Pb2442: blinatumomab redirects donor lymphocytes against cd19+ all without increasing the risk of bystander alloreactivity after haploidentical hematopoietic cell transplantation

Topic: 22. Stem cell transplantation - Clinical Background: TCR/CD19 bispecific antibody Blinatumomab is approved in patients with acute lymphoblastic leukemia (ALL). Blinatumomab alone or in combination with donor leukocyte infusions (DLI) has also been used after allogeneic hematopoietic cell transplantation (HCT) as a salvage therapy in relapsing patients, proving to be effective in a fraction of them with low incidence of graft-versus-host disease (GvHD). However, immunosuppressive drugs used as prophylaxis for GvHD hinder T cell function and might reduce the efficacy of the treatment. Because T-cell depleted haploidentical HCT with donor regulatory and conventional T cell immunotherapy (Treg/Tcon haplo-HCT) does not require post-transplant immunosuppression, it represents an ideal platform for the use of Blinatumomab with DLI. However, the risk of GvHD is particularly high when the donor is haploidentical. Aims: Aim 1. To evaluate if the treatment with Blinatumomab plus DLI can induce complete remission in CD19+ ALL patients relapsing after Treg/Tcon haplo-HCT, without causing GvHD. Aim 2. To investigate the function of T cells engaged with blinatumomab against allogeneic cell targets in vitro. Methods: Aim 1. We analyzed outcomes of patients who received Blinatumomab plus DLI for CD19+ ALL relapse after Treg/Tcon haplo-HCT. Aim 2. Proliferation and cytotoxicity of T cells from a healthy subject induced by a bscCD19xCD3 antibody in the presence of autologous vs allogeneic peripheral mononuclear cells (PBMCs) were assessed by a CFSE-dilution assay and a chromium-release assay, respectively. Results: Aim 1. Two patients with active CD19+ ALL at the time of transplant relapsed early (1 month and 4 months, respectively) after Treg/Tcon haplo-HCT. Both received Blinatumomab plus DLI as salvage therapy for 4 and 1 cycles, respectively. DLIs were infused during Blinatumomab treatment. None of them received any pharmacologic immune suppression before and after treatment. The patients tolerated up to 1x106/kg HLA-haploidentical donor lymphocytes without developing acute or chronic GvHD. Both patients achieved minimal residual disease negative complete remission. Disease eventually relapsed in extramedullary sites a few months after treatment. Aim 2. Because the patients did not develop GvHD despite the high doses of DLI and the absence of post-transplant immune suppression, we tested how Blinatumomab impacted on T cell alloreactivity in in vitro assays. While Blinatumomab enhanced T cell proliferation against allogeneic PBMCs, this effect was abolished when the target was depleted of B cells (Figure). Furthermore, Blinatumomab did not increase T cell cytotoxicity against allogeneic CD19 negative cells. In fact, T cell activation exerted by Blinatumomab was strictly dependent upon the presence of CD19+ cell targets and the bispecific antibody did not enhance T cell alloreactivity. Summary/Conclusion: Both patients achieved complete remission without GvHD despite the mismatch for one HLA haplotype with the donor and the absence of any pharmacological immunosuppression. Consistently, Blinatumomab enhanced T cell function only against CD19+ allogeneic cells. Therefore, it would appear that the TCR engagement by CD19 through Blinatumomab directs the whole repertoire against the target and prevents the expansions of clones against the recipient HLA. Thus, Blinatumomab and DLI is a safe and immediately available treatment option to urgently treat post-transplant relapsed ALL and its early pre-emptive use should be considered to improve outcomes of ALL patients at high risk of relapse.Keywords: Immunotherapy, ALL, DLI, Allogeneic hematopoietic stem cell transplant