Memory T-Cell Add Back and Prophylactic blinatumomab Post Tcrαβ Depleted Haploidentical Transplantation Results in Promising Outcomes in Pediatric Patients with High-Risk Acute Leukemia
Authors: Naik Swati , Li Ying , Zeng Emily , Selukar Subodh , Bhoopalan Senthil Velan , Epperly Rebecca , Renee Madden , Mamcarz Ewelina , Obeng Esther A. , Qudeimat Amr , Sharma Akshay , Suliman Ali Y , Talleur Aimee C. , Velasquez Mireya Paulina , Zebley Caitlin , Schell Sarah , Adams Polly , Metais Jean-Yves , Akel Salem M. , Gottschalk Stephen , Triplett Brandon M 
Published: December 2024

TCRαβ depletion of haploidentical donor (haplo) grafts allows for low rates of graft-vs-host disease (GVHD) but delays immune reconstitution (IR) in hematopoietic cell transplant (HCT) recipients. Adoptive transfer of donor T cells may enhance IR but is associated with risk of GVHD. CD45RA-negative (memory) T cells have low alloreactivity and retain specificity for viral antigens. We therefore chose to addback CD45RA-depleted T cells (memory T cells) following TCRαβ/CD19 depleted haploHCT to enhance IR without increasing risk of GHVD for children with high-risk acute leukemia. As the preparative regimen did not contain total body irradiation (TBI), patients with B-cell ALL received prophylactic blinatumomab (blina) to mitigate risk of relapse. Herein we report preliminary findings from this prospective clinical trial (NCT03849651).

From 2019 to 2023, 69 patients received haplo HCT (ALL: 34, AML:33, MDS:1, NHL: 1). The median age of recipients was 8.8 years (range: 0.5-21.6). Disease status at HCT was complete remission (CR)1 (n=28), CR2 (n=29), CR≥3 (n=11), and MDS (n=1). Donors included a parent (n=64) or sibling/other (n=5). All patients received a preparative regimen consisting of fludarabine, melphalan, cyclophosphamide, thiotepa, and anti-thymocyte globulin (days -5 to -3). No GVHD prophylaxis was used post HCT. Patients received memory T cells in 2 cohorts: an initial dose escalation cohort that enrolled 29 patients (T-cell dose/kg: 1x105: n=9; 1x106: n=10; 1x107: n=10) and a dose expansion cohort after maximal effective dose was chosen (T-cell dose of 1x107 /kg) that enrolled an additional 40 patients.

All patients but one engrafted with a median time to neutrophil engraftment of 10 days (range: 9-12). At a median of day +29 post-HCT (range: 22-57), 67 patients received memory T cell addback. At 4 weeks post-memory T cell addback, an increase in the mean CD3, CD8, and CD45RO+ T-cell counts (p&lt;0.0001, p=0.001, p=0.0001) was observed. Emerging memory T cells were functional as judged by Elispot assays and their ability to control viral reactivations. TCR repertoire was broad and comparable to donor by month 6. The incidence of acute GVHD within 28 days of memory T cells addback at dose level 1, 2 and 3 was 0% (0/9), 30% (3/10), and 2% (1/48) respectively. For the entire cohort, cumulative incidence of any grade acute GVHD, grade III-IV acute GVHD and chronic GVHD at 1 year was 26.2%, 10.1% and 3.1% respectively.

Twenty-six patients with ALL received blina at a median of 32 days after memory T cell addback; 69% (18/26) responded with B-cell aplasia (BCA). Median CD3 count prior to blina was higher in patients who developed BCA (530/μL) compared to those did not (135/μL). Relapses after blina occurred in 4/18 patients with BCA (CD19-pos: 2, CD19-neg: 1, unknown: 1), and 4/8 without BCA (CD19-pos: 3, unknown: 1). Two patients failed to complete blina due to toxicity, and one due to progressive disease. Overall survival and event free survival at 1-year were 87.7% and 73.6%. The cumulative incidence of relapse and non-relapse mortality at 1-year were 23.5% and 2.9%.

In conclusion, addback of memory T cells in doses up to 1x107 T cells/kg early after TCRαβ/CD19-depleted haplo HCT was safe and led to robust immune reconstitution with low rates of severe acute and chronic GVHD. Prophylactic infusion of blina after HCT in patients with ALL was associated with comparable rates of relapse to TBI-containing regimens and may present a strategy to avoid exposure to radiation. Thus, our approach of enhancing immune reconstitution post TCRαβ-depleted haploHCT with memory T cells for patients with hematological malignancies and incorporation of prophylactic blina for patients with ALL led to promising outcomes in this high-risk pediatric patient population.