{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:31:59Z","timestamp":1789014719470,"version":"build-2803163510"},"reference-count":31,"publisher":"American Society of Hematology","issue":"4","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,2,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Part 1 results of the open-label, randomized, global phase 3 SPARKLE trial supported continued assessment of ibrutinib with either modified rituximab, ifosfamide, carboplatin, and etoposide (RICE) or rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone (RVICI) in pediatric patients with relapsed\/refractory (R\/R) mature B-cell non-Hodgkin lymphoma (B-NHL). We report final results of Part 2 evaluating the efficacy of ibrutinib plus RICE or RVICI vs RICE\/RVICI alone. Patients aged 1 to 30 years (initial diagnosis &amp;lt;18 years) were randomized 2:1 to receive ibrutinib with or without RICE\/RVICI. Primary endpoint was event-free survival (EFS) based on independent committee-confirmed events. Fifty-one patients were enrolled. Median age was 15 years; Burkitt lymphoma, Burkitt leukemia, and Burkitt-like lymphoma (total: 45%) and diffuse large B-cell lymphoma\/primary mediastinal B-cell lymphoma (51%) were the most common subtypes. At the preplanned interim analysis, median EFS was 6.1 vs 7.0 months with ibrutinib plus RICE\/RVICI vs RICE\/RVICI, respectively (hazard ratio, 0.9; 90% confidence interval, 0.5-1.6; P\u00a0= .387); further enrollment was ceased. With ibrutinib plus RICE\/RVICI vs RICE\/RVICI, median overall survival was 14.1 vs 11.1 months, overall response rate was 69% vs 81%, and 46% vs 44% proceeded to stem cell transplantation. In both treatment arms, 100% of patients experienced grade \u22653 treatment-emergent adverse events. No EFS benefit was seen with ibrutinib. Salvage was generally poor in patients who received prior rituximab, regardless of treatment arm. No new safety signals were observed. Ibrutinib exposure in pediatric patients fell within the target range of exposure in adults. Trial is registered on www.clinicaltrials.gov (NCT02703272)<\/jats:p>","DOI":"10.1182\/bloodadvances.2022008802","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T15:35:59Z","timestamp":1671636959000},"page":"602-610","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":10,"title":["Ibrutinib plus RICE or RVICI for relapsed\/refractory mature B-cell non-Hodgkin lymphoma in children and young adults: SPARKLE trial"],"prefix":"10.1182","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2671-9972","authenticated-orcid":false,"given":"G. A. Amos","family":"Burke","sequence":"first","affiliation":[{"name":"1Department of Paediatric Haematology, Oncology and Palliative Care, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke\u2019s Hospital, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Vinti","sequence":"additional","affiliation":[{"name":"2Department of Pediatric Hematology\/Oncology and Cell and Gene Therapy, Ospedale Pediatrico Bambino Ges\u00f9, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edita","family":"Kabickova","sequence":"additional","affiliation":[{"name":"3Department of Pediatric Hematology and Oncology, Charles University and University Hospital Motol, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6482-1823","authenticated-orcid":false,"given":"Auke","family":"Beishuizen","sequence":"additional","affiliation":[{"name":"4Department of Hemato-Oncology, Princess M\u00e1xima Center for Pediatric Oncology, Utrecht, The Netherlands"},{"name":"5Department of Pediatric Hematology\/Oncology, Erasmus MC \u2013 Sophia Children\u2019s Hospital, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nurdan","family":"Tacyildiz","sequence":"additional","affiliation":[{"name":"6Department of Pediatric Hematology and Oncology, Ankara University Cebeci Hospital, Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5644-424X","authenticated-orcid":false,"given":"Anne","family":"Uyttebroeck","sequence":"additional","affiliation":[{"name":"7Department of Pediatric Hematology and Oncology, University Hospitals Leuven, Leuven, Belgium"},{"name":"8Department of Oncology, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyoung Jin","family":"Kang","sequence":"additional","affiliation":[{"name":"9Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Wide River Institute of Immunology, Seoul National University Children\u2019s Hospital, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9197-2494","authenticated-orcid":false,"given":"Flavio","family":"Luisi","sequence":"additional","affiliation":[{"name":"10Pediatric Oncology Institute, GRAACC, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0296-5207","authenticated-orcid":false,"given":"V\u00e9ronique","family":"Minard-Colin","sequence":"additional","affiliation":[{"name":"11Department of Pediatric and Adolescent Oncology, INSERM U1015, Gustave Roussy, Universit\u00e9 Paris-Saclay, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1151-829X","authenticated-orcid":false,"given":"Birgit","family":"Burkhardt","sequence":"additional","affiliation":[{"name":"12Pediatric Hematology and Oncology, University Hospital M\u00fcnster, M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monelle","family":"Tamegnon","sequence":"additional","affiliation":[{"name":"13Clinical Oncology, Janssen Research & Development, Raritan, NJ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Sun","sequence":"additional","affiliation":[{"name":"14Clinical Biostats, Janssen Research & Development, Raritan, NJ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeliene","family":"Curtis","sequence":"additional","affiliation":[{"name":"15Clinical Oncology, Janssen Research & Development, High Wycombe, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Deshpande","sequence":"additional","affiliation":[{"name":"13Clinical Oncology, Janssen Research & Development, Raritan, NJ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerri","family":"Nottage","sequence":"additional","affiliation":[{"name":"13Clinical Oncology, Janssen Research & Development, Raritan, NJ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Howes","sequence":"additional","affiliation":[{"name":"15Clinical Oncology, Janssen Research & Development, High Wycombe, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srimathi","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"16Oncology Translational Research, Janssen Research & Development, Lower Gwynedd Township, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepa","family":"Bhojwani","sequence":"additional","affiliation":[{"name":"17Cancer and Blood Disease Institute, Children\u2019s Hospital Los Angeles, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Norris","sequence":"additional","affiliation":[{"name":"18Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell","family":"Cairo","sequence":"additional","affiliation":[{"name":"19Departments of Pediatrics, Medicine, Pathology, Microbiology & Immunology, and Cell Biology, New York Medical College, Valhalla, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2023,2,20]]},"reference":[{"issue":"6","key":"2023081515544756900_bib1","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1111\/bjh.15764","article-title":"Childhood, adolescent and young adult non-Hodgkin lymphoma: current perspectives","volume":"185","author":"Cairo","year":"2019","journal-title":"Br J Haematol"},{"issue":"8","key":"2023081515544756900_bib2","doi-asserted-by":"crossref","first-page":"e27073","DOI":"10.1002\/pbc.27073","article-title":"NHL in adolescents and young adults: a unique population","volume":"65","author":"Hochberg","year":"2018","journal-title":"Pediatr Blood Cancer"},{"issue":"6","key":"2023081515544756900_bib3","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1111\/bjh.15734","article-title":"Mature B-NHL in children, adolescents and young adults: current therapeutic approach and emerging treatment strategies","volume":"185","author":"Egan","year":"2019","journal-title":"Br J Haematol"},{"issue":"1","key":"2023081515544756900_bib4","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/j.1365-2141.2005.05735.x","article-title":"The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence","volume":"131","author":"Burkhardt","year":"2005","journal-title":"Br J Haematol"},{"issue":"5","key":"2023081515544756900_bib5","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1111\/bjh.16461","article-title":"Treatment of relapsed\/refractory paediatric aggressive B-cell non-Hodgkin lymphoma","volume":"189","author":"Moleti","year":"2020","journal-title":"Br J Haematol"},{"issue":"6","key":"2023081515544756900_bib6","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1111\/bjh.15491","article-title":"Overall survival of children and adolescents with mature B cell non-Hodgkin lymphoma who had refractory or relapsed disease during or after treatment with FAB\/LMB 96: a report from the FAB\/LMB 96 study group","volume":"182","author":"Cairo","year":"2018","journal-title":"Br J Haematol"},{"issue":"9","key":"2023081515544756900_bib7","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.3390\/cancers13092075","article-title":"Treatment and outcome analysis of 639 relapsed non-Hodgkin lymphomas in children and adolescents and resulting treatment recommendations","volume":"13","author":"Burkhardt","year":"2021","journal-title":"Cancers (Basel)"},{"issue":"6","key":"2023081515544756900_bib8","doi-asserted-by":"crossref","first-page":"810","DOI":"10.3324\/haematol.2014.121434","article-title":"Outcome of and prognostic factors for relapse in children and adolescents with mature B-cell lymphoma and leukemia treated in three consecutive prospective \"Lymphomes Malins B\" protocols. A Societe Francaise des Cancers de l'Enfant study","volume":"100","author":"Jourdain","year":"2015","journal-title":"Haematologica"},{"issue":"14","key":"2023081515544756900_bib9","first-page":"1124","article-title":"Progressive or relapsed Burkitt lymphoma or leukemia in children and adolescents after BFM-type first-line therapy","volume":"135","author":"Woessmann","year":"2020","journal-title":"Blood"},{"issue":"2","key":"2023081515544756900_bib10","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/pbc.21753","article-title":"A\u00a0study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent\/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group","volume":"52","author":"Griffin","year":"2009","journal-title":"Pediatr Blood Cancer"},{"key":"2023081515544756900_bib11","unstructured":"Johnson and Johnson\n          . Janssen seeks approval of a new indication for IMBRUVICA\u00ae (ibrutinib) for use in patients with untreated mantle cell lymphoma.. Accessed 4 August 2022. https:\/\/www.jnj.com\/janssen-seeks-approval-of-a-new-indication-for-imbruvica-ibrutinib-for-use-in-patients-with-untreated-mantle-cell-lymphoma."},{"key":"2023081515544756900_bib12","unstructured":"EMEA\n          . Ibrutinib summary of product characteristics. Accessed 4 December 2020. https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/imbruvica."},{"key":"2023081515544756900_bib13","unstructured":"Imbruvica (ibrutinib). Prescribing information\n          . Janssen Biotech, Inc and Pharmacyclics LLC; 2020. Accessed November 2020. https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2020\/205552s030,210563s006lbl.pdf."},{"issue":"1","key":"2023081515544756900_bib14","doi-asserted-by":"crossref","first-page":"e1512455","DOI":"10.1080\/2162402X.2018.1512455","article-title":"Ibrutinib significantly inhibited Bruton's tyrosine kinase (BTK) phosphorylation, in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model","volume":"8","author":"Chu","year":"2019","journal-title":"Oncoimmunology"},{"issue":"4","key":"2023081515544756900_bib15","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1080\/10428194.2017.1349899","article-title":"Identification of potential ibrutinib combinations in hematological malignancies using a combination high-throughput screen","volume":"59","author":"Schaffer","year":"2018","journal-title":"Leuk Lymphoma"},{"issue":"16","key":"2023081515544756900_bib16","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1182\/blood-2017-08-802561","article-title":"A phase 1 study of ibrutinib in combination with R-ICE in patients with relapsed or primary refractory DLBCL","volume":"131","author":"Sauter","year":"2018","journal-title":"Blood"},{"issue":"8","key":"2023081515544756900_bib17","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1038\/s41375-020-0749-5","article-title":"Ibrutinib plus CIT for R\/R mature B-NHL in children (SPARKLE trial): initial safety, pharmacokinetics, and efficacy","volume":"34","author":"Burke","year":"2020","journal-title":"Leukemia"},{"issue":"18","key":"2023081515544756900_bib18","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1200\/JCO.2014.59.0745","article-title":"International pediatric non-Hodgkin lymphoma response criteria","volume":"33","author":"Sandlund","year":"2015","journal-title":"J\u00a0Clin Oncol"},{"issue":"18","key":"2023081515544756900_bib19","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1200\/JCO.2014.59.7203","article-title":"Revised international pediatric non-Hodgkin lymphoma staging system","volume":"33","author":"Rosolen","year":"2015","journal-title":"J\u00a0Clin Oncol"},{"issue":"3","key":"2023081515544756900_bib20","doi-asserted-by":"crossref","first-page":"549","DOI":"10.2307\/2530245","article-title":"A\u00a0multiple testing procedure for clinical trials","volume":"35","author":"O'Brien","year":"1979","journal-title":"Biometrics"},{"issue":"6","key":"2023081515544756900_bib21","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1111\/bjh.15940","article-title":"Rituximab in the treatment of childhood mature B-cell lymphoma: \"where do we go from here\"","volume":"185","author":"Cairo","year":"2019","journal-title":"Br J Haematol"},{"issue":"10","key":"2023081515544756900_bib22","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1002\/pbc.26105","article-title":"Relapsed\/refractory pediatric B-cell non-Hodgkin lymphoma treated with rituximab combination therapy: a report from the Japanese Pediatric Leukemia\/Lymphoma Study Group","volume":"63","author":"Osumi","year":"2016","journal-title":"Pediatr Blood Cancer"},{"issue":"9","key":"2023081515544756900_bib23","doi-asserted-by":"crossref","first-page":"e27873","DOI":"10.1002\/pbc.27873","article-title":"Outcome of relapse in children and adolescents with B-cell non-Hodgkin lymphoma and mature acute leukemia: a report from the French LMB study","volume":"66","author":"Rigaud","year":"2019","journal-title":"Pediatr Blood Cancer"},{"issue":"4","key":"2023081515544756900_bib24","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1200\/JCO.1999.17.4.1244","article-title":"Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group","volume":"17","author":"Cheson","year":"1999","journal-title":"J\u00a0Clin Oncol"},{"issue":"12","key":"2023081515544756900_bib25","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.3324\/haematol.13440","article-title":"R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL\/TAMO study","volume":"93","author":"Martin","year":"2008","journal-title":"Haematologica"},{"issue":"10","key":"2023081515544756900_bib26","doi-asserted-by":"crossref","first-page":"2232","DOI":"10.1007\/s12325-017-0612-x","article-title":"Rituximab in B-cell hematologic malignancies: a review of 20 years of clinical experience","volume":"34","author":"Salles","year":"2017","journal-title":"Adv Ther"},{"issue":"22","key":"2023081515544756900_bib27","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1182\/blood-2018-05-851154","article-title":"Molecular classification of primary mediastinal large B-cell lymphoma using routinely available tissue specimens","volume":"132","author":"Mottok","year":"2018","journal-title":"Blood"},{"issue":"1","key":"2023081515544756900_bib28","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.ijrobp.2021.03.035","article-title":"Primary mediastinal B cell lymphoma in the positron-emission tomography era executive summary of the american radium society appropriate use criteria","volume":"111","author":"Hoppe","year":"2021","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"2023081515544756900_bib29","unstructured":"US Food and Drug Administration\n          . FDA approves pembrolizumab for treatment of relapsed or refractory PMBCL. Accessed 23 September 2022. https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-pembrolizumab-treatment-relapsed-or-refractory-pmbcl."},{"issue":"12","key":"2023081515544756900_bib30","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1002\/ajh.25638","article-title":"Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma","volume":"94","author":"Munir","year":"2019","journal-title":"Am J Hematol"},{"key":"2023081515544756900_bib31","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.ejca.2019.01.013","article-title":"ACCELERATE and European Medicine Agency Paediatric Strategy Forum for medicinal product development for mature B-cell malignancies in children","volume":"110","author":"Pearson","year":"2019","journal-title":"Eur J Cancer"}],"container-title":["Blood Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/bloodadvances\/article-pdf\/7\/4\/602\/2071394\/blooda_adv-2022-008802-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/bloodadvances\/article-pdf\/7\/4\/602\/2071394\/blooda_adv-2022-008802-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T16:05:04Z","timestamp":1692115504000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/bloodadvances\/article\/7\/4\/602\/493769\/Ibrutinib-plus-RICE-or-RVICI-for-relapsed"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,20]]},"references-count":31,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,2,28]]}},"URL":"https:\/\/doi.org\/10.1182\/bloodadvances.2022008802","relation":{},"ISSN":["2473-9529","2473-9537"],"issn-type":[{"value":"2473-9529","type":"print"},{"value":"2473-9537","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,20]]}}}