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2. Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol

Author

Stutterheim, J, de Lorenzo, P, van der Sluin, I, Alten, J, Ancliffe, P, Attarbaschi, A, Aversa, L, Boer, J, Biondi, A, Brethon, B, Diaz, P, Cazzaniga, G, Escherich, G, Ferster, A, Kotecha, R, Lausen, B, Leung, A, Locatelli, F, Silverman, L, Stary, J, Szczepanski, T, van der Velden, V, Vora, A, Zuna, J, Schrappe, M, Valsecchi, M, Pieters, R, Stutterheim J., de Lorenzo P., van der Sluin I. M., Alten J., Ancliffe P., Attarbaschi A., Aversa L., Boer J. M., Biondi A., Brethon B., Diaz P., Cazzaniga G., Escherich G., Ferster A., Kotecha R. S., Lausen B., Leung A. W., Locatelli F., Silverman L., Stary J., Szczepanski T., van der Velden V. H. J., Vora A., Zuna J., Schrappe M., Valsecchi M. G., Pieters R., Stutterheim, J, de Lorenzo, P, van der Sluin, I, Alten, J, Ancliffe, P, Attarbaschi, A, Aversa, L, Boer, J, Biondi, A, Brethon, B, Diaz, P, Cazzaniga, G, Escherich, G, Ferster, A, Kotecha, R, Lausen, B, Leung, A, Locatelli, F, Silverman, L, Stary, J, Szczepanski, T, van der Velden, V, Vora, A, Zuna, J, Schrappe, M, Valsecchi, M, Pieters, R, Stutterheim J., de Lorenzo P., van der Sluin I. M., Alten J., Ancliffe P., Attarbaschi A., Aversa L., Boer J. M., Biondi A., Brethon B., Diaz P., Cazzaniga G., Escherich G., Ferster A., Kotecha R. S., Lausen B., Leung A. W., Locatelli F., Silverman L., Stary J., Szczepanski T., van der Velden V. H. J., Vora A., Zuna J., Schrappe M., Valsecchi M. G., and Pieters R.

Abstract

Background: The outcome of infants with KMT2A-germline acute lymphoblastic leukaemia (ALL) is superior to that of infants with KMT2A-rearranged ALL but has been inferior to non-infant ALL patients. Here, we describe the outcome and prognostic factors for 167 infants with KMT2A-germline ALL enrolled in the Interfant-06 study. Methods: Univariate analysis on prognostic factors (age, white blood cell count at diagnosis, prednisolone response and CD10 expression) was performed on KMT2A-germline infants in complete remission at the end of induction (EOI; n = 163). Bone marrow minimal residual disease (MRD) was measured in 73 patients by real-time quantitative polymerase chain reaction at various time points (EOI, n = 68; end of consolidation, n = 56; and before OCTADAD, n = 57). MRD results were classified as negative, intermediate (<5∗10−4), and high (≥5∗10−4). Results: The 6-year event-free and overall survival was 73.9% (standard error [SE] = 3.6) and 87.2% (SE = 2.7). Relapses occurred early, within 36 months from diagnosis in 28 of 31 (90%) infants. Treatment-related mortality was 3.6%. Age <6 months was a favourable prognostic factor with a 6-year disease-free survival (DFS) of 91% (SE = 9.0) compared with 71.7% (SE = 4.2) in infants >6 months of age (P = 0.04). Patients with high EOI MRD ≥5 × 10−4 had a worse outcome (6-year DFS 61.4% [SE = 12.4], n = 16), compared with patients with undetectable EOI MRD (6-year DFS 87.9% [SE = 6.6], n = 28) or intermediate EOI MRD <5 × 10−4 (6-year DFS 76.4% [SE = 11.3], n = 24; P = 0.02). Conclusion: We conclude that young age at diagnosis and low EOI MRD seem favourable prognostic factors in infants with KMT2A-germline ALL and should be considered for risk stratification in future clinical trials.

Published
2022

3. Epidemiological investigation of Pseudomonas aeruginosa isolates including multidrug-resistant serogroup O12 isolates, by use of a rapid and simplified multiple-locus variable-number of tandem repeats analysis and whole genome sequencing

Author

Bidet, P., primary, Birgy, A., additional, Brethon, B., additional, Dalle, J.H., additional, Mariani-Kurkdjian, P., additional, Courroux, C., additional, Monjault, A., additional, Gits-Muselli, M., additional, and Bonacorsi, S., additional

Published
2022
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4. Mise en place de recommandations thérapeutiques pour la prise en charge des neutropénies fébriles chez les enfants atteints de cancer : expérience du RIFHOP

Author

Le Carrer, L., Saulpic, J., Dubrel, M., Serinet, M.O., Pacquement, H., Raimondo, G., Tabone, M.D., Trioche, P., Mesples, B., Furioli, J., Perdereau, S., Seaumes, H., Guillon, M., Guillaumat, C., Chavlon Demersay, A., Chevallier, B., Brethon, B., Ferry, C., Gouraud, F., Belloy, M., Bensaid, P., Dallot, C., Pellegrino, B., Sarda, H., Michon, J., and Dufour, C.

Published
2014
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5. Global characteristics and outcomes of SARS-CoV-2 infection in children and adolescents with cancer (GRCCC): a cohort study

Author

Mukkada, S, Bhakta, N, Chantada, G, Chen, Y, Vedaraju, Y, Faughnan, L, Homsi, M, Muniz-Talavera, H, Ranadive, R, Metzger, M, Friedrich, P, Agulnik, A, Jeha, S, Lam, C, Dalvi, R, Hessissen, L, Moreira, D, Santana, V, Sullivan, M, Bouffet, E, Caniza, M, Devidas, M, Pritchard-Jones, K, Rodriguez-Galindo, C, Ribelles, A, Balduzzi, A, Elhaddad, A, Casanovas, A, Garcia Velazquez, A, Laptsevich, A, Chang, A, F. Sampaio A., L, Gonzalez Prieto, A, Lassaletta, A, Suarez M, A, Alcasabas, A, Colita, A, Morales La Madrid, A, Samudio, A, Tondo, A, Colombini, A, Kattamis, A, Lopez Facundo, N, Bhattacharyya, A, Alimi, A, Phulpin, A, Vakrmanova, B, Aksoy, B, Brethon, B, Kobuin, J, Nolasco Monteiro, C, Paillard, C, Vezina, C, Ceyhun, B, Hentea, C, Meazza, C, Ortiz-Morales, D, Solorzano, R, Arce Cabrera, D, Zama, D, Ghosh, D, Ramirez-Rivera, D, Calle Jara, D, Janic, D, Rey Helo, E, Gouache, E, Guerrero Quiroz, E, Lopez, E, Thebault, E, Maradiegue, E, de Berranger, E, Ebeid, F, Galaverna, F, Antillon-Klussmann, F, Espinoza Chacur, F, Negro, F, Carraro, F, Compagno, F, Barriga, F, Tamayo Pedraza, G, Sanchez Fernandez, G, Naidu, G, Tokuc, G, Alias, H, B Segocio, H, Boudiaf, H, Asetre Luna, I, Maia, I, Astigarraga, I, Maza, I, Montoya Vasquez, J, Jazbec, J, Lazic, J, Beck Dean, J, Rouger-Gaudichon, J, Contreras Gonzalez, J, Huerta Aragones, J, Fuster, J, Quintana, J, Palma, J, Svojgr, K, Quintero, K, Malic Tudor, K, Georgantzi, K, P Schultz, K, Urena Horno, L, Fraquelli, L, Meneghello, L, Shalaby, L, Macias Mora, L, A Renner, L, Nunes Silva, L, Sisinni, L, Hammad, M, Fernandez Sanmartin, M, Zubieta A, C, Drozdowski, M, Kourti, M, Palladino, M, Miranda Madrazo, M, Poiree, M, Popova, M, Melgar, M, Baragano, M, Aviles-Robles, M, Provenzi, M, Mendes Lins, M, Fatih Orhan, M, Villarroel, M, Jeronimo, M, Varas Palma, M, Rafie Raza, M, M Justin, M, Shaheen, N, Dominguez-Pinilla, N, Whipple, N, Andre, N, Hrusak, O, Velasco Puyo, P, Zacasa Vargas, P, Olate Mellado, P, Yola Gassant, P, Diaz Romero, P, De Santis, R, Kebudi, R, Boranbayeva, R, Vasquez, R, Segura, R, Rosado, R, Gomez, S, Raimbault, S, Gunasekera, S, Makkeyah, S, Buyukkapu Bay, S, M Gomez, S, Bouttefroy, S, Islam, S, Abouelnaga, S, Torres, S, Cesaro, S, Nunes, S, Rouxinol, S, Bhaumik, S, Saliyeva, S, Inostroza, T, Velasquez, T, Hnin, T, Noren-Nystrom, U, Baretta, V, Jimenez-Antolinez, Y, Perez Alonso, V, Ayer Miller, V, Gandemer, V, Lotero, V, Mishkova, V, Gomez-Garcia, W, Margaryan, Y, Syed, Y, Mukkada S., Bhakta N., Chantada G. L., Chen Y., Vedaraju Y., Faughnan L., Homsi M. R., Muniz-Talavera H., Ranadive R., Metzger M., Friedrich P., Agulnik A., Jeha S., Lam C., Dalvi R., Hessissen L., Moreira D. C., Santana V. M., Sullivan M., Bouffet E., Caniza M. A., Devidas M., Pritchard-Jones K., Rodriguez-Galindo C., Ribelles A. J., Balduzzi A., Elhaddad A., Casanovas A., Garcia Velazquez A., Laptsevich A., Chang A., F. Sampaio A. L., Gonzalez Prieto A., Lassaletta A., Suarez M A., Alcasabas A. P., Colita A., Morales La Madrid A., Samudio A., Tondo A., Colombini A., Kattamis A., Lopez Facundo N. A., Bhattacharyya A., Alimi A., Phulpin A., Vakrmanova B., Aksoy B. A., Brethon B., Kobuin J. B., Nolasco Monteiro C., Paillard C., Vezina C., Ceyhun B., Hentea C., Meazza C., Ortiz-Morales D., Solorzano R. D., Arce Cabrera D., Zama D., Ghosh D., Ramirez-Rivera D., Calle Jara D. A., Janic D., Rey Helo E., Gouache E., Guerrero Quiroz E., Lopez E., Thebault E., Maradiegue E., de Berranger E., Ebeid F. S. E., Galaverna F., Antillon-Klussmann F., Espinoza Chacur F., Negro F. D., Carraro F., Compagno F., Barriga F., Tamayo Pedraza G., Sanchez Fernandez G., Naidu G., Tokuc G., Alias H., B Segocio H. G., Boudiaf H., Asetre Luna I., Maia I., Astigarraga I., Maza I., Montoya Vasquez J. E., Jazbec J., Lazic J., Beck Dean J., Rouger-Gaudichon J., Contreras Gonzalez J. C., Huerta Aragones J., Fuster J. L., Quintana J., Palma J., Svojgr K., Quintero K., Malic Tudor K., Georgantzi K., P Schultz K. A., Urena Horno L., Fraquelli L., Meneghello L., Shalaby L., Macias Mora L. L., A Renner L., Nunes Silva L., Sisinni L., Hammad M., Fernandez Sanmartin M., Zubieta A C. M., Drozdowski M. C., Kourti M., Palladino M. M., Miranda Madrazo M. R., Poiree M., Popova M., Melgar M., Baragano M., Aviles-Robles M. J., Provenzi M., Mendes Lins M., Fatih Orhan M., Villarroel M., Jeronimo M., Varas Palma M., Rafie Raza M., M Justin M., Shaheen N., Dominguez-Pinilla N., Whipple N. S., Andre N., Hrusak O., Velasco Puyo P., Zacasa Vargas P., Olate Mellado P., Yola Gassant P., Diaz Romero P., De Santis R., Kebudi R., Boranbayeva R., Vasquez R., Segura R. A., Rosado R. E., Gomez S., Raimbault S., Gunasekera S., Makkeyah S. M., Buyukkapu Bay S., M Gomez S., Bouttefroy S., Islam S., Abouelnaga S., Torres S. F., Cesaro S., Nunes S., Rouxinol S., Bhaumik S., Saliyeva S., Inostroza T., Velasquez T., Hnin T. M., Noren-Nystrom U., Baretta V., Jimenez-Antolinez Y. V., Perez Alonso V., Ayer Miller V., Gandemer V., Lotero V., Mishkova V., Gomez-Garcia W., Margaryan Y., Syed Y., Mukkada, S, Bhakta, N, Chantada, G, Chen, Y, Vedaraju, Y, Faughnan, L, Homsi, M, Muniz-Talavera, H, Ranadive, R, Metzger, M, Friedrich, P, Agulnik, A, Jeha, S, Lam, C, Dalvi, R, Hessissen, L, Moreira, D, Santana, V, Sullivan, M, Bouffet, E, Caniza, M, Devidas, M, Pritchard-Jones, K, Rodriguez-Galindo, C, Ribelles, A, Balduzzi, A, Elhaddad, A, Casanovas, A, Garcia Velazquez, A, Laptsevich, A, Chang, A, F. Sampaio A., L, Gonzalez Prieto, A, Lassaletta, A, Suarez M, A, Alcasabas, A, Colita, A, Morales La Madrid, A, Samudio, A, Tondo, A, Colombini, A, Kattamis, A, Lopez Facundo, N, Bhattacharyya, A, Alimi, A, Phulpin, A, Vakrmanova, B, Aksoy, B, Brethon, B, Kobuin, J, Nolasco Monteiro, C, Paillard, C, Vezina, C, Ceyhun, B, Hentea, C, Meazza, C, Ortiz-Morales, D, Solorzano, R, Arce Cabrera, D, Zama, D, Ghosh, D, Ramirez-Rivera, D, Calle Jara, D, Janic, D, Rey Helo, E, Gouache, E, Guerrero Quiroz, E, Lopez, E, Thebault, E, Maradiegue, E, de Berranger, E, Ebeid, F, Galaverna, F, Antillon-Klussmann, F, Espinoza Chacur, F, Negro, F, Carraro, F, Compagno, F, Barriga, F, Tamayo Pedraza, G, Sanchez Fernandez, G, Naidu, G, Tokuc, G, Alias, H, B Segocio, H, Boudiaf, H, Asetre Luna, I, Maia, I, Astigarraga, I, Maza, I, Montoya Vasquez, J, Jazbec, J, Lazic, J, Beck Dean, J, Rouger-Gaudichon, J, Contreras Gonzalez, J, Huerta Aragones, J, Fuster, J, Quintana, J, Palma, J, Svojgr, K, Quintero, K, Malic Tudor, K, Georgantzi, K, P Schultz, K, Urena Horno, L, Fraquelli, L, Meneghello, L, Shalaby, L, Macias Mora, L, A Renner, L, Nunes Silva, L, Sisinni, L, Hammad, M, Fernandez Sanmartin, M, Zubieta A, C, Drozdowski, M, Kourti, M, Palladino, M, Miranda Madrazo, M, Poiree, M, Popova, M, Melgar, M, Baragano, M, Aviles-Robles, M, Provenzi, M, Mendes Lins, M, Fatih Orhan, M, Villarroel, M, Jeronimo, M, Varas Palma, M, Rafie Raza, M, M Justin, M, Shaheen, N, Dominguez-Pinilla, N, Whipple, N, Andre, N, Hrusak, O, Velasco Puyo, P, Zacasa Vargas, P, Olate Mellado, P, Yola Gassant, P, Diaz Romero, P, De Santis, R, Kebudi, R, Boranbayeva, R, Vasquez, R, Segura, R, Rosado, R, Gomez, S, Raimbault, S, Gunasekera, S, Makkeyah, S, Buyukkapu Bay, S, M Gomez, S, Bouttefroy, S, Islam, S, Abouelnaga, S, Torres, S, Cesaro, S, Nunes, S, Rouxinol, S, Bhaumik, S, Saliyeva, S, Inostroza, T, Velasquez, T, Hnin, T, Noren-Nystrom, U, Baretta, V, Jimenez-Antolinez, Y, Perez Alonso, V, Ayer Miller, V, Gandemer, V, Lotero, V, Mishkova, V, Gomez-Garcia, W, Margaryan, Y, Syed, Y, Mukkada S., Bhakta N., Chantada G. L., Chen Y., Vedaraju Y., Faughnan L., Homsi M. R., Muniz-Talavera H., Ranadive R., Metzger M., Friedrich P., Agulnik A., Jeha S., Lam C., Dalvi R., Hessissen L., Moreira D. C., Santana V. M., Sullivan M., Bouffet E., Caniza M. A., Devidas M., Pritchard-Jones K., Rodriguez-Galindo C., Ribelles A. J., Balduzzi A., Elhaddad A., Casanovas A., Garcia Velazquez A., Laptsevich A., Chang A., F. Sampaio A. L., Gonzalez Prieto A., Lassaletta A., Suarez M A., Alcasabas A. P., Colita A., Morales La Madrid A., Samudio A., Tondo A., Colombini A., Kattamis A., Lopez Facundo N. A., Bhattacharyya A., Alimi A., Phulpin A., Vakrmanova B., Aksoy B. A., Brethon B., Kobuin J. B., Nolasco Monteiro C., Paillard C., Vezina C., Ceyhun B., Hentea C., Meazza C., Ortiz-Morales D., Solorzano R. D., Arce Cabrera D., Zama D., Ghosh D., Ramirez-Rivera D., Calle Jara D. A., Janic D., Rey Helo E., Gouache E., Guerrero Quiroz E., Lopez E., Thebault E., Maradiegue E., de Berranger E., Ebeid F. S. E., Galaverna F., Antillon-Klussmann F., Espinoza Chacur F., Negro F. D., Carraro F., Compagno F., Barriga F., Tamayo Pedraza G., Sanchez Fernandez G., Naidu G., Tokuc G., Alias H., B Segocio H. G., Boudiaf H., Asetre Luna I., Maia I., Astigarraga I., Maza I., Montoya Vasquez J. E., Jazbec J., Lazic J., Beck Dean J., Rouger-Gaudichon J., Contreras Gonzalez J. C., Huerta Aragones J., Fuster J. L., Quintana J., Palma J., Svojgr K., Quintero K., Malic Tudor K., Georgantzi K., P Schultz K. A., Urena Horno L., Fraquelli L., Meneghello L., Shalaby L., Macias Mora L. L., A Renner L., Nunes Silva L., Sisinni L., Hammad M., Fernandez Sanmartin M., Zubieta A C. M., Drozdowski M. C., Kourti M., Palladino M. M., Miranda Madrazo M. R., Poiree M., Popova M., Melgar M., Baragano M., Aviles-Robles M. J., Provenzi M., Mendes Lins M., Fatih Orhan M., Villarroel M., Jeronimo M., Varas Palma M., Rafie Raza M., M Justin M., Shaheen N., Dominguez-Pinilla N., Whipple N. S., Andre N., Hrusak O., Velasco Puyo P., Zacasa Vargas P., Olate Mellado P., Yola Gassant P., Diaz Romero P., De Santis R., Kebudi R., Boranbayeva R., Vasquez R., Segura R. A., Rosado R. E., Gomez S., Raimbault S., Gunasekera S., Makkeyah S. M., Buyukkapu Bay S., M Gomez S., Bouttefroy S., Islam S., Abouelnaga S., Torres S. F., Cesaro S., Nunes S., Rouxinol S., Bhaumik S., Saliyeva S., Inostroza T., Velasquez T., Hnin T. M., Noren-Nystrom U., Baretta V., Jimenez-Antolinez Y. V., Perez Alonso V., Ayer Miller V., Gandemer V., Lotero V., Mishkova V., Gomez-Garcia W., Margaryan Y., and Syed Y.

Abstract

Background: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. Methods: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (<19 years) with cancer or having received a haematopoietic stem-cell transplantation. There were no centre-specific exclusion criteria. The registry was disseminated through professional networks through email and conferences and health-care providers were invited to submit all qualifying cases. Data for demographics, oncological diagnosis, clinical course, and cancer therapy details were collected. Primary outcomes were disease severity and modification to cancer-directed therapy. The registry remains open to data collection. Findings: Of 1520 submitted episodes, 1500 patients were included in the study between April 15, 2020, and Feb 1, 2021. 1319 patients had complete 30-day follow-up. 259 (19·9%) of 1301 patients had a severe or critical infection, and 50 (3·8%) of 1319 died with the cause attributed to COVID-19 infection. Modifications to cancer-directed therapy occurred in 609 (55·8%) of 1092 patients receiving active oncological treatment. Multivariable analysis revealed several factors associated with severe or critical illness, including World Bank low-income or lower-middle-income (odds ratio [OR] 5·8 [95% CI 3·8–8·8]; p<0·0001) and upper-middle-income (1·6 [1·2–2·2]; p=0·0024) country status; age 15–18 years (1·6 [1·1–2·2]; p=0·013); absolute lymphocyte count of 300 or less cells per mm3 (2·5 [1·8–3·4]; p<0·0001), absolute neutrophil count

Published
2021

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

Author

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

Abstract

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

Published
2022

9. Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol

Author

Stutterheim, J., de Lorenzo, P., van der Sluis, I. M., Alten, J., Ancliffe, P., Attarbaschi, A., Aversa, L., Boer, J. M., Biondi, A., Brethon, B., Diaz, P., Cazzaniga, G., Escherich, G., Ferster, A., Kotecha, R. S., Lausen, B., Leung, A. W., Locatelli, Franco, Silverman, L., Stary, J., Szczepanski, T., van der Velden, V. H. J., Vora, A., Zuna, J., Schrappe, M., Valsecchi, M. G., Pieters, R., Locatelli F. (ORCID:0000-0002-7976-3654), Stutterheim, J., de Lorenzo, P., van der Sluis, I. M., Alten, J., Ancliffe, P., Attarbaschi, A., Aversa, L., Boer, J. M., Biondi, A., Brethon, B., Diaz, P., Cazzaniga, G., Escherich, G., Ferster, A., Kotecha, R. S., Lausen, B., Leung, A. W., Locatelli, Franco, Silverman, L., Stary, J., Szczepanski, T., van der Velden, V. H. J., Vora, A., Zuna, J., Schrappe, M., Valsecchi, M. G., Pieters, R., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Background: The outcome of infants with KMT2A-germline acute lymphoblastic leukaemia (ALL) is superior to that of infants with KMT2A-rearranged ALL but has been inferior to non-infant ALL patients. Here, we describe the outcome and prognostic factors for 167 infants with KMT2A-germline ALL enrolled in the Interfant-06 study. Methods: Univariate analysis on prognostic factors (age, white blood cell count at diagnosis, prednisolone response and CD10 expression) was performed on KMT2A-germline infants in complete remission at the end of induction (EOI; n = 163). Bone marrow minimal residual disease (MRD) was measured in 73 patients by real-time quantitative polymerase chain reaction at various time points (EOI, n = 68; end of consolidation, n = 56; and before OCTADAD, n = 57). MRD results were classified as negative, intermediate (<5∗10−4), and high (≥5∗10−4). Results: The 6-year event-free and overall survival was 73.9% (standard error [SE] = 3.6) and 87.2% (SE = 2.7). Relapses occurred early, within 36 months from diagnosis in 28 of 31 (90%) infants. Treatment-related mortality was 3.6%. Age <6 months was a favourable prognostic factor with a 6-year disease-free survival (DFS) of 91% (SE = 9.0) compared with 71.7% (SE = 4.2) in infants >6 months of age (P = 0.04). Patients with high EOI MRD ≥5 × 10−4 had a worse outcome (6-year DFS 61.4% [SE = 12.4], n = 16), compared with patients with undetectable EOI MRD (6-year DFS 87.9% [SE = 6.6], n = 28) or intermediate EOI MRD <5 × 10−4 (6-year DFS 76.4% [SE = 11.3], n = 24; P = 0.02). Conclusion: We conclude that young age at diagnosis and low EOI MRD seem favourable prognostic factors in infants with KMT2A-germline ALL and should be considered for risk stratification in future clinical trials.

Published
2022

10. Temporary contraindication to chemotherapy due to toxicity: blinatumomab's effectiveness in paediatric patients with B‐acute lymphoblastic leukaemia.

Author

Collignon, C., Domenech, C., Ducassou, S., Pluchart, C., Bruno, B., Pasquet, M., Simon, P., Petit, A., Rialland‐Battisti, F., and Brethon, B.

Subjects
CHILD patients, LYMPHOBLASTIC leukemia, HEMATOPOIETIC stem cell transplantation
Abstract

Another patient had an interruption of the treatment with blinatumomab because of hyperammonemia on the second cycle, but this patient had a portocaval shunt. Only one other patient had blast after treatment with blinatumomab, but this patient did not have myelogram before treatment with blinatumomab and had a prolonged interruption of treatment. Only one patient had >5% medullary blasts, 15 patients (65%) had negative MRD and 7 (30%) patients had detectable MRD. [Extracted from the article]

Published
2023
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11. Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol

Author

Stutterheim, J., primary, de Lorenzo, P., additional, van der Sluis, I.M., additional, Alten, J., additional, Ancliffe, P., additional, Attarbaschi, A., additional, Aversa, L., additional, Boer, J.M., additional, Biondi, A., additional, Brethon, B., additional, Diaz, P., additional, Cazzaniga, G., additional, Escherich, G., additional, Ferster, A., additional, Kotecha, R.S., additional, Lausen, B., additional, Leung, Alex WK., additional, Locatelli, F., additional, Silverman, L., additional, Stary, J., additional, Szczepanski, T., additional, van der Velden, V.H.J., additional, Vora, A., additional, Zuna, J., additional, Schrappe, M., additional, Valsecchi, M.G., additional, and Pieters, R., additional

Published
2022
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12. Outcome of infants younger than 1 year with acute lymphoblastic leukemia treated with the interfant-06 protocol: Results from an international phase III randomized study

Author

Pieters, R, De Lorenzo, P, Ancliffe, P, Aversa, L, Brethon, B, Biondi, A, Campbell, M, Escherich, G, Ferster, A, Gardner, R, Kotecha, R, Lausen, B, Li, C, Locatelli, F, Attarbaschi, A, Peters, C, Rubnitz, J, Silverman, L, Stary, J, Szczepanski, T, Vora, A, Schrappe, M, Valsecchi, M, Pieters R., De Lorenzo P., Ancliffe P., Aversa L. A., Brethon B., Biondi A., Campbell M., Escherich G., Ferster A., Gardner R. A., Kotecha R. S., Lausen B., Li C. K., Locatelli F., Attarbaschi A., Peters C., Rubnitz J. E., Silverman L. B., Stary J., Szczepanski T., Vora A., Schrappe M., Valsecchi M. G., Pieters, R, De Lorenzo, P, Ancliffe, P, Aversa, L, Brethon, B, Biondi, A, Campbell, M, Escherich, G, Ferster, A, Gardner, R, Kotecha, R, Lausen, B, Li, C, Locatelli, F, Attarbaschi, A, Peters, C, Rubnitz, J, Silverman, L, Stary, J, Szczepanski, T, Vora, A, Schrappe, M, Valsecchi, M, Pieters R., De Lorenzo P., Ancliffe P., Aversa L. A., Brethon B., Biondi A., Campbell M., Escherich G., Ferster A., Gardner R. A., Kotecha R. S., Lausen B., Li C. K., Locatelli F., Attarbaschi A., Peters C., Rubnitz J. E., Silverman L. B., Stary J., Szczepanski T., Vora A., Schrappe M., and Valsecchi M. G.

Abstract

PURPOSE Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A (MLL) gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national and international study groups, tested whether myeloid-style consolidation chemotherapy is superior to lymphoid style, the role of stemcell transplantation (SCT), and which factors had independent prognostic value. MATERIALS AND METHODS Three risk groups were defined: low risk (LR): KMT2A germline; high risk (HR): KMT2A-rearranged and older than 6 months with WBC count 300 3 109/L or more or a poor prednisone response; and medium risk (MR): all other KMT2A-rearranged cases. Patients in the MR and HR groups were randomly assigned to receive the lymphoid course low-dose cytosine arabinoside [araC], 6-mercaptopurine, cyclophosphamide (IB) or experimental myeloid courses, namely araC, daunorubicin, etoposide (ADE) and mitoxantrone, araC, etoposide (MAE). RESULTS A total of 651 infants were included, with 6-year event-free survival (EFS) and overall survival of 46.1% (SE, 2.1) and 58.2% (SE, 2.0). In West European/North American groups, 6-year EFS and overall survival were 49.4% (SE, 2.5) and 62.1% (SE, 2.4), which were 10% to 12% higher than in other countries. The 6-year probability of disease-free survival was comparable for the randomized arms (ADE1MAE 39.3% [SE 4.0; n = 169] v IB 36.8% [SE, 3.9; n = 161]; log-rank P = .47). The 6-year EFS rate of patients in the HR group was 20.9% (SE, 3.4) with the intention to undergo SCT; only 46% of them received SCT, because many had early events. KMT2A rearrangement was the strongest prognostic factor for EFS, followed by age, WBC count, and prednisone response. CONCLUSION Early intensification with postinduction myeloid-type chemotherapy courses did not significantly improve outcome for infant ALL compared with the lymphoid-type course IB. Outcome for infant ALL in Interfant- 06 did not improve compared with that in Interfant-99.

Published
2019

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

Author

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

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

15. Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol

Author

Stutterheim, J., van der Sluis, I. M., de Lorenzo, P., Alten, J., Ancliffe, P., Attarbaschi, A., Brethon, B., Biondi, A., Campbell, M., Cazzaniga, G., Escherich, G., Ferster, A., Kotecha, R. S., Lausen, B., Li, C. K., Lo Nigro, L., Locatelli, Franco, Marschalek, R., Meyer, C., Schrappe, M., Stary, J., Vora, A., Zuna, J., van der Velden, V. H. J., Szczepanski, T., Valsecchi, M. G., Pieters, R., Locatelli F. (ORCID:0000-0002-7976-3654), Stutterheim, J., van der Sluis, I. M., de Lorenzo, P., Alten, J., Ancliffe, P., Attarbaschi, A., Brethon, B., Biondi, A., Campbell, M., Cazzaniga, G., Escherich, G., Ferster, A., Kotecha, R. S., Lausen, B., Li, C. K., Lo Nigro, L., Locatelli, Franco, Marschalek, R., Meyer, C., Schrappe, M., Stary, J., Vora, A., Zuna, J., van der Velden, V. H. J., Szczepanski, T., Valsecchi, M. G., Pieters, R., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

PURPOSE: Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide). MATERIALS AND METHODS: MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged KMT2A, immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10-4), and high (≥ 5 × 10-4). RESULTS: EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively (P = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively (P < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively (P < .0001), while for myeloid-style-treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9). CONCLUSION: This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% v 23.2%), whereas patients with low EOI MRD may bene

Published
2021

16. A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study)

Author

Brivio, E., Locatelli, Franco, Lopez-Yurda, M., Malone, A., Diaz-de-Heredia, C., Bielorai, B., Rossig, C., van der Velden, V. H. J., Ammerlaan, A. C. J., Thano, A., van der Sluis, I. M., den Boer, M. L., Chen, Y., Sleight, B., Brethon, B., Nysom, K., Sramkova, L., Ora, I., Vinti, L., Chen-Santel, C., Zwaan, C. M., Locatelli F. (ORCID:0000-0002-7976-3654), Brivio, E., Locatelli, Franco, Lopez-Yurda, M., Malone, A., Diaz-de-Heredia, C., Bielorai, B., Rossig, C., van der Velden, V. H. J., Ammerlaan, A. C. J., Thano, A., van der Sluis, I. M., den Boer, M. L., Chen, Y., Sleight, B., Brethon, B., Nysom, K., Sramkova, L., Ora, I., Vinti, L., Chen-Santel, C., Zwaan, C. M., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

This phase 1 study investigated the recommended phase 2 dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple relapsed/refractory (R/R) CD22+ acute lymphoblastic leukemia (ALL). Patients (age ≥1 year or <18 years) received 3 doses of InO (days 1, 8, and 15) per course. Dose escalation was based on dose-limiting toxicities (DLTs) during course 1. Dose level 1 (DL1) was 1.4 mg/m2 (0.6, 0.4, 0.4 mg/m2) and DL2 was 1.8 mg/m2 (0.8, 0.5, 0.5 mg/m2). Secondary end points included safety, antileukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLTs) were enrolled. In course 1, the first cohort had 1 of 6 (DL1) and 2 of 5 (DL2) patients who experienced DLTs; subsequent review considered DL2 DLTs to be non–dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, in which 0 of 6 (DL1) and 1 of 6 (DL2) patients had a DLT. Twenty-three patients experienced grade 3 to 4 adverse events; hepatic sinusoidal obstruction syndrome was reported in 2 patients after subsequent chemotherapy. Overall response rate after course 1 was 80% (95% confidence interval [CI], 59% to 93%) (20 of 25 patients; DL1: 75% [95% CI, 43% to 95%], DL2: 85% [95% CI, 55% to 98%]). Of the responders, 84% (95% CI, 60% to 97%) achieved minimal residual disease (MRD)-negative complete response, and 12-month overall survival was 40% (95% CI, 25% to 66%). Nine patients received hematopoietic stem cell transplantation or chimeric antigen receptor T cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating antileukemic activity in heavily pretreated children with CD22+ R/R ALL. RP2D was established as 1.8 mg/m2 per course, as in adults. This trial was registered at https://www.clinicaltrialsregister.eu as EUDRA-CT 2016-000227-71. Key Points: • The recommended phase 2 dose of InO for

Published
2021

17. Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol

Author

Stutterheim, J, van der Sluis, I, de Lorenzo, P, Alten, J, Ancliffe, P, Attarbaschi, A, Brethon, B, Biondi, A, Campbell, M, Cazzaniga, G, Escherich, G, Ferster, A, Kotecha, R, Lausen, B, Li, C, Lo Nigro, L, Locatelli, F, Marschalek, R, Meyer, C, Schrappe, M, Stary, J, Vora, A, Zuna, J, van der Velden, V, Szczepanski, T, Valsecchi, M, Pieters, R, Stutterheim, Janine, van der Sluis, Inge M, de Lorenzo, Paola, Alten, Julia, Ancliffe, Philip, Attarbaschi, Andishe, Brethon, Benoit, Biondi, Andrea, Campbell, Myriam, Cazzaniga, Giovanni, Escherich, Gabriele, Ferster, Alina, Kotecha, Rishi S, Lausen, Birgitte, Li, Chi Kong, Lo Nigro, Luca, Locatelli, Franco, Marschalek, Rolf, Meyer, Claus, Schrappe, Martin, Stary, Jan, Vora, Ajay, Zuna, Jan, van der Velden, Vincent H J, Szczepanski, Tomasz, Valsecchi, Maria Grazia, Pieters, Rob, Stutterheim, J, van der Sluis, I, de Lorenzo, P, Alten, J, Ancliffe, P, Attarbaschi, A, Brethon, B, Biondi, A, Campbell, M, Cazzaniga, G, Escherich, G, Ferster, A, Kotecha, R, Lausen, B, Li, C, Lo Nigro, L, Locatelli, F, Marschalek, R, Meyer, C, Schrappe, M, Stary, J, Vora, A, Zuna, J, van der Velden, V, Szczepanski, T, Valsecchi, M, Pieters, R, Stutterheim, Janine, van der Sluis, Inge M, de Lorenzo, Paola, Alten, Julia, Ancliffe, Philip, Attarbaschi, Andishe, Brethon, Benoit, Biondi, Andrea, Campbell, Myriam, Cazzaniga, Giovanni, Escherich, Gabriele, Ferster, Alina, Kotecha, Rishi S, Lausen, Birgitte, Li, Chi Kong, Lo Nigro, Luca, Locatelli, Franco, Marschalek, Rolf, Meyer, Claus, Schrappe, Martin, Stary, Jan, Vora, Ajay, Zuna, Jan, van der Velden, Vincent H J, Szczepanski, Tomasz, Valsecchi, Maria Grazia, and Pieters, Rob

Abstract

Purpose: Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide). Materials and methods: MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged KMT2A, immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10-4), and high (≥ 5 × 10-4). Results: EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively (P = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively (P < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively (P < .0001), while for myeloid-style-treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9). Conclusion: This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% v 23.2%), whereas patients with low EOI MRD may bene

Published
2021

19. Parental comprehension and satisfaction in informed consent in paediatric clinical trials: a prospective study on childhood leukaemia

Author

Chappuy, H., Baruchel, A., Leverger, G., Oudot, C., Brethon, B., Haouy, S., Auvrignon, A., Davous, D., Doz, F., and Treluyer, J.M.

Subjects
Patient satisfaction -- Demographic aspects, Patient satisfaction -- Research, Health literacy -- Demographic aspects, Health literacy -- Research, Leukemia in children -- Care and treatment, Leukemia in children -- Research, Parental consent -- Research, Clinical trials -- Laws, regulations and rules, Government regulation
Published
2010

22. Blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia: results of the RIALTO trial, an expanded access study

Author

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

Abstract

NO ABSTRACT

Published
2020

24. Outcome of infants younger than 1 year with acute lymphoblastic leukemia treated with the interfant-06 protocol: Results from an international phase III randomized study

Author

Pieters, R., De Lorenzo, P., Ancliffe, P., Aversa, L. A., Brethon, B., Biondi, A., Campbell, M., Escherich, G., Ferster, A., Gardner, R. A., Kotecha, R. S., Lausen, B., Li, C. K., Locatelli, Franco, Attarbaschi, A., Peters, C., Rubnitz, J. E., Silverman, L. B., Stary, J., Szczepanski, T., Vora, A., Schrappe, M., Valsecchi, M. G., Locatelli F. (ORCID:0000-0002-7976-3654), Pieters, R., De Lorenzo, P., Ancliffe, P., Aversa, L. A., Brethon, B., Biondi, A., Campbell, M., Escherich, G., Ferster, A., Gardner, R. A., Kotecha, R. S., Lausen, B., Li, C. K., Locatelli, Franco, Attarbaschi, A., Peters, C., Rubnitz, J. E., Silverman, L. B., Stary, J., Szczepanski, T., Vora, A., Schrappe, M., Valsecchi, M. G., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

PURPOSE Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A (MLL) gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national and international study groups, tested whether myeloid-style consolidation chemotherapy is superior to lymphoid style, the role of stemcell transplantation (SCT), and which factors had independent prognostic value. MATERIALS AND METHODS Three risk groups were defined: low risk (LR): KMT2A germline; high risk (HR): KMT2A-rearranged and older than 6 months with WBC count 300 3 109/L or more or a poor prednisone response; and medium risk (MR): all other KMT2A-rearranged cases. Patients in the MR and HR groups were randomly assigned to receive the lymphoid course low-dose cytosine arabinoside [araC], 6-mercaptopurine, cyclophosphamide (IB) or experimental myeloid courses, namely araC, daunorubicin, etoposide (ADE) and mitoxantrone, araC, etoposide (MAE). RESULTS A total of 651 infants were included, with 6-year event-free survival (EFS) and overall survival of 46.1% (SE, 2.1) and 58.2% (SE, 2.0). In West European/North American groups, 6-year EFS and overall survival were 49.4% (SE, 2.5) and 62.1% (SE, 2.4), which were 10% to 12% higher than in other countries. The 6-year probability of disease-free survival was comparable for the randomized arms (ADE1MAE 39.3% [SE 4.0; n = 169] v IB 36.8% [SE, 3.9; n = 161]; log-rank P = .47). The 6-year EFS rate of patients in the HR group was 20.9% (SE, 3.4) with the intention to undergo SCT; only 46% of them received SCT, because many had early events. KMT2A rearrangement was the strongest prognostic factor for EFS, followed by age, WBC count, and prednisone response. CONCLUSION Early intensification with postinduction myeloid-type chemotherapy courses did not significantly improve outcome for infant ALL compared with the lymphoid-type course IB. Outcome for infant ALL in Interfant- 06 did not improve compared with that in Interfant-99.

Published
2019

25. Durable remissions in TCF3-HLF positive acute lymphoblastic leukemia with blinatumomab and stem cell transplantation

Author

Mouttet, B., Vinti, L., Ancliff, P., Bodmer, N., Brethon, B., Cario, G., Chen-Santel, C., Elitzur, S., Hazar, V., Kunz, J., Moricke, A., Stein, J., Vora, A., Yaman, Y., Schrappe, M., Anak, S., Baruchel, A., Locatelli, Franco, Stackelberg, A. V., Stanulla, M., Bourquin, J. -P., Locatelli F. (ORCID:0000-0002-7976-3654), Mouttet, B., Vinti, L., Ancliff, P., Bodmer, N., Brethon, B., Cario, G., Chen-Santel, C., Elitzur, S., Hazar, V., Kunz, J., Moricke, A., Stein, J., Vora, A., Yaman, Y., Schrappe, M., Anak, S., Baruchel, A., Locatelli, Franco, Stackelberg, A. V., Stanulla, M., Bourquin, J. -P., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

no abstract

Published
2019

27. Phase I/Phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia

Author

Von Stackelberg, A, Locatelli, F, Zugmaier, G, Handgretinger, R, Trippett, T, Rizzari, C, Bader, P, O'Brien, M, Brethon, B, Bhojwani, D, Schlegel, P, Borkhardt, A, Rheingold, S, Cooper, T, Zwaan, C, Barnette, P, Messina, C, Michel, G, Dubois, S, Hu, K, Zhu, M, Whitlock, J, Gore, L, Von Stackelberg A., Locatelli F., Zugmaier G., Handgretinger R., Trippett T. M., Rizzari C., Bader P., O'brien M. M., Brethon B., Bhojwani D., Schlegel P. G., Borkhardt A., Rheingold S. R., Cooper T. M., Zwaan C. M., Barnette P., Messina C., Michel G., Dubois S. G., Hu K., Zhu M., Whitlock J. A., Gore L., Von Stackelberg, A, Locatelli, F, Zugmaier, G, Handgretinger, R, Trippett, T, Rizzari, C, Bader, P, O'Brien, M, Brethon, B, Bhojwani, D, Schlegel, P, Borkhardt, A, Rheingold, S, Cooper, T, Zwaan, C, Barnette, P, Messina, C, Michel, G, Dubois, S, Hu, K, Zhu, M, Whitlock, J, Gore, L, Von Stackelberg A., Locatelli F., Zugmaier G., Handgretinger R., Trippett T. M., Rizzari C., Bader P., O'brien M. M., Brethon B., Bhojwani D., Schlegel P. G., Borkhardt A., Rheingold S. R., Cooper T. M., Zwaan C. M., Barnette P., Messina C., Michel G., Dubois S. G., Hu K., Zhu M., Whitlock J. A., and Gore L.

Abstract

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. Weevaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children , 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 mg/m2d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 mg/m2d for the first 7 days, followed by 15 mg/m2d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade $ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new t

Published
2016

28. Late effects in survivors of infantile acute leukemia: a study of the L.E.A program

Author

Gandemer, V, primary, Bonneau, J, additional, Oudin, C, additional, Berbis, J, additional, Bertrand, Y, additional, Tabone, M-D, additional, Ducassou, S, additional, Chastagner, P, additional, Brethon, B, additional, Dalle, J-H, additional, Thouvenin, S, additional, Poiree, M, additional, Plantaz, D, additional, Kanold, J, additional, Sirvent, N, additional, Lutz, P, additional, Hamidou, Z, additional, Baruchel, A, additional, Leverger, G, additional, Auquier, P, additional, and Michel, G, additional

Published
2017
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29. Phase I/Phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia

Author

Von Stackelberg, A., Locatelli, Franco, Zugmaier, G., Handgretinger, R., Trippett, T. M., Rizzari, C., Bader, P., O'Brien, M. M., Brethon, B., Bhojwani, D., Schlegel, P. G., Borkhardt, A., Rheingold, S. R., Cooper, T. M., Zwaan, C. M., Barnette, P., Messina, C., Michel, G., Dubois, S. G., Hu, K., Zhu, M., Whitlock, J. A., Gore, L., Locatelli F. (ORCID:0000-0002-7976-3654), Von Stackelberg, A., Locatelli, Franco, Zugmaier, G., Handgretinger, R., Trippett, T. M., Rizzari, C., Bader, P., O'Brien, M. M., Brethon, B., Bhojwani, D., Schlegel, P. G., Borkhardt, A., Rheingold, S. R., Cooper, T. M., Zwaan, C. M., Barnette, P., Messina, C., Michel, G., Dubois, S. G., Hu, K., Zhu, M., Whitlock, J. A., Gore, L., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. Weevaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children , 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 mg/m2d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 mg/m2d for the first 7 days, followed by 15 mg/m2d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade $ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new t

Published
2016

30. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis

Author

Flex, E., Jaiswal, M., Pantaleoni, F., Martinelli, S., Strullu, M., Fansa, E.K., Caye, A., Luca, A. De, Lepri, F., Dvorsky, R., Pannone, L., Paolacci, S., Zhang, S.C., Fodale, V., Bocchinfuso, G., Rossi, C., Burkitt-Wright, E.M., Farrotti, A., Stellacci, E., Cecchetti, S., Ferese, R., Bottero, L., Castro, S. de, Fenneteau, O., Brethon, B., Sanchez, M., Roberts, A.E., Yntema, H.G., Burgt, I. van der, Cianci, P., Bondeson, M.L., Digilio, M.C., Zampino, G., Kerr, B., Aoki, Y., Loh, M.L., Palleschi, A., Schiavi, E. Di, Care, A., Selicorni, A., Dallapiccola, B., Cirstea, I.C., Stella, L., Zenker, M., Gelb, B.D., Cave, H., Ahmadian, M.R., Tartaglia, M., Flex, E., Jaiswal, M., Pantaleoni, F., Martinelli, S., Strullu, M., Fansa, E.K., Caye, A., Luca, A. De, Lepri, F., Dvorsky, R., Pannone, L., Paolacci, S., Zhang, S.C., Fodale, V., Bocchinfuso, G., Rossi, C., Burkitt-Wright, E.M., Farrotti, A., Stellacci, E., Cecchetti, S., Ferese, R., Bottero, L., Castro, S. de, Fenneteau, O., Brethon, B., Sanchez, M., Roberts, A.E., Yntema, H.G., Burgt, I. van der, Cianci, P., Bondeson, M.L., Digilio, M.C., Zampino, G., Kerr, B., Aoki, Y., Loh, M.L., Palleschi, A., Schiavi, E. Di, Care, A., Selicorni, A., Dallapiccola, B., Cirstea, I.C., Stella, L., Zenker, M., Gelb, B.D., Cave, H., Ahmadian, M.R., and Tartaglia, M.

Abstract

Item does not contain fulltext, RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2(S2G) mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.

Published
2014

32. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis

Author

Flex, E., primary, Jaiswal, M., additional, Pantaleoni, F., additional, Martinelli, S., additional, Strullu, M., additional, Fansa, E. K., additional, Caye, A., additional, De Luca, A., additional, Lepri, F., additional, Dvorsky, R., additional, Pannone, L., additional, Paolacci, S., additional, Zhang, S.-C., additional, Fodale, V., additional, Bocchinfuso, G., additional, Rossi, C., additional, Burkitt-Wright, E. M. M., additional, Farrotti, A., additional, Stellacci, E., additional, Cecchetti, S., additional, Ferese, R., additional, Bottero, L., additional, Castro, S., additional, Fenneteau, O., additional, Brethon, B., additional, Sanchez, M., additional, Roberts, A. E., additional, Yntema, H. G., additional, Van Der Burgt, I., additional, Cianci, P., additional, Bondeson, M.-L., additional, Cristina Digilio, M., additional, Zampino, G., additional, Kerr, B., additional, Aoki, Y., additional, Loh, M. L., additional, Palleschi, A., additional, Di Schiavi, E., additional, Care, A., additional, Selicorni, A., additional, Dallapiccola, B., additional, Cirstea, I. C., additional, Stella, L., additional, Zenker, M., additional, Gelb, B. D., additional, Cave, H., additional, Ahmadian, M. R., additional, and Tartaglia, M., additional

Published
2014
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33. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system philadelphia chromosome positive leukemia

Author

Porkka, K. (Kimmo), Koskenvesa, P. (Perttu), Lundan, T. (Tuija), Rimpiläinen, J. (Johanna), Mustjoki, S. (Satu), Smykla, R. (Richard), Wild, R. (Robert), Luo, R. (Roger), Arnan, M. (Montserrat), Brethon, B. (Benoit), Eccersley, L. (Lydia), Hjorth-Hansen, H. (Henrik), Höglund, M. (Martin), Klamova, H. (Hana), Knutsen, H. (Håvar), Parikh, S. (Suhag), Raffoux, E. (Emmanuel), Gruber, F. (Franz), Brito-Babapulle, F. (Finella), Dombret, H. (Hervé), Duarte, R.F. (Rafael), Elonen, E. (Erkki), Paquette, R. (Ron), Zwaan, C.M. (Michel), Lee, F.Y.F. (Francis), Porkka, K. (Kimmo), Koskenvesa, P. (Perttu), Lundan, T. (Tuija), Rimpiläinen, J. (Johanna), Mustjoki, S. (Satu), Smykla, R. (Richard), Wild, R. (Robert), Luo, R. (Roger), Arnan, M. (Montserrat), Brethon, B. (Benoit), Eccersley, L. (Lydia), Hjorth-Hansen, H. (Henrik), Höglund, M. (Martin), Klamova, H. (Hana), Knutsen, H. (Håvar), Parikh, S. (Suhag), Raffoux, E. (Emmanuel), Gruber, F. (Franz), Brito-Babapulle, F. (Finella), Dombret, H. (Hervé), Duarte, R.F. (Rafael), Elonen, E. (Erkki), Paquette, R. (Ron), Zwaan, C.M. (Michel), and Lee, F.Y.F. (Francis)

Abstract

Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasatinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a pre-clinical mouse model of intracranial Ph+ leukemia. Clinical dasatinib treatment in patients with CNS Ph+ leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasatinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials. gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).

Published
2008
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34. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia

Author

Porkka, K, Koskenvesa, P, Lundan, T, Rimpilainen, J, Mustjoki, S, Smykla, R, Wild, R, Luo, R, Arnan, M, Brethon, B, Eccersley, L, Hjorth-Hansen, H, Hoglund, M, Klamova, H, Knutsen, H, Parikh, S, Raffoux, E, Gruber, F, Brito-Babapulle, F, Dombret, H, Duarte, RF, Elonen, E, Paquette, R, Zwaan, C.M., Lee, FYF, Porkka, K, Koskenvesa, P, Lundan, T, Rimpilainen, J, Mustjoki, S, Smykla, R, Wild, R, Luo, R, Arnan, M, Brethon, B, Eccersley, L, Hjorth-Hansen, H, Hoglund, M, Klamova, H, Knutsen, H, Parikh, S, Raffoux, E, Gruber, F, Brito-Babapulle, F, Dombret, H, Duarte, RF, Elonen, E, Paquette, R, Zwaan, C.M., and Lee, FYF

Published
2008

35. Indications and outcomes of antifungal therapy in French patients with haematological conditions or recipients of haematopoietic stem cell transplantation

Author

Herbrecht, R., primary, Caillot, D., additional, Cordonnier, C., additional, Auvrignon, A., additional, Thiebaut, A., additional, Brethon, B., additional, Michallet, M., additional, Mahlaoui, N., additional, Bertrand, Y., additional, Preziosi, P., additional, Ruiz, F., additional, Gorin, N.-C., additional, and Gangneux, J.-P., additional

Published
2012
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36. Diagnosis of Fanconi anemia in patients with bone marrow failure

Author

Pinto, F. O., primary, Leblanc, T., additional, Chamousset, D., additional, Le Roux, G., additional, Brethon, B., additional, Cassinat, B., additional, Larghero, J., additional, de Villartay, J.-P., additional, Stoppa-Lyonnet, D., additional, Baruchel, A., additional, Socie, G., additional, Gluckman, E., additional, and Soulier, J., additional

Published
2009
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39. Treatment of childhood autoimmune haemolytic anaemia with rituximab.

Author

Quartier P, Brethon B, Philippet P, Landman-Parker J, Le Deist F, Fischer A, Quartier, P, Brethon, B, Philippet, P, Landman-Parker, J, Le Deist, F, and Fischer, A

Abstract

Autoimmune haemolytic anaemia commonly has a severe course in young children, thus requiring multiple immunosuppressive treatments. Five children with refractory idiopathic autoimmune haemolytic anaemia, and one child with the disease after bone-marrow transplantation, were treated with rituximab-a monoclonal antibody against CD20. Tolerance of the treatment was good. However, circulating Bcells were absent and hypogammaglobulinaemia was seen for 9 months after treatment. All patients remained in complete remission 15-22 months after the start of rituximab therapy. Corticosteroids and immunosuppressive drugs were stopped or their dose markedly reduced. We suggest that rituximab could be a valuable treatment for autoimmune haemolytic anaemia, although a long-lasting but transient B-cell deficiency develops. [ABSTRACT FROM AUTHOR]

Published
2001
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40. Efficacy and tolerability of gemtuzumab ozogamicin (anti-CD33 monoclonal antibody, CMA-676, Mylotarg®) in children with relapsed/refractory myeloid leukemia

Author

Bertrand Yves, Leblanc Thierry, Yakouben Karima, Galambrun Claire, Auvrignon Anne, Brethon Benoit, Leverger Guy, and Baruchel André

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Gemtuzumab ozogamicin (GO) is a cytotoxic anti-CD33 monoclonal antibody that has given promising preliminary results in adult myeloid CD33+ AML. We conducted a retrospective multicenter study of 12 children treated with GO on a compassionate basis (median age 5.5 y). Three patients (2 MDS/AML, 1 JMML) were refractory to first-line treatment, 8 patients with de novo AML were in refractory first relapse, and one patient with de novo AML was in 2nd relapse after stem cell transplantation (SCT). CD33 expression exceeded 20% in all cases. Methods GO was administered alone, at a unit dose of 3–9 mg/m2, once (3 patients), twice (3 patients), three (5 patients) or five times (1 patient). Mean follow-up was 128 days (8–585 d). Results There were three complete responses (25%) leading to further curative treatment (SCT). Treatment failed in the other nine patients, and only one patient was alive at the end of follow-up. NCI-CTC grade III/IV adverse events comprised hematological toxicity (n = 12), hypertransaminasemia (n = 2), allergy and hyperbilirubinemia (1 case each). There was only one major adverse event (grade IV allergy). No case of sinusoidal obstruction syndrome occurred. Conclusion These results warrant a prospective trial of GO in a larger population of children with AML.

Published
2006
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41. Global characteristics and outcomes of SARS-CoV-2 infection in children and adolescents with cancer (GRCCC): a cohort study

Author

Sheena Mukkada, Nickhill Bhakta, Guillermo L Chantada, Yichen Chen, Yuvanesh Vedaraju, Lane Faughnan, Maysam R Homsi, Hilmarie Muniz-Talavera, Radhikesh Ranadive, Monika Metzger, Paola Friedrich, Asya Agulnik, Sima Jeha, Catherine Lam, Rashmi Dalvi, Laila Hessissen, Daniel C Moreira, Victor M Santana, Michael Sullivan, Eric Bouffet, Miguela A Caniza, Meenakshi Devidas, Kathy Pritchard-Jones, Carlos Rodriguez-Galindo, A Juan Ribelles, Adriana Balduzzi, Alaa Elhaddad, Alejandra Casanovas, Alejandra Garcia Velazquez, Aliaksandra Laptsevich, Alicia Chang, Alessandra Lamenha F. Sampaio, Almudena González Prieto, Alvaro Lassaletta, Amaranto Suarez M, Ana Patricia Alcasabas, Anca Colita, Andres Morales La Madrid, Angélica Samudio, Annalisa Tondo, Antonella Colombini, Antonis Kattamis, N Araceli Lopez Facundo, Arpita Bhattacharyya, Aurélia Alimi, Aurélie Phulpin, Barbora Vakrmanova, Basak A Aksoy, Benoit Brethon, Jator Brian Kobuin, Carla Nolasco Monteiro, Catherine Paillard, Catherine Vezina, Bozkurt Ceyhun, Cristiana Hentea, Cristina Meazza, Daniel Ortiz-Morales, Roque Daniel Solorzano, Daniela Arce Cabrera, Daniele Zama, Debjani Ghosh, Diana Ramírez-Rivera, Doris A Calle Jara, Dragana Janic, Elianneth Rey Helo, Elodie Gouache, Enmanuel Guerrero Quiroz, Enrique Lopez, Eric Thebault, Essy Maradiegue, Eva de Berranger, Fatma S E Ebeid, Federica Galaverna, Federico Antillon-Klussmann, Felipe Espinoza Chacur, Fernando Daniel Negro, Francesca Carraro, Francesca Compagno, Francisco Barriga, Gabriela Tamayo Pedraza, Gissela Sanchez Fernandez, Gita Naidu, Gülnur Tokuc, Hamidah Alias, Hannah Grace B Segocio, Houda Boudiaf, Imelda Asetre Luna, Iris Maia, Itziar Astigarraga, Ivan Maza, Jacqueline E Montoya Vásquez, Janez Jazbec, Jelena Lazic, Jeniffer Beck Dean, Jeremie Rouger-Gaudichon, Johanny Carolina Contreras González, Jorge Huerta Aragonés, José L Fuster, Juan Quintana, Julia Palma, Karel Svojgr, Karina Quintero, Karolina Malic Tudor, Kleopatra Georgantzi, Kris Ann P Schultz, Laura Ureña Horno, Lidia Fraquelli, Linda Meneghello, Lobna Shalaby, Lola L Macias Mora, Lorna A Renner, Luciana Nunes Silva, Luisa Sisinni, Mahmoud Hammad, M Fernández Sanmartín, C Marcela Zubieta A, María Constanza Drozdowski, Maria Kourti, Marcela María Palladino, Maria R Miranda Madrazo, Marilyne Poiree, Marina Popova, Mario Melgar, Marta Baragaño, Martha J Avilés-Robles, Massimo Provenzi, Mecneide Mendes Lins, Mehmet Fatih Orhan, Milena Villarroel, Mónica Jerónimo, Mónica Varas Palma, Muhammad Rafie Raza, Mulindwa M Justin, Najma Shaheen, Nerea Domínguez-Pinilla, Nicholas S Whipple, Nicolas André, Ondrej Hrusak, Pablo Velasco Puyó, Pamela Zacasa Vargas, Paola Olate Mellado, Pascale Yola Gassant, Paulina Diaz Romero, Raffaella De Santis, Rejin Kebudi, Riza Boranbayeva, Roberto Vasquez, Romel A. Segura, Roy Enrique Rosado, Sandra Gómez, Sandra Raimbault, Sanjeeva Gunasekera, Sara M Makkeyah, Sema Buyukkapu Bay, Sergio M Gómez, Séverine Bouttefroy, Shahnoor Islam, Sherif Abouelnaga, Silvio Fabio Torres, Simone Cesaro, Sofia Nunes, Soraia Rouxinol, Sucharita Bhaumik, Symbat Saliyeva, Tamara Inostroza, Thelma Velasquez, Tint Myo Hnin, Ulrika Norén-Nyström, Valentina Baretta, Yajaira Valentine Jimenez-Antolinez, Vanesa Pérez Alonso, Vanessa Ayer Miller, Virginie Gandemer, Viviana Lotero, Volha Mishkova, Wendy Gómez-García, Yeva Margaryan, Yumna Syed, Mukkada S., Bhakta N., Chantada G.L., Chen Y., Vedaraju Y., Faughnan L., Homsi M.R., Muniz-Talavera H., Ranadive R., Metzger M., Friedrich P., Agulnik A., Jeha S., Lam C., Dalvi R., Hessissen L., Moreira D.C., Santana V.M., Sullivan M., Bouffet E., Caniza M.A., Devidas M., Pritchard-Jones K., Rodriguez-Galindo C., Ribelles A.J., Balduzzi A., Elhaddad A., Casanovas A., Garcia Velazquez A., Laptsevich A., Chang A., F. Sampaio A.L., Gonzalez Prieto A., Lassaletta A., Suarez M A., Alcasabas A.P., Colita A., Morales La Madrid A., Samudio A., Tondo A., Colombini A., Kattamis A., Lopez Facundo N.A., Bhattacharyya A., Alimi A., Phulpin A., Vakrmanova B., Aksoy B.A., Brethon B., Kobuin J.B., Nolasco Monteiro C., Paillard C., Vezina C., Ceyhun B., Hentea C., Meazza C., Ortiz-Morales D., Solorzano R.D., Arce Cabrera D., Zama D., Ghosh D., Ramirez-Rivera D., Calle Jara D.A., Janic D., Rey Helo E., Gouache E., Guerrero Quiroz E., Lopez E., Thebault E., Maradiegue E., de Berranger E., Ebeid F.S.E., Galaverna F., Antillon-Klussmann F., Espinoza Chacur F., Negro F.D., Carraro F., Compagno F., Barriga F., Tamayo Pedraza G., Sanchez Fernandez G., Naidu G., Tokuc G., Alias H., B Segocio H.G., Boudiaf H., Asetre Luna I., Maia I., Astigarraga I., Maza I., Montoya Vasquez J.E., Jazbec J., Lazic J., Beck Dean J., Rouger-Gaudichon J., Contreras Gonzalez J.C., Huerta Aragones J., Fuster J.L., Quintana J., Palma J., Svojgr K., Quintero K., Malic Tudor K., Georgantzi K., P Schultz K.A., Urena Horno L., Fraquelli L., Meneghello L., Shalaby L., Macias Mora L.L., A Renner L., Nunes Silva L., Sisinni L., Hammad M., Fernandez Sanmartin M., Zubieta A C.M., Drozdowski M.C., Kourti M., Palladino M.M., Miranda Madrazo M.R., Poiree M., Popova M., Melgar M., Baragano M., Aviles-Robles M.J., Provenzi M., Mendes Lins M., Fatih Orhan M., Villarroel M., Jeronimo M., Varas Palma M., Rafie Raza M., M Justin M., Shaheen N., Dominguez-Pinilla N., Whipple N.S., Andre N., Hrusak O., Velasco Puyo P., Zacasa Vargas P., Olate Mellado P., Yola Gassant P., Diaz Romero P., De Santis R., Kebudi R., Boranbayeva R., Vasquez R., Segura R.A., Rosado R.E., Gomez S., Raimbault S., Gunasekera S., Makkeyah S.M., Buyukkapu Bay S., M Gomez S., Bouttefroy S., Islam S., Abouelnaga S., Torres S.F., Cesaro S., Nunes S., Rouxinol S., Bhaumik S., Saliyeva S., Inostroza T., Velasquez T., Hnin T.M., Noren-Nystrom U., Baretta V., Jimenez-Antolinez Y.V., Perez Alonso V., Ayer Miller V., Gandemer V., Lotero V., Mishkova V., Gomez-Garcia W., Margaryan Y., Syed Y., Mukkada, S, Bhakta, N, Chantada, G, Chen, Y, Vedaraju, Y, Faughnan, L, Homsi, M, Muniz-Talavera, H, Ranadive, R, Metzger, M, Friedrich, P, Agulnik, A, Jeha, S, Lam, C, Dalvi, R, Hessissen, L, Moreira, D, Santana, V, Sullivan, M, Bouffet, E, Caniza, M, Devidas, M, Pritchard-Jones, K, Rodriguez-Galindo, C, Ribelles, A, Balduzzi, A, Elhaddad, A, Casanovas, A, Garcia Velazquez, A, Laptsevich, A, Chang, A, F. Sampaio A., L, Gonzalez Prieto, A, Lassaletta, A, Suarez M, A, Alcasabas, A, Colita, A, Morales La Madrid, A, Samudio, A, Tondo, A, Colombini, A, Kattamis, A, Lopez Facundo, N, Bhattacharyya, A, Alimi, A, Phulpin, A, Vakrmanova, B, Aksoy, B, Brethon, B, Kobuin, J, Nolasco Monteiro, C, Paillard, C, Vezina, C, Ceyhun, B, Hentea, C, Meazza, C, Ortiz-Morales, D, Solorzano, R, Arce Cabrera, D, Zama, D, Ghosh, D, Ramirez-Rivera, D, Calle Jara, D, Janic, D, Rey Helo, E, Gouache, E, Guerrero Quiroz, E, Lopez, E, Thebault, E, Maradiegue, E, de Berranger, E, Ebeid, F, Galaverna, F, Antillon-Klussmann, F, Espinoza Chacur, F, Negro, F, Carraro, F, Compagno, F, Barriga, F, Tamayo Pedraza, G, Sanchez Fernandez, G, Naidu, G, Tokuc, G, Alias, H, B Segocio, H, Boudiaf, H, Asetre Luna, I, Maia, I, Astigarraga, I, Maza, I, Montoya Vasquez, J, Jazbec, J, Lazic, J, Beck Dean, J, Rouger-Gaudichon, J, Contreras Gonzalez, J, Huerta Aragones, J, Fuster, J, Quintana, J, Palma, J, Svojgr, K, Quintero, K, Malic Tudor, K, Georgantzi, K, P Schultz, K, Urena Horno, L, Fraquelli, L, Meneghello, L, Shalaby, L, Macias Mora, L, A Renner, L, Nunes Silva, L, Sisinni, L, Hammad, M, Fernandez Sanmartin, M, Zubieta A, C, Drozdowski, M, Kourti, M, Palladino, M, Miranda Madrazo, M, Poiree, M, Popova, M, Melgar, M, Baragano, M, Aviles-Robles, M, Provenzi, M, Mendes Lins, M, Fatih Orhan, M, Villarroel, M, Jeronimo, M, Varas Palma, M, Rafie Raza, M, M Justin, M, Shaheen, N, Dominguez-Pinilla, N, Whipple, N, Andre, N, Hrusak, O, Velasco Puyo, P, Zacasa Vargas, P, Olate Mellado, P, Yola Gassant, P, Diaz Romero, P, De Santis, R, Kebudi, R, Boranbayeva, R, Vasquez, R, Segura, R, Rosado, R, Gomez, S, Raimbault, S, Gunasekera, S, Makkeyah, S, Buyukkapu Bay, S, M Gomez, S, Bouttefroy, S, Islam, S, Abouelnaga, S, Torres, S, Cesaro, S, Nunes, S, Rouxinol, S, Bhaumik, S, Saliyeva, S, Inostroza, T, Velasquez, T, Hnin, T, Noren-Nystrom, U, Baretta, V, Jimenez-Antolinez, Y, Perez Alonso, V, Ayer Miller, V, Gandemer, V, Lotero, V, Mishkova, V, Gomez-Garcia, W, Margaryan, Y, and Syed, Y

Subjects
Male, Pediatrics, medicine.medical_specialty, COVID-19, Children, adolescents, cancer, Adolescent, MEDLINE, Severity of Illness Index, Health systems, Neoplasms, purl.org/becyt/ford/3.2 [https], Severity of illness, medicine, Humans, Child, Children, Pandemics, Pandemic, business.industry, SARS-CoV-2, Risk Factor, Infant, Newborn, Infant, Cancer, COVID-19, Odds ratio, Articles, medicine.disease, Transplantation, Oncology, Child, Preschool, Cohort, Absolute neutrophil count, Neoplasm, purl.org/becyt/ford/3 [https], Female, Cohort Studie, business, Delivery of Health Care, Human, Cohort study
Abstract

Background: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. Methods: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (

Published
2021

42. Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol

Author

Tomasz Szczepański, Claus Meyer, Maria Grazia Valsecchi, Jan Stary, Birgitte Lausen, Alina Ferster, Gabriele Escherich, Inge M. van der Sluis, Martin Schrappe, Myriam Campbell, Vincent H.J. van der Velden, Giovanni Cazzaniga, Rishi S. Kotecha, Luca Lo Nigro, Julia Alten, Andishe Attarbaschi, Franco Locatelli, Andrea Biondi, Ajay Vora, Rolf Marschalek, Chi Kong Li, Jan Zuna, Benoit Brethon, Rob Pieters, Paola De Lorenzo, Philip Ancliffe, Janine Stutterheim, Stutterheim, J, van der Sluis, I, de Lorenzo, P, Alten, J, Ancliffe, P, Attarbaschi, A, Brethon, B, Biondi, A, Campbell, M, Cazzaniga, G, Escherich, G, Ferster, A, Kotecha, R, Lausen, B, Li, C, Lo Nigro, L, Locatelli, F, Marschalek, R, Meyer, C, Schrappe, M, Stary, J, Vora, A, Zuna, J, van der Velden, V, Szczepanski, T, Valsecchi, M, Pieters, R, and Immunology

Subjects
Oncology, Cancer Research, medicine.medical_specialty, biology, business.industry, KMT2A gene, Lymphoblastic Leukemia, Incidence (epidemiology), medicine.disease, Minimal residual disease, Infant Acute Lymphoblastic Leukemia, Minimal Residual Disease, Infant Acute Lymphoblastic Leukemia, KMT2A, KMT2A, MRD, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, SDG 3 - Good Health and Well-being, Internal medicine, biology.protein, Medicine, Neoplasm, business, ALL
Abstract

PURPOSE Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide). MATERIALS AND METHODS MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged KMT2A, immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10−4), and high (≥ 5 × 10−4). RESULTS EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively ( P = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively ( P < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively ( P < .0001), while for myeloid-style–treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9). CONCLUSION This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% v 23.2%), whereas patients with low EOI MRD may benefit from ALL-like consolidation (DFS 78.2% v 45.0%). Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.

Published
2021

43. Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol

Author

Lewis B. Silverman, G Escherich, J. Stary, I M van der Sluin, Benoit Brethon, Franco Locatelli, Ajay Vora, Martin Schrappe, Judith M. Boer, Maria Grazia Valsecchi, V H J van der Velden, Rishi S. Kotecha, Birgitte Lausen, Alina Ferster, P De Lorenzo, Andishe Attarbaschi, Philip Ancliffe, Jan Zuna, Janine Stutterheim, P Diaz, Alex Wk Leung, Luis Aversa, Andrea Biondi, Tomasz Szczepański, Julia Alten, Gianni Cazzaniga, Rob Pieters, Immunology, Stutterheim, J, de Lorenzo, P, van der Sluin, I, Alten, J, Ancliffe, P, Attarbaschi, A, Aversa, L, Boer, J, Biondi, A, Brethon, B, Diaz, P, Cazzaniga, G, Escherich, G, Ferster, A, Kotecha, R, Lausen, B, Leung, A, Locatelli, F, Silverman, L, Stary, J, Szczepanski, T, van der Velden, V, Vora, A, Zuna, J, Schrappe, M, Valsecchi, M, and Pieters, R

Subjects
Male, Cancer Research, medicine.medical_specialty, Neoplasm, Residual, Prognosi, Immunology, Gastroenterology, Biochemistry, SDG 3 - Good Health and Well-being, Internal medicine, White blood cell, hemic and lymphatic diseases, Medicine, Humans, Univariate analysis, biology, KMT2A-germline, business.industry, Infant, Cell Biology, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Minimal residual disease, Survival Analysis, Clinical trial, KMT2A, Standard error, medicine.anatomical_structure, Germ Cells, Treatment Outcome, MRD, Oncology, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, biology.protein, Prednisolone, Female, Bone marrow, business, ALL, medicine.drug
Abstract

Background The outcome of infants with KMT2A-germline ALL is much better than of infants with KMT2A-rearranged ALL, but still worse than of non-infant ALL patients. Here, we describe the outcome and prognostic factors for infants with KMT2A-germline ALL treated on Interfant-06 protocol. Methods 167 infants with KMT2A-germline ALL were enrolled in Interfant-06. Univariate analysis on prognostic factors (age, WBC at diagnosis, prednisolone response and CD10 expression) was performed on KMT2A-germline infants in complete remission at the end of induction (EOI) (n=163). Bone marrow minimal residual disease (MRD) was measured in 73 patients, by real-time quantitative PCR of immunoglobulin genes and/or T-cell receptor genes, at various time points (EOI, n= 68, end of consolidation (EOC) n= 56, and before OCTADAD (n=57)). MRD results were classified as negative, intermediate (< 5*10 -4), and high (≥5*10 -4). Genetic data on NUTM1 rearrangements and MRD were available in 53 patients. Results The 6-year event free survival [SE] and overall survival [ SE] was 73.9% (3,6) and 87.2% (2.7). 28 of 31 (90%) relapses occurred early, within 2 years of diagnosis. Treatment related mortality was 3.6%. Age 6 months of age (p=0.04). Of the MRD timepoints, MRD at end of induction (EOI) was most prognostic for outcome. At EOI, 76.5% (n=52/68) of patients were either MRD negative (41.2%, n=28) or intermediate MRD (35.3%, n=24). 23.5% (n=16) had high EOI MRD, which was associated with significantly lower 6-year DFS (SE), compared to patients with intermediate or negative EOI MRD (61.4% (12.4), 76.4% (11.3) and 87.9% (6.6), respectively; p=0.02, Figure 1a). At EOC, 55.4% (n=31/56) of patients were MRD negative. Outcome by MRD levels at EOC was not significantly different (p=0.24); the 6-year DFS (SE) of negative and intermediate EOC MRD patients was 89.0% (6.0) and 72.7 % (10.6), respectively, while only one of the 5 patients with high EOC MRD relapsed in BM and CNS (Figure 1b). MRD data for both EOI and EOC were available for 55 patients. Of these patients, 18 were MRD negative at EOI and EOC, with a 6-year DFS 93.3% (SE, 6.4). Five patients had negative EOI MRD, but showed intermediate EOC MRD levels; none of these patients relapsed. There were 12 of 55 patients who were MRD positive at EOI and became MRD negative at EOC. These patients had a 6-year DFS of 82.5 % (SE, 11.3). Patients with detectable disease at both timepoints had a 6-year DFS of 68.3% (SE,10.8) (n=20, Figure 1c). At the end of MARMA (TP5), 77.2% (n=44/57) of patients were MRD negative. MRD at TP5 was significantly related to DFS (Figure 1d); the 6-year DFS was 89.6% (SE, 5.0) for MRD negative patients, compared to 65.6% (SE, 14.0) for patients with intermediate MRD levels (p= 0.039). In the current study, NUTM1 status was known in 53 patients with MRD data. Of them, 13 harbored a NUTM1-rearrangement. Seven out of 11 (63.6%) were aged< 6 months and 6 out of 42 (14.3%) were older. None of them relapsed, despite positive EOI MRD detected in 8 cases. Conclusion We conclude that young age at diagnosis and low EOI MRD are favorable prognostic factors in infants with KMT2A-germline ALL. However, the prognostic value of MRD is not as strong as in infants with KMT2A-rearranged ALL or older children with ALL. This can partly be explained by the differences in genetic makeup of infants with KMT2A-germline ALL, thus supporting the hypothesis that in the future a combined MRD- and genetic-based stratification of KMT2A-g infants might be considered Figure 1 Figure 1. Disclosures Biondi: Colmmune: Honoraria; Bluebird: Other: Advisory Board; Novartis: Honoraria; Incyte: Consultancy, Other: Advisory Board; Amgen: Honoraria. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Schrappe: Novartis: Honoraria, Other: research support; SigmaTau: Other: research support; Amgen: Other: research support; Servier: Honoraria; Novartis: Honoraria; JazzPharma: Honoraria; JazzPharma: Honoraria, Other: research support; SHIRE: Other: research support; Servier: Honoraria, Other: research support.

Published
2022

44. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

Author

Rupert Handgretinger, Phillip Barnette, Benoit Brethon, Chiara Messina, Christian M. Zwaan, Franco Locatelli, Steven G. DuBois, Lia Gore, Peter Bader, Gérard Michel, Kuolung Hu, Carmelo Rizzari, Paul G. Schlegel, James A. Whitlock, Maureen M. O'Brien, Min Zhu, Tanya M. Trippett, Todd M. Cooper, Deepa Bhojwani, Gerhard Zugmaier, Susan R. Rheingold, Arend von Stackelberg, Arndt Borkhardt, Pediatrics, Von Stackelberg, A, Locatelli, F, Zugmaier, G, Handgretinger, R, Trippett, T, Rizzari, C, Bader, P, O'Brien, M, Brethon, B, Bhojwani, D, Schlegel, P, Borkhardt, A, Rheingold, S, Cooper, T, Zwaan, C, Barnette, P, Messina, C, Michel, G, Dubois, S, Hu, K, Zhu, M, Whitlock, J, and Gore, L

Subjects
Cancer Research, bispecific, Pharmacology, Gastroenterology, Antineoplastic Agent, 0302 clinical medicine, blinatumomab, Antibodies, Bispecific, antibodies, Single-Blind Method, Infusions, Intravenou, Infusions, Intravenous, Child, adolescent, antibodies, bispecific, antineoplastic agents, child, disease-free survival, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Hypokalemia, Treatment Outcome, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Oncology, Child, Preschool, 030220 oncology & carcinogenesis, Blinatumomab, Survival Analysi, medicine.symptom, Human, medicine.drug, medicine.medical_specialty, Adolescent, Maximum Tolerated Dose, Anemia, Antineoplastic Agents, Disease-Free Survival, Drug Administration Schedule, Follow-Up Studie, 03 medical and health sciences, Refractory, Internal medicine, medicine, Humans, Adverse effect, Survival analysis, Dose-Response Relationship, Drug, business.industry, Complete Minimal Residual Disease Response, medicine.disease, Survival Analysis, Respiratory failure, business, Follow-Up Studies, 030215 immunology
Abstract

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m2/d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m2/d for the first 7 days, followed by 15 µg/m2/d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.

Published
2016

45. A phase 1/2, open-label, dose-escalation study of midostaurin in children with relapsed or refractory acute leukaemia

Author

Franca Fagioli, Carmelo Rizzari, C. Michel Zwaan, Carlo Dufour, Catherine Dutreix, Emmanuelle Besse, Stefan Söderhäll, Phoenix A. Ho, Rob Pieters, Ronald W. Stam, Benoit Brethon, Matteo Luciani, Zwaan, C, Söderhäll, S, Brethon, B, Luciani, M, Rizzari, C, Stam, R, Besse, E, Dutreix, C, Fagioli, F, Ho, P, Dufour, C, Pieters, R, and Pediatrics

Subjects
Oncology, acute leukaemia, medicine.medical_specialty, paediatric, business.industry, Hematology, FLT3, midostaurin, relapsed/refractory, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Refractory, chemistry, 030220 oncology & carcinogenesis, Internal medicine, Relapsed refractory, Dose escalation, Medicine, Midostaurin, Open label, business, 030215 immunology
Published
2019

46. Outcome of infants younger than 1 year with acute lymphoblastic leukemia treated with the interfant-06 protocol: Results from an international phase III randomized study

Author

Jan Stary, Luis Aversa, Andrea Biondi, Rishi S. Kotecha, Birgitte Lausen, Martin Schrappe, Andishe Attarbaschi, Jeffrey E. Rubnitz, Gabriele Escherich, Rebecca Gardner, Ajay Vora, Lewis B. Silverman, Christina Peters, Paola De Lorenzo, Benoit Brethon, Rob Pieters, Alina Ferster, Philip Ancliffe, Franco Locatelli, Maria Grazia Valsecchi, Tomasz Szczepański, Myriam Campbell, Chi Kong Li, Pieters, R, De Lorenzo, P, Ancliffe, P, Aversa, L, Brethon, B, Biondi, A, Campbell, M, Escherich, G, Ferster, A, Gardner, R, Kotecha, R, Lausen, B, Li, C, Locatelli, F, Attarbaschi, A, Peters, C, Rubnitz, J, Silverman, L, Stary, J, Szczepanski, T, Vora, A, Schrappe, M, and Valsecchi, M

Subjects
Oncology, Male, Cancer Research, medicine.medical_specialty, Myeloid, Lymphoblastic Leukemia, acute lymphoblastic leukemia, Infants, Acute Lymphoblastic Leukemia, Interfant-06 Protocol, Disease-Free Survival, law.invention, Randomized controlled trial, law, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, randomized study, treatment, Survival rate, Cyclophosphamide, Germ-Line Mutation, Etoposide, Gene Rearrangement, biology, business.industry, Mercaptopurine, Daunorubicin, Cytarabine, Infant, Newborn, Infant, Gene rearrangement, Histone-Lysine N-Methyltransferase, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Clinical trial, Survival Rate, KMT2A, medicine.anatomical_structure, Treatment Outcome, Multicenter study, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, biology.protein, Female, Mitoxantrone, business, ALL, Myeloid-Lymphoid Leukemia Protein
Abstract

PURPOSE Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A ( MLL) gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national and international study groups, tested whether myeloid-style consolidation chemotherapy is superior to lymphoid style, the role of stem-cell transplantation (SCT), and which factors had independent prognostic value. MATERIALS AND METHODS Three risk groups were defined: low risk (LR): KMT2A germline; high risk (HR): KMT2A-rearranged and older than 6 months with WBC count 300 × 109/L or more or a poor prednisone response; and medium risk (MR): all other KMT2A-rearranged cases. Patients in the MR and HR groups were randomly assigned to receive the lymphoid course low-dose cytosine arabinoside [araC], 6-mercaptopurine, cyclophosphamide (IB) or experimental myeloid courses, namely araC, daunorubicin, etoposide (ADE) and mitoxantrone, araC, etoposide (MAE). RESULTS A total of 651 infants were included, with 6-year event-free survival (EFS) and overall survival of 46.1% (SE, 2.1) and 58.2% (SE, 2.0). In West European/North American groups, 6-year EFS and overall survival were 49.4% (SE, 2.5) and 62.1% (SE, 2.4), which were 10% to 12% higher than in other countries. The 6-year probability of disease-free survival was comparable for the randomized arms (ADE+MAE 39.3% [SE 4.0; n = 169] v IB 36.8% [SE, 3.9; n = 161]; log-rank P = .47). The 6-year EFS rate of patients in the HR group was 20.9% (SE, 3.4) with the intention to undergo SCT; only 46% of them received SCT, because many had early events. KMT2A rearrangement was the strongest prognostic factor for EFS, followed by age, WBC count, and prednisone response. CONCLUSION Early intensification with postinduction myeloid-type chemotherapy courses did not significantly improve outcome for infant ALL compared with the lymphoid-type course IB. Outcome for infant ALL in Interfant-06 did not improve compared with that in Interfant-99.

Published
2019

47. Monocentric experience of venetoclax-based regimen in paediatric refractory and relapsed AML/MDS.

Author

Cousson S, Calvo C, Goldwirt L, Simonin M, Roupret-Serzec J, Dourthe MÉ, Strullu M, Baruchel A, Dalle JH, and Brethon B

Abstract

BCL-2 inhibitor venetoclax demonstrates promising efficacy in paediatric relapsed/refractory acute myeloid leukaemia (r/r AML). This retrospective analysis evaluated 12 patients treated with venetoclax-based regimens under compassionate use for r/r myeloid malignancies. The overall response rate (ORR) was 41.6%, with complete response (CR) achieved in 33% of patients. Three patients successfully underwent allogeneic haematopoietic scell transplantation (HSCT) after venetoclax bridging therapy. Venetoclax demonstrated a favourable safety profile with manageable side effects. These findings suggest venetoclax's potential as a valuable therapeutic option for paediatric r/r AML, particularly for heavily pretreated patients. Further investigation in larger multicentre trials is warranted to refine treatment strategy., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Published
2024
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48. Inotuzumab ozogamicin combined with chemotherapy in pediatric B-cell precursor CD22 + acute lymphoblastic leukemia: results of the phase IB ITCC-059 trial.

Author

Pennesi E, Brivio E, Ammerlaan ACJ, Jiang Y, Van der Velden VHJ, Beverloo HB, Sleight B, Locatelli F, Brethon B, Rossig C, Engstler G, Nilsson A, Bruno B, Petit A, Bielorai B, Rizzari C, Rialland F, Rubio-San-Simón A, Sirvent FJB, Diaz-de-Heredia C, Rives S, and Zwaan CM

Subjects
Humans, Child, Male, Female, Child, Preschool, Adolescent, Treatment Outcome, Dexamethasone administration & dosage, Dexamethasone therapeutic use, Vincristine administration & dosage, Vincristine therapeutic use, Infant, Inotuzumab Ozogamicin administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma mortality, Sialic Acid Binding Ig-like Lectin 2 antagonists & inhibitors
Abstract

Inotuzumab ozogamicin (InO) is a CD22-directed antibody conjugated with calicheamicin. The phase IB of the ITCC-059 trial tested InO combined with chemotherapy in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Relapsed /refractory CD22+ BCP-ALL pediatric patients were enrolled. The primary objective was to establish the recommended phase II dose (RP2D). Secondary objectives included preliminary efficacy and tolerability. InO was combined with 1.5 mg/m2 of vincristine (days 3, 10, 17, 24), 20 mg/m2 of dexamethasone (2 5-day blocks, then amended), and intrathecal therapy. A rolling-6 design was used testing InO from 0.8 to 1.8 mg/m2/cycle. Between May 2020 and April 2022, 30 patients were treated, and 29 were evaluable for dose limiting toxicities (DLT). At 1.1 mg/m2/cycle, two of four patients had DLT (liver toxicity). InO was de-escalated to 0.8 mg/m2/cycle (N=6) without DLT while awaiting a protocol amendment to reduce dexamethasone dose to 10 mg/m2. Post amendment, InO was re-escalated to 1.1 mg/m2/cycle (N=6, 1 DLT), then to 1.4 mg/m2/ cycle (N=3, no DLT), and finally to 1.8 mg/m2/cycle (N=7, 1 DLT). Three additional patients were treated in an expansion cohort. The pooled response rate was 80% (24/30; 95% confidence interval [CI]: 61.4-92.3) and, among responders, 66.7% achieved minimal residual disease negativity. The RP2D of InO combined with vincristine, dexamethasone and intrathecal therapy was declared at 1.8 mg/m2/cycle (1.5 mg/m2/cycle after remission) in a fractioned schedule. This combination showed a response rate similar to the single agent cohorts of this trial, with liver toxicity issues at the initial higher dexamethasone dose (clinicaltrials gov. Identifier: NTR5736).

Published
2024
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50. Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059.

Author

Wu JH, Pennesi E, Bautista F, Garrett M, Fukuhara K, Brivio E, Ammerlaan ACJ, Locatelli F, van der Sluis IM, Rossig C, Chen-Santel C, Bielorai B, Petit A, Starý J, Díaz-de-Heredia C, Rives S, O'Marcaigh A, Rizzari C, Engstler G, Nysom K, Rubio-San-Simón A, Bruno B, Bertrand Y, Brethon B, Rialland F, Plat G, Dirksen U, Sramkova L, Zwaan CM, and Huitema ADR

Subjects
Humans, Child, Male, Female, Adolescent, Child, Preschool, Adult, Young Adult, Middle Aged, Models, Biological, Recurrence, Infant, Aged, Inotuzumab Ozogamicin pharmacokinetics, Inotuzumab Ozogamicin administration & dosage, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma blood, Antineoplastic Agents, Immunological pharmacokinetics, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Agents, Immunological therapeutic use
Abstract

Background and Objective: Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL., Methods: From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data., Results: Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 10 3 ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants., Conclusions: The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability., (© 2024. The Author(s).)

Published
2024
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