P1402: Infusion of 14 Days Blinatunomab in Combination With Chemotherapy for 46-Day Mrd+ Pediatric B-All Patients in Intermediate/High-Risk Group Results in MRD Conversion.

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Despite the efficacy of blinatunomab (blin) in adults with measurable residual disease (MRD) has been proved [Gökbuget, Blood 2018], studies in children with primary MRD positivity (MRD+) are still lacking. Furthermore, the conventional single course of blin takes 4 weeks and is associated with a high risk of ICANS. Aims: Herein, we conducted an exploratory trial of 14 days of blin monotherapy (blin-14days-therapy) in combination with an ALL-Chemotherapy protocol in children with MRD+ (≥0.01%) at the day 46 and evaluated the early efficacy and safety of this approach (chictr.org.cn:ChiCTR2100053318). Methods: We conducted a single-arm, open-label, single-center exploratory study of blin (14 days) in 9 pediatric patients with day46 MRD+ newly diagnosed B-ALL in intermediate/high-risk (IR/HR) groups. Induced chemotherapy regimen (VDLP+CAM) was planned prior to blin infusion. Intensive therapy (CAMplus) was allowed per protocol. Blin was administered by continuous intravenous infusion over 14 days, at a dose of 15μg/m2/d (weight ≤45kg) or 28μg/d (weight >45kg). The chemotherapy regimen was continued after the end of infusion. Signed informed consent was obtained from each participating patient’s guardian. The primary objective of the study was to assess the MRD response of blin-14days-therapy after induced/intensive therapy. Key secondary endpoints included safety and tolerability, 2-year event-free survival (EFS) and overall survival (OS). MRD was assessed using real-time quantitative polymerase chain reaction and flow cytometry. The toxicity was graded by CTCAE 5.0. Results: Between May. 2022 and Nov. 2022, 9 pediatric patients were enrolled onto our trial. The median age of patients was 6 (range: 1-15) years old. The median percentage of pre-treatment MRD was 0.09% (range: 0.03-2.50%). Seven to ten days after the end of infusion, all(100%) patients had MRD negative remission and achieved molecular complete remission (mCR). Eight (89%) patients experienced adverse events (AEs) of any grade, with 1 experiencing grade 3 AEs. No grade 4 or higher event related to blin was observed. CRS occurred in 7 (78%) patients with 5 (56%) grade 1 CRS, 2 (22%) of grade 2, and no grade 3 or higher CRS. Peripheral sensory neuropathy was observed in 1 (11%) patient with grade 3 ICANS. The most frequent manifestation of CRS was fever, particularly a moderate fever of >38.3℃. The median time to CRS onset from blin infusion was 1.25 days (range: 1-4), and the median time to resolution was 2 days. All CRS and ICANS events were managed including early intervention before blin infusion and when fever of ≥37.3℃ occurred. The change of IL-6 and IL-10 levels before and after infusion were selectively shown in Fig 1A and 1B. The peak levels of these two cytokines were observed when CRS occurred. When detectable circulating B cells rapidly disappeared from peripheral blood after start of infusion, T cells declined rapidly. After a swift drop, these cells recovered to pre-treatment levels and expanded over baseline during the further course of the single treatment cycle (Fig 1C and 1D). This pattern was observed in all of 4 evaluable patients. Summary/Conclusion: Initial data from this exploratory study demonstrate that blin-14days-therapy with chemotherapy has encouraging clinical activity and a manageable safety profile in pediatric patients with day46 MRD+ B-ALL in IR/HR groups. T cells expand rapidly after a swift decline, persist at relatively high levels for prolonged periods, and demonstrate better efficacy. Follow-up of this study is ongoing and updated efficacy and safety results will be presented.