{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T06:34:58Z","timestamp":1775198098337,"version":"3.50.1"},"reference-count":32,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana Ricerca sul Cancro","doi-asserted-by":"crossref","award":["MFAG 2009"],"award-info":[{"award-number":["MFAG 2009"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"crossref"}]},{"name":"IBISCUS-ets"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with most cases arising from B-cell precursors expressing the CD19 marker. CD19 negativity in B-lineage ALL (B-ALL) is very rare de novo and poses diagnostic and therapeutic challenges. Sometimes, de novo CD19-negative B-ALL is associated with hypercalcemia, which is a potentially life-threatening metabolic disorder in children, rarely occurring in cancers. Most often it is reported in solid tumors, and few cases are reported in pediatric acute leukemia. CD19-negative B-ALL relapse is also an increasing dramatic event, secondary to immunotherapy. We describe a ten-month-old infant presenting with hypercalcemia, anemia, and osteolytic bone lesions. Bone marrow analysis revealed CD10-positive and CD19-negative B-ALL. The patient achieved complete remission but later experienced two relapses and died of respiratory failure after a second allogeneic hematopoietic stem cell transplantation (HSCT). Only nine cases of de novo CD19-negative B-ALL have been reported so far. Many are associated with hypercalcemia and osteolytic lesions. However, here we highlight the clinical impact of the more common secondary form of CD19-negative B-ALL as a relapse of CD19-positive ALL, right after the administration of targeted immunotherapy.<\/jats:p>","DOI":"10.3390\/ijms27073203","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T10:09:21Z","timestamp":1775038161000},"page":"3203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD19-Negative Acute Lymphoblastic Leukemia (ALL): A Case Report and Review of Literature on a Rare Phenomenon De Novo and a Future Induced Struggle in Relapse"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3066-7672","authenticated-orcid":false,"given":"Marta","family":"Arrabito","sequence":"first","affiliation":[{"name":"Center of Pediatric Hematology Oncology, Azienda Policlinico, San Marco, 95123 Catania, Italy"},{"name":"Cytogenetic-Cytofluorimetric-Molecular Biology Lab, Center of Pediatric Hematology Oncology, Azienda Policlinico, San Marco, 95123 Catania, Italy"},{"name":"XLI Cycle of PhD Program in Translational Biomedicine, University of Catania, 95100 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuela","family":"Cannata","sequence":"additional","affiliation":[{"name":"Center of Pediatric Hematology Oncology, Azienda Policlinico, San Marco, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piera","family":"Samperi","sequence":"additional","affiliation":[{"name":"Center of Pediatric Hematology Oncology, Azienda Policlinico, San Marco, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela La","family":"Rosa","sequence":"additional","affiliation":[{"name":"Cytogenetic-Cytofluorimetric-Molecular Biology Lab, Center of Pediatric Hematology Oncology, Azienda Policlinico, San Marco, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2480-1799","authenticated-orcid":false,"given":"Luca Lo","family":"Nigro","sequence":"additional","affiliation":[{"name":"Center of Pediatric Hematology Oncology, Azienda Policlinico, San Marco, 95123 Catania, Italy"},{"name":"Cytogenetic-Cytofluorimetric-Molecular Biology Lab, Center of Pediatric Hematology Oncology, Azienda Policlinico, San Marco, 95123 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.pcl.2014.09.004","article-title":"Biology of Childhood Acute Lymphoblastic Leukemia","volume":"62","author":"Bhojwani","year":"2015","journal-title":"Pediatr. Clin. N. Am."},{"key":"ref_2","first-page":"561","article-title":"B-Cell Markers on Lymphoblasts in Acute Lymphoblastic Leukaemia","volume":"17","author":"Bloomfield","year":"1974","journal-title":"Clin. Exp. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"596","DOI":"10.4103\/IJPM.IJPM_379_17","article-title":"CD19-Negative B-Lineage Acute Lymphoblastic Leukemia: A Diagnostic and Therapeutic Challenge","volume":"60","author":"Bansal","year":"2017","journal-title":"Indian J. Pathol. Microbiol."},{"key":"ref_4","first-page":"38","article-title":"Severe Hypercalcemia: A Rare and Unusual Presentation of Childhood Acute Lymphoblastic Leukemia","volume":"8","author":"Bahoush","year":"2014","journal-title":"Int. J. Hematol. Oncol. Stem Cell Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3960","DOI":"10.1182\/blood.V89.11.3960","article-title":"Prognostic Significance of Fluorescence Intensity of Surface Marker Expression in Childhood B-Precursor Acute Lymphoblastic Leukemia. A Pediatric Oncology Group Study","volume":"89","author":"Borowitz","year":"1997","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1038\/leu.2012.120","article-title":"EuroFlow Antibody Panels for Standardized N-Dimensional Flow Cytometric Immunophenotyping of Normal, Reactive and Malignant Leukocytes","volume":"26","author":"Lhermitte","year":"2012","journal-title":"Leukemia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2246","DOI":"10.1200\/JCO.19.00261","article-title":"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","volume":"37","author":"Pieters","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1182\/blood.2020007848","article-title":"A Phase 1 Study of Inotuzumab Ozogamicin in Pediatric Relapsed\/Refractory Acute Lymphoblastic Leukemia (ITCC-059 Study)","volume":"137","author":"Brivio","year":"2021","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/cyto.b.21373","article-title":"CD19 Negative Precursor B Acute Lymphoblastic Leukemia (B-ALL)\u2014Immunophenotypic Challenges in Diagnosis and Monitoring: A Study of Three Cases","volume":"92","author":"Ghodke","year":"2017","journal-title":"Cytom. Part B Clin."},{"key":"ref_10","first-page":"253","article-title":"A Case of CD45-, CD19- Precursor B Cell Acute Lymphoblastic Leukemia with an Atypical Morphology","volume":"27","author":"Moon","year":"2007","journal-title":"Korean J. Lab. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/pbc.20063","article-title":"CD19 Negative Precursor B Acute Lymphoblastic Leukemia Presenting with Hypercalcemia","volume":"43","author":"Sultan","year":"2004","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/1097-0142(19930701)72:1<256::AID-CNCR2820720145>3.0.CO;2-D","article-title":"Hypercalcemia Complicating Childhood Malignancies","volume":"72","author":"McKay","year":"1993","journal-title":"Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"244","DOI":"10.11604\/pamj.2017.26.244.10506","article-title":"Osteolytic Bone Lesions, Severe Hypercalcemia without Circulating Blasts: Unusual Presentation of Childhood Acute Lymphoblastic Leukemia","volume":"26","author":"Bechir","year":"2017","journal-title":"Pan Afr. Med. J."},{"key":"ref_14","first-page":"563291","article-title":"T(17;19) in Children with Acute Lymphocytic Leukemia: A Report of 3 Cases and a Review of the Literature","volume":"2013","author":"Minson","year":"2013","journal-title":"Case Rep. Hematol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.4103\/0973-1482.187240","article-title":"Severe Hypercalcemia: A Rare and Unusual Presentation of Acute Lymphoblastic Leukemia","volume":"14","author":"Dhivyasree","year":"2018","journal-title":"J. Cancer Res. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"542","DOI":"10.3332\/ecancer.2015.542","article-title":"Hypercalcaemia with Disseminated Osteolytic Lesions: A Rare Presentation of Childhood Acute Lymphoblastic Leukaemia","volume":"9","author":"Lokadasan","year":"2015","journal-title":"Ecancermedicalscience"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e301","DOI":"10.1097\/MPH.0000000000001822","article-title":"Hypercalcemia and Disseminated Osteolytic Lesions With Normal Blood Counts and Absence of Circulating Blasts: A Rare Presentation of Childhood B-Lymphoblastic Leukemia","volume":"43","author":"Khayyam","year":"2021","journal-title":"J. Pediatr. Hematol.\/Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1002\/pbc.20782","article-title":"PTHrP-independent Hypercalcemia with Increased Proinflammatory Cytokines and Bone Resorption in Two Children with CD19-negative Precursor B Acute Lymphoblastic Leukemia","volume":"49","author":"Niizuma","year":"2007","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1159\/000495741","article-title":"Malignancy-Associated Hypercalcemia Related with Receptor Activator of NF-\u03baB Ligand (RANKL) Expression in T-Cell Acute Lymphoblastic Leukemia","volume":"141","author":"Tahara","year":"2019","journal-title":"Acta Haematol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.3109\/10428194.2014.963579","article-title":"CD19-Negative B-Lymphoblastic Leukemia Associated with Hypercalcemia, Lytic Bone Lesions and Aleukemic Presentation","volume":"56","author":"Hussein","year":"2015","journal-title":"Leuk. Lymphoma"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1080\/10428194.2023.2232496","article-title":"Incidence of CD19-Negative Relapse after CD19-Targeted Immunotherapy in R\/R BCP Acute Lymphoblastic Leukemia: A Review","volume":"64","author":"Locatelli","year":"2023","journal-title":"Leuk. Lymphoma"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/s41408-017-0023-x","article-title":"CD19-Negative Relapse of Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia Following Blinatumomab Treatment","volume":"7","author":"Hrusak","year":"2017","journal-title":"Blood Cancer J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e31950","DOI":"10.1002\/pbc.31950","article-title":"Multiple Lineage Switches in a Pediatric Case With a KMT2A::AFF1-Positive Acute Lymphoblastic Leukemia: How Cell Plasticity Induces Immunotherapy Failure","volume":"72","author":"Arrabito","year":"2025","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2406","DOI":"10.1182\/blood-2015-08-665547","article-title":"Acquisition of a CD19-Negative Myeloid Phenotype Allows Immune Escape of MLL-Rearranged B-ALL from CD19 CAR-T-Cell Therapy","volume":"127","author":"Gardner","year":"2016","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.exphem.2021.07.002","article-title":"Does Lineage Plasticity Enable Escape from CAR-T Cell Therapy? Lessons from MLL-r Leukemia","volume":"100","author":"Liao","year":"2021","journal-title":"Exp. Hematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/s41467-021-21168-6","article-title":"Single-Cell Profiling Identifies Pre-Existing CD19-Negative Subclones in a B-ALL Patient with CD19-Negative Relapse after CAR-T Therapy","volume":"12","author":"Rabilloud","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1158\/2159-8290.CD-15-1020","article-title":"Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy","volume":"5","author":"Sotillo","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1097\/CJI.0000000000000169","article-title":"CD19 Isoforms Enabling Resistance to CART-19 Immunotherapy Are Expressed in B-ALL Patients at Initial Diagnosis","volume":"40","author":"Fischer","year":"2017","journal-title":"J. Immunother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1038\/s41591-018-0146-z","article-title":"Genetic Mechanisms of Target Antigen Loss in CAR19 Therapy of Acute Lymphoblastic Leukemia","volume":"24","author":"Orlando","year":"2018","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e28980","DOI":"10.1002\/pbc.28980","article-title":"Inotuzumab Ozogamicin Following Allogeneic Hematopoietic Stem Cell Transplantation Successfully Rescued Relapse of CD19-negative Acute Lymphoblastic Leukemia after CAR-T Cell Therapy","volume":"68","author":"Kamitori","year":"2021","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_31","first-page":"e70177","article-title":"Inotuzumab Ozogamicin as a Bridge to Stem Cell Transplantation in Relapsed Pediatric BCP-ALL After Tisagenlecleucel: A Case Series","volume":"8","author":"Aertgeerts","year":"2025","journal-title":"Cancer Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e011549","DOI":"10.1136\/jitc-2025-011549","article-title":"CD22-Targeted Chimeric Antigen Receptor-Modified T Cells for Children and Adults with Relapse of B-Cell Acute Lymphoblastic Leukemia after CD19-Directed Immunotherapy","volume":"13","author":"Myers","year":"2025","journal-title":"J. Immunother. Cancer"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/7\/3203\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T04:27:17Z","timestamp":1775190437000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/7\/3203"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,1]]},"references-count":32,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27073203"],"URL":"https:\/\/doi.org\/10.3390\/ijms27073203","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,1]]}}}