Characteristics and Outcome Determinants in Children, Adolescents and Young Adults Who Failed Tisagenlecleucel for B-Cell Acute Lymphoblastic Leukemia
Authors: Lecornec Nicolas , Rabian Florence , Dourthe Marie-Emilie , Chevillon Florian , Yakouben Karima , Chaillou Delphine , Caillat-Zucman Sophie , Cuffel Alexis , Lesprit Emmanuelle , Arnould Anne , Naudin Jérome , Roupret-Serzec Julie , Parquet Nathalie , Brignier Anne , Guerin-El Khourouj Valerie , Lainey Elodie , Caye-Eude Aurélie , Arfeuille Chloe , Clappier Emmanuelle , Kim Rathana , Mathis Stéphanie , Chaix Marie-Laure , Azoulay Elie , Dalle Jean-Hugues , Madelaine Isabelle , Larghero Jerome , Baruchel André , Boissel Nicolas 
Published: December 2024

Tisagenlecleucel (tisa-cel), an autologous anti-CD19 chimeric antigen receptor T-cell (CAR T-cell), has dramatically improved the outcome of children, adolescents, and young adults (AYAs) with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). Despite a high early complete remission (CR) rate and remarkable long-term outcome in clinical trials confirmed by real-world evidence studies, between 30 and 50% of patients experience early failure or relapse after tisa-cel infusion. Limited data are available on the characteristics and the determinants of the outcome of patients who failed tisa-cel therapy.
We report on 52 children and AYAs who experienced early failure (n=13) or relapse (n=39) following tisa-cel for R/R BCP-ALL. All patients were infused at Robert Debré and Saint-Louis University Hospitals, Paris, France, between June 30, 2016, and January 1, 2022. Early failure after tisa-cel was defined as the absence of CR or CR with incomplete count recovery (CRi), or the persistence of any level of positive measurable residual disease (MRD) at day 28 (D28) post-tisa-cel infusion. In patients who achieved a MRD-negative CR/CRi, a relapse was defined by the reappearance of ≥ 1% blasts in blood or ≥ 5% in bone marrow (BM), any extra-medullary relapse, or any level of positive MRD.
The median age at tisa-cel infusion was 13 years (range, 1-27). Twelve patients (23%) exhibited high-risk genetic features defined as KMT2A-rearrangement, TCF3::PBX1 fusion, TCF3::HLF fusion, TP53 mutation, or hypodiploidy. BM disease burden at lymphodepletion (LD) and CNS status were comparable among patients with early failure or in relapse. Patients who experienced early failure were more likely to have received pre-tisa-cel inotuzumab ozogamicin (InO, 7/13 (54%) vs 6/39 (21%), p= .01). In the relapse subgroup, median time from tisa-cel infusion to relapse was 188 days (IQR, 126 - 315). Among the 52 patients, 18 (35%) had a morphological disease at the time of failure/relapse diagnosis. This rate increase to 57% (29/51) at the time of post-tisa-cel salvage therapy initiation. CD19 expression was positive in 34/50 evaluable patients (65%), comparable between subgroups.
The most frequent used drugs in salvage therapy were steroids, vinca alkaloids, and 6-mercaptopurine. InO was given in 14 patients, blinatumomab in 15 patients, and 10 patients received a second CAR-T infusion. Among the 29 patients with morphological disease at salvage therapy initiation, 17 reached a new CR, including 14 with negative MRD. The loss of CD19 antigen was the only factor associated with a lower CR rate after salvage therapy (OR 0.16, 95%CI[0.03-0.90], p=.04). Four patients achieved a CR after a second CAR T-cell infusion, including 2 with negative MRD. Eighteen patients were bridged to a hematopoietic stem cell transplantation (HSCT), with 7 of them undergoing a second transplant. Eleven patients developed acute graft versus host disease, including 4 cases of grade 3 and higher. Six patients presented a sinusoidal obstruction syndrome, with 5 cases being grade 3 and higher. All 6 received InO as part of their salvage therapy. One month after HSCT, 12/18 patients were in CR with 11 of them having negative MRD.
With a median follow-up of 24.1 months, the median overall survival (OS) of the entire cohort was 14.5 months, with a 2-year OS estimate of 38.7% (95%CI[24.1-53.0]). The 2-year OS for patients with early failure or relapse was 47.0% (95%CI[25.1-88.1] and 36.0% (95%CI[22.3-58.2]), respectively (p=.47). Patients with an overt disease at the start of salvage therapy had a shorter OS compared to those with only positive MRD disease (19.6%, 95%CI[6.0-38.9] vs 64.3%, 95%CI[39.2-81.2], p=.01). In univariate Cox model, the loss of CD19 antigen (HR 2.84, 95%CI[1.30-6.17], p&lt;.01), prior InO exposure (HR 3.44, 95%CI[1.56-7.58], p&lt;.01), and a high tumor burden prior tisa-cel infusion (HR 6.66, 95%CI[2.87-15.5], p&lt;.01) were associated with a shorter OS.
This real-world study indicates that patients who failed tisa-cel therapy display poor outcome, but some may still benefit from salvage therapy. Key factors influencing outcomes include the loss of CD19 and disease aggressiveness, such as tumor burden prior to tisa-cel treatment and previous exposure to InO. Additionally, bridging to HSCT can offer a curative option, although it carries a high risk of toxicity as reported in advanced disease stages.