Driving Cell Therapy in Treatment of MRD-Positive Acute Pediatric Lymphoblastic Leukemia after Allogeneic-HSCT: Blinatumomab + DLI

Background

Persistence of Measurable Residual Disease (MRD > 10^-4) in Acute Lymphoblastic Leukemia (ALL) is high risk for relapse after allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) with a very dismal prognosis. The role of Donor Lymphocytes Infusion (DLI) in the treatment of MRD-positive ALL is still debated, while favorable results have been observed in the treatment of MRD-positive relapse with the CD3-CD19 bi-specific T cell engager blinatumomab.

Methods

Three pediatric patients with high risk B-ALL were treated according to AEIOP ALL 2009 and AIEOP ALL 2017 protocols and referred for allo-HSCT. Two patients were male. Median age was 16 years (3-17). Patient 1 was primary refractory to 2 lines of chemotherapy and blinatumomab and achieved MRD-positive complete remission (CR) after 2 courses of inotuzumab. Patient 2, affected by secondary ALL, achieved CR1 after 1 course of chemotherapy and subsequently received 2 courses of blinatumomab, due to treatment chemotherapy-associated toxicity, achieving MRD-negative CR1. Patient 3 developed CNS relapse during maintenance, then received salvage therapy according to the INTREALL HR 2010 and 1 course of blinatumomab, achieving MRD-positive CR1.

Results

All patients underwent allo-HSCT and were MRD-positive at 8, 31 and 23 weeks post allo-HSCT, respectively. All patients discontinued immunosuppressive therapy and received 4, 1 and 3 courses of DLI + blinatumomab, respectively. Blinatumomab was started one week after each dose of DLI. Only patient 1 experienced grade 2 liver GvHD. None of the patients experienced serious adverse events needing blinatumomab discontinuation. All 3 patients reached an MRD-negative complete remission (CR). Median follow-up post HSCT was 30 months (11-30). Patient 2 and 3 are still in CR with persistent negative MRD, while patient 1 died for disease relapse (isolated CNS relapse).

Conclusions

The role of cellular therapy with DLI is still debated. Blinatumomab directs T cells to bind CD19 present on malignant B cells and engages CD3 on T cells causing activation and inducing cytotoxicity against the ALL cells. The use of blinatumomab allowed recruitment of fit donor-derived T lymphocytes (not exposed to immune suppressive agents) against ALL B cells. This hypothesis is supported by the fact that patient 1, who received blinatumomab pre-HSCT and had disease progression (probably due to the lack of T cells showed by flow cytometry), achieved MRD-negative response after receiving DLI+blinatumomab post-transplant. All patients reached MRD-negative status and 2 subsequently developed CNS relapse; none received CNS prophylaxis post-HSCT. We hypothesize that blinatumomab + DLI is able to clear the hematological disease, but it is not effective in preventing CNS relapse.

Wierda:Juno Therapeutics: Research Funding; Oncternal Therapeutics: Research Funding; AstraZeneca: Research Funding; F. Hoffmann-La Roche Ltd.: Research Funding; Numab Therapeutics: Research Funding; Eli Lilly: Research Funding; Nurix Therapeutics: Research Funding; AbbVie: Research Funding; Genentech, Inc.: Research Funding; Cyclacel Pharmaceuticals Inc: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Research Funding; Acerta Pharma: Research Funding; Loxo Oncology: Research Funding; GSK: Research Funding; Oncternal Therapeutics: Research Funding; BMS: Research Funding; National Comprehensive Care Center (NCCN): Other: Financial relationship (Chair, CLL); Novartis: Research Funding; Kite: Research Funding; Accutar Biotechnology: Research Funding.