Short-Term Blinatumomab Combined with Early Chemotherapy for Newly Diagnosed Pediatric Patients with B-Cell Acute Lymphoblastic Leukemia

More treatment options are available for pediatric patients (pts) with newly diagnosed measurable residual disease positive (MRD-pos) B-ALL. As the efficacy of blinatumomab (Blin) has been confirmed in adult pts, early chemotherapy combined with immunotherapy has become a new focus in the treatment of pediatric B-ALL. The conventional single course of Blin lasts 4 weeks and is associated with a high risk of CRS. Therefore, we developed a prospective trial to evaluate short-term Blin in sequence with chemotherapy in this pts population (ChiCTR2100053318).

Pts aged 1 month (mo) to 18 years (yrs) with CD19-positive, Day46 MRD-pos B-cell ALL were eligible. Blin was administered before consolidation therapy by continuous intravenous infusion over 14 days (Blin-14d), at a dose of 15ug/m²/d (weight ≤45kg) or 28ug/d (weight >45kg). The chemotherapy protocol was continued after Blin-14d therapy. Signed informed consent was obtained from each patient’s guardian. The primary endpoint was MRD complete remission (CR) response rate to Blin-14d. Secondary objectives include safety of Blin-14d and comparison of long-term efficacy between Blin-14d and Non-Blin-14d. MRD was assessed using droplet digtial quantitative polymerase chain reaction (ddPCR) and multiparameter flow cytometry (MFC). The pharmacodynamics of Blin-14d, including changes in lymphocyte subpopulation and cytokine levels, was assessed by MFC-based analyses. The toxicity was graded by CTCAE 5.0.

Between June 2022 and March 2024, 56 eligible pts were included, of which 30 (54%) received Blin-14d, constituting the Blin-14d group (pt#1 to 30), while the remaining constituted the Non-Blin-14d group (pt#N1 to 26). For Blin-14d group, the median age of pts was 6.38 (1.58-15.43) yrs old. The median percentage of pre-treatment MRD was 0.09% (0.01-2.50%). For Non-Blin-14d group, the median age was 10.45 (2.25-17.00) yrs old. The median MRD at Day46 was 0.025% (0.01-17.69%).

During the Blin-14d infusion, 14 (47%) pts were dose escalated and 16 (53%) pts received full dose. The median level of IL-6 at day2 was 17.78 pg/ml vs 57.29 pg/ml (p=0.0130) and the incidence of adverse events (AEs) was 57% vs 94% (p=0.0309). In general, 23 (77%) pts experienced AEs of any grade, with 2 (8%) experiencing grade 3 AEs, including severe numbness of limbs and ALT increasing. No grade 4 or higher event related to Blin was observed. The most frequent manifestation of AEs was fever, particularly a moderate fever of >38.3℃. Prior to the Blin-14d therapy, 23 (77%) pts received induction therapy and 7 (23%) received induction plus early intensification therapy (EIT). The median total T-cell count was 1287/ul vs 1308/ul (p>0.10) at the end of Blin-14d infusion and 1961/ul vs 1165/ul (p=0.0127) one week later, suggesting the possibility of premature T-cell exhaustion caused by EIT. All of pts (100%) were in MFC-MRD-neg remission and 29 (97%) achieved molecular complete remission (mCR) one week after the end of Blin-14d.

The final follow-up was on July 1, 2024. The median time to first detection of MRD-neg in bone marrow was significantly earlier in Blin-14d group compared to Non-Blin-14d [3.0 (2.4-4.4) mos vs 3.3 (0.66-11.0) mos, p=0.0199]. The median follow-up after initiation of induction treatment was 14.1 (3.6-27.5) mos in Blin-14d group and 14.4 (3.3-28.2) mos in Non-Blin-14d group, with similar EFS in the two groups (92.3% vs 84.7%, p=0.2206).

In Blin-14d group, pt#3 MFC-MRD relapsed 14.9 mos after Blin-14d, then received a higher dose of chemotherapy and reached MFC-MRD-CR2 at the last follow-up (23.3 mos after Blin-14d). Pt#9 ddPCR-MRD relapsed 5.2 mos after Blin-14d and underwent allo-HSCT and is alive now (19.4 mos). In Non-Blin-14d group, 13 (50%) pts had treatment deviations, among whom 2 pts received Blin-14d after consolidation therapy and 3 received Blin-28d for persistent MRD>0.01%, and 3 pts underwent CAR-T for D46 MRD>5%. Two pts (#N9 and #N20) had bone marrow relapse and pt#N13 MFC-MRD relapsed. Pt#N9 was lost to follow-up. Pt#N13 and pt#N20 underwent allo-HSCT and are alive.

Preliminary data from this prospective study showed encouraging clinical activity and manageable safety profile for Blin-14d therapy, which also demonstrated earlier responses and therapeutic consistency compared to Non-Blin-14d group. For newly diagnosed pediatric B-ALL patients with MRD-pos, early chemotherapy followed by short-term blinatumomab would be a promising option.