{"doi":"10.1111/bjh.70288","title":"Philadelphia chromosome‐positive acute lymphoblastic leukaemia in children and adolescents: A changing treatment landscape and a methodological challenge","abstract":"Approximately 3%–5% of paediatric acute lymphoblastic leukaemia (ALL) is driven by the BCR::ABL1 fusion gene resulting from t(9;22)(q34;q11.2), known as Philadelphia chromosome-positive (Ph+) ALL. As the treatment landscape of Ph+ ALL has rapidly shifted in the era of chemoimmunotherapy and tyrosine kinase inhibitors (TKIs), this perspective letter brings together experts to review treatment evolution of paediatric Ph+ ALL over the last two decades, highlight ongoing challenges and delineating future directions in optimizing therapy in successor paediatric Ph+ ALL trials. As shown in large ‘Ponte di Legno’ intergroup retrospective studies, before TKIs, the 7-year event-free survival (EFS) and overall survival (OS) of Ph+ ALL children were ~30% and ~40%, respectively, with intensive multi-agent chemotherapy and haematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) offered to all patients with a suitable donor (see references in Supplementary Material).1 An addition of TKIs in subsequent trials led to rapid disease clearance and significant long-term survival improvement. Multiple studies conducted during the past two decades by the European intergroup study on Ph+ ALL (EsPhALL) and/or the Children's Oncology Group (COG) demonstrated significant improvements with 5-year EFS and OS of approximately 60% and 80%, respectively, with continuous TKI-based chemotherapy regimens (Table 1, see references in Supplementary Material).2-6 Importantly, similar EFS and OS rates were observed across trials, regardless of TKI generation (imatinib or dasatinib) and chemotherapy backbone. This precision medicine paradigm also reduced treatment-related toxicity, via omission of prophylactic cranial irradiation for nearly all patients and substantial decrease of HSCT use in CR1. Overall, modern TKI-based therapies have transformed paediatric Ph+ ALL from the once-least favourable subtype of ALL into a more curable entity. Imatinib 340 mg/m2 Post-induction: 18 IT 5 years: 69% (57%–83%) 5 years: 79% (68%–92%) Dasatinib 60 mg/m2 Post day 15 induction: 18 IT 5 years: 60% (46%–74%) 5 years: 86% (76%–96%) Imatinib 300 mg/m2 Post IB: 17 IT + 3 if CNS3 5 years: 57% (49%–65%) 5 years: 72% (64%–79%) Dasatinib 60 mg/m2 Post day 15 IA: 17 IT 5 years: 55% (45%–64%) 5 years: 82% (73%–88%) Modified Total XV-XVI Modified Total XV-XVI Dasatinib 80 mg/m2 Since diagnosis: 19 IT 4 years: 71%a (56%–90%) 4 years: 88%a (81%–96%) Imatinib 300 mg/m2 Since diagnosis: 19 IT 4 years: 49%a (32%–75%) 4 years: 69%a (56%–86%) HSCT in CR1 for children with Ph+ ALL has diminished over the last 20 years from approximately 80% in the EsPhALL2004 trial7 to <10% of patients in the most recent trials (reserved to patients with poor minimal residual disease (MRD) response after 10-week therapy, irrespective of ‘high-risk’ genetics such as IKZF1-plus, whose prognostic relevance remains unclear). The OS of paediatric Ph+ ALL also substantially improved from 40% in the pre-TKI era to 80% with TKI-containing regimens, highlighting post-relapse salvageability in the TKI era. Most patients with relapsed Ph+ ALL can now achieve the second complete remission (CR2) or beyond and proceed to HSCT consolidation (about 30% undergo HSCT in CR2); moreover, the high salvage rates reported in trials do not fully reflect the remarkable recent successes of modern B-cell antigen-targeted immunotherapies, such as blinatumomab, inotuzumab or chimeric antigen receptor T-cell therapies8 (see references in Supplementary Material) which may ultimately improve OS rates further and/or reduce morbidity in post-relapse therapy. Indeed, the incorporation of blinatumomab plus TKI with minimal chemotherapy represents a major paradigm shift in the front-line treatment of adult Ph+ ALL, prompting investigation of analogous strategies in paediatrics. The newly opened international AALL2131/EsPhALL2022 (NCT 06124157, EU CT number 2025-520982-39-00) pilot study with continuous TKI replaces the trad","journal":"British Journal of Haematology","year":2025,"id":587151,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9589,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":826719,"name":"Maria Grazia Valsecchi","orcid":null,"position":1,"is_corresponding":false},{"id":759919,"name":"Thai Hoa Tran","orcid":"0000-0002-8712-6233","position":2,"is_corresponding":false},{"id":1502763,"name":"Jan Zuna","orcid":null,"position":3,"is_corresponding":false},{"id":1502224,"name":"Veronica Leoni","orcid":"0000-0001-8419-4241","position":4,"is_corresponding":false},{"id":1502764,"name":"G. Cario","orcid":null,"position":5,"is_corresponding":false},{"id":456887,"name":"Grazia Fazio","orcid":"0000-0001-7077-8422","position":6,"is_corresponding":false},{"id":1502765,"name":"Virginie Gandemer","orcid":null,"position":7,"is_corresponding":false},{"id":273631,"name":"Sarah K. Tasian","orcid":"0000-0003-1327-1662","position":8,"is_corresponding":false},{"id":1502225,"name":"Inge M. van der Sluis","orcid":"0000-0002-5822-7668","position":9,"is_corresponding":false},{"id":1418207,"name":"Nicolò Peccatori","orcid":"0009-0004-9779-4165","position":10,"is_corresponding":false},{"id":1502766,"name":"R. Parasole","orcid":null,"position":11,"is_corresponding":false},{"id":764309,"name":"Stefania Monterisi","orcid":"0000-0002-8802-9742","position":12,"is_corresponding":false},{"id":301504,"name":"Mignon L. Loh","orcid":"0000-0003-4099-4700","position":13,"is_corresponding":false},{"id":355165,"name":"Meenakshi Devidas","orcid":"0000-0002-1099-3478","position":14,"is_corresponding":false},{"id":301503,"name":"Stephen P. Hunger","orcid":"0000-0002-5492-3957","position":15,"is_corresponding":false},{"id":381791,"name":"John A. Kairalla","orcid":"0009-0005-2430-2921","position":16,"is_corresponding":false},{"id":1502767,"name":"Paola De Lorenzo","orcid":null,"position":17,"is_corresponding":false},{"id":321136,"name":"Lewis B. Silverman","orcid":"0009-0007-7275-7650","position":18,"is_corresponding":false},{"id":853466,"name":"Andrea Biondi","orcid":"0000-0003-1072-665X","position":19,"is_corresponding":false},{"id":630454,"name":"Adriana Balduzzi","orcid":"0000-0002-5879-0610","position":0,"is_corresponding":true}],"reference_count":14,"raw_metadata":null,"created_at":"2026-07-19T02:59:36.020030Z","pmid":"41448829","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}