Use of Targeted Lymphocyte Depletion as a Personalized Approach to Improve Engraftment and Disease Control Following Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation Using HLA-Matched Unrelated Donors

Abstract 3530

Reduced-intensity allogeneic stem cell transplantation (RIST) using unrelated donors (URD) is associated with delayed full donor chimerism, higher rejection rates, and increased risk of graft versus host disease (GVHD) compared to RIST with HLA-matched sibling donors. We have previously reported a strategy of targeted lymphocyte depletion (TLD) to facilitate early full-donor chimerism in patients receiving RIST from HLA-matched siblings. TLD attempts to compensate for variability in host immune status, using CD4⁺ T-lymphocytes as a surrogate marker, by giving repetitive cycles of disease-specific conventional-dose chemotherapy to deplete host lymphocytes and provide tumor cytoreduction prior to RIST. We initiated a prospective pilot trial of TLD in the setting of RIST from 10/10 HLA-matched URD. TLD was achieved by using disease-specific induction chemotherapy (EPOCH-F/R or FLAG) for 0–3 cycles to reach a target lymphocyte count of <100 CD4⁺ cells/μl. All patients received conditioning with fludarabine 30 mg/m²/day × 4 days and cyclophosphamide 1200 mg/m²/day IV × 4 days followed by T-cell replete mobilized peripheral blood allografts from 10/10 HLA-matched URD. For GVHD prophylaxis, patients were randomized to receive either tacrolimus/sirolimus/methotrexate (TMS) or alemtuzumab/cyclosporine (AC) to study whether the effects of TLD varied with GVHD regimen. Twenty patients (median age 53 yrs; range, 24–70) with advanced or high-risk hematologic malignancies (median prior regimens = 4, chemoresistant disease = 35%) were enrolled in the study. Thirteen patients required TLD chemotherapy per protocol; the other 7 patients met the targeted lymphocyte goal at enrollment (n = 6) or could not receive additional chemotherapy due to disease related cytopenias (n = 1). Median CD3⁺, CD4⁺, and CD8⁺ lymphocyte counts at enrollment were: 416 cells/μl (22-4112), 243 cells/μl (8-2058), and 217 cells/μl (11-2173), respectively. Immediately prior to conditioning chemotherapy, median CD3⁺, CD4⁺, and CD8⁺ counts for all 20 patients were: 142 cells/μl (22-850), 85 cells/μl (8-259), and 69 cells/μl (11-635) respectively. All 20 patients engrafted; there were no late graft failures. At Day +14, median CD3⁺ chimerism was 94% (range 30–100%), CD14⁺/15⁺ chimerism was 99% (range 6–100%), and whole blood chimerism was 98% (range 11–100%). Patients maintained chimerism as evidenced by 100% median chimerism in the CD3⁺, CD14⁺/15⁺ and whole blood compartments at Day+28 which persisted at Day +100. There was a borderline significant difference seen between patients on the TMS vs AC GVHD prophylaxis arms in both median CD3⁺ (99% vs 86%; p=0.025) and CD14⁺/15⁺ (100% vs 93%, p=0.020) chimerism at Day +14, which was no longer significant by Day +28. At Day +100, the cumulative incidence of grades II-IV and grades III-IV acute GVHD was 35% and 10% respectively. At a median follow-up of 18 months, the cumulative incidence of chronic GVHD was 65%. Treatment-related mortality at Day +100 and 1 year was 5% and 17%, respectively. Actuarial event-free and overall survival at 1 year after transplantation was 70% and 85% respectively. By Day +28 post-transplant, 50% of patients (n = 10) had achieved or maintained a complete remission (CR). Three additional CRs were observed by Day +100 without addition of donor lymphocyte infusion. Of the patients alive at one year (n = 17), 82% were in CR (n = 14). The cumulative incidence of relapse at 1 year after transplantation was 15%. The strategy of using TLD prior to RIST permits a personalized approach to reduce host lymphocytes in patients with high risk and advanced hematologic malignancies. The host lymphodepletion achieved with TLD may result in increased availability of homeostatic cytokines for donor lymphocytes promoting the achievement of rapid and full donor chimerism and enhancing the graft versus tumor effect in patients with aggressive disease. These pilot data suggest that TLD leads to a high rate of post transplant CRs with a comparably low relapse rate and acceptable treatment related mortality. Based on these encouraging data, a study is currently underway assessing TLD in patients undergoing RIST using mismatched URD.