Use of a Fc-Optimized CD19 Antibody for Treatment of MRD in Pediatric Patients with B-Lineage Acute Lymphoblastic Leukemia

Abstract 581

Primary refractory or relapsed B-lineage acute lymphoblastic leukemia can be successfully treated by allogeneic stem cell transplantation (SCT). However, relapse remains still a major risk and will be significantly influenced by residual disease prior to or after SCT. In addition to standard chemotherapy, immunotherapeutic approaches are assumed to be able to reduce or clear persistent minimal disease. Here we investigated an Fc-optimized chimerized CD19 antibody on a compassionate use basis in pediatric patients at very high risk prior to and after allogeneic, HLA matched (n=2) or mismatched (n=9) first or subsequent SCT. Through its improved capability to recruit FcγRIIIA bearing effector cells, this mAb mediates enhanced ADCC by NK cells but no complement lysis. 11 patients with B-lineage ALL (CR2 with MRD>10⁻⁴, n=3; ≥CR3, n=4; active disease, n=4; 8/11 had previous SCTs) received a mean number of 10 (range 1–30) infusions with an anti-CD19 mAb (4G7SDIE) over 6 hours weekly or every second week posttransplant. In 7 patients, additional infusions were given prior to transplant. Dosages ranged from 5 to 50 mg/m². The infusions were well tolerated without any severe side effects; only fever or headache was observed in a few patients (n=4). Minimal residual disease (MRD) or overt relapse (>50% blasts) was detectable in bone marrow aspirates prior to therapeutic mAb administration in 5/11 and 2/11 patients, respectively. Prophylactic CD19mAb infusions were given posttransplant without measurable MRD levels in 4/11 patients and in another 2 patients (who did not respond to pretransplant CD19mAb because of overt relapse but reached MRD negativity after SCT) due to an extremely high relapse risk. In 4 out of 5 patients with detectable MRD, leukemic load was reduced for at least 1 log or eradicated by the mAb. 2 out of those patients relapsed, 2 other patients are in molecular remission since 270 and 350 days. Both patients with overt relapse did not respond. 2/6 patients with prophylactic mAb infusions relapsed after 121 and 186 days, 4 other patients remain in molecular remission since 52–180 days. Taken together, a response could be documented in 4/7 patients; a total of 6/11 patients are in molecular remission (median follow up 157 days). Concomitant in vitro investigations showed that NK cells of the patients exerted insufficient lysis of primary B-lineage ALL blasts (mean specific lysis: 4,00%). However, lysis could be significantly increased by adding autologous patient serum taken after antibody treatment (mean specific lysis: 20,33 %, p = 0.0001, student's t-test) or by adding 1 μg/ml 4G7SDIE (mean specific lysis: 34.84 %, p < 0.0001). Activity of patient NK cells was similar to NK cells of healthy donors. ADCC relevant serum titers of biologically active CD19mAb were detectable up to 7 days after antibody infusion. In conclusion, promising antileukemic effects have been observed in vitro and in vivo in this pilot study and a further clinical trial has to address the question whether this approach will be able to reduce relapse rates.