Immunotherapy refractoriness and early post-alloHCT relapse define ultra-high-risk B-ALL after CD19 CAR T-cell therapy

CD19-directed CAR T-cell therapy (CART19) has transformed relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) management, but the prognostic impact of immunotherapy sensitivity and post-allogeneic hematopoietic cell transplantation (alloHCT) relapse timing in real-world practice remains unclear. We retrospectively analyzed EBMT registry patients with R/R B-ALL treated with CART19 (2016-2023), stratifying by prior alloHCT and classifying prior blinatumomab and inotuzumab ozogamicin (InO) as naïve, responder (CR/CRi), or refractory. Among 345 patients (173/172 adults/children), median age was 18 years (range 1.1-78.2); 58% were alloHCT-exposed, 27% blinatumomab-exposed, 29% InO-exposed, and 52% had pre-lymphodepletion morphological disease. With a median follow-up of 2.3 years, the 3-month MRD-negative complete remission cumulative incidence was 78%; 2-year overall survival (OS) and event-free survival (EFS) were 65% and 49%. In alloHCT-naïve patients, 2-year OS/EFS were 83%/60% (blinatumomab responders), 65%/55% (blinatumomab-naïve), and 31%/17% (blinatumomab-refractory); for InO, OS/EFS were 68%/54% (naïve), 62%/55% (responders), and 22%/18% (refractory). In alloHCT-exposed patients, blinatumomab category did not discriminate outcomes, whereas InO refractoriness was associated with inferior OS/EFS (49%/29%) versus InO-naïve (71%/54%) and responders (60%/38%). Early relapse after alloHCT (<6 vs ≥6 months) was associated with worse 2-year OS (43% vs 74%) and EFS (31% vs 54%). In multivariable models, immunotherapy refractoriness independently predicted inferior EFS (HR 2.56 in alloHCT-naïve; HR 2.20 in alloHCT-exposed); overt morphological disease at lymphodepletion in alloHCT-naïve (HR 3.34) and early post-alloHCT relapse (HR 1.85) further worsened EFS. These findings support pragmatic pre-CAR T risk stratification and prioritization of trials or intensified strategies for refractory disease and early post-alloHCT relapse.

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Journal
Blood Advances
Published
2026-09-30
DOI
https://doi.org/10.1182/bloodadvances.2026019855
Primary Topic
CAR-T cell therapy research
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article
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article

Immunotherapy refractoriness and early post-alloHCT relapse define ultra-high-risk B-ALL after CD19 CAR T-cell therapy

Shatha Farhan, Richard Mitchell, Krzysztof Kałwak, Y Beguin et al.
Blood Advances
CAR-T cell therapy research
article

Immunotherapy refractoriness and early post-alloHCT relapse define ultra-high-risk B-ALL after CD19 CAR T-cell therapy

Shatha Farhan, Richard Mitchell, Krzysztof Kałwak, Y Beguin, Julio Delgado, Susana Rives, Fabio Ciceri, David Beauvais, Giebel Sebastian, Antonio Pérez‐Martínez, Thomas Pabst, Federica Sorà, Valentín Ortiz‐Maldonado, Stephan Mielke, Muriel Paganessi, Jurgen H. E. Kuball, Giorgio Ottaviano, Arnon Nagler, Olaf Penack, Anna Alonso‐Saladrigues, Sowjanya Vuyyala, Samppa J. Ryhänen, Núria Martínez‐Cibrián, Emma Nicholson, Adriana Balduzzi, Nazaret Sánchez‐Sierra, Andishe Attarbaschi, Pere Barba, Eva Michel, Soeren Lykke Petersen, Fizza Imran, Annalisa Ruggeri, José Antonio Pérez-Simón, Anne-Charlotte Teyssier, Malte von Bonin, Jacques-Emmanuel Galimard, Cristina Castilla-Llorente
article en

Abstract

CD19-directed CAR T-cell therapy (CART19) has transformed relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) management, but the prognostic impact of immunotherapy sensitivity and post-allogeneic hematopoietic cell transplantation (alloHCT) relapse timing in real-world practice remains unclear. We retrospectively analyzed EBMT registry patients with R/R B-ALL treated with CART19 (2016-2023), stratifying by prior alloHCT and classifying prior blinatumomab and inotuzumab ozogamicin (InO) as naïve, responder (CR/CRi), or refractory. Among 345 patients (173/172 adults/children), median age was 18 years (range 1.1-78.2); 58% were alloHCT-exposed, 27% blinatumomab-exposed, 29% InO-exposed, and 52% had pre-lymphodepletion morphological disease. With a median follow-up of 2.3 years, the 3-month MRD-negative complete remission cumulative incidence was 78%; 2-year overall survival (OS) and event-free survival (EFS) were 65% and 49%. In alloHCT-naïve patients, 2-year OS/EFS were 83%/60% (blinatumomab responders), 65%/55% (blinatumomab-naïve), and 31%/17% (blinatumomab-refractory); for InO, OS/EFS were 68%/54% (naïve), 62%/55% (responders), and 22%/18% (refractory). In alloHCT-exposed patients, blinatumomab category did not discriminate outcomes, whereas InO refractoriness was associated with inferior OS/EFS (49%/29%) versus InO-naïve (71%/54%) and responders (60%/38%). Early relapse after alloHCT (<6 vs ≥6 months) was associated with worse 2-year OS (43% vs 74%) and EFS (31% vs 54%). In multivariable models, immunotherapy refractoriness independently predicted inferior EFS (HR 2.56 in alloHCT-naïve; HR 2.20 in alloHCT-exposed); overt morphological disease at lymphodepletion in alloHCT-naïve (HR 3.34) and early post-alloHCT relapse (HR 1.85) further worsened EFS. These findings support pragmatic pre-CAR T risk stratification and prioritization of trials or intensified strategies for refractory disease and early post-alloHCT relapse.

Blood Advances
Università Cattolica del Sacro Cuore (IT), Hospital Sant Joan de Déu Barcelona (ES), Royal Marsden NHS Foundation Trust (GB), Mayo Clinic (US), Karolinska University Hospital (SE), University of Helsinki (FI), Henry Ford Health System (US), University of Liège (BE), Sheba Medical Center (IL), Helsinki University Hospital (FI), University Hospital of Bern (CH), Instituto de Salud Carlos III (ES), Institut Gustave Roussy (FR), Copenhagen University Hospital (DK), Rigshospitalet (DK), Karolinska Institutet (SE), University Medical Center Utrecht (NL), Centre Hospitalier Universitaire de Lille (FR), Wroclaw Medical University (PL), Spanish National Cancer Research Centre (ES), Centre Hospitalier Universitaire de Montpellier (FR), Hospital La Paz Institute for Health Research (ES), Ospedale Papa Giovanni XXIII (IT), Azienda Ospedaliera San Gerardo (IT), Centre for Biomedical Network Research on Rare Diseases (ES), Hospital Clínic de Barcelona (ES), Royal Marsden Hospital (GB), St Anna Children's Hospital (AT), Sydney Children's Hospital (AU), Vall d'Hebron Hospital Universitari (ES), IRCCS Ospedale San Raffaele (IT), Mayo Clinic in Florida (US), Sydney Children’s Hospitals Network (AU), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), Hospital Universitario Virgen del Rocío (ES), University Hospital Carl Gustav Carus (DE), European Society for Blood and Marrow Transplantation (FR), Technische Universität Dresden (DE), Charité - Universitätsmedizin Berlin (DE)
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