Prophylactic Administration Of Ex VIVO Co-Stimulated Donor Lymphocyte Infusion (DLI) From Related And Unrelated Donors After Reduced Intensity Conditioning For High Risk Hematologic Malignancies

Abstract

Enhancing the graft versus tumor (GvT) effect without graft versus host disease (GvHD) is critical to the success of reduced intensity (RIC) strategies for allogeneic transplantation. Despite establishing donor lymphohematopoiesis, relapse rates remain high. Standard DLI given at relapse or prophylactically to enhance donor chimerism has met with limited success in improving transplant outcomes. Co-stimulation of donor T-cells, using anti-CD3/CD28 coated beads to serve as artificial APCs, may reverse functional T cell tolerance, thereby restoring immune responsiveness and potentiate GVT. Unlike standard DLI, ex vivo co-stimulation may enhance T cell activity by removing and activating T cells outside of a tumor-induced immunosuppressive milieu. We report the preliminary results of a feasibility trial of ex vivo co-stimulated DLI from sibling and unrelated donors given ‘prophylactically’ at 4 and 6 months after RIC allogeneic transplantation for patients (pts) with high-risk hematologic malignancy.Methods: 15 pts have undergone RIC with alemtuzumab, Fludarabine,Busulfan with peripheral blood stem cell transplantation (PBSCT) and planned activated DLI (pADLI) at 4 months (1 × 107 CD3+/kg) and 6 months (1 × 108 CD3+/kg) post-transplant in the absence of GvHD or relapse. All pts received tacrolimus and methotrexate as GvHD prophylaxis.Results: 8 pts (AML, n = 6; ALL CR1 n = 2) received grafts from HLA-identical sibling donors, 7 (AML n = 5; MDS n = 1; ALL, n = 1) from matched unrelated donors. Donor hematopoiesis was established in all patients. Of the 11 infusions given to date, there has been no infusion-related toxicity, confirming the safety and feasibility of this strategy. 8 pts have received the first of 2 planned infusions of pADLI. Of the remaining 7 pts, 4 infusions are upcoming, 1 was precluded by early relapse, and 2 were precluded by early NRRM. Of the 8 pts who received their initial pADLI#1, 3 have received a second infusion. 5 pts did not receive pADLI#2 because of relapse (n = 3), GvHD (n = 1), and transient uveitis in the absence of GvHD (n = 1). Overall incidence of acute GvHD (aGvHD) has been low; 1 pt developed aGvHD prior to pADLI#1, and 1 pt developed aGvHD after pADLI #1. No patient has developed chronic GvHD.Conclusion: Preliminary results of this trial demonstrates that RIC with PBSCT followed by ex vivo costimulated pADLI for poor prognosis hematologic malignancies is safe and feasible with potential for enhancing GvT without increasing GvHD. Enhancing the graft versus tumor (GvT) effect without graft versus host disease (GvHD) is critical to the success of reduced intensity (RIC) strategies for allogeneic transplantation. Despite establishing donor lymphohematopoiesis, relapse rates remain high. Standard DLI given at relapse or prophylactically to enhance donor chimerism has met with limited success in improving transplant outcomes. Co-stimulation of donor T-cells, using anti-CD3/CD28 coated beads to serve as artificial APCs, may reverse functional T cell tolerance, thereby restoring immune responsiveness and potentiate GVT. Unlike standard DLI, ex vivo co-stimulation may enhance T cell activity by removing and activating T cells outside of a tumor-induced immunosuppressive milieu. We report the preliminary results of a feasibility trial of ex vivo co-stimulated DLI from sibling and unrelated donors given ‘prophylactically’ at 4 and 6 months after RIC allogeneic transplantation for patients (pts) with high-risk hematologic malignancy. Methods: 15 pts have undergone RIC with alemtuzumab, Fludarabine,Busulfan with peripheral blood stem cell transplantation (PBSCT) and planned activated DLI (pADLI) at 4 months (1 × 107 CD3+/kg) and 6 months (1 × 108 CD3+/kg) post-transplant in the absence of GvHD or relapse. All pts received tacrolimus and methotrexate as GvHD prophylaxis. Results: 8 pts (AML, n = 6; ALL CR1 n = 2) received grafts from HLA-identical sibling donors, 7 (AML n = 5; MDS n = 1; ALL, n = 1) from matched unrelated donors. Donor hematopoiesis was established in all patients. Of the 11 infusions given to date, there has been no infusion-related toxicity, confirming the safety and feasibility of this strategy. 8 pts have received the first of 2 planned infusions of pADLI. Of the remaining 7 pts, 4 infusions are upcoming, 1 was precluded by early relapse, and 2 were precluded by early NRRM. Of the 8 pts who received their initial pADLI#1, 3 have received a second infusion. 5 pts did not receive pADLI#2 because of relapse (n = 3), GvHD (n = 1), and transient uveitis in the absence of GvHD (n = 1). Overall incidence of acute GvHD (aGvHD) has been low; 1 pt developed aGvHD prior to pADLI#1, and 1 pt developed aGvHD after pADLI #1. No patient has developed chronic GvHD. Conclusion: Preliminary results of this trial demonstrates that RIC with PBSCT followed by ex vivo costimulated pADLI for poor prognosis hematologic malignancies is safe and feasible with potential for enhancing GvT without increasing GvHD.