F., Fox, M. L., Mahlaoui, N., Gennery, A. R., Lankester, A. C., Beier, R., Bernardo, M. E., Bigley, V., Lindemans, C. A., Burns, S. O., Carpenter, B., Dybko, J., Gungor, T., Hauck, F., Lum, S. H., Balashov, D., Meisel, R., Moshous, D., Schulz, A., Speckmann, C., Slatter, M. A., Strahm, B., Uckan-Cetinkaya, D., Meyts, I., Vallee, T. C., Wynn, R., Neven, B., Morris, E. C., Aiuti, A., Maschan, A., Aljurf, M., Gedde-Dahl, T., Gurman, G., Bordon, V., Krivan, G., Locatelli, Franco, Porta, F., Valcarcel, D., Beguin, Y., Faraci, M., Kroger, N., Kulagin, A., Shaw, P. J., Veelken, J. H., Diaz de Heredia, C., Fagioli, F., Felber, M., Gruhn, B., Holter, W., Rossig, C., Sedlacek, P., Apperley, J., Ayas, M., Bodova, I., Choi, G., Cornelissen, J. J., Sirvent, A., Khan, A., Kupesiz, A., Lenhoff, S., Ozdogu, H., von der Weid, N., Rovira, M., Schots, R., Vinh, D. C., Locatelli F. (ORCID:0000-0002-7976-3654), Albert, M. H., Sirait, T., Eikema, D. -J., Bakunina, K., Wehr, C., Suarez, F., Fox, M. L., Mahlaoui, N., Gennery, A. R., Lankester, A. C., Beier, R., Bernardo, M. E., Bigley, V., Lindemans, C. A., Burns, S. O., Carpenter, B., Dybko, J., Gungor, T., Hauck, F., Lum, S. H., Balashov, D., Meisel, R., Moshous, D., Schulz, A., Speckmann, C., Slatter, M. A., Strahm, B., Uckan-Cetinkaya, D., Meyts, I., Vallee, T. C., Wynn, R., Neven, B., Morris, E. C., Aiuti, A., Maschan, A., Aljurf, M., Gedde-Dahl, T., Gurman, G., Bordon, V., Krivan, G., Locatelli, Franco, Porta, F., Valcarcel, D., Beguin, Y., Faraci, M., Kroger, N., Kulagin, A., Shaw, P. J., Veelken, J. H., Diaz de Heredia, C., Fagioli, F., Felber, M., Gruhn, B., Holter, W., Rossig, C., Sedlacek, P., Apperley, J., Ayas, M., Bodova, I., Choi, G., Cornelissen, J. J., Sirvent, A., Khan, A., Kupesiz, A., Lenhoff, S., Ozdogu, H., von der Weid, N., Rovira, M., Schots, R., Vinh, D. C., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.

Published
2022

6. A Multi-Center, Open-Label, Single-Arm Trial to Evaluate the Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency

Author

Santamaria M, Neth O, Douglass JA, Krivan G, Kobbe R, Bernatowska E, Grigoriadou S, Bethune C, Chandra A, Horneff G, Borte M, Sonnenschein A, Kralickova P, Ramón SS, Langguth D, Gonzalez-Granado LI, Alsina L, Querolt M, Griffin R, Hames C, Mondou E, Price J, Sanz A, and Lin J

Subjects
Primary immunodeficiency, immunoglobulin replacement therapy, GTI1503, subcutaneous, 20% immunoglobulin
Abstract

Purpose The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI). Methods Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject's previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year >= 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured. Results Sixty-one subjects (19 children [ 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate. Conclusions IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI.

Published
2022

7. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations

Author

Tim Niehues, Catherine Waruiru, Conleth Feighery, Uwe Schauer, Virginie Courteille, Kai Lehmberg, Ingo Müller, I. Esteves, Henner Morbach, Michael Borte, Patrick Hundsdoerfer, Klaus Schwarz, Ewelina Gowin, Alessandro Aiuti, Andreas Holbro, Federica Barzaghi, João Farela Neves, Dagmar Graf, Hannah Tamary, Veneta Milenova, Benedikt Boetticher, Eleonora Gambineri, Vera Goda, Alia Eldash, Jan-Christian Wasmuth, Fabio Candotti, Svetlana O. Sharapova, Markus Metzler, Juergen Brunner, Anna Hilfanova, Brindusa Ruxandra Capilna, Pere Soler-Palacín, Arnau Antolí, Horst von Bernuth, Vassilios Lougaris, Maria Carrabba, Bernd H. Belohradsky, Julian Thalhammer, Nathalie de Vergnes, Peter Olbrich, Peter Kopač, Leif G. Hanitsch, Alexandra Nieters, Filomeen Haerynck, Juliana Gabzdilova, Sezin Aydemir, Rabab El Hawary, Patrick F.K. Yong, Maria Giovanna Danieli, Alberto Tommasini, Sandra Steinmann, Ulrich Baumann, Figen Dogu, Elisabeth Förster-Waldl, Carolina Marasco, Donato Amodio, Lorenzo Lodi, Xavier Solanich, Caterina Cancrini, Brigita Sitkauskiene, Torsten Witte, Clementina Vanessa, Nima Rezaei, Jean-Christophe Goffard, Kirsten Wittke, Emmanouil Liatsis, Helen Baxendale, Susana L. Silva, Bodo Grimbacher, Henrike Ritterbusch, Evangelia Farmaki, Safa Meshaal, Sujal Ghosh, Larysa Kostyuchenko, David Edgar, Simone Cesaro, R Zeuner, Nerea Salmón Rodríguez, Isabella Quinti, Stephan Ehl, Pauline Brosselin, Joerg C. Henes, Pilar Llobet Agulló, Rosa Maria Dellepiane, Andrea Meinhardt, Marina Kojić, Georgios Sogkas, Stephan Borte, Catharina Schuetz, Suheyla Ocak, Karin Marschall, Lukas M. Gasteiger, Stefan Raffac, Sofia Tantou, Sadia Noorani, Matthaios Speletas, Philippe Randrianomenjanahary, Ursula Holzer, Ayca Kiykim, Johannes G. Liese, Angelo Vacca, Gisela Fecker, Ekrem Unal, Koen J. van Aerde, Alba Parra-Martínez, Kaan Boztug, Sophie Stiehler, Sybille Landwehr-Kenzel, Claudio Pignata, Jennifer Neubert, Janine Reichenbach, Shahnaz Parvin, Sarah Goddard, Andrea Schroll, Dirk Holzinger, Asghar Aghamohammadi, Hassan Abolhassani, Johannes Trück, Estela Paz-Artal, Shereen M. Reda, Anna Shcherbina, Maria Raptaki, Jaroslava Orosova, Beata Wolska-Kuśnierz, Tessa Kerre, Gerrit Ahrenstorf, Ben Zion Garty, Dirk Foell, Benjamin Becker, Ulrike F. Demel, Androniki Kapousouzi, Abraham Rutgers, Klaus Warnatz, Gemma Rocamora Blanch, Stephan Rusch, Luis M. Allende, Dalia Abd Elaziz, Safa Baris, Jorisvan Montfrans, Dominik T. Schneider, Raphael Scheible, Juana Gil-Herrera, Gerhard Kindle, Annarosa Soresina, Giovanna Fabio, Uwe Wintergerst, Emilia Faria, Maria Fasshauer, Silvia Ricci, Aisha Elmarsafy, Barbara Pietrucha, Carsten Speckmann, Nizar Mahlaoui, Ulrich Heininger, Isabelle Meyts, Matthew Buckland, Efimia Papadopoulou-Alataki, Robin Kobbe, A Herwadkar, Sebastian F. N. Bode, Ali Sobh, László Maródi, Baldassarre Martire, Chiara Azzari, Maximilian Heeg, Katja Masjosthusmann, Michael H. Albert, Matteo Chinello, Juan Luis Santos-Pérez, Aarnoud Huissoon, Tanya I. Coulter, Hendrik Schulze-Koops, Norbert Graf, Radwa Alkady, Jolanta Bernatoniene, Seraina Prader, Alenka Gagro, Joachim Roesler, Taco W. Kuijpers, Ewa Więsik-Szewczyk, Maria Elena Maccari, Conrad Ferdinand Lippert, Miriam González-Amores, Johannes Dirks, Daniel E Pleguezuelo, Christof M. Kramm, Anders Fasth, Volker Schuster, Olov Ekwall, Nikolaus Rieber, Javier Carbone, Petra Kaiser-Labusch, Diana Ernst, Lucia Augusta Baselli, Luis Ignacio Gonzalez-Granado, Maria Kanariou, Stefanie S. V. Henriet, Sigune Goldacker, Kerstin Felgentreff, Oana Joean, Fine Roosens, Fabian Hauck, Eva C. Schwaneck, Milos Jesenak, Manfred Hoenig, Lenka Kapustova, Christoph Boesecke, Alain Fischer, Sara Pereira da Silva, Julia Körholz, Ansgar Schulz, Carolynne Schwarze-Zander, Mikko Seppänen, Nermeen Galal, Nora Naumann-Bartsch, Tomaz Garcez, Peter Ciznar, Klara M. Posfay-Barbe, Zelimir Pavle Eric, Reinhold E. Schmidt, Hermann J. Girschick, Sabine Heine, Anika-Kerstin Biegner, Annick A. J. M. van de Ven, Stefan Schreiber, J. Merlijn van den Berg, Nurit Assia Batzir, Alexandra Jablonka, Kim Stol, Gregor Dückers, Antonios G.A. Kolios, Ioannis Kakkas, Christian Klemann, Marina N. Guseva, Sofia Grigoriadou, Elif Karakoc-Aydiner, Antonio Marzollo, Peter D. Arkwright, Urs C. Steiner, Sara Sebnem Kilic, Romina Dieli-Crimi, Gergely Kriván, Monika Sparber-Sauer, Marco Cazzaniga, Fulvio Porta, Paraskevi Maggina, Tomas Milota, Robbert G. M. Bredius, Martine Pergent, Klaus Tenbrock, Jana Pachlopnik Schmid, Florentia Dimitriou, Cathal Laurence Steele, Helen Bourne, Anna Bobcakova, Gerd Horneff, Judith Potjewijd, Marc Schmalzing, Tobias Ankermann, Paul Ryan, Oksana Boyarchuk, Necil Kutukculer, Carl Friedrich Classen, Zita Chovancová, Moira Thomas, Cinzia Milito, Michaela Bitzenhofer-Grüber, Faranaz Atschekzei, Eva Hlaváčková, Viviana Moschese, Julie Smet, Hans-Hartmut Peter, Carla Teixeira, Sabine M El-Helou, Suzanne de Kruijf Bazen, Helmut Wittkowski, Donate Jakoby, Marina Garcia-Prat, Esther de Vries, Richard Herriot, Sven Kracker, Alessandro Plebani, Lisa Göschl, Laura Hora Marques, Anna Sediva, Jiri Litzman, Mark M. Gompels, Renate Krüger, Şefika İlknur Kökçü Karadağ, Nadine Binder, Anna Szaflarska, Peter Jandus, Lisa Ibberson, Johann Greil, Ulf Schulze-Sturm, Mehtap Sirin, Aydan Ikinciogullari, Edyta Heropolitańska-Pliszka, Michael E. Weiss, Alla Skapenko, Lukas Wisgrill, Hana Alachkar, Uta Behrends, Silvia Sánchez-Ramón, Maria N. Hatzistilianou, Otilia Petrovicova, Darko Richter, Zoreh Nademi, Jürgen K. Rockstroh, Sohilla Lotfy, Markus G. Seidel, Timothy Ronan Leahy, Audra Blažienė, Translational Immunology Groningen (TRIGR), Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, ARD - Amsterdam Reproduction and Development, University of Zurich, Ehl, Stephan, Thalhammer, J., Kindle, G., Nieters, A., Rusch, S., Seppanen, M. R. J., Fischer, A., Grimbacher, B., Edgar, D., Buckland, M., Mahlaoui, N., Ehl, S., Boztug, K., Brunner, J., Demel, U. F., Forster-Waldl, E., Gasteiger, L. M., Goschl, L., Kojic, M., Schroll, A., Seidel, M. G., Wintergerst, U., Wisgrill, L., Sharapova, S. O., Goffard, J. -C., Kerre, T., Meyts, I., Roosens, F., Smet, J., Haerynck, F., Eric, Z. P., Milenova, V., Gagro, A., Richter, D., Chovancova, Z., Hlavackova, E., Litzman, J., Milota, T., Sediva, A., Elaziz, D. A., Alkady, R. S., El Sayed El Hawary, R., Eldash, A. S., Galal, N., Lotfy, S., Meshaal, S. S., Reda, S. M., Sobh, A., Elmarsafy, A., Brosselin, P., Courteille, V., De Vergnes, N., Kracker, S., Pergent, M., Randrianomenjanahary, P., Ahrenstorf, G., Albert, M. H., Ankermann, T., Atschekzei, F., Baumann, U., Becker, B. C., Behrends, U., Belohradsky, B. H., Biegner, A. -K., Binder, N., Bode, S. F. N., Boesecke, C., Boetticher, B., Borte, M., Borte, S., Classen, C. F., Dirks, J., Duckers, G., El-Helou, S., Ernst, D., Fasshauer, M., Fecker, G., Felgentreff, K., Foell, D., Ghosh, S., Girschick, H. J., Goldacker, S., Graf, N., Graf, D., Greil, J., Hanitsch, L. G., Hauck, F., Heeg, M., Heine, S. I., Henes, J. C., Hoenig, M., Holzer, U., Holzinger, D., Horneff, G., Hundsdoerfer, P., Jablonka, A., Jakoby, D., Joean, O., Kaiser-Labusch, P., Klemann, C., Kobbe, R., Korholz, J., Kramm, C. M., Kruger, R., Landwehr-Kenzel, S., Lehmberg, K., Liese, J. G., Lippert, C. F., Maccari, M. E., Masjosthusmann, K., Meinhardt, A., Metzler, M., Morbach, H., Muller, I., Naumann-Bartsch, N., Neubert, J., Niehues, T., Peter, H. -H., Rieber, N., Ritterbusch, H., Rockstroh, J. K., Roesler, J., Schauer, U., Scheible, R., Schmalzing, M., Schmidt, R. E., Schneider, D. T., Schreiber, S., Schuetz, C., Schulz, A., Schulze-Koops, H., Schulze-Sturm, U., Schuster, V., Schwaneck, E. C., Schwarz, K., Schwarze-Zander, C., Sirin, M., Skapenko, A., Sogkas, G., Sparber-Sauer, M., Speckmann, C., Steinmann, S., Stiehler, S., Tenbrock, K., von Bernuth, H., Warnatz, K., Wasmuth, J. -C., Weiss, M., Witte, T., Wittke, K., Wittkowski, H., Zeuner, R. A., Farmaki, E., Hatzistilianou, M. N., Kakkas, I., Kanariou, M. G., Kapousouzi, A., Liatsis, E., Maggina, P., Papadopoulou-Alataki, E., Raptaki, M., Speletas, M., Tantou, S., Goda, V., Krivan, G., Marodi, L., Abolhassani, H., Aghamohammadi, A., Rezaei, N., Feighery, C., Leahy, T. R., Ryan, P., Batzir, N. A., Garty, B. Z., Tamary, H., Aiuti, A., Amodio, D., Azzari, C., Barzaghi, F., Baselli, L. A., Cancrini, C., Carrabba, M., Cazzaniga, M., Cesaro, S., Chinello, M., Danieli, M. G., Dellepiane, R. M., Fabio, G., Gambineri, E., Lodi, L., Lougaris, V., Marasco, C., Martire, B., Marzollo, A., Milito, C., Moschese, V., Pignata, C., Plebani, A., Porta, F., Quinti, I., Ricci, S., Soresina, A., Tommasini, A., Vacca, A., Vanessa, C., Blaziene, A., Sitkauskiene, B., Gowin, E., Heropolitanska-Pliszka, E., Pietrucha, B., Szaflarska, A., Wiesik-Szewczyk, E., Wolska-Kusnierz, B., Esteves, I., Faria, E., Marques, L. H., Neves, J. F., Silva, S. L., Teixeira, C., Pereira da Silva, S., Capilna, B. R., Guseva, M. N., Shcherbina, A., Bobcakova, A., Ciznar, P., Gabzdilova, J., Jesenak, M., Kapustova, L., Orosova, J., Petrovicova, O., Raffac, S., Kopac, P., Allende, L. M., Antoli, A., Blanch, G. R., Carbone, J., Dieli-Crimi, R., Garcia-Prat, M., Gil-Herrera, J., Gonzalez-Granado, L. I., Agullo, P. L., Olbrich, P., Parra-Martinez, A., Paz-Artal, E., Pleguezuelo, D. E., Rodriguez, N. S., Sanchez-Ramon, S., Santos-Perez, J. L., Solanich, X., Soler-Palacin, P., Gonzalez-Amores, M., Ekwall, O., Fasth, A., Bitzenhofer-Gruber, M., Candotti, F., Dimitriou, F., Heininger, U., Holbro, A., Jandus, P., Kolios, A. G. A., Marschall, K., Schmid, J. P., Posfay-Barbe, K. M., Prader, S., Reichenbach, J., Steiner, U. C., Truck, J., Bredius, R. G., de Kruijf- Bazen, S., de Vries, E., Henriet, S. S. V., Kuijpers, T. W., Potjewijd, J., Rutgers, A., Stol, K., van Aerde, K. J., Van den Berg, J. M., van de Ven, A. A. J. M., Montfrans, J., Aydemir, S., Baris, S., Dogu, F., Ikinciogullari, A., Karakoc-Aydiner, E., Kilic, S. S., Kiykim, A., Kokcu Karadag, S. I., Kutukculer, N., Ocak, S., Unal, E., Boyarchuk, O., Hilfanova, A., Kostyuchenko, L. V., Alachkar, H., Arkwright, P. D., Baxendale, H. E., Bernatoniene, J., Coulter, T. I., Garcez, T., Goddard, S., Gompels, M. M., Grigoriadou, S., Herriot, R., Herwadkar, A., Huissoon, A., Ibberson, L., Nademi, Z., Noorani, S., Parvin, S., Steele, C. L., Thomas, M., Waruiru, C., Yong, P. F. K., and Bourne, H.

Subjects
0301 basic medicine, Male, Pediatrics, syndromic, Sex Factor, Disease, registry, medicine.disease_cause, Cohort Studies, 0302 clinical medicine, Primary Immunodeficiency Disease, inborn error of immunity, Immunology and Allergy, warning signs, Age Factor, Registries, Family history, presenting symptom, Child, Primary immunodeficiency, Granuloma, autoimmune, immune dysregulation, inflammatory, Adult, Autoimmune Diseases, Female, Humans, Infections, Lymphoproliferative Disorders, Middle Aged, Primary Immunodeficiency Diseases, Sex Factors, Age Factors, 10177 Dermatology Clinic, Infections/epidemiology, 3. Good health, Settore MED/02, Warning signs, Lymphoproliferative Disorder, 2723 Immunology and Allergy, Infection, Human, medicine.medical_specialty, Immunology, 610 Medicine & health, Malignancy, primary immunodeficiency, Autoimmune Disease, 03 medical and health sciences, Immunity, Autoimmune Diseases/epidemiology, medicine, 2403 Immunology, business.industry, warning sign, Common variable immunodeficiency, Granuloma/epidemiology, Immune dysregulation, medicine.disease, Primary Immunodeficiency Diseases/epidemiology, 030104 developmental biology, Lymphoproliferative Disorders/epidemiology, Cohort Studie, business, 030215 immunology
Abstract

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Published
2021

8. Outcomes of allogeneic haematopoietic cell transplantation for myelofibrosis in children and adolescents: the retrospective study of the EBMT Paediatric Diseases WP.

Author

Wachowiak J, Galimard JE, Dalissier A, Rihani R, AlSaedi H, Wynn RF, Dalle JH, Peffault de Latour R, Sedlacek P, Balduzzi A, Schroeder T, Bodova I, Gonzalez Vicent M, Gruhn B, Hamladji RM, Krivan G, Patrick K, Sobkowiak-Sobierajska A, Stepensky P, Unal A, Amrolia P, Perez Martinez A, Rialland F, Aljurf M, Isgro A, Toren A, Bierings M, Corbacioglu S, and Kałwak K

Subjects
Humans, Child, Retrospective Studies, Child, Preschool, Adolescent, Male, Female, Infant, Transplantation Conditioning methods, Allografts, Transplantation, Homologous methods, Treatment Outcome, Disease-Free Survival, Survival Rate, Primary Myelofibrosis therapy, Primary Myelofibrosis mortality, Hematopoietic Stem Cell Transplantation methods
Abstract

This retrospective study evaluated 35 children (median age 5.2 years; range 0.4-18) with myelofibrosis (MF), including 33 with primary myelofibrosis and 2 with secondary myelofibrosis transplanted from matched sibling donor (MSD) (n = 17) or non-MSD (n = 18) between 2000 and 2022. Conditioning was usually chemotherapy-based (n = 33) and myeloablative (n = 32). Fifteen patients received bone marrow (BM), 14 haematopoietic cells (HC) from peripheral blood (PB), and 6 from cord blood (CB). Day +100 acute GvHD II-IV incidence was significantly lower after MSD-haematopoietic cell transplantation (MSD-HCT) than after non-MSD-HCT [18.8% (4.3-41.1) vs 58.8% (31-78.6); p = 0.01]. Six-year non-relapse mortality (NRM) was 18% (7.1-32.8), relapse incidence was 15.9% (5.6-30.9), progression-free survival (PFS) was 66.1% (47-79.7), GvHD-free relapse-free survival was 50% (30.6-66.7), and overall survival (OS) was 71.1% (51.4-84). Six-year PFS and OS were significantly higher after BM transplantation compared to HCT from other sources [85.1% (52.3-96.1) vs 50.8% (26.3-71), p = 0.03, and 90.9% (50.8-98.7) vs 54% (28.1-74.2), p = 0.01, respectively], whereas NRM was significantly lower [0% vs 32% (12.3-53.9); p = 0.02]. This first multicentre study on outcomes of allogeneic HCT in children with myelofibrosis proves feasibility and curative effect of transplantation in these children, suggests that bone marrow transplantation is associated with better outcomes, and indicates the need for further studies., (© 2024. The Author(s).)

Published
2024
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9. Low rate of nonrelapse mortality in under-4-year-olds with ALL given chemotherapeutic conditioning for HSCT: a phase 3 FORUM study.

Author

Bader P, Pötschger U, Dalle JH, Moser LM, Balduzzi A, Ansari M, Buechner J, Güngör T, Ifversen M, Krivan G, Pichler H, Renard M, Staciuk R, Sedlacek P, Stein J, Heusel JR, Truong T, Wachowiak J, Yesilipek A, Locatelli F, and Peters C

Subjects
Child, Child, Preschool, Humans, Recurrence, Thiotepa therapeutic use, Transplantation Conditioning adverse effects, Busulfan analogs & derivatives, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma etiology
Abstract

Abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). For young children, total body irradiation (TBI) is associated with severe late sequelae. In the FORUM study (NCT01949129), we assessed safety, event-free survival (EFS), and overall survival (OS) of 2 TBI-free conditioning regimens in children aged <4 years with ALL. Patients received fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo) before HSCT. From 2013 to 2021, 191 children received transplantation and were observed for ≥6 months (median follow-up: 3 years). The 3-year OS was 0.63 (95% confidence interval [95% CI], 0.52-0.72) and 0.76 (95% CI, 0.64-0.84) for Flu/Thio/Bu and Flu/Thio/Treo (P = .075), respectively. Three-year EFS was 0.52 (95% CI, 0.41-0.61) and 0.51 (95% CI, 0.39-0.62), respectively (P = .794). Cumulative incidence of nonrelapse mortality (NRM) and relapse at 3 years were 0.06 (95% CI, 0.02-0.12) vs 0.03 (95% CI: <0.01-0.09) (P = .406) and 0.42 (95% CI, 0.31-0.52) vs 0.45 (95% CI, 0.34-0.56) (P = .920), respectively. Grade >1 acute graft-versus-host disease (GVHD) occurred in 29% of patients receiving Flu/Thio/Bu and 17% of those receiving Flu/Thio/Treo (P = .049), whereas grade 3/4 occurred in 10% and 9%, respectively (P = .813). The 3-year incidence of chronic GVHD was 0.07 (95% CI, 0.03-0.13) vs 0.05 (95% CI, 0.02-0.11), respectively (P = .518). In conclusion, both chemotherapeutic conditioning regimens were well tolerated and NRM was low. However, relapse was the major cause of treatment failure. This trial was registered at www.clinicaltrials.gov as #NCT01949129., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Published
2024
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10. Use of eculizumab in children with allogeneic haematopoietic stem cell transplantation associated thrombotic microangiopathy - a multicentre retrospective PDWP and IEWP EBMT study.

Author

Svec P, Elfeky R, Galimard JE, Higham CS, Dalissier A, Quigg TC, Bueno Sanchez D, Han Lum S, Faraci M, Cole T, Pichler H, Benítez-Carabante MI, Horakova J, Gonzalez-Vicent M, Yanir A, Fagioli F, Wölfl M, von der Weid N, Protheroe R, Krivan G, Speckmann C, James B, Avcin SL, Bertrand Y, Verna M, Riha P, Patrick K, Cesaro S, Kalwak K, Bierings M, Büchner J, Mellgren K, Prohászka Z, Neven B, Lankester A, and Corbacioglu S

Subjects
Child, Humans, Retrospective Studies, Antibodies, Monoclonal, Humanized, Thrombotic Microangiopathies drug therapy, Thrombotic Microangiopathies etiology, Thrombotic Microangiopathies diagnosis, Hematopoietic Stem Cell Transplantation adverse effects
Abstract

Terminal complement blockade by humanised monoclonal antibody eculizumab has been used to treat transplantation-associated thrombotic microangiopathy (TA-TMA) in recent years. This retrospective international study conducted by the Paediatric Diseases (PDWP) and Inborn Error Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT) describes outcome and response of 82 paediatric patients from 29 centres who developed TA-TMA and were treated with eculizumab between January 2014 and May 2019. The median time from hematopoietic stem cell transplantation (HSCT) to TA-TMA manifestation was 92 days (range: 7-606) and from TA-TMA diagnosis to the start of eculizumab treatment 6 days (range: 0-135). Most patients received eculizumab weekly (72%, n = 55) with a standard weight (kg)-based dose (78%, n = 64). Six months from beginning of eculizumab therapy, the cumulative incidence of TA-TMA resolution was 36.6% (95% CI: 26.2-47) and the overall survival (OS) was 47.1% (95% CI: 35.9-57.5). All 43 patients with unresolved TA-TMA died. The cause of death was HSCT-related in 41 patients. This study also documents poor outcome of patients without aGvHD and their frequent concomitant viral infections. Considering recent publications, intensified eculizumab dosing and complement monitoring could potentially improve upon outcomes observed in this study., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2023
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11. Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.

Author

Geier CB, Ellison M, Cruz R, Pawar S, Leiss-Piller A, Zmajkovicova K, McNulty SM, Yilmaz M, Evans MO 2nd, Gordon S, Ujhazi B, Wiest I, Abolhassani H, Aghamohammadi A, Barmettler S, Bhar S, Bondarenko A, Bolyard AA, Buchbinder D, Cada M, Cavieres M, Connelly JA, Dale DC, Deordieva E, Dorsey MJ, Drysdale SB, Ehl S, Elfeky R, Fioredda F, Firkin F, Förster-Waldl E, Geng B, Goda V, Gonzalez-Granado L, Grunebaum E, Grzesk E, Henrickson SE, Hilfanova A, Hiwatari M, Imai C, Ip W, Jyonouchi S, Kanegane H, Kawahara Y, Khojah AM, Kim VH, Kojić M, Kołtan S, Krivan G, Langguth D, Lau YL, Leung D, Miano M, Mersyanova I, Mousallem T, Muskat M, Naoum FA, Noronha SA, Ouederni M, Ozono S, Richmond GW, Sakovich I, Salzer U, Schuetz C, Seeborg FO, Sharapova SO, Sockel K, Volokha A, von Bonin M, Warnatz K, Wegehaupt O, Weinberg GA, Wong KJ, Worth A, Yu H, Zharankova Y, Zhao X, Devlin L, Badarau A, Csomos K, Keszei M, Pereira J, Taveras AG, Beaussant-Cohen SL, Ong MS, Shcherbina A, and Walter JE

Subjects
Humans, Receptors, CXCR4 genetics, Disease Progression, Immunologic Deficiency Syndromes diagnosis, Immunologic Deficiency Syndromes epidemiology, Immunologic Deficiency Syndromes genetics, Warts diagnosis, Warts epidemiology, Warts genetics, Agammaglobulinemia genetics, Neutropenia genetics, Lymphopenia complications
Abstract

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts., (© 2022. The Author(s).)

Published
2022
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12. Correction to: A Multi-center, Open-Label, Single-Arm Trial to Evaluate the Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency.

Author

Santamaria M, Neth O, Douglass JA, Krivan G, Kobbe R, Bernatowska E, Grigoriadou S, Bethune C, Chandra A, Horneff G, Borte M, Sonnenschein A, Kralickova P, Ramón SS, Langguth DD, Gonzalez-Granado LI, Alsina L, Querolt M, Griffin R, Hames C, Mondou E, Price J, Sanz A, and Lin J

Published
2022
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13. Author Correction: Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice.

Author

Wang L, Aschenbrenner D, Zeng Z, Cao X, Mayr D, Mehta M, Capitani M, Warner N, Pan J, Wang L, Li Q, Zuo T, Cohen-Kedar S, Lu J, Ardy RC, Mulder DJ, Dissanayake D, Peng K, Huang Z, Li X, Wang Y, Wang X, Li S, Bullers S, Gammage AN, Warnatz K, Schiefer AI, Krivan G, Goda V, Kahr WHA, Lemaire M, Lu CY, Siddiqui I, Surette MG, Kotlarz D, Engelhardt KR, Griffin HR, Rottapel R, Decaluwe H, Laxer RM, Proietti M, Hambleton S, Elcombe S, Guo CH, Grimbacher B, Dotan I, Ng SC, Freeman SA, Snapper SB, Klein C, Boztug K, Huang Y, Li D, Uhlig HH, and Muise AM

Published
2022
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14. Multicenter Experience of Hematopoietic Stem Cell Transplantation in WHIM Syndrome.

Author

Laberko A, Deordieva E, Krivan G, Goda V, Bhar S, Kawahara Y, Rao K, Worth A, McDermott DH, Balashov D, Maschan A, and Shcherbina A

Subjects
Child, Humans, Primary Immunodeficiency Diseases, Receptors, CXCR4 genetics, Hematopoietic Stem Cell Transplantation, Neutropenia complications, Neutropenia therapy, Warts diagnosis, Warts genetics, Warts therapy
Abstract

Purpose: WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a rare disease, caused by CXCR4 gene mutations, which incorporates features of combined immunodeficiency, congenital neutropenia, and a predisposition to human papillomavirus infection. Established conventional treatment for WHIM syndrome does not fully prevent infectious complications in these patients. Only single case reports of hematopoietic stem cell transplantation (HSCT) efficacy in WHIM have been published., Methods: To summarize current information on HSCT efficacy in disease treatment, seven pediatric patients with WHIM syndrome who underwent allogeneic HSCT were identified in five centers worldwide., Results: All patients presented early after birth with neutropenia. Two of seven patients exhibited severe disease complications: poorly controlled autoimmunity (arthritis and anemia) in one and progressive myelofibrosis with recurrent infections in the other. The remaining patients received HSCT to correct milder disease symptoms (recurrent respiratory infections, progressing thrombocytopenia) and/or to preclude severe disease course in older age. All seven patients engrafted but one developed graft rejection and died of infectious complications after third HSCT. Three other patients experienced severe viral infections after HSCT (including post-transplant lymphoproliferative disease in one) which completely resolved with therapy. At last follow-up (median 6.7 years), all six surviving patients were alive with full donor chimerism. One patient 1.4 years after HSCT had moderate thrombocytopenia and delayed immune recovery; the others had adequate immune recovery and were free of prior disease symptoms., Conclusion: HSCT in WHIM syndrome corrects neutropenia and immunodeficiency, and leads to resolution of autoimmunity and recurrent infections, including warts., (© 2021. The Author(s).)

Published
2022
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