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Introduction Prophylactic, donor lymphocyte infusion (DLI) is used to augment immune recovery and graft vs. tumor effect following a T-cell depleted alloSCT. However, it carries the risk of inducing severe GvHD. Our pre-clinical murine studies have implicated the naive T-cell, defined by CD62L marker, as the primary driver of alloreactivity. We hypothesize that transferring selected memory T-cells without naive-T cells would endow the patient with cells that do not cause GvHD while augmenting host defense against infection and tumor recurrence. Objectives The goal of the study was to determine the maximum tolerated dose of a prophylactic, delayed DLI that has been depleted of naive T-cells. Methods We enrolled 16 adult patients, median age 54 who met following criteria; a. underwent an alemtuzumab or thymoglobulin-containing non-myeloablative allogeneic transplant from an HLA-identical family donor or an 8/8 HLA-matched unrelated donor (MUD), b. at least 60 days from day of transplantation, c. no active acute GvHD grade II or higher. Primary diseases were CLL; n=1, MM; n=2, MF; n=1, NHL; n=5, MDS; n=1, AML; n=6. A dedicated, non-mobilized donor apheresis procedure was performed following enrollment. Naive, CD45RA+ T-cells were depleted from the collection under an IND using the Miltenyi clinimacs system. A standard phase I, 3+3 dose escalation schema was employed. The dose-limiting toxicity of the DLI was defined as development of grade III/IV acute GvHD within 90 days of the DLI. Results The DLI was infused on median 112.5 days (76 to 280 days) following transplant. 8 patients received matched sibling grafts and 8 received MUD grafts. 3 patients each received naive T-cell depleted CD3+ dose of 1 × 105/kg, 1 × 106/kg, and 5 × 106/kg. The top dose of 1 × 107/kg was expanded to 7 patients. No dose limiting toxicity or adverse event attributable to the DLI was observed at any dose level. 1 patient developed grade 2 acute GvHD and 1 developed moderate chronic GvHD attributable to the DLI. 4 patients had relapsed disease; 2 in the lowest dose and 2 in the highest dose levels. With a median follow-up of 2.75 years, 2-year relapse free and overall survivals are 56.25% and 68.75%, respectively (Fig 1 and 2). NK cells, CD3+T lymphocytes, CD4+ T lymphocytes and CD8+ T lymphocytes show positive correlations of 0.24, 0.40, 0.42 and 0.38 respectively with time following the DLI (Fig 3). Conclusion A prophylactic, naive T-cell depleted DLI can be provided safely, without significant risk of acute GvHD at a dose of 1 × 10e7 CD3/kg. Larger studies in a more homogeneous patient population will be needed to confirm the impact on immune recovery and relapse prevention. [ABSTRACT FROM AUTHOR]