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

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.