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2. Four Additional Doses of PEG-L-Asparaginase during the Consolidation Phase in the AIEOP-BFM ALL 2009 Protocol Do Not Improve Outcome and Increase Toxicity in High-Risk ALL: Results of a Randomized Study

Author

Conter, V, Valsecchi, M, Cario, G, Zimmermann, M, Attarbaschi, A, Stary, J, Niggli, F, Dalla Pozza, L, Elitzur, S, Silvestri, D, Locatelli, F, Moricke, A, Engstler, G, Smisek, P, Bodmer, N, Barbaric, D, Izraeli, S, Rizzari, C, Boos, J, Buldini, B, Zucchetti, M, Von Stackelberg, A, Matteo, C, Lehrnbecher, T, Lanvers-Kaminsky, C, Cazzaniga, G, Gruhn, B, Biondi, A, Schrappe, M, Conter V., Valsecchi M. G., Cario G., Zimmermann M., Attarbaschi A., Stary J., Niggli F., Dalla Pozza L., Elitzur S., Silvestri D., Locatelli F., Moricke A., Engstler G., Smisek P., Bodmer N., Barbaric D., Izraeli S., Rizzari C., Boos J., Buldini B., Zucchetti M., Von Stackelberg A., Matteo C., Lehrnbecher T., Lanvers-Kaminsky C., Cazzaniga G., Gruhn B., Biondi A., Schrappe M., Conter, V, Valsecchi, M, Cario, G, Zimmermann, M, Attarbaschi, A, Stary, J, Niggli, F, Dalla Pozza, L, Elitzur, S, Silvestri, D, Locatelli, F, Moricke, A, Engstler, G, Smisek, P, Bodmer, N, Barbaric, D, Izraeli, S, Rizzari, C, Boos, J, Buldini, B, Zucchetti, M, Von Stackelberg, A, Matteo, C, Lehrnbecher, T, Lanvers-Kaminsky, C, Cazzaniga, G, Gruhn, B, Biondi, A, Schrappe, M, Conter V., Valsecchi M. G., Cario G., Zimmermann M., Attarbaschi A., Stary J., Niggli F., Dalla Pozza L., Elitzur S., Silvestri D., Locatelli F., Moricke A., Engstler G., Smisek P., Bodmer N., Barbaric D., Izraeli S., Rizzari C., Boos J., Buldini B., Zucchetti M., Von Stackelberg A., Matteo C., Lehrnbecher T., Lanvers-Kaminsky C., Cazzaniga G., Gruhn B., Biondi A., and Schrappe M.

Abstract

PURPOSEThe AIEOP-BFM ALL 2009 protocol included, at the end of the induction phase, a randomized study of patients with high-risk (HR) ALL to investigate if an intensive exposure to pegylated L-asparaginase (PEG-ASNASE, 2,500 IU/sqm once a week × 4) on top of BFM consolidation phase IB allowed us to decrease minimal residual disease (MRD) and improve outcome.PATIENTS AND METHODSA total of 1,097 patients presented, from June 2010 to February 2017, with one or more of the following HR criteria: KMT2A::AFF1 rearrangement, hypodiploidy, prednisone poor response, poor bone marrow response at day 15 (Flow MRD ≥10%), or no complete remission (CR) at the end of induction. Of them, 809 (85.1%) were randomly assigned to receive (404) or not receive (405) four weekly doses of PEG-ASNASE.RESULTSBy intention to treat (ITT) analysis, there was no significant difference in the proportion of patients with polimerase chain reaction MRD ≥5 × 10-4 at the end of phase IB in the experimental versus control arm (13.9% v 17.0%, P =.25). The 5-year event-free survival (median follow-up 6.3 years) by ITT in the experimental and control arms was 70.4% (2.3) versus 75.0% (2.2; P =.18), and the 5-year overall survival was 81.5% (2.0) versus 84.0% (1.9; P =.25), respectively. The corresponding 5-year cumulative incidence of death in CR was 9.5% (1.5) versus 5.7% (1.2; P =.08), and that of relapse was 17.7% (1.9) versus 17.2% (1.9), respectively (P =.94). Adverse reactions in phase IB occurred in 22.2% and 8.9% of patients in the experimental and control arm, respectively (P <.001).CONCLUSIONAdditional PEG-ASNASE in phase IB did not translate into a benefit for decreasing relapse incidence but was associated with higher toxicity. Further improvements with conventional chemotherapy might be difficult in the context of intensive treatment protocols.

Published
2024

3. Musculoskeletal manifestations of childhood cancer and differential diagnosis with juvenile idiopathic arthritis (ONCOREUM): a multicentre, cross-sectional study

Author

Amatruda, M, Atzeni, C, Bertolini, P, Bigucci, B, Caniglia, M, Cappella, M, Cattalini, M, Cefalo, MG, Cellini, M, Cortis, E, Davì, S, De Benedetti, F, Di Cataldo, A, Fabbri, E, Fagioli, F, Fontanili, I, Garaventa, A, Gicchino, MF, Ladogana, S, Locatelli, F, Magnolato, A, Marsili, M, Martino, S, Mascarin, M, Messina, C, Micalizzi, C, Porta, F, Rizzari, C, Civino, Adele, Alighieri, Giovanni, Prete, Eleonora, Caroleo, Anna Maria, Magni-Manzoni, Silvia, Vinti, Luciana, Romano, Micol, Santoro, Nicola, Filocamo, Giovanni, Belotti, Tamara, Santarelli, Francesca, Gorio, Chiara, Ricci, Francesca, Colombini, Antonella, Pastore, Serena, Cesaro, Simone, Barone, Patrizia, Verzegnassi, Federico, Olivieri, Alma Nunzia, Ficara, Monica, Miniaci, Angela, Russo, Giovanna, Gallizzi, Romina, Pericoli, Roberta, Breda, Luciana, Mura, Rossella, Podda, Rosa Anna, Onofrillo, Daniela, Lattanzi, Bianca, Tirtei, Elisa, Maggio, Maria Cristina, De Santis, Raffaela, Consolini, Rita, Arlotta, Annalisa, La Torre, Francesco, Mainardi, Chiara, Pelagatti, Maria Antonietta, Coassin, Elisa, Capolsini, Ilaria, Burnelli, Roberta, Tornesello, Assunta, Soscia, Francesca, De Fanti, Alessandro, Rigante, Donato, Pizzato, Cristina, De Fusco, Carmela, Abate, Massimo Eraldo, Roncadori, Andrea, Rossi, Elisa, Stabile, Giulia, Biondi, Andrea, Lepore, Loredana, Conter, Valentino, Rondelli, Roberto, Pession, Andrea, and Ravelli, Angelo

Published
2021
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4. Hypersensitivity Reactions to Native E. coli L-asparaginase in Children with Acute Lymphoblastic Leukemia Treated in Trial ALL-BFM 2000: Impact of Treatment Schedule and Type of Glucocorticoid in Induction

Author

Moricke, A, Rizzari, C, Alten, J, Attarbaschi, A, Beier, R, Biondi, A, Burkhardt, B, Bodmer, N, Boos, J, Cario, G, Conter, V, Flotho, C, Kulozik, A, Lanvers-Kaminsky, C, Mann, G, Niggli, F, Silvestri, D, Von Stackelberg, A, Stanulla, M, Valsecchi, M, Schrappe, M, Zimmermann, M, Moricke A., Rizzari C., Alten J., Attarbaschi A., Beier R., Biondi A., Burkhardt B., Bodmer N., Boos J., Cario G., Conter V., Flotho C., Kulozik A., Lanvers-Kaminsky C., Mann G., Niggli F., Silvestri D., Von Stackelberg A., Stanulla M., Valsecchi MG., Schrappe M., Zimmermann M., Moricke, A, Rizzari, C, Alten, J, Attarbaschi, A, Beier, R, Biondi, A, Burkhardt, B, Bodmer, N, Boos, J, Cario, G, Conter, V, Flotho, C, Kulozik, A, Lanvers-Kaminsky, C, Mann, G, Niggli, F, Silvestri, D, Von Stackelberg, A, Stanulla, M, Valsecchi, M, Schrappe, M, Zimmermann, M, Moricke A., Rizzari C., Alten J., Attarbaschi A., Beier R., Biondi A., Burkhardt B., Bodmer N., Boos J., Cario G., Conter V., Flotho C., Kulozik A., Lanvers-Kaminsky C., Mann G., Niggli F., Silvestri D., Von Stackelberg A., Stanulla M., Valsecchi MG., Schrappe M., and Zimmermann M.

Published
2023

5. Improved survival and MRD remission with blinatumomab vs. chemotherapy in children with first high-risk relapse B-ALL

Author

Locatelli, F, Zugmaier, G, Rizzari, C, Morris, J, Gruhn, B, Klingebiel, T, Parasole, R, Linderkamp, C, Flotho, C, Petit, A, Micalizzi, C, Zeng, Y, Desai, R, Kormany, W, Eckert, C, Moricke, A, Sartor, M, Hrusak, O, Peters, C, Saha, V, Vinti, L, von Stackelberg, A, Locatelli F., Zugmaier G., Rizzari C., Morris J. D., Gruhn B., Klingebiel T., Parasole R., Linderkamp C., Flotho C., Petit A., Micalizzi C., Zeng Y., Desai R., Kormany W. N., Eckert C., Moricke A., Sartor M., Hrusak O., Peters C., Saha V., Vinti L., von Stackelberg A., Locatelli, F, Zugmaier, G, Rizzari, C, Morris, J, Gruhn, B, Klingebiel, T, Parasole, R, Linderkamp, C, Flotho, C, Petit, A, Micalizzi, C, Zeng, Y, Desai, R, Kormany, W, Eckert, C, Moricke, A, Sartor, M, Hrusak, O, Peters, C, Saha, V, Vinti, L, von Stackelberg, A, Locatelli F., Zugmaier G., Rizzari C., Morris J. D., Gruhn B., Klingebiel T., Parasole R., Linderkamp C., Flotho C., Petit A., Micalizzi C., Zeng Y., Desai R., Kormany W. N., Eckert C., Moricke A., Sartor M., Hrusak O., Peters C., Saha V., Vinti L., and von Stackelberg A.

Published
2023

6. Incidence and Characteristics of Hypersensitivity Reactions to PEG-asparaginase Observed in 6136 Children with Acute Lymphoblastic Leukemia Enrolled in the AIEOP-BFM ALL 2009 Study Protocol

Author

Rizzari, C, Möricke, A, Valsecchi, M, Conter, V, Zimmermann, M, Silvestri, D, Attarbaschi, A, Niggli, F, Barbaric, D, Stary, J, Elitzur, S, Cario, G, Vinti, L, Boos, J, Zucchetti, M, Lanvers-Kaminsky, C, Von Stackelberg, A, Biondi, A, Schrappe, M, Rizzari C., Möricke A., Valsecchi M. G., Conter V., Zimmermann M., Silvestri D., Attarbaschi A., Niggli F., Barbaric D., Stary J., Elitzur S., Cario G., Vinti L., Boos J., Zucchetti M., Lanvers-Kaminsky C., Von Stackelberg A., Biondi A., Schrappe M., Rizzari, C, Möricke, A, Valsecchi, M, Conter, V, Zimmermann, M, Silvestri, D, Attarbaschi, A, Niggli, F, Barbaric, D, Stary, J, Elitzur, S, Cario, G, Vinti, L, Boos, J, Zucchetti, M, Lanvers-Kaminsky, C, Von Stackelberg, A, Biondi, A, Schrappe, M, Rizzari C., Möricke A., Valsecchi M. G., Conter V., Zimmermann M., Silvestri D., Attarbaschi A., Niggli F., Barbaric D., Stary J., Elitzur S., Cario G., Vinti L., Boos J., Zucchetti M., Lanvers-Kaminsky C., Von Stackelberg A., Biondi A., and Schrappe M.

Abstract

The incidence of hypersensitivity reactions (HSRs) to PEG-asparaginase (PEG-ASNase) was evaluated in 6136 children with ALL enrolled in the AIEOP-BFM ALL 2009 study. Patients with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) were stratified as standard-risk/medium-risk (MR)/high-risk (HR) and those with T-ALL as non-High/HR. PEG-ASNase was administered intravenously at 2500 IU/sqm/dose. All patients received 2 PEG-ASNase doses in induction; thereafter non-HR versus HR patients received 1 versus 6 PEG-ASNase doses, respectively. After the single regular dose of PEG-ASNase at the beginning of delayed intensification, BCP-ALL-MR patients were randomized to receive 9 additional PEG-ASNase doses every 2 weeks (experimental arm [EA]) versus none (standard arm [SA]); HR patients were randomized to receive, in consolidation, 4 weekly PEG-ASNase doses (EA) versus none (SA). The HSR cumulative incidence (CI) was estimated adjusting for competing risks. An HSR occurred in 472 of 6136 (7.7%) patients. T-non- HR/BCP-Standard-Risk, BCP-MR-SA, BCP-MR-EA, HR-SA and HR-EA patients had 1-year-CI-HSR (±SE) rates of 5.2% (0.5), 5.2% (0.5), 4.0% (0.8), 20.2% (1.2), and 6.4% (1.3), respectively. The randomized intensification of PEG-ASNase did not significantly impact on HSR incidence in BCP-MR patients (1-y-CI-HSR 3.8% [0.8] versus 3.2% [0.6] in MR-EA versus MR-SA; P = 0.55), while impacted significantly in HR patients (1-y-CI-HSR 6.4% [1.3] versus 17.9% [1.8] in HR-EA and HR-SA, respectively; P < 0.001). The CI-HSR was comparable among non-HR groups and was not increased by a substantial intensification of PEG-ASNase in the BCP-MR-EA group whilst it was markedly higher in HR-SA than in HR-EA patients, suggesting that, in such a chemotherapy context, a continuous exposure to PEG-ASNase reduces the risk of developing an HSR.

Published
2023

7. Incidence and Characteristics of Hypersensitivity Reactions to PEG-asparaginase Observed in 6136 Children with Acute Lymphoblastic Leukemia Enrolled in the AIEOP-BFM ALL 2009 Study Protocol

Author

Rizzari C., Möricke A., Valsecchi M. G., Conter V., Zimmermann M., Silvestri D., Attarbaschi A., Niggli F., Barbaric D., Stary J., Elitzur S., Cario G., Vinti L., Boos J., Zucchetti M., Lanvers-Kaminsky C., Von Stackelberg A., Biondi A., Schrappe M., Rizzari, C, Möricke, A, Valsecchi, M, Conter, V, Zimmermann, M, Silvestri, D, Attarbaschi, A, Niggli, F, Barbaric, D, Stary, J, Elitzur, S, Cario, G, Vinti, L, Boos, J, Zucchetti, M, Lanvers-Kaminsky, C, Von Stackelberg, A, Biondi, A, and Schrappe, M

Subjects
MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, acute lymphoblastic leukemia, childhood, chemoterapy, asparaginase
Abstract

The incidence of hypersensitivity reactions (HSRs) to PEG-asparaginase (PEG-ASNase) was evaluated in 6136 children with ALL enrolled in the AIEOP-BFM ALL 2009 study. Patients with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) were stratified as standard-risk/medium-risk (MR)/high-risk (HR) and those with T-ALL as non-High/HR. PEG-ASNase was administered intravenously at 2500 IU/sqm/dose. All patients received 2 PEG-ASNase doses in induction; thereafter non-HR versus HR patients received 1 versus 6 PEG-ASNase doses, respectively. After the single regular dose of PEG-ASNase at the beginning of delayed intensification, BCP-ALL-MR patients were randomized to receive 9 additional PEG-ASNase doses every 2 weeks (experimental arm [EA]) versus none (standard arm [SA]); HR patients were randomized to receive, in consolidation, 4 weekly PEG-ASNase doses (EA) versus none (SA). The HSR cumulative incidence (CI) was estimated adjusting for competing risks. An HSR occurred in 472 of 6136 (7.7%) patients. T-non- HR/BCP-Standard-Risk, BCP-MR-SA, BCP-MR-EA, HR-SA and HR-EA patients had 1-year-CI-HSR (±SE) rates of 5.2% (0.5), 5.2% (0.5), 4.0% (0.8), 20.2% (1.2), and 6.4% (1.3), respectively. The randomized intensification of PEG-ASNase did not significantly impact on HSR incidence in BCP-MR patients (1-y-CI-HSR 3.8% [0.8] versus 3.2% [0.6] in MR-EA versus MR-SA; P = 0.55), while impacted significantly in HR patients (1-y-CI-HSR 6.4% [1.3] versus 17.9% [1.8] in HR-EA and HR-SA, respectively; P < 0.001). The CI-HSR was comparable among non-HR groups and was not increased by a substantial intensification of PEG-ASNase in the BCP-MR-EA group whilst it was markedly higher in HR-SA than in HR-EA patients, suggesting that, in such a chemotherapy context, a continuous exposure to PEG-ASNase reduces the risk of developing an HSR.

Published
2023

8. Hypersensitivity Reactions to Native E. coli L-asparaginase in Children with Acute Lymphoblastic Leukemia Treated in Trial ALL-BFM 2000: Impact of Treatment Schedule and Type of Glucocorticoid in Induction

Author

Moricke A., Rizzari C., Alten J., Attarbaschi A., Beier R., Biondi A., Burkhardt B., Bodmer N., Boos J., Cario G., Conter V., Flotho C., Kulozik A., Lanvers-Kaminsky C., Mann G., Niggli F., Silvestri D., Von Stackelberg A., Stanulla M., Valsecchi MG., Schrappe M., Zimmermann M., Moricke, A, Rizzari, C, Alten, J, Attarbaschi, A, Beier, R, Biondi, A, Burkhardt, B, Bodmer, N, Boos, J, Cario, G, Conter, V, Flotho, C, Kulozik, A, Lanvers-Kaminsky, C, Mann, G, Niggli, F, Silvestri, D, Von Stackelberg, A, Stanulla, M, Valsecchi, M, Schrappe, M, and Zimmermann, M

Subjects
acute lymphoblastic leukemia, immunotherapy, MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, chemotherapy, childhood
Published
2023

9. Mucopolysaccharidosis-Plus Syndrome, a Rapidly Progressive Disease: Favorable Impact of a Very Prolonged Steroid Treatment on the Clinical Course in a Child

Author

Faraguna, M, Musto, F, Crescitelli, V, Iascone, M, Spaccini, L, Tonduti, D, Fedeli, T, Kullmann, G, Canonico, F, Cattoni, A, Dell'Acqua, F, Rizzari, C, Gasperini, S, Faraguna M. C., Musto F., Crescitelli V., Iascone M., Spaccini L., Tonduti D., Fedeli T., Kullmann G., Canonico F., Cattoni A., Dell'acqua F., Rizzari C., Gasperini S., Faraguna, M, Musto, F, Crescitelli, V, Iascone, M, Spaccini, L, Tonduti, D, Fedeli, T, Kullmann, G, Canonico, F, Cattoni, A, Dell'Acqua, F, Rizzari, C, Gasperini, S, Faraguna M. C., Musto F., Crescitelli V., Iascone M., Spaccini L., Tonduti D., Fedeli T., Kullmann G., Canonico F., Cattoni A., Dell'acqua F., Rizzari C., and Gasperini S.

Abstract

Mucopolysaccharidosis-plus syndrome (MPS-PS) is a novel autosomal recessive disorder caused by a mutation in the VPS33A gene. This syndrome presents with typical symptoms of mucopolysaccharidosis, as well as congenital heart defects, renal, and hematopoietic system disorders. To date, twenty-four patients have been described. There is no specific therapy for MPS-PS; clinical management is therefore limited to symptoms management. The clinical course is rapidly progressive, and most patients die before 1–2 years of age. We describe a currently 6-year-old male patient with MPS-PS presenting with multiorgan involvement. Symptoms started at four months of age when he progressively suffered from numerous acute and potentially life-threatening events. When he was two years old, he developed secondary hemophagocytic lymphohistiocytosis (HLH), which was successfully treated with steroids. To date, this child represents the oldest patient affected by MPS-PS described in the literature and the first one presenting with a life-threatening secondary HLH. The prolonged steroid treatment allowed a stabilization of his general and hematological conditions and probably determined an improvement of his psychomotor milestones and new neurological acquisitions with an improvement of quality of life. HLH should be suspected and adequately treated in MPS-PS patients presenting with suggestive symptoms of the disease. The usefulness of a prolonged steroid treatment to improve the clinical course of children with MPS-PS deserves further investigation.

Published
2022

10. Prognostic significance of chromosomal abnormalities at relapse in children with relapsed acute myeloid leukemia: A retrospective cohort study of the Relapsed AML 2001/01 Study

Author

Klein, K, Beverloo, H, Zimmermann, M, Raimondi, S, von Neuhoff, C, de Haas, V, van Weelderen, R, Cloos, J, Abrahamsson, J, Bertrand, Y, Dworzak, M, Fynn, A, Gibson, B, Ha, S, Harrison, C, Hasle, H, Elitzur, S, Leverger, G, Maschan, A, Razzouk, B, Reinhardt, D, Rizzari, C, Smisek, P, Creutzig, U, Kaspers, G, Klein K., Beverloo H. B., Zimmermann M., Raimondi S. C., von Neuhoff C., de Haas V., van Weelderen R., Cloos J., Abrahamsson J., Bertrand Y., Dworzak M., Fynn A., Gibson B., Ha S. -Y., Harrison C. J., Hasle H., Elitzur S., Leverger G., Maschan A., Razzouk B., Reinhardt D., Rizzari C., Smisek P., Creutzig U., Kaspers G. J. L., Klein, K, Beverloo, H, Zimmermann, M, Raimondi, S, von Neuhoff, C, de Haas, V, van Weelderen, R, Cloos, J, Abrahamsson, J, Bertrand, Y, Dworzak, M, Fynn, A, Gibson, B, Ha, S, Harrison, C, Hasle, H, Elitzur, S, Leverger, G, Maschan, A, Razzouk, B, Reinhardt, D, Rizzari, C, Smisek, P, Creutzig, U, Kaspers, G, Klein K., Beverloo H. B., Zimmermann M., Raimondi S. C., von Neuhoff C., de Haas V., van Weelderen R., Cloos J., Abrahamsson J., Bertrand Y., Dworzak M., Fynn A., Gibson B., Ha S. -Y., Harrison C. J., Hasle H., Elitzur S., Leverger G., Maschan A., Razzouk B., Reinhardt D., Rizzari C., Smisek P., Creutzig U., and Kaspers G. J. L.

Abstract

Background: In addition to treatment response, cytogenetic and molecular aberrations are the most important prognostic factors in children with de novo acute myeloid leukemia (AML). However, little is known about cytogenetics at the time of relapse. Methods: This international study analyzed the prognostic value of cytogenetic profiles and karyotypic changes in pediatric relapsed AML in relation to the probability of event-free (pEFS) and overall survival (pOS). For this purpose, cytogenetic reports from all patients registered on the Relapsed AML 2001/01 Study were reviewed and classified. Results: Cytogenetic information at relapse was available for 403 (71%) of 569 registered patients. Frequently detected aberrations at relapse were t(8;21)(q22;q22) (n = 60) and inv(16)(p13.1q22)/t(16;16)(p13.1;q22) (n = 24), both associated with relatively good outcome (4-year pOS 59% and 71%, respectively). Monosomy 7/7q−, t(9;11)(p22;q23), t(10;11)(p12;q23), and complex karyotypes were associated with poor outcomes (4-year pOS 17%, 19%, 22%, and 22%, respectively). Of 261 (65%) patients for whom cytogenetic data were reliable at both diagnosis and relapse, pEFS was inferior for patients with karyotypic instability (n = 128, 49%), but pOS was similar. Unstable karyotypes with both gain and loss of aberrations were associated with inferior outcome. Early treatment response, time to relapse, and cytogenetic profile at time of relapse were the most important prognostic factors, both outweighing karytoypic instability per se. Conclusion: The cytogenetic subgroup at relapse is an independent risk factor for (event-free) survival. Cytogenetic assessment at the time of relapse is of high importance and may contribute to improved risk-adapted treatment for children with relapsed AML.

Published
2022

11. Pharmacological and clinical monitoring in children with acute lymphoblastic leukemia treated with a biogeneric PEG-l-asparaginase product

Author

Matteo, C, Colombini, A, Bettini, L, Porcu, L, Barzaghi, S, Ceruti, T, Silvestri, D, Amoroso, A, Dell'Acqua, F, Gotti, G, Nastasi, C, Zucchetti, M, Rizzari, C, Matteo C., Colombini A., Bettini L. R., Porcu L., Barzaghi S., Ceruti T., Silvestri D., Amoroso A., Dell'Acqua F., Gotti G., Nastasi C., Zucchetti M., Rizzari C., Matteo, C, Colombini, A, Bettini, L, Porcu, L, Barzaghi, S, Ceruti, T, Silvestri, D, Amoroso, A, Dell'Acqua, F, Gotti, G, Nastasi, C, Zucchetti, M, Rizzari, C, Matteo C., Colombini A., Bettini L. R., Porcu L., Barzaghi S., Ceruti T., Silvestri D., Amoroso A., Dell'Acqua F., Gotti G., Nastasi C., Zucchetti M., and Rizzari C.

Abstract

Background: l-Asparaginase (ASP) plays a crucial role in the treatment of childhood acute lymphoblastic leukemia (ALL). Currently, different ASP products are available in the market, including both native and pegylated drugs. Several biogeneric Escherichia coli ASP (GEN-ASP) products have been developed in response to shortages and expensiveness of the native E. coli ASP innovator compounds, but some concerns have been raised about their quality. Recently, a number of generic pegylated ASP products (GEN-PEG-ASP) have been marketed to substitute for the innovator product (PEG-ASP). Methods: Clinical courses and serum asparaginase activity (SAA) levels were monitored in 12 children with ALL, who were treated in our institution with two doses of a GEN-PEG-ASP product, given IV at 2500 IU/m2 during the remission induction phase. Results were compared with those obtained in a reference cohort of 35 patients treated in our institution, who received the innovator PEG-ASP product at same dosage and within the same chemotherapy background. Results: Compared to the reference cohort treated with PEG-ASP, SAA levels were significantly lower in the 12 patients receiving GEN-PEG-ASP (p <.0001); a higher proportion of ASP-associated hypersensitivity reactions (2/12 vs. 0/35; p =.061) and silent inactivation (3/12 vs. 0/35; p =.014) were observed in comparison with the reference cohort. Conclusions: Our results highlighted different pharmacological profiles and different rates of hypersensitivity reactions and silent inactivation in the GEN-PEG-ASP cohort compared to those treated with the innovator product. Our findings suggest that a rigorous clinical attention and a thorough pharmacological monitoring are advisable in patients treated with GEN-PEG-ASP products.

Published
2022

12. NUP214–ABL1 fusion in childhood T-ALL

Author

Veltri, G, Sandei, M, Silvestri, D, Bresolin, S, Pession, A, Santoro, N, Ziino, O, Veltroni, M, Rizzari, C, Biffi, A, Valsecchi, M, Conter, V, Buldini, B, Accordi, B, Serafin, V, Veltri G., Sandei M., Silvestri D., Bresolin S., Pession A., Santoro N., Ziino O., Veltroni M., Rizzari C., Biffi A., Valsecchi M. G., Conter V., Buldini B., Accordi B., Serafin V., Veltri, G, Sandei, M, Silvestri, D, Bresolin, S, Pession, A, Santoro, N, Ziino, O, Veltroni, M, Rizzari, C, Biffi, A, Valsecchi, M, Conter, V, Buldini, B, Accordi, B, Serafin, V, Veltri G., Sandei M., Silvestri D., Bresolin S., Pession A., Santoro N., Ziino O., Veltroni M., Rizzari C., Biffi A., Valsecchi M. G., Conter V., Buldini B., Accordi B., and Serafin V.

Published
2022

13. Impact of Antibodies Against Polyethylene Glycol on the Pharmacokinetics of PEGylated Asparaginase in Children with Acute Lymphoblastic Leukaemia: A Population Pharmacokinetic Approach

Author

Siebel, C, Lanvers-Kaminsky, C, Alten, J, Smisek, P, Nath, C, Rizzari, C, Boos, J, Wurthwein, G, Siebel C., Lanvers-Kaminsky C., Alten J., Smisek P., Nath C. E., Rizzari C., Boos J., Wurthwein G., Siebel, C, Lanvers-Kaminsky, C, Alten, J, Smisek, P, Nath, C, Rizzari, C, Boos, J, Wurthwein, G, Siebel C., Lanvers-Kaminsky C., Alten J., Smisek P., Nath C. E., Rizzari C., Boos J., and Wurthwein G.

Abstract

Background and Objectives: Besides allergic reactions, antibodies against polyethylene glycol (PEG) have been associated with reduced PEG-asparaginase (PEG-ASNase) activity. Population pharmacokinetics (popPK) allow for an in-depth investigation of the influence of anti-PEG antibodies on PEG-ASNase pharmacokinetics. Methods: PEG-ASNase activity (6261 samples) and anti-PEG antibodies (2082/6412 samples prior to/post administration) in 1444 children with acute lymphoblastic leukaemia treated in the AIEOP-BFM ALL 2009 trial were evaluated. Patients received two doses of PEG-ASNase during induction (2500 U/m2, intravenous, biweekly) and a third dose during reinduction treatment. Anti-PEG IgG and IgM measured prior to and post administration were explored for their influence on the initial clearance of PEG-ASNase using a previously established popPK model. Categorical and continuous antibody data, including each isotype individually as well as in combination, were assessed. Results: High pre-existing levels of anti-PEG antibodies increase the initial drug clearance. Analysed separately, both anti-PEG IgGprior and IgMprior were significant covariates; the stronger effect was observed for anti-PEG IgMprior. Hockey stick models best described the data. For anti-PEG IgMprior, each additional log unit above the estimated cut point was related to a 41.4% increase in initial clearance after the first dose in induction. Antibody levels below the cut point were not associated with an effect on clearance. The combination of both isotypes did not provide additional information compared to anti-PEG IgMprior alone. Antibody levels post administration were not associated with an effect on clearance. Conclusion: Pre-existing antibodies against PEG-ASNase significantly increased the initial clearance in a subgroup of patients showing high antibody levels. (Trial registration: EU clinical trials register; EudraCT No: 2007-004270-43; first registered 23 October 2009.)

Published
2022

14. Challenging Management of Severe Differentiation Syndrome in Pediatric Acute Promyelocytic Leukemia Treated with ATRA/ATO

Author

Molinaro, A, Zanta, D, Moleti, M, Giona, F, Conter, V, Rizzari, C, Biondi, A, Testi, A, Molinaro A., Zanta D., Moleti M. L., Giona F., Conter V., Rizzari C., Biondi A., Testi A. M., Molinaro, A, Zanta, D, Moleti, M, Giona, F, Conter, V, Rizzari, C, Biondi, A, Testi, A, Molinaro A., Zanta D., Moleti M. L., Giona F., Conter V., Rizzari C., Biondi A., and Testi A. M.

Published
2022

15. Global effort to evacuate Ukrainian children with cancer and blood disorders who have been affected by war

Author

Agulnik, A, Kizyma, R, Salek, M, Wlodarski, M, Pogorelyy, M, Oszer, A, Yakimkova, T, Nogovitsyna, Y, Dutkiewicz, M, Dalle, J, Dirksen, U, Eggert, A, Fernandez-Teijeiro, A, Greiner, J, Kraal, K, Mueller, A, Sramkova, L, Zecca, M, Wise, P, Mlynarski, W, Avula, M, Adyrov, M, Berlanga, P, Blackwood, C, Bouffet, E, Czauderna, P, de Koning, L, dos Reis Farinha, N, Foster, W, Graetz, D, Gupta, S, Holter, W, Hough, R, Kliuchkivska, K, Kolenova, A, Kolodrubiec, J, Moreira, D, Mukkada, S, Mykychak, I, Raciborska, A, Salman, Z, Sopilnyak, A, Tyupa, S, Vinitsky, A, Wobst, N, Miller, B, Rasul, S, Rodriguez-Galindo, C, Alanbousi, I, Alexander, S, Apel, A, Bal, W, Balwierz, W, Basset-Salom, L, Bastardo Blanco, D, Bauer, K, Bayazitov, I, Bhakta, N, Bien, E, Bieniek, K, Blair, S, Bodak, K, Bordeianu, I, Braganca, J, Bucurenci, M, Budny, E, Budzyn, A, Bumgardner, C, Burditt, R, Burnside Clapp, V, Bykov, V, Canete, A, Carnelli, M, Cela, E, Cepowska, Z, Chaber, R, Cherner-Drieux, A, Chubata, M, Clough, H, Czernicka - Siwecka, J, Czyzewski, K, Dashchakovska, O, Dembowska-Baginska, B, Derwich, K, Dommett, R, Dorosh, O, Drabko, K, Dragomir, M, Dworzak, M, Dyma, S, Earl, J, English, M, Evseev, D, Farren, B, Fedyk, N, Ferneza, S, Fox Irwin, L, Galazkowski, R, Ganieva, G, Garanzha, V, Gelman, M, Godzinski, J, Goeres, A, Golban, R, Griksaitis, M, Hampel, M, Hastings, S, Heenen, D, Hill, M, Holiuk, I, Hutnik, L, Irga-Jaworska, N, Istomin, O, Janczar, S, Kacharian, A, Kalwak, K, Karolczyk, G, Karpenko, N, Katsubo, H, Kaznowska, B, Kentsis, A, Ketteler, P, Kienesberger, A, Kiselev, R, Kizyma, Z, Klymniuk, H, Kostiuk, Y, Kowalik, T, Kozlova, O, Kozubenko, V, Kramar, T, Krawczuk-Rybak, M, Kulemzina, I, Kurkowska, P, Kuzyk, A, Ladenstein, R, Laguna, P, Lassaletta, A, Lehmberg, K, Leontieva, O, Liashenko, S, Loizou, L, Lucchetta, S, Lupo, M, Lysytsia, L, Lysytsia, O, Machnik, K, Mainland, J, Matczak, K, Matysiak, M, Mayeur, P, Minervina, A, Mishkova, V, Mizia-Malarz, A, Morales La Madrid, A, Moreno, L, Moskvin, V, Muszynska-Roslan, K, Nelson, A, Ociepa, T, Oltolini, S, Onipko, N, Pappas, A, Patel, A, Patrahau, A, Pauley, J, Pavlenko, Y, Pavlovych, A, Peregud-Pogorzelski, J, Perek-Polnik, M, Perez, V, Perez-Martinez, A, Pikman, Y, Pitozzi, G, Portugal, R, Posternak, V, Prete, A, Pritchard-Jones, K, Radaelli, A, Reeves, T, Reinhardt, D, Reshetnyak, A, Rider, A, Rizzari, C, Rizzi, D, Rodriguez Hermosillo, K, Ronenko, O, Rostowska, A, Rudko, L, Sakaan, F, Sakhar, N, Savva, N, Scaccaglia, D, Schaeffer, E, Schneider, C, Scobie, N, Semeniuk, O, Shevchyk, R, Shuler, A, Shvets, S, Skoczen, S, Smeal, W, Sokolowski, I, Sonkin, A, Stepanjuk, A, Spota, A, Sterba, J, Styczynski, J, Svintsova, O, Synyuta, A, Szczepanski, T, Szczucinski, P, Szmyd, B, Tasso Cereceda, M, Teliuk, A, Tomanek, I, Topping, P, Torrent, M, Trelinska, J, Troyanovska, O, Trubnikova, E, Tsurkan, L, Tsymbalyuk-Voloshyn, I, Urasinski, T, Urbanek-Dadela, A, Vasilieva, N, Vasilyeva, A, Verdu-Amoros, J, Vilcu-Bajurean, N, Vinitsky, L, Volpe, G, Vorobel, O, Wachowiak, J, Wasiak, M, Wiedower, L, Wuenschel, L, Wysocki, M, Yurieva, M, Zagurska, A, Zakharenko, S, Zakharenko, A, Zapotochna, K, Zawitkowska, J, Agulnik A., Kizyma R., Salek M., Wlodarski M. W., Pogorelyy M., Oszer A., Yakimkova T., Nogovitsyna Y., Dutkiewicz M., Dalle J. -H., Dirksen U., Eggert A., Fernandez-Teijeiro A., Greiner J., Kraal K., Mueller A., Sramkova L., Zecca M., Wise P. H., Mlynarski W., Avula M., Adyrov M. V., Berlanga P., Blackwood C. A., Bouffet E., Czauderna P. S., de Koning L. A., dos Reis Farinha N. J., Foster W. B., Graetz D. E., Gupta S., Holter W., Hough R. E., Kliuchkivska K., Kolenova A., Kolodrubiec J., Moreira D. C., Mukkada S. T., Mykychak I., Raciborska A., Salman Z. S., Sopilnyak A., Tyupa S., Vinitsky A., Wobst N. M., Miller B. A., Rasul S. S., Rodriguez-Galindo C., Alanbousi I., Alexander S. W., Apel A., Bal W. A., Balwierz W. A., Basset-Salom L., Bastardo Blanco D., Bauer K. J., Bayazitov I. T., Bhakta N. H., Bien E. I., Bieniek K. A., Blair S. J., Bodak K. I., Bordeianu I. M., Braganca J. M., Bucurenci M. S., Budny E. B., Budzyn A., Bumgardner C. C., Burditt R. N., Burnside Clapp V. G., Bykov V., Canete A., Carnelli M., Cela E., Cepowska Z. P., Chaber R., Cherner-Drieux A., Chubata M., Clough H. M., Czernicka - Siwecka J., Czyzewski K., Dashchakovska O., Dembowska-Baginska B. M., Derwich K., Dommett R., Dorosh O., Drabko K. A., Dragomir M. D., Dworzak M., Dyma S., Earl J. D., English M. W., Evseev D. A., Farren B. S., Fedyk N., Ferneza S., Fox Irwin L. E., Galazkowski R. M., Ganieva G., Garanzha V., Gelman M. S., Godzinski J. K., Goeres A. F., Golban R., Griksaitis M. J., Hampel M. A., Hastings S. G., Heenen D. L., Hill M. C., Holiuk I., Hutnik L. M., Irga-Jaworska N., Istomin O., Janczar S. L., Kacharian A., Kalwak K., Karolczyk G. M., Karpenko N. M., Katsubo H., Kaznowska B. J., Kentsis A., Ketteler P., Kienesberger A., Kiselev R., Kizyma Z., Klymniuk H., Kostiuk Y., Kowalik T., Kozlova O., Kozubenko V., Kramar T., Krawczuk-Rybak M., Kulemzina I., Kurkowska P., Kuzyk A. S., Ladenstein R. L., Laguna P. J., Lassaletta A., Lehmberg K., Leontieva O., Liashenko S., Loizou L. G., Lucchetta S. A., Lupo M. W., Lysytsia L., Lysytsia O., Machnik K. A., Mainland J. A., Matczak K. E., Matysiak M. J., Mayeur P., Minervina A. A., Mishkova V., Mizia-Malarz A. J., Morales La Madrid A., Moreno L., Moskvin V. P., Muszynska-Roslan K. M., Nelson A. J., Ociepa T., Oltolini S., Onipko N., Pappas A., Patel A. B., Patrahau A., Pauley J. L., Pavlenko Y., Pavlovych A., Peregud-Pogorzelski J., Perek-Polnik M., Perez V., Perez-Martinez A., Pikman Y., Pitozzi G., Portugal R. G., Posternak V. V., Prete A., Pritchard-Jones K., Radaelli A., Reeves T., Reinhardt D., Reshetnyak A. V., Rider A. J., Rizzari C., Rizzi D., Rodriguez Hermosillo K. G., Ronenko O., Rostowska A. O., Rudko L., Sakaan F. M., Sakhar N., Savva N. N., Scaccaglia D., Schaeffer E. H., Schneider C. U., Scobie N., Semeniuk O., Shevchyk R., Shuler A. I., Shvets S., Skoczen S. P., Smeal W. J., Sokolowski I., Sonkin A. A., Stepanjuk A. I., Spota A., Sterba J., Styczynski J., Svintsova O., Synyuta A. V., Szczepanski T., Szczucinski P. K., Szmyd B. M., Tasso Cereceda M., Teliuk A., Tomanek I., Topping P., Torrent M., Trelinska J., Troyanovska O., Trubnikova E., Tsurkan L. G., Tsymbalyuk-Voloshyn I., Urasinski T. F., Urbanek-Dadela A., Vasilieva N., Vasilyeva A., Verdu-Amoros J., Vilcu-Bajurean N., Vinitsky L., Volpe G., Vorobel O., Wachowiak J. T., Wasiak M. S., Wiedower L. A., Wuenschel L. I., Wysocki M. S., Yurieva M., Zagurska A., Zakharenko S. S., Zakharenko A. V., Zapotochna K., Zawitkowska J. E., Agulnik, A, Kizyma, R, Salek, M, Wlodarski, M, Pogorelyy, M, Oszer, A, Yakimkova, T, Nogovitsyna, Y, Dutkiewicz, M, Dalle, J, Dirksen, U, Eggert, A, Fernandez-Teijeiro, A, Greiner, J, Kraal, K, Mueller, A, Sramkova, L, Zecca, M, Wise, P, Mlynarski, W, Avula, M, Adyrov, M, Berlanga, P, Blackwood, C, Bouffet, E, Czauderna, P, de Koning, L, dos Reis Farinha, N, Foster, W, Graetz, D, Gupta, S, Holter, W, Hough, R, Kliuchkivska, K, Kolenova, A, Kolodrubiec, J, Moreira, D, Mukkada, S, Mykychak, I, Raciborska, A, Salman, Z, Sopilnyak, A, Tyupa, S, Vinitsky, A, Wobst, N, Miller, B, Rasul, S, Rodriguez-Galindo, C, Alanbousi, I, Alexander, S, Apel, A, Bal, W, Balwierz, W, Basset-Salom, L, Bastardo Blanco, D, Bauer, K, Bayazitov, I, Bhakta, N, Bien, E, Bieniek, K, Blair, S, Bodak, K, Bordeianu, I, Braganca, J, Bucurenci, M, Budny, E, Budzyn, A, Bumgardner, C, Burditt, R, Burnside Clapp, V, Bykov, V, Canete, A, Carnelli, M, Cela, E, Cepowska, Z, Chaber, R, Cherner-Drieux, A, Chubata, M, Clough, H, Czernicka - Siwecka, J, Czyzewski, K, Dashchakovska, O, Dembowska-Baginska, B, Derwich, K, Dommett, R, Dorosh, O, Drabko, K, Dragomir, M, Dworzak, M, Dyma, S, Earl, J, English, M, Evseev, D, Farren, B, Fedyk, N, Ferneza, S, Fox Irwin, L, Galazkowski, R, Ganieva, G, Garanzha, V, Gelman, M, Godzinski, J, Goeres, A, Golban, R, Griksaitis, M, Hampel, M, Hastings, S, Heenen, D, Hill, M, Holiuk, I, Hutnik, L, Irga-Jaworska, N, Istomin, O, Janczar, S, Kacharian, A, Kalwak, K, Karolczyk, G, Karpenko, N, Katsubo, H, Kaznowska, B, Kentsis, A, Ketteler, P, Kienesberger, A, Kiselev, R, Kizyma, Z, Klymniuk, H, Kostiuk, Y, Kowalik, T, Kozlova, O, Kozubenko, V, Kramar, T, Krawczuk-Rybak, M, Kulemzina, I, Kurkowska, P, Kuzyk, A, Ladenstein, R, Laguna, P, Lassaletta, A, Lehmberg, K, Leontieva, O, Liashenko, S, Loizou, L, Lucchetta, S, Lupo, M, Lysytsia, L, Lysytsia, O, Machnik, K, Mainland, J, Matczak, K, Matysiak, M, Mayeur, P, Minervina, A, Mishkova, V, Mizia-Malarz, A, Morales La Madrid, A, Moreno, L, Moskvin, V, Muszynska-Roslan, K, Nelson, A, Ociepa, T, Oltolini, S, Onipko, N, Pappas, A, Patel, A, Patrahau, A, Pauley, J, Pavlenko, Y, Pavlovych, A, Peregud-Pogorzelski, J, Perek-Polnik, M, Perez, V, Perez-Martinez, A, Pikman, Y, Pitozzi, G, Portugal, R, Posternak, V, Prete, A, Pritchard-Jones, K, Radaelli, A, Reeves, T, Reinhardt, D, Reshetnyak, A, Rider, A, Rizzari, C, Rizzi, D, Rodriguez Hermosillo, K, Ronenko, O, Rostowska, A, Rudko, L, Sakaan, F, Sakhar, N, Savva, N, Scaccaglia, D, Schaeffer, E, Schneider, C, Scobie, N, Semeniuk, O, Shevchyk, R, Shuler, A, Shvets, S, Skoczen, S, Smeal, W, Sokolowski, I, Sonkin, A, Stepanjuk, A, Spota, A, Sterba, J, Styczynski, J, Svintsova, O, Synyuta, A, Szczepanski, T, Szczucinski, P, Szmyd, B, Tasso Cereceda, M, Teliuk, A, Tomanek, I, Topping, P, Torrent, M, Trelinska, J, Troyanovska, O, Trubnikova, E, Tsurkan, L, Tsymbalyuk-Voloshyn, I, Urasinski, T, Urbanek-Dadela, A, Vasilieva, N, Vasilyeva, A, Verdu-Amoros, J, Vilcu-Bajurean, N, Vinitsky, L, Volpe, G, Vorobel, O, Wachowiak, J, Wasiak, M, Wiedower, L, Wuenschel, L, Wysocki, M, Yurieva, M, Zagurska, A, Zakharenko, S, Zakharenko, A, Zapotochna, K, Zawitkowska, J, Agulnik A., Kizyma R., Salek M., Wlodarski M. W., Pogorelyy M., Oszer A., Yakimkova T., Nogovitsyna Y., Dutkiewicz M., Dalle J. -H., Dirksen U., Eggert A., Fernandez-Teijeiro A., Greiner J., Kraal K., Mueller A., Sramkova L., Zecca M., Wise P. H., Mlynarski W., Avula M., Adyrov M. V., Berlanga P., Blackwood C. A., Bouffet E., Czauderna P. S., de Koning L. A., dos Reis Farinha N. J., Foster W. B., Graetz D. E., Gupta S., Holter W., Hough R. E., Kliuchkivska K., Kolenova A., Kolodrubiec J., Moreira D. C., Mukkada S. T., Mykychak I., Raciborska A., Salman Z. S., Sopilnyak A., Tyupa S., Vinitsky A., Wobst N. M., Miller B. A., Rasul S. S., Rodriguez-Galindo C., Alanbousi I., Alexander S. W., Apel A., Bal W. A., Balwierz W. A., Basset-Salom L., Bastardo Blanco D., Bauer K. J., Bayazitov I. T., Bhakta N. H., Bien E. I., Bieniek K. A., Blair S. J., Bodak K. I., Bordeianu I. M., Braganca J. M., Bucurenci M. S., Budny E. B., Budzyn A., Bumgardner C. C., Burditt R. N., Burnside Clapp V. G., Bykov V., Canete A., Carnelli M., Cela E., Cepowska Z. P., Chaber R., Cherner-Drieux A., Chubata M., Clough H. M., Czernicka - Siwecka J., Czyzewski K., Dashchakovska O., Dembowska-Baginska B. M., Derwich K., Dommett R., Dorosh O., Drabko K. A., Dragomir M. D., Dworzak M., Dyma S., Earl J. D., English M. W., Evseev D. A., Farren B. S., Fedyk N., Ferneza S., Fox Irwin L. E., Galazkowski R. M., Ganieva G., Garanzha V., Gelman M. S., Godzinski J. K., Goeres A. F., Golban R., Griksaitis M. J., Hampel M. A., Hastings S. G., Heenen D. L., Hill M. C., Holiuk I., Hutnik L. M., Irga-Jaworska N., Istomin O., Janczar S. L., Kacharian A., Kalwak K., Karolczyk G. M., Karpenko N. M., Katsubo H., Kaznowska B. J., Kentsis A., Ketteler P., Kienesberger A., Kiselev R., Kizyma Z., Klymniuk H., Kostiuk Y., Kowalik T., Kozlova O., Kozubenko V., Kramar T., Krawczuk-Rybak M., Kulemzina I., Kurkowska P., Kuzyk A. S., Ladenstein R. L., Laguna P. J., Lassaletta A., Lehmberg K., Leontieva O., Liashenko S., Loizou L. G., Lucchetta S. A., Lupo M. W., Lysytsia L., Lysytsia O., Machnik K. A., Mainland J. A., Matczak K. E., Matysiak M. J., Mayeur P., Minervina A. A., Mishkova V., Mizia-Malarz A. J., Morales La Madrid A., Moreno L., Moskvin V. P., Muszynska-Roslan K. M., Nelson A. J., Ociepa T., Oltolini S., Onipko N., Pappas A., Patel A. B., Patrahau A., Pauley J. L., Pavlenko Y., Pavlovych A., Peregud-Pogorzelski J., Perek-Polnik M., Perez V., Perez-Martinez A., Pikman Y., Pitozzi G., Portugal R. G., Posternak V. V., Prete A., Pritchard-Jones K., Radaelli A., Reeves T., Reinhardt D., Reshetnyak A. V., Rider A. J., Rizzari C., Rizzi D., Rodriguez Hermosillo K. G., Ronenko O., Rostowska A. O., Rudko L., Sakaan F. M., Sakhar N., Savva N. N., Scaccaglia D., Schaeffer E. H., Schneider C. U., Scobie N., Semeniuk O., Shevchyk R., Shuler A. I., Shvets S., Skoczen S. P., Smeal W. J., Sokolowski I., Sonkin A. A., Stepanjuk A. I., Spota A., Sterba J., Styczynski J., Svintsova O., Synyuta A. V., Szczepanski T., Szczucinski P. K., Szmyd B. M., Tasso Cereceda M., Teliuk A., Tomanek I., Topping P., Torrent M., Trelinska J., Troyanovska O., Trubnikova E., Tsurkan L. G., Tsymbalyuk-Voloshyn I., Urasinski T. F., Urbanek-Dadela A., Vasilieva N., Vasilyeva A., Verdu-Amoros J., Vilcu-Bajurean N., Vinitsky L., Volpe G., Vorobel O., Wachowiak J. T., Wasiak M. S., Wiedower L. A., Wuenschel L. I., Wysocki M. S., Yurieva M., Zagurska A., Zakharenko S. S., Zakharenko A. V., Zapotochna K., and Zawitkowska J. E.

Published
2022

16. Blinatumomab in Children and Adolescents with Relapsed/Refractory B Cell Precursor Acute Lymphoblastic Leukemia: A Real-Life Multicenter Retrospective Study in Seven AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) Centers

Author

Beneduce, G, De Matteo, A, Stellato, P, Testi, A, Bertorello, N, Colombini, A, Putti, M, Rizzari, C, Cesaro, S, Cellini, M, Barisone, E, Petruzziello, F, Menna, G, Parasole, R, Beneduce G., De Matteo A., Stellato P., Testi A. M., Bertorello N., Colombini A., Putti M. C., Rizzari C., Cesaro S., Cellini M., Barisone E., Petruzziello F., Menna G., Parasole R., Beneduce, G, De Matteo, A, Stellato, P, Testi, A, Bertorello, N, Colombini, A, Putti, M, Rizzari, C, Cesaro, S, Cellini, M, Barisone, E, Petruzziello, F, Menna, G, Parasole, R, Beneduce G., De Matteo A., Stellato P., Testi A. M., Bertorello N., Colombini A., Putti M. C., Rizzari C., Cesaro S., Cellini M., Barisone E., Petruzziello F., Menna G., and Parasole R.

Abstract

Five-year event-free survival in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) currently exceeds 80–85%. However, 15–20% of patients still experience a relapsed/refractory disease. From 1 January 2015 to 31 December 2020, thirty-nine patients, 0–21 years old with r/r BCP-ALL were treated with blinatumomab with the aim of inducing remission (n = 13) or reducing MRD levels (n = 26) in the frame of different multiagent chemotherapy schedules, in seven AIEOP centers. Patients were treated in compassionate and/or off-label settings and were not enrolled in any controlled clinical trials. Treatment was well tolerated; 22 (56.4%) patients reported adverse events (AE) on a total of 46 events registered, of which 27 (58.7%) were ≤2 grade according to CTCAE. Neurological AEs were 18 (39.1%); only two patients required transient blinatumomab discontinuation. Complete remission (CR) rate was 46% for the 13 patients treated with ≥5% blasts and 81% PCR/FC MRD negativity in the 26 patients with blasts < 5%. Median relapse-free survival was 33.4 months (95% CI; 7.5–59.3); median overall survival was not reached over a mean follow-up of 16 months. In our study, as in other real-life experiences, blinatumomab proved to be effective and well-tolerated, able to induce a high rate of CR and MRD negativity.

Published
2022

17. Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia: results from a phase II trial

Author

Pennesi, E, Michels, N, Brivio, E, van der Velden, V, Jiang, Y, Thano, A, Ammerlaan, A, Boer, J, Beverloo, H, Sleight, B, Chen, Y, Vormoor-Burger, B, Rives, S, Bielorai, B, Rossig, C, Petit, A, Rizzari, C, Engstler, G, Stary, J, Bautista Sirvent, F, Chen-Santel, C, Bruno, B, Bertrand, Y, Rialland, F, Plat, G, Reinhardt, D, Vinti, L, Von Stackelberg, A, Locatelli, F, Zwaan, C, Pennesi E., Michels N., Brivio E., van der Velden V. H. J., Jiang Y., Thano A., Ammerlaan A. J. C., Boer J. M., Beverloo H. B., Sleight B., Chen Y., Vormoor-Burger B., Rives S., Bielorai B., Rossig C., Petit A., Rizzari C., Engstler G., Stary J., Bautista Sirvent F. J., Chen-Santel C., Bruno B., Bertrand Y., Rialland F., Plat G., Reinhardt D., Vinti L., Von Stackelberg A., Locatelli F., Zwaan C. M., Pennesi, E, Michels, N, Brivio, E, van der Velden, V, Jiang, Y, Thano, A, Ammerlaan, A, Boer, J, Beverloo, H, Sleight, B, Chen, Y, Vormoor-Burger, B, Rives, S, Bielorai, B, Rossig, C, Petit, A, Rizzari, C, Engstler, G, Stary, J, Bautista Sirvent, F, Chen-Santel, C, Bruno, B, Bertrand, Y, Rialland, F, Plat, G, Reinhardt, D, Vinti, L, Von Stackelberg, A, Locatelli, F, Zwaan, C, Pennesi E., Michels N., Brivio E., van der Velden V. H. J., Jiang Y., Thano A., Ammerlaan A. J. C., Boer J. M., Beverloo H. B., Sleight B., Chen Y., Vormoor-Burger B., Rives S., Bielorai B., Rossig C., Petit A., Rizzari C., Engstler G., Stary J., Bautista Sirvent F. J., Chen-Santel C., Bruno B., Bertrand Y., Rialland F., Plat G., Reinhardt D., Vinti L., Von Stackelberg A., Locatelli F., and Zwaan C. M.

Abstract

Inotuzumab Ozogamicin is a CD22-directed antibody conjugated to calicheamicin, approved in adults with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (BCP-ALL). Patients aged 1–18 years, with R/R CD22 + BCP-ALL were treated at the RP2D of 1.8 mg/m2. Using a single-stage design, with an overall response rate (ORR) ≤ 30% defined as not promissing and ORR > 55% as expected, 25 patients needed to be recruited to achieve 80% power at 0.05 significance level. Thirty-two patients were enrolled, 28 were treated, 27 were evaluable for response. The estimated ORR was 81.5% (95%CI: 61.9–93.7%), and 81.8% (18/22) of the responding subjects were minimal residual disease (MRD) negative. The study met its primary endpoint. Median follow up of survivors was 16 months (IQR: 14.49–20.07). One year Event Free Survival was 36.7% (95% CI: 22.2–60.4%), and Overall Survival was 55.1% (95% CI: 39.1−77.7%). Eighteen patients received consolidation (with HSCT and/or CAR T-cells therapy). Sinusoidal obstructive syndrome (SOS) occurred in seven patients. MRD negativity seemed correlated to calicheamicin sensitivity in vitro, but not to CD22 surface expression, saturation, or internalization. InO was effective in this population. The most relevant risk was the occurrence of SOS, particularly when InO treatment was followed by HSCT.

Published
2022

18. Daratumumab with or without chemotherapy in relapsed and refractory acute lymphoblastic leukemia. A retrospective observational Campus ALL study

Author

Cerrano, M, Bonifacio, M, Olivi, M, Curti, A, Malagola, M, Dargenio, M, Scattolin, A, Papayannidis, C, Forghieri, F, Gurrieri, C, Tanasi, I, Zappasodi, P, Starza, R, Fracchiolla, N, Chiusolo, P, Giaccone, L, Del Principe, M, Giglio, F, Defina, M, Favre, C, Rizzari, C, Castella, B, Pizzolo, G, Ferrara, F, Chiaretti, S, Foa, R, Cerrano M., Bonifacio M., Olivi M., Curti A., Malagola M., Dargenio M., Scattolin A. M., Papayannidis C., Forghieri F., Gurrieri C., Tanasi I., Zappasodi P., Starza R. L., Fracchiolla N. S., Chiusolo P., Giaccone L., Del Principe M. I., Giglio F., Defina M., Favre C., Rizzari C., Castella B., Pizzolo G., Ferrara F., Chiaretti S., Foa R., Cerrano, M, Bonifacio, M, Olivi, M, Curti, A, Malagola, M, Dargenio, M, Scattolin, A, Papayannidis, C, Forghieri, F, Gurrieri, C, Tanasi, I, Zappasodi, P, Starza, R, Fracchiolla, N, Chiusolo, P, Giaccone, L, Del Principe, M, Giglio, F, Defina, M, Favre, C, Rizzari, C, Castella, B, Pizzolo, G, Ferrara, F, Chiaretti, S, Foa, R, Cerrano M., Bonifacio M., Olivi M., Curti A., Malagola M., Dargenio M., Scattolin A. M., Papayannidis C., Forghieri F., Gurrieri C., Tanasi I., Zappasodi P., Starza R. L., Fracchiolla N. S., Chiusolo P., Giaccone L., Del Principe M. I., Giglio F., Defina M., Favre C., Rizzari C., Castella B., Pizzolo G., Ferrara F., Chiaretti S., and Foa R.

Published
2022

20. Pre-existing antibodies against polyethylene glycol reduce asparaginase activities on first administration of pegylated E. coli asparaginase in children with acute lymphocytic leukemia

Author

Khalil, A, Wurthwein, G, Golitsch, J, Hempel, G, Fobker, M, Gerss, J, Moricke, A, Zimmermann, M, Smisek, P, Zucchetti, M, Nath, C, Attarbaschi, A, Von Stackelberg, A, Gokbuget, N, Rizzari, C, Conter, V, Schrappe, M, Boos, J, Lanvers-Kaminsky, C, Khalil A., Wurthwein G., Golitsch J., Hempel G., Fobker M., Gerss J., Moricke A., Zimmermann M., Smisek P., Zucchetti M., Nath C., Attarbaschi A., Von Stackelberg A., Gokbuget N., Rizzari C., Conter V., Schrappe M., Boos J., Lanvers-Kaminsky C., Khalil, A, Wurthwein, G, Golitsch, J, Hempel, G, Fobker, M, Gerss, J, Moricke, A, Zimmermann, M, Smisek, P, Zucchetti, M, Nath, C, Attarbaschi, A, Von Stackelberg, A, Gokbuget, N, Rizzari, C, Conter, V, Schrappe, M, Boos, J, Lanvers-Kaminsky, C, Khalil A., Wurthwein G., Golitsch J., Hempel G., Fobker M., Gerss J., Moricke A., Zimmermann M., Smisek P., Zucchetti M., Nath C., Attarbaschi A., Von Stackelberg A., Gokbuget N., Rizzari C., Conter V., Schrappe M., Boos J., and Lanvers-Kaminsky C.

Abstract

Antibodies against polyethylene glycol (PEG) in healthy subjects raise concerns about the efficacy of pegylated drugs. We evaluated the prevalence of antibodies against PEG among patients with acute lymphoblastic leukemia (ALL) prior to and/or immediately after their first dose of pegylated E.coli asparaginase (PEG-ASNase). Serum samples of 701 children, 673 with primary ALL, 28 with relapsed ALL, and 188 adults with primary ALL were analyzed for anti-PEG IgG and IgM. Measurements in 58 healthy infants served as reference to define cut-points for antibody-positive and -negative samples. Anti-PEG antibodies were detected in ALL patients prior the first PEG-ASNase with a prevalence of 13.9% (anti-PEG IgG) and 29.1% (anti-PEG IgM). After administration of PEG-ASNase the prevalence of anti-PEG antibodies decreased to 4.2% for anti-PEG IgG and to 4.5% for anti-PEG IgM. Pre-existing anti-PEG antibodies did not inhibit PEG-ASNase activity but significantly reduced PEGASNase activity levels in a concentration dependent manner. Although pre-existing anti-PEG antibodies did not boost, pre-existing anti-PEG IgG were significantly associated with firstexposure hypersensitivity reactions (CTCAE grade 2) (p.

Published
2022

21. Improved survival and MRD remission with blinatumomab vs. chemotherapy in children with first high-risk relapse B-ALL

Author

Locatelli, Franco, Zugmaier, G., Rizzari, C., Morris, J. D., Gruhn, B., Klingebiel, T., Parasole, R., Linderkamp, C., Flotho, C., Petit, A., Micalizzi, C., Zeng, Y., Desai, R., Kormany, W. N., Eckert, C., Moricke, A., Sartor, M., Hrusak, O., Peters, C., Saha, V., Vinti, L., von Stackelberg, A., Locatelli F. (ORCID:0000-0002-7976-3654), Locatelli, Franco, Zugmaier, G., Rizzari, C., Morris, J. D., Gruhn, B., Klingebiel, T., Parasole, R., Linderkamp, C., Flotho, C., Petit, A., Micalizzi, C., Zeng, Y., Desai, R., Kormany, W. N., Eckert, C., Moricke, A., Sartor, M., Hrusak, O., Peters, C., Saha, V., Vinti, L., von Stackelberg, A., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

NO ABSTRACT

Published
2023

22. Population Pharmacokinetics of PEGylated Asparaginase in Children with Acute Lymphoblastic Leukemia: Treatment Phase Dependency and Predictivity in Case of Missing Data

Author

Wurthwein, G, Lanvers-Kaminsky, C, Siebel, C, Gerss, J, Moricke, A, Zimmermann, M, Stary, J, Smisek, P, Schrappe, M, Rizzari, C, Zucchetti, M, Hempel, G, Wicha, S, Boos, J, Wurthwein G., Lanvers-Kaminsky C., Siebel C., Gerss J., Moricke A., Zimmermann M., Stary J., Smisek P., Schrappe M., Rizzari C., Zucchetti M., Hempel G., Wicha S. G., Boos J., Wurthwein, G, Lanvers-Kaminsky, C, Siebel, C, Gerss, J, Moricke, A, Zimmermann, M, Stary, J, Smisek, P, Schrappe, M, Rizzari, C, Zucchetti, M, Hempel, G, Wicha, S, Boos, J, Wurthwein G., Lanvers-Kaminsky C., Siebel C., Gerss J., Moricke A., Zimmermann M., Stary J., Smisek P., Schrappe M., Rizzari C., Zucchetti M., Hempel G., Wicha S. G., and Boos J.

Abstract

Background and Objectives: The pharmacokinetics of polyethylene glycol-conjugated asparaginase (PEG-ASNase) are characterized by an increase in elimination over time, a marked increase in ASNase activity levels from induction to reinduction, and high inter- and intraindividual variability. A population pharmacokinetic (PopPK) model is required to estimate individual dose intensity, despite gaps in monitoring compliance. Methods: In the AIEOP-BFM ALL 2009 trial, two PEG-ASNase administrations (2500 U/m2 intravenously) during induction (14-day interval) and one administration during reinduction were administered in children with acute lymphoblastic leukemia. ASNase activity levels were monitored weekly. A PopPK model was used for covariate modeling and external validation. The predictivity of the model in case of missing data was tested for observations, as well as for the derived parameters of the area under the concentration time curve (AUC0-∞) and time above different thresholds. Results: Compared to the first administration in induction (1374 patients, 6069 samples), the initial clearance and volume of distribution decreased by 11.0% and 15.9%, respectively, during the second administration during induction and by 41.2% and 28.4% during reinduction. Furthermore, the initial clearance linearly increased for children aged > 8 years and was 7.1% lower for females. The model was successfully externally validated (1253 patients, 5523 samples). In case of missing data, > 52% of the predictions for observations and > 82% for derived parameters were within ± 20% of the nominal value. Conclusion: A PopPK model that describes the complex pharmacokinetics of PEG-ASNase was successfully externally validated. AUC0−∞ or time above different thresholds, which are parameters describing dose intensity, can be estimated with high predictivity, despite missing data. (www.clinicaltrials.gov, NCT01117441, first submitted date: May 3, 2010).

Published
2021

23. Outcome of relapsed/refractory acute promyelocytic leukaemia in children, adolescents and young adult patients — a 25-year Italian experience

Author

Testi, A, Mohamed, S, Diverio, D, Piciocchi, A, Menna, G, Rizzari, C, Timeus, F, Micalizzi, C, Lo Nigro, L, Santoro, N, Masetti, R, Micheletti, M, Ziino, O, Onofrillo, D, Ladogana, S, Putti, C, Pierani, P, Arena, V, Zecca, M, Foa, R, Locatelli, F, Testi A. M., Mohamed S., Diverio D., Piciocchi A., Menna G., Rizzari C., Timeus F., Micalizzi C., Lo Nigro L., Santoro N., Masetti R., Micheletti M. V., Ziino O., Onofrillo D., Ladogana S., Putti C., Pierani P., Arena V., Zecca M., Foa R., Locatelli F., Testi, A, Mohamed, S, Diverio, D, Piciocchi, A, Menna, G, Rizzari, C, Timeus, F, Micalizzi, C, Lo Nigro, L, Santoro, N, Masetti, R, Micheletti, M, Ziino, O, Onofrillo, D, Ladogana, S, Putti, C, Pierani, P, Arena, V, Zecca, M, Foa, R, Locatelli, F, Testi A. M., Mohamed S., Diverio D., Piciocchi A., Menna G., Rizzari C., Timeus F., Micalizzi C., Lo Nigro L., Santoro N., Masetti R., Micheletti M. V., Ziino O., Onofrillo D., Ladogana S., Putti C., Pierani P., Arena V., Zecca M., Foa R., and Locatelli F.

Published
2021

24. Recommendations by the European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA) Working Group on preparedness of clinical trials about paediatric medicines process

Author

Siapkara, A, Fracasso, C, Egger, G, Rizzari, C, Trasorras, C, Athanasiou, D, Turner, M, Siapkara A., Fracasso C., Egger G. F., Rizzari C., Trasorras C. S., Athanasiou D., Turner M. A., Siapkara, A, Fracasso, C, Egger, G, Rizzari, C, Trasorras, C, Athanasiou, D, Turner, M, Siapkara A., Fracasso C., Egger G. F., Rizzari C., Trasorras C. S., Athanasiou D., and Turner M. A.

Abstract

Conduct of clinical trials in babies, children and young people is often hindered by issues that could have been foreseen before the trial opened; that is, some clinical trials are often underprepared. In order to identify a good approach to trial preparedness, the European Network of Paediatric Research at the European Medicines Agency formed a working group. The Working Group included representation from regulators, industry, academics, paediatric clinical research networks and parents. The Working Group consulted widely about how to prepare for paediatric clinical trials. The Group's detailed recommendations have been published (https://www.ema.europa.eu/en/documents/other/preparedness-medicines-clinical-trials-paediatrics-recommendations-enpr-ema-working-group-trial-en.pdf). This paper is a summary of the key recommendations including the following: start early, preferably in parallel to designing the medicine's development plan and individual protocols; identify the rationale and clinical need; listen to the perspectives of children and families, and of patient advocacy groups; identify how many people will be eligible for the trial; identify the resources needed, such as clinical facilities (including play therapy) and out-of-pocket expenditure by participants and their families; use all available data to estimate what is possible; present information about preparedness in a structured way; deploy proportionate resources to support the preparation of trials. A well-prepared, well-designed trial is likely to require fewer changes during its course, be run in a shorter time frame and achieve expected objectives.

Published
2021

25. A phase 2 study of nilotinib in pediatric patients with CML: Long-term update on growth retardation and safety

Author

Hijiya, N, Maschan, A, Rizzari, C, Shimada, H, Dufour, C, Goto, H, Kang, H, Guinipero, T, Karakas, Z, Bautista, F, Ducassou, S, Yoo, K, Zwaan, C, Millot, F, Patterson, B, Samis, J, Aimone, P, Allepuz, A, Titorenko, K, Sosothikul, D, Hijiya N., Maschan A., Rizzari C., Shimada H., Dufour C., Goto H., Kang H. J., Guinipero T., Karakas Z., Bautista F., Ducassou S., Yoo K. H., Zwaan C. M., Millot F., Patterson B., Samis J., Aimone P., Allepuz A., Titorenko K., Sosothikul D., Hijiya, N, Maschan, A, Rizzari, C, Shimada, H, Dufour, C, Goto, H, Kang, H, Guinipero, T, Karakas, Z, Bautista, F, Ducassou, S, Yoo, K, Zwaan, C, Millot, F, Patterson, B, Samis, J, Aimone, P, Allepuz, A, Titorenko, K, Sosothikul, D, Hijiya N., Maschan A., Rizzari C., Shimada H., Dufour C., Goto H., Kang H. J., Guinipero T., Karakas Z., Bautista F., Ducassou S., Yoo K. H., Zwaan C. M., Millot F., Patterson B., Samis J., Aimone P., Allepuz A., Titorenko K., and Sosothikul D.

Abstract

The phase 2, open-label study (DIALOG) of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) met its coprimary end points, showing sustained nilotinib efficacy in patients with newly diagnosed (ND) or imatinib/dasatinib resistant/intolerant (R/I) CML. This update assessed growth and safety profiles in patients who had completed ≥48, 28-day treatment cycles of nilotinib 230 mg/m2 twice daily, or previously discontinued the study. Height was assessed regularly and reported using standard deviation scores (SDSs) based on World Health Organization growth charts. All data were summarized descriptively (cutoff, 6 March 2019). Overall, 33 patients in the R/I cohort and 25 patients in the ND cohort received nilotinib. Each cohort showed a negative slope in height SDS over the course of the study, indicating attenuated growth rates during nilotinib treatment: overall median change from baseline in height SDS after 48 cycles was 20.54 SDS (range, 2 1.6 to 0.4) and 20.91 SDS (21.4 to 20.1) in R/I and ND cohorts, respectively. Patients in the R/I cohort were shorter at baseline than those in the ND cohort, and remained so throughout the study. The most common all-cause adverse events were increased blood bilirubin (53.4%), headache (46.6%), pyrexia (37.9%), and increased alanine transferase (36.2%). Apart from the impact on growth, the safety profile of nilotinib was generally consistent with previous reports. This study was registered on www.clinicaltrials.gov at #NCT01844765.

Published
2021

26. Can recombinant technology address asparaginase Erwinia chrysanthemi shortages?

Author

Maese, L, Rizzari, C, Coleman, R, Power, A, van der Sluis, I, Rau, R, Maese L., Rizzari C., Coleman R., Power A., van der Sluis I., Rau R. E., Maese, L, Rizzari, C, Coleman, R, Power, A, van der Sluis, I, Rau, R, Maese L., Rizzari C., Coleman R., Power A., van der Sluis I., and Rau R. E.

Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Bacterial L-asparaginase has played an important role in ALL treatment for several decades; however, hypersensitivity reactions to Escherichia coli-derived asparaginases often preclude their use. Inability to receive asparaginase due to hypersensitivities is associated with poor patient outcomes. Erwinia chrysanthemi-derived asparaginase (ERW) is an effective, non-cross-reactive treatment option, but is limited in supply. Consequently, alternative asparaginase preparations are needed to ensure asparaginase availability for patients with hypersensitivities. Recombinant technology can potentially address this unmet need by programming cells to produce recombinant asparaginase. JZP-458, a recombinant Erwinia asparaginase derived from a novel Pseudomonas fluorescens expression platform with no immunologic cross-reactivity to E. coli-derived asparaginases, has the same primary amino acid sequence as ERW, with comparable activity based on in vitro measurements. The efficient manufacturing of JZP-458 would provide an additional asparaginase preparation for patients with hypersensitivities.

Published
2021

27. CD56, HLA-DR, and CD45 recognize a subtype of childhood AML harboring CBFA2T3-GLIS2 fusion transcript

Author

Zangrando, A, Cavagnero, F, Scarparo, P, Varotto, E, Francescato, S, Tregnago, C, Cuccurullo, R, Fagioli, F, Nigro, L, Masetti, R, Putti, M, Rizzari, C, Santoro, N, Pession, A, Pigazzi, M, Locatelli, F, Basso, G, Buldini, B, Zangrando A., Cavagnero F., Scarparo P., Varotto E., Francescato S., Tregnago C., Cuccurullo R., Fagioli F., Nigro L. L., Masetti R., Putti M. C., Rizzari C., Santoro N., Pession A., Pigazzi M., Locatelli F., Basso G., Buldini B., Zangrando, A, Cavagnero, F, Scarparo, P, Varotto, E, Francescato, S, Tregnago, C, Cuccurullo, R, Fagioli, F, Nigro, L, Masetti, R, Putti, M, Rizzari, C, Santoro, N, Pession, A, Pigazzi, M, Locatelli, F, Basso, G, Buldini, B, Zangrando A., Cavagnero F., Scarparo P., Varotto E., Francescato S., Tregnago C., Cuccurullo R., Fagioli F., Nigro L. L., Masetti R., Putti M. C., Rizzari C., Santoro N., Pession A., Pigazzi M., Locatelli F., Basso G., and Buldini B.

Abstract

The presence of CBFA2T3-GLIS2 fusion gene has been identified in childhood Acute Myeloid Leukemia (AML). In view of the genomic studies indicating a distinct gene expression profile, we evaluated the role of immunophenotyping in characterizing a rare subtype of AML-CBFA2T3-GLIS2 rearranged. Immunophenotypic data were obtained by studying a cohort of 20 pediatric CBFA2T3-GLIS2-AML and 77 AML patients not carrying the fusion transcript. Enrolled cases were included in the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) AML trials and immunophenotypes were compared using different statistical approaches. By multiple computational procedures, we identified two main core antigens responsible for the identification of the CBFA2T3-GLIS2-AML. CD56 showed the highest performance in single marker evaluation (AUC = 0.89) and granted the most accurate prediction when used in combination with HLA-DR (AUC = 0.97) displaying a 93% sensitivity and 99% specificity. We also observed a weak-to-negative CD45 expression, being exceptional in AML. We here provide evidence that the combination of HLA-DR negativity and intense bright CD56 expression detects a rare and aggressive pediatric AML genetic lesion improving the diagnosis performance.

Published
2021

28. Musculoskeletal manifestations of childhood cancer and differential diagnosis with juvenile idiopathic arthritis (ONCOREUM): a multicentre, cross-sectional study

Author

Civino, A, Alighieri, G, Prete, E, Caroleo, A, Magni-Manzoni, S, Vinti, L, Romano, M, Santoro, N, Filocamo, G, Belotti, T, Santarelli, F, Gorio, C, Ricci, F, Colombini, A, Pastore, S, Cesaro, S, Barone, P, Verzegnassi, F, Olivieri, A, Ficara, M, Miniaci, A, Russo, G, Gallizzi, R, Pericoli, R, Breda, L, Mura, R, Podda, R, Onofrillo, D, Lattanzi, B, Tirtei, E, Maggio, M, De Santis, R, Consolini, R, Arlotta, A, La Torre, F, Mainardi, C, Pelagatti, M, Coassin, E, Capolsini, I, Burnelli, R, Tornesello, A, Soscia, F, De Fanti, A, Rigante, D, Pizzato, C, De Fusco, C, Abate, M, Roncadori, A, Rossi, E, Stabile, G, Biondi, A, Lepore, L, Conter, V, Rondelli, R, Pession, A, Ravelli, A, Amatruda, M, Atzeni, C, Bertolini, P, Bigucci, B, Caniglia, M, Cappella, M, Cattalini, M, Cefalo, M, Cellini, M, Cortis, E, Davi, S, De Benedetti, F, Di Cataldo, A, Fabbri, E, Fagioli, F, Fontanili, I, Garaventa, A, Gicchino, M, Ladogana, S, Locatelli, F, Magnolato, A, Marsili, M, Martino, S, Mascarin, M, Messina, C, Micalizzi, C, Porta, F, Rizzari, C, Civino A., Alighieri G., Prete E., Caroleo A. M., Magni-Manzoni S., Vinti L., Romano M., Santoro N., Filocamo G., Belotti T., Santarelli F., Gorio C., Ricci F., Colombini A., Pastore S., Cesaro S., Barone P., Verzegnassi F., Olivieri A. N., Ficara M., Miniaci A., Russo G., Gallizzi R., Pericoli R., Breda L., Mura R., Podda R. A., Onofrillo D., Lattanzi B., Tirtei E., Maggio M. C., De Santis R., Consolini R., Arlotta A., La Torre F., Mainardi C., Pelagatti M. A., Coassin E., Capolsini I., Burnelli R., Tornesello A., Soscia F., De Fanti A., Rigante D., Pizzato C., De Fusco C., Abate M. E., Roncadori A., Rossi E., Stabile G., Biondi A., Lepore L., Conter V., Rondelli R., Pession A., Ravelli A., Amatruda M., Atzeni C., Bertolini P., Bigucci B., Caniglia M., Cappella M., Cattalini M., Cefalo M. G., Cellini M., Cortis E., Davi S., De Benedetti F., Di Cataldo A., Fabbri E., Fagioli F., Fontanili I., Garaventa A., Gicchino M. F., Ladogana S., Locatelli F., Magnolato A., Marsili M., Martino S., Mascarin M., Messina C., Micalizzi C., Porta F., Rizzari C., Civino, A, Alighieri, G, Prete, E, Caroleo, A, Magni-Manzoni, S, Vinti, L, Romano, M, Santoro, N, Filocamo, G, Belotti, T, Santarelli, F, Gorio, C, Ricci, F, Colombini, A, Pastore, S, Cesaro, S, Barone, P, Verzegnassi, F, Olivieri, A, Ficara, M, Miniaci, A, Russo, G, Gallizzi, R, Pericoli, R, Breda, L, Mura, R, Podda, R, Onofrillo, D, Lattanzi, B, Tirtei, E, Maggio, M, De Santis, R, Consolini, R, Arlotta, A, La Torre, F, Mainardi, C, Pelagatti, M, Coassin, E, Capolsini, I, Burnelli, R, Tornesello, A, Soscia, F, De Fanti, A, Rigante, D, Pizzato, C, De Fusco, C, Abate, M, Roncadori, A, Rossi, E, Stabile, G, Biondi, A, Lepore, L, Conter, V, Rondelli, R, Pession, A, Ravelli, A, Amatruda, M, Atzeni, C, Bertolini, P, Bigucci, B, Caniglia, M, Cappella, M, Cattalini, M, Cefalo, M, Cellini, M, Cortis, E, Davi, S, De Benedetti, F, Di Cataldo, A, Fabbri, E, Fagioli, F, Fontanili, I, Garaventa, A, Gicchino, M, Ladogana, S, Locatelli, F, Magnolato, A, Marsili, M, Martino, S, Mascarin, M, Messina, C, Micalizzi, C, Porta, F, Rizzari, C, Civino A., Alighieri G., Prete E., Caroleo A. M., Magni-Manzoni S., Vinti L., Romano M., Santoro N., Filocamo G., Belotti T., Santarelli F., Gorio C., Ricci F., Colombini A., Pastore S., Cesaro S., Barone P., Verzegnassi F., Olivieri A. N., Ficara M., Miniaci A., Russo G., Gallizzi R., Pericoli R., Breda L., Mura R., Podda R. A., Onofrillo D., Lattanzi B., Tirtei E., Maggio M. C., De Santis R., Consolini R., Arlotta A., La Torre F., Mainardi C., Pelagatti M. A., Coassin E., Capolsini I., Burnelli R., Tornesello A., Soscia F., De Fanti A., Rigante D., Pizzato C., De Fusco C., Abate M. E., Roncadori A., Rossi E., Stabile G., Biondi A., Lepore L., Conter V., Rondelli R., Pession A., Ravelli A., Amatruda M., Atzeni C., Bertolini P., Bigucci B., Caniglia M., Cappella M., Cattalini M., Cefalo M. G., Cellini M., Cortis E., Davi S., De Benedetti F., Di Cataldo A., Fabbri E., Fagioli F., Fontanili I., Garaventa A., Gicchino M. F., Ladogana S., Locatelli F., Magnolato A., Marsili M., Martino S., Mascarin M., Messina C., Micalizzi C., Porta F., and Rizzari C.

Abstract

Background: Presenting symptoms of childhood cancers might mimic those of rheumatic diseases. However, the evidence available to guide differential diagnosis remains scarce. Preventing wrong or delayed diagnosis is therefore important to avoid incorrect administration of glucocorticoid or immunosuppressive therapy and worsening of prognosis. As such, we aimed to assess the prevalence and characteristics of presenting musculoskeletal manifestations in patients at cancer onset and to identify the factors that differentiate childhood malignancies with arthropathy from juvenile idiopathic arthritis. Methods: We did a multicentre, cross-sectional study at 25 paediatric haemato-oncology centres and 22 paediatric rheumatology centres in Italy. We prospectively recruited patients who were younger than 16 years that were newly diagnosed with cancer or juvenile idiopathic arthritis. We excluded patients with glucocorticoid pre-treatment (>1 mg/kg per day of oral prednisone or equivalent for ≥2 consecutive weeks). We collected data for patients with a new diagnosis of cancer or juvenile idiopathic arthritis using an electronic case report form on a web-based platform powered by the Cineca Interuniversity Consortium. The primary outcome was to describe the frequency and characteristics of musculoskeletal manifestations at cancer onset; and the secondary outcome was to identify factors that could discriminate malignancies presenting with arthropathy, with or without other musculoskeletal symptoms, from juvenile idiopathic arthritis using multivariable logistic regression analysis. Findings: Between May 1, 2015, and May 31, 2018, 1957 patients were eligible, of which 1277 (65%) had cancer and 680 (35%) had juvenile idiopathic arthritis. Musculoskeletal symptoms occurred in 324 (25% [95% CI 23·0–27·8]) of 1277 patients with cancer, of whom 207 had arthropathy. Patients with malignant bone tumours had the highest frequency of musculoskeletal symptoms (53 [80%] of 66), followed b

Published
2021

29. Recurrent genetic fusions redefine MLL germ line acute lymphoblastic leukemia in infants

Author

Fazio, G, Bardini, M, De Lorenzo, P, Grioni, A, Quadri, M, Pedace, L, Corral Abascal, L, Palamini, S, Palmi, C, Buldini, B, Vinti, L, Parasole, R, Barisone, E, Zecca, M, Favre, C, Locatelli, F, Conter, V, Rizzari, C, Valsecchi, M, Biondi, A, Cazzaniga, G, Fazio G., Bardini M., De Lorenzo P., Grioni A., Quadri M., Pedace L., Corral Abascal L., Palamini S., Palmi C., Buldini B., Vinti L., Parasole R., Barisone E., Zecca M., Favre C., Locatelli F., Conter V., Rizzari C., Valsecchi M. G., Biondi A., Cazzaniga G., Fazio, G, Bardini, M, De Lorenzo, P, Grioni, A, Quadri, M, Pedace, L, Corral Abascal, L, Palamini, S, Palmi, C, Buldini, B, Vinti, L, Parasole, R, Barisone, E, Zecca, M, Favre, C, Locatelli, F, Conter, V, Rizzari, C, Valsecchi, M, Biondi, A, Cazzaniga, G, Fazio G., Bardini M., De Lorenzo P., Grioni A., Quadri M., Pedace L., Corral Abascal L., Palamini S., Palmi C., Buldini B., Vinti L., Parasole R., Barisone E., Zecca M., Favre C., Locatelli F., Conter V., Rizzari C., Valsecchi M. G., Biondi A., and Cazzaniga G.

Abstract

B-cell precursor (BCP) acute lymphoblastic leukemia (BCP-ALL) in infants (ie, children age <1 year) is a rare disease traditionally subdivided into MLL-rearranged (alias KMT2A; MLL-R) and MLL germ line (MLL-G) subtypes. MLL gene rearrangements occur in ∼75% of infants with BCP-ALL1-3 and are typically associated with a mixed-lineage phenotype.4 MLL rearrangements originate prenatally in utero5 and play a role in transcription factor dysregulation.6 MLL-R BCP-ALL in infants is associated with dismal outcomes.1-3 Infants with MLL-G ALL treated with intensive therapies in the Interfant-06 protocol may have a relatively favorable prognosis, with a 6-year event-free survival (EFS) rate of 73.9%,2 slightly inferior to that observed in older children with BCP-ALL.1,2 Of interest, a recent study from the Japanese Pediatric Leukemia/Lymphoma Study Group MLL-10 trial reported more favorable outcomes in infants

Published
2021

30. A novel homozygous disruptive PRF1 variant (K285Sfs*4) causes very early-onset of familial hemophagocytic lymphohystiocytosis type 2

Author

Saettini, F, Castelli, I, Provenzi, M, Fazio, G, Quadri, M, Cazzaniga, G, Sala, S, Dell'Acqua, F, Sieni, E, Coniglio, M, Pezzoli, L, Iascone, M, Vendemini, F, Balduzzi, A, Biondi, A, Rizzari, C, Bonanomi, S, Saettini F., Castelli I., Provenzi M., Fazio G., Quadri M., Cazzaniga G., Sala S., Dell'Acqua F., Sieni E., Coniglio M. L., Pezzoli L., Iascone M., Vendemini F., Balduzzi A. C., Biondi A., Rizzari C., Bonanomi S., Saettini, F, Castelli, I, Provenzi, M, Fazio, G, Quadri, M, Cazzaniga, G, Sala, S, Dell'Acqua, F, Sieni, E, Coniglio, M, Pezzoli, L, Iascone, M, Vendemini, F, Balduzzi, A, Biondi, A, Rizzari, C, Bonanomi, S, Saettini F., Castelli I., Provenzi M., Fazio G., Quadri M., Cazzaniga G., Sala S., Dell'Acqua F., Sieni E., Coniglio M. L., Pezzoli L., Iascone M., Vendemini F., Balduzzi A. C., Biondi A., Rizzari C., and Bonanomi S.

Published
2021

31. Challenging Management of Severe Differentiation Syndrome in Pediatric Acute Promyelocytic Leukemia Treated with ATRA/ATO

Author

Molinaro A., Zanta D., Moleti M. L., Giona F., Conter V., Rizzari C., Biondi A., Testi A. M., Molinaro, A, Zanta, D, Moleti, M, Giona, F, Conter, V, Rizzari, C, Biondi, A, and Testi, A

Subjects
Infectious Diseases, Differentiation Syndrome, ATRA/ATO combination, Acute Promyelocytic Leukemia, Hematology, Children
Abstract

The ATRA/ATO combination treatment of acute promyelocytic leukemia (APL) represents a paradigm of successful targeted and chemotherapy-free treatment in oncology. This therapeutic strategy is aimed at sparing patients from chemotherapy toxicity, while maintaining an excellent survival with a low risk of relapse. Main induction treatment-related complications are differentiation syndrome (DS) and hyperleukocytosis, which is related to DS and its severity. In the period December 2019 – December 2020, 8 children with newly diagnosed APL underwent induction therapy with ATRA/ATO in our center. In patients with WBC≥10x109/L two doses of Gemtuzumab Ozogamicin (GO) were added. In case of severe DS or hyperleukocytosis the differentiating agents were discontinued, high dose dexamethasone (DXM) and/or hydroxyurea (HU) were recommended. Five patients presented WBC

Published
2021

32. CD56, HLA-DR, and CD45 recognize a subtype of childhood AML harboring CBFA2T3-GLIS2 fusion transcript

Author

Zangrando, A., Cavagnero, F., Scarparo, P., Varotto, E., Francescato, S., Tregnago, C., Cuccurullo, R., Fagioli, F., Nigro, L. L., Masetti, R., Putti, M. C., Rizzari, C., Santoro, N., Pession, A., Pigazzi, M., Locatelli, F., Basso, G., Buldini, B., Zangrando, A, Cavagnero, F, Scarparo, P, Varotto, E, Francescato, S, Tregnago, C, Cuccurullo, R, Fagioli, F, Nigro, L, Masetti, R, Putti, M, Rizzari, C, Santoro, N, Pession, A, Pigazzi, M, Locatelli, F, Basso, G, Buldini, B, Zangrando A., Cavagnero F., Scarparo P., Varotto E., Francescato S., Tregnago C., Cuccurullo R., Fagioli F., Nigro L.L., Masetti R., Putti M.C., Rizzari C., Santoro N., Pession A., Pigazzi M., Locatelli F., Basso G., and Buldini B.

Subjects
Oncogene Proteins, Fusion, Brief Report, HLA-DR Antigens, acute myeloid leukemia, Repressor Proteins, CBFA2T3‐GLIS2, Leukemia, Myeloid, Acute, computational analysi, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, immunophenotyping, computational analysis, hemic and lymphatic diseases, Humans, CBFA2T3-GLIS2, Child, Transcriptome
Abstract

The presence of CBFA2T3‐GLIS2 fusion gene has been identified in childhood Acute Myeloid Leukemia (AML). In view of the genomic studies indicating a distinct gene expression profile, we evaluated the role of immunophenotyping in characterizing a rare subtype of AML‐CBFA2T3‐GLIS2 rearranged. Immunophenotypic data were obtained by studying a cohort of 20 pediatric CBFA2T3‐GLIS2‐AML and 77 AML patients not carrying the fusion transcript. Enrolled cases were included in the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) AML trials and immunophenotypes were compared using different statistical approaches. By multiple computational procedures, we identified two main core antigens responsible for the identification of the CBFA2T3‐GLIS2‐AML. CD56 showed the highest performance in single marker evaluation (AUC = 0.89) and granted the most accurate prediction when used in combination with HLA‐DR (AUC = 0.97) displaying a 93% sensitivity and 99% specificity. We also observed a weak‐to‐negative CD45 expression, being exceptional in AML. We here provide evidence that the combination of HLA‐DR negativity and intense bright CD56 expression detects a rare and aggressive pediatric AML genetic lesion improving the diagnosis performance.

Published
2021

33. P359: IMPROVED OVERALL SURVIVAL AND MRD CLEARANCE WITH BLINATUMOMAB VS CHEMOTHERAPY AS PRE-TRANSPLANT CONSOLIDATION IN PEDIATRIC HIGH-RISK FIRST-RELAPSE B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL)

Author

Locatelli, F., primary, Zugmaier, G., additional, Rizzari, C., additional, Morris, J., additional, Gruhn, B., additional, Klingebiel, T., additional, Parasole, R., additional, Linderkamp, C., additional, Flotho, C., additional, Petit, A., additional, Micalizzi, C., additional, Zeng, Y., additional, Desai, R., additional, Kormany, W., additional, Eckert, C., additional, Möricke, A., additional, Sartor, M., additional, Hrusak, O., additional, Peters, C., additional, Saha, V., additional, Vinti, L., additional, and von Stackelberg, A., additional

Published
2022
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34. Flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients on anticancer treatment

Author

Hrusak, O, Kalina, T, Wolf, J, Balduzzi, A, Provenzi, M, Rizzari, C, Rives, S, del Pozo Carlavilla, M, Alonso, M, Dominguez-Pinilla, N, Bourquin, J, Schmiegelow, K, Attarbaschi, A, Grillner, P, Mellgren, K, van der Werff ten Bosch, J, Pieters, R, Brozou, T, Borkhardt, A, Escherich, G, Lauten, M, Stanulla, M, Smith, O, Yeoh, A, Elitzur, S, Vora, A, Li, C, Ariffin, H, Kolenova, A, Dallapozza, L, Farah, R, Lazic, J, Manabe, A, Styczynski, J, Kovacs, G, Ottoffy, G, Felice, M, Buldini, B, Conter, V, Stary, J, Schrappe, M, Hrusak O., Kalina T., Wolf J., Balduzzi A., Provenzi M., Rizzari C., Rives S., del Pozo Carlavilla M., Alonso M. E. V., Dominguez-Pinilla N., Bourquin J. -P., Schmiegelow K., Attarbaschi A., Grillner P., Mellgren K., van der Werff ten Bosch J., Pieters R., Brozou T., Borkhardt A., Escherich G., Lauten M., Stanulla M., Smith O., Yeoh A. E. J., Elitzur S., Vora A., Li C. -K., Ariffin H., Kolenova A., Dallapozza L., Farah R., Lazic J., Manabe A., Styczynski J., Kovacs G., Ottoffy G., Felice M. S., Buldini B., Conter V., Stary J., Schrappe M., Hrusak, O, Kalina, T, Wolf, J, Balduzzi, A, Provenzi, M, Rizzari, C, Rives, S, del Pozo Carlavilla, M, Alonso, M, Dominguez-Pinilla, N, Bourquin, J, Schmiegelow, K, Attarbaschi, A, Grillner, P, Mellgren, K, van der Werff ten Bosch, J, Pieters, R, Brozou, T, Borkhardt, A, Escherich, G, Lauten, M, Stanulla, M, Smith, O, Yeoh, A, Elitzur, S, Vora, A, Li, C, Ariffin, H, Kolenova, A, Dallapozza, L, Farah, R, Lazic, J, Manabe, A, Styczynski, J, Kovacs, G, Ottoffy, G, Felice, M, Buldini, B, Conter, V, Stary, J, Schrappe, M, Hrusak O., Kalina T., Wolf J., Balduzzi A., Provenzi M., Rizzari C., Rives S., del Pozo Carlavilla M., Alonso M. E. V., Dominguez-Pinilla N., Bourquin J. -P., Schmiegelow K., Attarbaschi A., Grillner P., Mellgren K., van der Werff ten Bosch J., Pieters R., Brozou T., Borkhardt A., Escherich G., Lauten M., Stanulla M., Smith O., Yeoh A. E. J., Elitzur S., Vora A., Li C. -K., Ariffin H., Kolenova A., Dallapozza L., Farah R., Lazic J., Manabe A., Styczynski J., Kovacs G., Ottoffy G., Felice M. S., Buldini B., Conter V., Stary J., and Schrappe M.

Abstract

Introduction: Since the beginning of COVID-19 pandemic, it is known that the severe course of the disease occurs mostly among the elderly, whereas it is rare among children and young adults. Comorbidities, in particular, diabetes and hypertension, clearly associated with age, besides obesity and smoke, are strongly associated with the need for intensive treatment and a dismal outcome. A weaker immunity of the elderly has been proposed as a possible explanation of this uneven age distribution. Thus, there is concern that children treated for cancer may allso be at risk for an unfavourable course of infection. Along the same line, anecdotal information from Wuhan, China, mentioned a severe course of COVID-19 in a child treated for leukaemia. Aim and methods: We made a flash survey on COVID-19 incidence and severity among children on anticancer treatment. Respondents were asked by email to fill in a short Web-based survey. Results: We received reports from 25 countries, where approximately 10,000 patients at risk are followed up. At the time of the survey, more than 200 of these children were tested, nine of whom were positive for COVID-19. Eight of the nine cases had asymptomatic to mild disease, and one was just diagnosed with COVID-19. We also discuss preventive measures that are in place or should be taken and treatment options in immunocompromised children with COVID-19. Conclusion: Thus, even children receiving anticancer chemotherapy may have a mild or asymptomatic course of COVID-19. While we should not underestimate the risk of developing a more severe course of COVID-19 than that observed here, the intensity of preventive measures should not cause delays or obstructions in oncological treatment.

Published
2020

35. Legionellosis in paediatrics [Legionellosi in pediatria]

Author

Impagnatiello, L, Bersanini, C, Spinelli, M, Ferrari, G, Biondi, A, Rizzari, C, Impagnatiello L., Bersanini C., Spinelli M., Ferrari G. M., Biondi A., Rizzari C., Impagnatiello, L, Bersanini, C, Spinelli, M, Ferrari, G, Biondi, A, Rizzari, C, Impagnatiello L., Bersanini C., Spinelli M., Ferrari G. M., Biondi A., and Rizzari C.

Published
2020

36. Randomized post-induction and delayed intensification therapy in high-risk pediatric acute lymphoblastic leukemia: long-term results of the international AIEOP-BFM ALL 2000 trial

Author

Attarbaschi, A, Mann, G, Zimmermann, M, Bader, P, Barisone, E, Basso, G, Biondi, A, Cario, G, Cazzaniga, G, Colombini, A, Flotho, C, Kuhlen, M, Lang, P, Lauten, M, Linderkamp, C, Locatelli, F, Lo Nigro, L, Moricke, A, Niggli, F, Panzer-Grumayer, R, Parasole, R, Peters, C, Caterina Putti, M, Rizzari, C, Suttorp, M, Valsecchi, M, Conter, V, Schrappe, M, Attarbaschi A., Mann G., Zimmermann M., Bader P., Barisone E., Basso G., Biondi A., Cario G., Cazzaniga G., Colombini A., Flotho C., Kuhlen M., Lang P., Lauten M., Linderkamp C., Locatelli F., Lo Nigro L., Moricke A., Niggli F., Panzer-Grumayer R., Parasole R., Peters C., Caterina Putti M., Rizzari C., Suttorp M., Valsecchi M. G., Conter V., Schrappe M., Attarbaschi, A, Mann, G, Zimmermann, M, Bader, P, Barisone, E, Basso, G, Biondi, A, Cario, G, Cazzaniga, G, Colombini, A, Flotho, C, Kuhlen, M, Lang, P, Lauten, M, Linderkamp, C, Locatelli, F, Lo Nigro, L, Moricke, A, Niggli, F, Panzer-Grumayer, R, Parasole, R, Peters, C, Caterina Putti, M, Rizzari, C, Suttorp, M, Valsecchi, M, Conter, V, Schrappe, M, Attarbaschi A., Mann G., Zimmermann M., Bader P., Barisone E., Basso G., Biondi A., Cario G., Cazzaniga G., Colombini A., Flotho C., Kuhlen M., Lang P., Lauten M., Linderkamp C., Locatelli F., Lo Nigro L., Moricke A., Niggli F., Panzer-Grumayer R., Parasole R., Peters C., Caterina Putti M., Rizzari C., Suttorp M., Valsecchi M. G., Conter V., and Schrappe M.

Published
2020

37. FLT3-ITD in Children with Early T-cell Precursor (ETP) Acute Lymphoblastic Leukemia: Incidence and Potential Target for Monitoring Minimal Residual Disease (MRD)

Author

Locatelli, F, Lo Nigro, L, Andriano, N, Buldini, B, Silvestri, D, Villa, T, Parasole, R, Barisone, E, Testi, A, Biondi, A, Valsecchi, M, Rizzari, C, Conter, V, Basso, G, Cazzaniga, G, Locatelli, Franco, Lo Nigro, Luca, Andriano, Nellina, Buldini, Barbara, Silvestri, Daniela, Villa, Tiziana, Parasole, Rosanna, Barisone, Elena, Testi, Anna Maria, Biondi, Andrea, Valsecchi, Maria Grazia, Rizzari, Carmelo, Conter, Valentino, Basso, Giuseppe, Cazzaniga, Giovanni, Locatelli, F, Lo Nigro, L, Andriano, N, Buldini, B, Silvestri, D, Villa, T, Parasole, R, Barisone, E, Testi, A, Biondi, A, Valsecchi, M, Rizzari, C, Conter, V, Basso, G, Cazzaniga, G, Locatelli, Franco, Lo Nigro, Luca, Andriano, Nellina, Buldini, Barbara, Silvestri, Daniela, Villa, Tiziana, Parasole, Rosanna, Barisone, Elena, Testi, Anna Maria, Biondi, Andrea, Valsecchi, Maria Grazia, Rizzari, Carmelo, Conter, Valentino, Basso, Giuseppe, and Cazzaniga, Giovanni

Abstract

Early T‐cell precursor (ETP) is an aggressive form of acute lymphoblastic leukemia (ALL), associated with high risk of relapse. This leukemia subtype shows a higher prevalence of mutations, typically associated with acute myeloid leukemia (AML), including RAS and FLT3 mutations. FLT3‐ ITD was identified in 35% cases of adult ETP‐ALL, but data in the pediatric counterpart are lacking. ETPs frequently lack immunoglobulin (IG) and T‐cell receptor (TR) gene rearrangements, used for minimal residual disease (MRD) monitoring. Among 718 T‐ALL enrolled in Italy into AIEOP‐BFM‐ ALL2000, AIEOP‐ALLR2006, and AIEOP‐BFM‐ALL2009 consecutive protocols, 86 patients (12%) were identified as ETP and 77 out of 86 children were studied for the presence of FLT3‐ITD. A total of 10 out of 77 (13%) ETP cases were FLT3‐ITD positive. IG/TR MRD monitoring was feasible only in four cases. FLT3‐ITD MRD monitoring was performed using real‐time PCR in all FLT3‐ITD positive ETP cases. A comparison between IG/TR and FLT3‐ITD resulted in comparable findings. Our study demonstrated that the FLT3‐ITD prevalence in children was lower (13%) than that reported in adult ETP‐ALL. FLT3‐ITD can be used as a marker for sensitive molecular MRD monitoring in ETP‐ALL when IG/TR markers are not available, potentially selecting those patients who should spare allogeneic hematopoietic stem cell transplantation (HSCT). Finally, the FLT3 pathway is a robust druggable target in this aggressive form of leukemia.

Published
2022

38. FLT3‐ITD in Children with Early T‐cell Precursor (ETP) Acute Lymphoblastic Leukemia: Incidence and Potential Target for Monitoring Minimal Residual Disease (MRD)

Author

Lo Nigro, L., Andriano, N., Buldini, B., Silvestri, D., Villa, T., Locatelli, Franco, Parasole, R., Barisone, E., Testi, A. M., Biondi, A., Valsecchi, M. G., Rizzari, C., Conter, V., Basso, G., Cazzaniga, G., Locatelli F. (ORCID:0000-0002-7976-3654), Lo Nigro, L., Andriano, N., Buldini, B., Silvestri, D., Villa, T., Locatelli, Franco, Parasole, R., Barisone, E., Testi, A. M., Biondi, A., Valsecchi, M. G., Rizzari, C., Conter, V., Basso, G., Cazzaniga, G., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Early T‐cell precursor (ETP) is an aggressive form of acute lymphoblastic leukemia (ALL), associated with high risk of relapse. This leukemia subtype shows a higher prevalence of mutations, typically associated with acute myeloid leukemia (AML), including RAS and FLT3 mutations. FLT3‐ ITD was identified in 35% cases of adult ETP‐ALL, but data in the pediatric counterpart are lacking. ETPs frequently lack immunoglobulin (IG) and T‐cell receptor (TR) gene rearrangements, used for minimal residual disease (MRD) monitoring. Among 718 T‐ALL enrolled in Italy into AIEOP‐BFM‐ ALL2000, AIEOP‐ALLR2006, and AIEOP‐BFM‐ALL2009 consecutive protocols, 86 patients (12%) were identified as ETP and 77 out of 86 children were studied for the presence of FLT3‐ITD. A total of 10 out of 77 (13%) ETP cases were FLT3‐ITD positive. IG/TR MRD monitoring was feasible only in four cases. FLT3‐ITD MRD monitoring was performed using real‐time PCR in all FLT3‐ITD positive ETP cases. A comparison between IG/TR and FLT3‐ITD resulted in comparable findings. Our study demonstrated that the FLT3‐ITD prevalence in children was lower (13%) than that reported in adult ETP‐ALL. FLT3‐ITD can be used as a marker for sensitive molecular MRD monitoring in ETP‐ALL when IG/TR markers are not available, potentially selecting those patients who should spare allogeneic hematopoietic stem cell transplantation (HSCT). Finally, the FLT3 pathway is a robust druggable target in this aggressive form of leukemia.

Published
2022

39. PAX5 fusion genes are frequent in poor risk childhood acute lymphoblastic leukaemia and can be targeted with BIBF1120

Author

Fazio, G., Bresolin, S., Silvestri, D., Quadri, M., Saitta, C., Vendramini, E., Buldini, B., Palmi, C., Bardini, M., Grioni, A., Rigamonti, S., Galbiati, M., Mecca, S., Savino, A. M., Peloso, A., Tu, J. -W., Bhatia, S., Borkhardt, A., Micalizzi, C., Lo Nigro, L., Locatelli, Franco, Conter, V., Rizzari, C., Valsecchi, M. G., te Kronnie, G., Biondi, A., Cazzaniga, G., Locatelli F. (ORCID:0000-0002-7976-3654), Fazio, G., Bresolin, S., Silvestri, D., Quadri, M., Saitta, C., Vendramini, E., Buldini, B., Palmi, C., Bardini, M., Grioni, A., Rigamonti, S., Galbiati, M., Mecca, S., Savino, A. M., Peloso, A., Tu, J. -W., Bhatia, S., Borkhardt, A., Micalizzi, C., Lo Nigro, L., Locatelli, Franco, Conter, V., Rizzari, C., Valsecchi, M. G., te Kronnie, G., Biondi, A., Cazzaniga, G., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Background: Despite intensive risk-based treatment protocols, 15% of paediatric patients with B-Cell Precursor Acute Lymphoblastic Leukaemia (BCP-ALL) experience relapse. There is urgent need of novel strategies to target poor prognosis subgroups, like PAX5 translocated. Methods: We considered 289 childhood BCP-ALL cases consecutively enrolled in Italy in the AIEOP-BFM ALL2000/R2006 protocols and we performed extensive molecular profiling, integrating gene expression, copy number analyses and fusion genes discovery by target-capture NGS. We developed preclinical strategies to target PAX5 fusion genes. Findings: We identified 135 cases without recurrent genetic rearrangements. Among them, 59 patients (43·7%) had a Ph-like signature; the remaining cases were identified as ERG-related (26%), High-Hyperdiploid-like (17%), ETV6::RUNX1-like (8·9%), MEF2D-rearranged (2·2%) or KMT2A-like (1·5%). A poor prognosis was associated with the Ph-like signature, independently from other high-risk features. Interestingly, PAX5 was altered in 54·4% of Ph-like compared to 16·2% of non-Ph-like cases, with 7 patients carrying PAX5 fusions (PAX5t), involving either novel (ALDH18A1, IKZF1, CDH13) or known (FBRSL1, AUTS2, DACH2) partner genes. PAX5t cases have a specific driver activity signature, extending to multiple pathways including LCK hyperactivation. Among FDA-approved drugs and inhibitors, we selected Dasatinib, Bosutinib and Foretinib, in addition to Nintedanib, known to be LCK ligands. We demonstrated the efficacy of the LCK-inhibitor BIBF1120/Nintedanib, as single agent or in combination with conventional chemotherapy, both ex vivo and in patient-derived xenograft model, showing a synergistic effect with dexamethasone. Interpretation: This study provides new insights in high-risk Ph-like leukaemia and identifies a potential therapy for targeting PAX5-fusion poor risk group. Funding: Ricerca Finalizzata-Giovani Ricercatori (Italian Ministry of Health), AIRC, Transcall, Fondazion

Published
2022

40. Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia: results from a phase II trial

Author

Pennesi, E., Michels, N., Brivio, E., van der Velden, V. H. J., Jiang, Y., Thano, A., Ammerlaan, A. J. C., Boer, J. M., Beverloo, H. B., Sleight, B., Chen, Y., Vormoor-Burger, B., Rives, S., Bielorai, B., Rossig, C., Petit, A., Rizzari, C., Engstler, G., Stary, J., Bautista Sirvent, F. J., Chen-Santel, C., Bruno, B., Bertrand, Y., Rialland, F., Plat, G., Reinhardt, D., Vinti, L., Von Stackelberg, A., Locatelli, Franco, Zwaan, C. M., Locatelli F. (ORCID:0000-0002-7976-3654), Pennesi, E., Michels, N., Brivio, E., van der Velden, V. H. J., Jiang, Y., Thano, A., Ammerlaan, A. J. C., Boer, J. M., Beverloo, H. B., Sleight, B., Chen, Y., Vormoor-Burger, B., Rives, S., Bielorai, B., Rossig, C., Petit, A., Rizzari, C., Engstler, G., Stary, J., Bautista Sirvent, F. J., Chen-Santel, C., Bruno, B., Bertrand, Y., Rialland, F., Plat, G., Reinhardt, D., Vinti, L., Von Stackelberg, A., Locatelli, Franco, Zwaan, C. M., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Inotuzumab Ozogamicin is a CD22-directed antibody conjugated to calicheamicin, approved in adults with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (BCP-ALL). Patients aged 1–18 years, with R/R CD22 + BCP-ALL were treated at the RP2D of 1.8 mg/m2. Using a single-stage design, with an overall response rate (ORR) ≤ 30% defined as not promissing and ORR > 55% as expected, 25 patients needed to be recruited to achieve 80% power at 0.05 significance level. Thirty-two patients were enrolled, 28 were treated, 27 were evaluable for response. The estimated ORR was 81.5% (95%CI: 61.9–93.7%), and 81.8% (18/22) of the responding subjects were minimal residual disease (MRD) negative. The study met its primary endpoint. Median follow up of survivors was 16 months (IQR: 14.49–20.07). One year Event Free Survival was 36.7% (95% CI: 22.2–60.4%), and Overall Survival was 55.1% (95% CI: 39.1−77.7%). Eighteen patients received consolidation (with HSCT and/or CAR T-cells therapy). Sinusoidal obstructive syndrome (SOS) occurred in seven patients. MRD negativity seemed correlated to calicheamicin sensitivity in vitro, but not to CD22 surface expression, saturation, or internalization. InO was effective in this population. The most relevant risk was the occurrence of SOS, particularly when InO treatment was followed by HSCT.

Published
2022

41. PAX5 fusion genes are frequent in poor risk childhood acute lymphoblastic leukaemia and can be targeted with BIBF1120

Author

Fazio, G, Bresolin, S, Silvestri, D, Quadri, M, Saitta, C, Vendramini, E, Buldini, B, Palmi, C, Bardini, M, Grioni, A, Rigamonti, S, Galbiati, M, Mecca, S, Savino, A, Peloso, A, Tu, J, Bhatia, S, Borkhardt, A, Micalizzi, C, Lo Nigro, L, Locatelli, F, Conter, V, Rizzari, C, Valsecchi, M, Te Kronnie, G, Biondi, A, Cazzaniga, G, Fazio, Grazia, Bresolin, Silvia, Silvestri, Daniela, Quadri, Manuel, Saitta, Claudia, Vendramini, Elena, Buldini, Barbara, Palmi, Chiara, Bardini, Michela, Grioni, Andrea, Rigamonti, Silvia, Galbiati, Marta, Mecca, Stefano, Savino, Angela Maria, Peloso, Alberto, Tu, Jia-Wey, Bhatia, Sanil, Borkhardt, Arndt, Micalizzi, Concetta, Lo Nigro, Luca, Locatelli, Franco, Conter, Valentino, Rizzari, Carmelo, Valsecchi, Maria Grazia, Te Kronnie, Geertruij, Biondi, Andrea, Cazzaniga, Giovanni, Fazio, G, Bresolin, S, Silvestri, D, Quadri, M, Saitta, C, Vendramini, E, Buldini, B, Palmi, C, Bardini, M, Grioni, A, Rigamonti, S, Galbiati, M, Mecca, S, Savino, A, Peloso, A, Tu, J, Bhatia, S, Borkhardt, A, Micalizzi, C, Lo Nigro, L, Locatelli, F, Conter, V, Rizzari, C, Valsecchi, M, Te Kronnie, G, Biondi, A, Cazzaniga, G, Fazio, Grazia, Bresolin, Silvia, Silvestri, Daniela, Quadri, Manuel, Saitta, Claudia, Vendramini, Elena, Buldini, Barbara, Palmi, Chiara, Bardini, Michela, Grioni, Andrea, Rigamonti, Silvia, Galbiati, Marta, Mecca, Stefano, Savino, Angela Maria, Peloso, Alberto, Tu, Jia-Wey, Bhatia, Sanil, Borkhardt, Arndt, Micalizzi, Concetta, Lo Nigro, Luca, Locatelli, Franco, Conter, Valentino, Rizzari, Carmelo, Valsecchi, Maria Grazia, Te Kronnie, Geertruij, Biondi, Andrea, and Cazzaniga, Giovanni

Abstract

Background: Despite intensive risk-based treatment protocols, 15% of paediatric patients with B-Cell Precursor Acute Lymphoblastic Leukaemia (BCP-ALL) experience relapse. There is urgent need of novel strategies to target poor prognosis subgroups, like PAX5 translocated. Methods: We considered 289 childhood BCP-ALL cases consecutively enrolled in Italy in the AIEOP-BFM ALL2000/R2006 protocols and we performed extensive molecular profiling, integrating gene expression, copy number analyses and fusion genes discovery by target-capture NGS. We developed preclinical strategies to target PAX5 fusion genes. Findings: We identified 135 cases without recurrent genetic rearrangements. Among them, 59 patients (43·7%) had a Ph-like signature; the remaining cases were identified as ERG-related (26%), High-Hyperdiploid-like (17%), ETV6::RUNX1-like (8·9%), MEF2D-rearranged (2·2%) or KMT2A-like (1·5%). A poor prognosis was associated with the Ph-like signature, independently from other high-risk features. Interestingly, PAX5 was altered in 54·4% of Ph-like compared to 16·2% of non-Ph-like cases, with 7 patients carrying PAX5 fusions (PAX5t), involving either novel (ALDH18A1, IKZF1, CDH13) or known (FBRSL1, AUTS2, DACH2) partner genes. PAX5t cases have a specific driver activity signature, extending to multiple pathways including LCK hyperactivation. Among FDA-approved drugs and inhibitors, we selected Dasatinib, Bosutinib and Foretinib, in addition to Nintedanib, known to be LCK ligands. We demonstrated the efficacy of the LCK-inhibitor BIBF1120/Nintedanib, as single agent or in combination with conventional chemotherapy, both ex vivo and in patient-derived xenograft model, showing a synergistic effect with dexamethasone. Interpretation: This study provides new insights in high-risk Ph-like leukaemia and identifies a potential therapy for targeting PAX5-fusion poor risk group. Funding: Ricerca Finalizzata-Giovani Ricercatori (Italian Ministry of Health), AIRC, Transcall, Fondazion

Published
2022

42. Osteonecrosis in paediatric acute lymphoblastic leukaemia: Incidence, risk factors, radiological patterns and evolution in a single-centre cohort

Author

Brivio, E, Cossio, A, Borra, D, Silvestri, D, Prunotto, G, Colombini, A, Verna, M, Rizzari, C, Biondi, A, Conter, V, Valsecchi, M, Balduzzi, A, Brivio, Erica, Cossio, Andrea, Borra, Davide, Silvestri, Daniela, Prunotto, Giulia, Colombini, Antonella, Verna, Marta, Rizzari, Carmelo, Biondi, Andrea, Conter, Valentino, Valsecchi, Maria Grazia, Balduzzi, Adriana, Brivio, E, Cossio, A, Borra, D, Silvestri, D, Prunotto, G, Colombini, A, Verna, M, Rizzari, C, Biondi, A, Conter, V, Valsecchi, M, Balduzzi, A, Brivio, Erica, Cossio, Andrea, Borra, Davide, Silvestri, Daniela, Prunotto, Giulia, Colombini, Antonella, Verna, Marta, Rizzari, Carmelo, Biondi, Andrea, Conter, Valentino, Valsecchi, Maria Grazia, and Balduzzi, Adriana

Abstract

Osteonecrosis (ON) is a well-known sequela of paediatric acute lymphoblastic leukaemia (ALL) treatment. Incidence differs substantially among studies and the clinical significance of radiological findings is not fully established. We analysed 256 consecutive patients with ALL treated in our Institution between October 2010 and December 2016. Within the cohort, 41 developed ON, with a mean 5-year cumulative incidence of 18.5 (standard error, SE, 5.7)% overall. The mean (SE) 5-year cumulative incidence of ON was 12.7 (2.1)% after censoring upon stem cell transplantation (SCT) and/or relapse. Patients aged >= 10 years and patients allocated to the high-risk stratum had a 10-fold and fivefold higher risk of ON respectively. The risk of ON was more than double in relapsed patients, whereas no significant impact of gender, immunophenotype and SCT was demonstrated. Multiple lesions (median four joints involved per patient) were detected by magnetic resonance imaging in all but one patient, with the knee being the most affected joint. Lesions affecting convex joint surfaces experienced the worst evolution, whereas most lesions on diaphyses and concave surfaces remained radiologically stable or disappeared during follow-up. ON has a high prevalence in paediatric ALL, presenting with multiple lesions. Lesions involving convex surfaces were at higher risk of radiological deterioration.

Published
2022

43. Daratumumab with or without chemotherapy in relapsed and refractory acute lymphoblastic leukemia. A retrospective observational Campus ALL study

Author

Cerrano, M., Bonifacio, M., Olivi, M., Curti, A., Malagola, M., Dargenio, M., Scattolin, A. M., Papayannidis, C., Forghieri, F., Gurrieri, C., Tanasi, I., Zappasodi, P., Starza, R. L., Fracchiolla, N. S., Chiusolo, Patrizia, Giaccone, L., Del Principe, M. I., Giglio, F., Defina, M., Favre, C., Rizzari, C., Castella, B., Pizzolo, G., Ferrara, F., Chiaretti, S., Foa, R., Chiusolo P. (ORCID:0000-0002-1355-1587), Cerrano, M., Bonifacio, M., Olivi, M., Curti, A., Malagola, M., Dargenio, M., Scattolin, A. M., Papayannidis, C., Forghieri, F., Gurrieri, C., Tanasi, I., Zappasodi, P., Starza, R. L., Fracchiolla, N. S., Chiusolo, Patrizia, Giaccone, L., Del Principe, M. I., Giglio, F., Defina, M., Favre, C., Rizzari, C., Castella, B., Pizzolo, G., Ferrara, F., Chiaretti, S., Foa, R., and Chiusolo P. (ORCID:0000-0002-1355-1587)

Abstract

n/a

Published
2022

45. Combination antifungal therapy for invasive mold infections among pediatric patients with hematological malignancies: Data from a real-life case-series

Author

Peri, A, Verna, M, Biffi, S, Alagna, L, Longhi, B, Migliorino, G, Foresti, S, Bandera, A, Rovelli, A, Rizzari, C, Gori, A, Colombini, A, Peri A. M., Verna M., Biffi S., Alagna L., Longhi B., Migliorino G. M., Foresti S., Bandera A., Rovelli A., Rizzari C., Gori A., Colombini A., Peri, A, Verna, M, Biffi, S, Alagna, L, Longhi, B, Migliorino, G, Foresti, S, Bandera, A, Rovelli, A, Rizzari, C, Gori, A, Colombini, A, Peri A. M., Verna M., Biffi S., Alagna L., Longhi B., Migliorino G. M., Foresti S., Bandera A., Rovelli A., Rizzari C., Gori A., and Colombini A.

Abstract

Background: Invasive mold infections in children with hematological malignancies are associated with high mortality rates. The use of combination antifungal therapy in cases with a severe clinical course is increasing, although information on the efficacy and safety of this approach is limited. Methods: We present a case series of 13 children affected by hemato-oncological disorders who received combination antifungal therapy for invasive mold infections at our center (Pediatric Hematology, San Gerardo Hospital, Monza, Italy) from 2011 to 2016, with the aim of describing their clinical characteristics, types of infections, treatment regimens, clinical outcomes, and treatment safety. Medical records were retrospectively reviewed in order to describe patients’ charac-teristics. Results: Combination antifungal therapy included liposomal amphotericin associated with caspofungin (5/13, 38.4%), voriconazole (5/13, 38.4%), or posaconazole (3/13, 23.1%). The 12-week treatment response rate was 69.2% (6/13 patients showed complete response, 3/13 partial re-sponse). The crude mortality was 30.7% (4/13): half was related to invasive mold infections (2/13, 15.38%) and half to disease progression (2/13, 15.38%). Overall, treatment was well tolerated, and we did not observe any permanent discontinuation of antifungals due to related side effects. Conclusions: In our experience, combination antifungal therapy seems to be a safe option in im-munocompromised children with invasive mold infections. Well-designed studies are needed to confirm the safety of this approach and to better understand its efficacy in the pediatric setting.

Published
2019

46. Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome–positive chronic myeloid leukemia

Author

Hijiya, N, Maschan, A, Rizzari, C, Shimada, H, Dufour, C, Goto, H, Kang, H, Guinipero, T, Karakas, Z, Bautista, F, Ducassou, S, Yoo, K, Zwaan, C, Millot, F, Aimone, P, Allepuz, A, Quenet, S, Hourcade-Potelleret, F, Hertle, S, Sosothikul, D, Hijiya N., Maschan A., Rizzari C., Shimada H., Dufour C., Goto H., Kang H. J., Guinipero T., Karakas Z., Bautista F., Ducassou S., Yoo K. H., Zwaan C. M., Millot F., Aimone P., Allepuz A., Quenet S., Hourcade-Potelleret F., Hertle S., Sosothikul D., Hijiya, N, Maschan, A, Rizzari, C, Shimada, H, Dufour, C, Goto, H, Kang, H, Guinipero, T, Karakas, Z, Bautista, F, Ducassou, S, Yoo, K, Zwaan, C, Millot, F, Aimone, P, Allepuz, A, Quenet, S, Hourcade-Potelleret, F, Hertle, S, Sosothikul, D, Hijiya N., Maschan A., Rizzari C., Shimada H., Dufour C., Goto H., Kang H. J., Guinipero T., Karakas Z., Bautista F., Ducassou S., Yoo K. H., Zwaan C. M., Millot F., Aimone P., Allepuz A., Quenet S., Hourcade-Potelleret F., Hertle S., and Sosothikul D.

Abstract

Chronic myeloid leukemia (CML) is rare in children and accounts for £15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome–positive (Ph1) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance or intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph1 CML-CP R/I to imatinib or dasatinib or newly diagnosed Ph1 CML-CP. Data presented are from analyses with minimum follow-up of up to 24 cycles (1 cycle is 28 days). Fifty-nine patients with Ph1 CML-CP were enrolled, and 58 were treated (R/I, n 5 33; newly diagnosed, n 5 25). Major molecular response (MMR) rate at cycle 6 in the R/I cohort was 39.4% (primary end point); 57.6% of patients achieved or maintained MMR and 81.8% achieved or maintained complete cytogenetic response (CCyR) by 24 cycles. In patients with newly diagnosed disease, rates of MMR by cycle 12 and CCyR at cycle 12 were 64.0% each (primary end points); by cycle 24, cumulative MMR and CCyR rates were 68.0% and 84.0%, respectively. The safety profile of nilotinib in pediatric patients was generally comparable with the known safety profile in adults, although cardiovascular events were not observed in this study, and hepatic laboratory abnormalities were more frequent; no new safety signals were identified. In summary, nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with Ph1 CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01844765. (Blood. 2019;134(23):2036-2045).

Published
2019

47. Nationwide central diagnosis review for childhood solid tumors: From concept to realization of an Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) integrated project

Author

Spreafico, F, Quarello, P, Alaggio, R, Collini, P, Haupt, R, Mastronuzzi, A, Prete, A, Rabusin, M, Rizzari, C, Schumacher, F, Zecca, M, Pession, A, Fagioli, F, Spreafico F., Quarello P., Alaggio R., Collini P., Haupt R., Mastronuzzi A., Prete A., Rabusin M., Rizzari C., Schumacher F., Zecca M., Pession A., Fagioli F., Spreafico, F, Quarello, P, Alaggio, R, Collini, P, Haupt, R, Mastronuzzi, A, Prete, A, Rabusin, M, Rizzari, C, Schumacher, F, Zecca, M, Pession, A, Fagioli, F, Spreafico F., Quarello P., Alaggio R., Collini P., Haupt R., Mastronuzzi A., Prete A., Rabusin M., Rizzari C., Schumacher F., Zecca M., Pession A., and Fagioli F.

Published
2019

48. Pharmacokinetics and Pharmacodynamics of Conventional-Dose vs Triple-Dose Oseltamivir in Severely Immunocompromised Children with Influenza

Author

Bautista, F, Engelhard, D, Rizzari, C, Baka, M, Saavedra-Lozano, J, Lopez-Medina, E, Nasmyth-Miller, C, Hernandez-Sanchez, J, Sturm, S, Bautista F., Engelhard D., Rizzari C., Baka M., Saavedra-Lozano J., Lopez-Medina E., Nasmyth-Miller C., Hernandez-Sanchez J., Sturm S., Bautista, F, Engelhard, D, Rizzari, C, Baka, M, Saavedra-Lozano, J, Lopez-Medina, E, Nasmyth-Miller, C, Hernandez-Sanchez, J, Sturm, S, Bautista F., Engelhard D., Rizzari C., Baka M., Saavedra-Lozano J., Lopez-Medina E., Nasmyth-Miller C., Hernandez-Sanchez J., and Sturm S.

Abstract

This randomized phase 1b study evaluated the pharmacokinetics/pharmacodynamics of conventional-dose (30-75 mg twice daily [BID]) vs triple-dose (90-225 mg BID; weight-adjusted) oseltamivir for treatment of influenza in severely immunocompromised children <13 years. Oseltamivir carboxylate (OC) Cmax and AUC0-12h were ~2-fold higher with triple-dose vs conventional-dose oseltamivir. Increased dose/exposure of oseltamivir/OC did not improve virological outcomes or reduce viral resistance. Median time to cessation of viral shedding was similar with triple-dose and conventional-dose oseltamivir (150.7 vs 157.1 hours, respectively); median time to alleviation of baseline fever was longer with conventional-dose oseltamivir (28.4 vs 11.3 hours). No new safety signals were identified.

Published
2019

49. Outcome of adolescent patients with acute lymphoblastic leukaemia aged 10–14 years as compared with those aged 15–17 years: Long-term results of 1094 patients of the AIEOP-BFM ALL 2000 study

Author

Testi, A, Attarbaschi, A, Valsecchi, M, Moricke, A, Cario, G, Niggli, F, Silvestri, D, Bader, P, Kuhlen, M, Parasole, R, Putti, M, Lang, P, Flotho, C, Mann, G, Rizzari, C, Barisone, E, Locatelli, F, Linderkamp, C, Lauten, M, Suttorp, M, Zimmermann, M, Basso, G, Biondi, A, Conter, V, Schrappe, M, Testi A. M., Attarbaschi A., Valsecchi M. G., Moricke A., Cario G., Niggli F., Silvestri D., Bader P., Kuhlen M., Parasole R., Putti M. C., Lang P., Flotho C., Mann G., Rizzari C., Barisone E., Locatelli F., Linderkamp C., Lauten M., Suttorp M., Zimmermann M., Basso G., Biondi A., Conter V., Schrappe M., Testi, A, Attarbaschi, A, Valsecchi, M, Moricke, A, Cario, G, Niggli, F, Silvestri, D, Bader, P, Kuhlen, M, Parasole, R, Putti, M, Lang, P, Flotho, C, Mann, G, Rizzari, C, Barisone, E, Locatelli, F, Linderkamp, C, Lauten, M, Suttorp, M, Zimmermann, M, Basso, G, Biondi, A, Conter, V, Schrappe, M, Testi A. M., Attarbaschi A., Valsecchi M. G., Moricke A., Cario G., Niggli F., Silvestri D., Bader P., Kuhlen M., Parasole R., Putti M. C., Lang P., Flotho C., Mann G., Rizzari C., Barisone E., Locatelli F., Linderkamp C., Lauten M., Suttorp M., Zimmermann M., Basso G., Biondi A., Conter V., and Schrappe M.

Abstract

Background: Adolescents (aged 10–17 years) with acute lymphoblastic leukaemia (ALL) have unfavourable disease features and an inferior outcome when compared with younger children, but it is still unclear if differences in disease biology and prognosis exist between adolescents older or younger than 15 years. Methods: We retrospectively analysed outcomes of 1094 adolescents with ALL, aged 10–17 years, treated within the AIEOP-BFM ALL 2000 trial, overall and by the age groups 10–14 and 15–17 years. Findings: Compared with younger children (aged 1–9 years, n = 3647), adolescents had a statistically inferior 5-year event-free survival (EFS) [74.6% (1.3) vs. 84.4% (0.6)] and overall survival (OS) [83.4% (1.1) vs. 92.7% (0.4); p < 0.001]. Clinical and biological disease characteristics did not differ between the two subgroups of adolescents, including minimal residual disease (MRD) results during initial therapy, except for ETV6-RUNX1 frequency and gender. With a median follow-up of 8.8 years, the 5-year EFS and OS were 76.2% (1.5) and 84.9% (1.3), respectively, for those aged 10–14 years and 70.0% (2.8) and 78.8% (2.5) for those aged 15–17 years (p = 0.06; 0.05). There was no significant difference in the cumulative incidence of relapses [17.8% (1.4) and 18.3% (2.4); p = 0.98], while the incidence of treatment-related deaths as a first event was 2.6% (0.6) versus 7.4% (1.6) (p < 0.001) with, in particular, a higher incidence in the high-risk arm. Interpretation: Further prospective studies and biological investigations are required to define optimal treatment for adolescents, in particular for those aged 15–17 years. Newer agents (immunotherapy, targeted therapy) in early treatment phases of patients at higher risk of treatment failure could replace most toxic treatment elements, with the aim of reducing both toxicity and the risk of relapses.

Published
2019

50. ActivinA: a new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells

Author

Portale, F, Cricrì, G, Bresolin, S, Lupi, M, Gaspari, S, Silvestri, D, Russo, B, Marino, N, Ubezio, P, Pagni, F, Vergani, P, Te Kronnie, G, Valsecchi, M, Locatelli, F, Rizzari, C, Biondi, A, Dander, E, D'Amico, G, Portale F, Cricrì G, Bresolin S, Lupi M, Gaspari S, Silvestri D, Russo B, Marino N, Ubezio P, Pagni F, Vergani P, Te Kronnie G, Valsecchi MG, Locatelli F, Rizzari C, Biondi A, Dander E, D'Amico G., Portale, F, Cricrì, G, Bresolin, S, Lupi, M, Gaspari, S, Silvestri, D, Russo, B, Marino, N, Ubezio, P, Pagni, F, Vergani, P, Te Kronnie, G, Valsecchi, M, Locatelli, F, Rizzari, C, Biondi, A, Dander, E, D'Amico, G, Portale F, Cricrì G, Bresolin S, Lupi M, Gaspari S, Silvestri D, Russo B, Marino N, Ubezio P, Pagni F, Vergani P, Te Kronnie G, Valsecchi MG, Locatelli F, Rizzari C, Biondi A, Dander E, and D'Amico G.

Abstract

B-cell precursor-acute lymphoblastic leukemia modulates the bone marrow (BM) niche to become leukemia-supporting and chemo-protective by reprogramming the stromal microenvironment. New therapies targeting the interplay between leukemia and stroma can help improve disease outcome. We identified ActivinA, a TGF-b family member with a well-described role in promoting several solid malignancies, as a factor favoring leukemia that could represent a new potential target for therapy. ActivinA resulted over-expressed in the leukemic BM and its production was strongly induced in mesenchymal stromal cells after culture with leukemic cells. Moreover, MSCs isolated from BM of leukemic patients showed an intrinsic ability to secrete higher amounts of ActivinA compared to their normal counterparts. The pro-inflammatory leukemic BM microenvironment synergized with leukemic cells to induce stromal-derived ActivinA. Gene expression analysis of ActivinA-treated leukemic cells showed that this protein was able to significantly influence motility-associated pathways. Interestingly, ActivinA promoted random motility and CXCL12-driven migration of leukemic cells, even at suboptimal chemokine concentrations, characterizing the leukemic niche. Conversely, ActivinA severely impaired CXCL12-induced migration of healthy CD34 + cells. This opposite effect can be explained by the ability of ActivinA to increase intracellular calcium only in leukemic cells, boosting cytoskeleton dynamics through a higher rate of actin polymerization. Moreover, by stimulating the invasiveness of the leukemic cells, ActivinA was found to be a leukemia-promoting factor. Importantly, the ability of ActivinA to enhance BM engraftment and the metastatic potential of leukemic cells was confirmed in a xenograft mouse model of the disease. Overall, ActivinA was seen to be a key factor in conferring a migratory advantage to leukemic cells over healthy hematopoiesis within the leukemic niche.

Published
2019

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