Low Disease Burden Pre-CAR-T Cell Therapy for Children and AYA with B-ALL Is Associated with an Impaired Outcome When Obtained through Intensification of the Bridging Therapy
Authors: Lecornec Nicolas , Dourthe Marie-Emilie , Rabian Florence , Yakouben Karima , Chevillon Florian , 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 , Mathis Stéphanie , Chaix Marie-Laure , Azoulay Elie , Dalle Jean-Hugues , Madelaine Isabelle , Larghero Jerome , Boissel Nicolas , Baruchel André 
Published: December 2023

Rationale. The role of bridging therapy, i.e., treatment between apheresis and lymphodepletion (LD) preceding tisagenlecleucel (tisa-cel) infusion for relapsed/refractory B cell acute lymphoblastic leukemia (R/R BCP-ALL) is still unclear. We report a retrospective study on our experience on 81 children, adolescents, and young adults with R/R BCP-ALL who underwent apheresis with an intent to receive tisa-cel infusion, between March 2016 and October 2020.

Methods. Bridging therapy intensity was classified into two intensity groups. A high intensity bridging (HIB) regimen, used in 23 patients (pts), was defined as the use of more than 4 intravenous anti-leukemic drugs per week and/or the need of secondary intensification of bridging therapy, the latter being the case in 19 pts (83%). A low-intensity bridging (LIB), in general a combination of vincristine, steroids +/-asparaginase, was used in 58 pts. The aim of the study was to evaluate the impact of HIB versus LIB on tisa-cel efficacy. Factors associated with a failure to infuse tisa-cel were also explored.

Results. Patients had a median age of 15 years (range: 1-19). Tisa-cel indication was a primary refractory disease for 5 pts (6%), a first post-allo-HSCT relapse for 47 pts (58%) and a second relapse or more for 29 pts (36%). Patients who received a HIB therapy were more likely to have high-risk genetic features (39% vs 12%, p= .01) and/or a primary refractory disease (17% vs 2%, p=.02). Grade 3+ non-infectious and infectious adverse events during bridging therapy were also more likely in this group, albeit in a non-statistically significant way (35% vs 16 %, p= .07 and 52% vs 34 %, p= .21; respectively).

Nine patients (11%) were not infused (disease progression: 3 pts; toxicity: 5 pts (sinusoidal obstruction syndrome: 1 pt, encephalopathy: 2 pts, fungal infection; 1 pt, hemoptysis: 1 pt); and CD19 negativation: 1 pt). A high pre-apheresis tumor burden ( p=.01), the occurrence ( p=.01), and the number of grade ≥ 3 adverse events during bridging period ( p&lt;.01) were associated with a higher risk of tisa-cel non-infusion, while HIB was not ( p=.73). The 72 remaining patients (89%) finally received tisa-cel infusion, 52 (64%) after a LIB therapy and 20 (25%) after a HIB therapy. Despite a comparable BM disease burden at apheresis between the LIB and the HIB groups, patients presenting a high disease burden prior to LD (bone marrow (BM) blasts &gt; 50%) were more frequent in the HIB group ( p&lt; .01). When compared to patients who received a LIB, patients treated with a HIB had a worst, albeit non-statistically different cumulative incidence of relapse (CIR) (SHR 1.94, 95% CI [0.95-3.91], p=.07), an inferior 18-month event-free survival (EFS) (26.9% vs 54.1%; p=.02) and a lower 18-month overall survival (OS) (50.9% vs 88.8%; p&lt;.01). Considering a threshold at 50% BM blasts, patients who presented a high disease burden prior to LD had poorer early response rates (D28 minimal residual disease (MRD) negativity: 85% vs 69%, p&lt; .01), a higher, albeit non-statistically different CIR (SHR 2.27, 95% CI [0.98-5.27], p=.06), an inferior 18-month EFS (26.9% vs 51.3%; p=.02) and a lower 18-month OS (22.6% vs 91.5%; p&lt;.01).

We then asked if the bridge intensity, aimed at achieving a low disease burden before LD, could influence patient outcomes. Median percentages of BM blast infiltration were similar after LIB (0%) and HIB therapy (1%, p=.87) in patients with ≤50% BM blast at LD. In these patients, a prior HIB regimen was associated with a higher rate of detectable MRD at D28 (40% vs 8%, p=.02), an inferior 18-month EFS (18.0% vs 57.5%; p=.02) and a higher, albeit non-statistically different CIR (SHR 2.05, 95%CI [0.87-4.88], p=.1). The 18-month OS did not differ between groups (74.0% vs 94.6%; p=.15), suggesting that these patients may respond to further lines of treatment after relapse. The outcome of patients presenting a low disease burden at LD after a HIB regimen was thus similar to those with a high disease burden at LD.

Conclusion. This study confirms the prognostic value of a high disease burden pre-LD but also reveals that a low disease burden prior tisa-cel therapy is associated with an impaired outcome when obtained through intensification of the bridging therapy. Additional post-tisa-cel therapies should be considered in this group of patients.