Targeted Lymphocyte Depletion: A Personalized Approach to Achieve Rapid Complete Donor Chimerism and Enhance Graft-Versus-Tumor Effects Following Reduced Intensity Allogeneic Stem Cell Transplantation for High-Risk Hematologic Malignancies.

Abstract 656

Reduced intensity allogeneic stem cell transplantation (RIST) is associated with decreased transplant-related mortality (TRM), broadening the pool of patients who could potentially benefit from allogeneic cellular therapy. However, RIST historically results in mixed chimerism, has higher relapse rates and has limited efficacy in chemotherapy-refractory hematologic malignancies. In order to enhance graft-versus-tumor effects, we have developed a strategy of targeted lymphocyte depletion (TLD), which attempts to compensate for variability in host immune status and facilitate early full-donor chimerism. TLD involves the use of repetitive cycles of disease-specific conventional-dose chemotherapy to provide both tumor cytoreduction and lymphocyte depletion prior to RIST. The number of TLD cycles (0-3 maximum) is based on reaching a target CD4⁺ count <100 cells/μl; patients with higher pre-TLD CD4⁺ counts require more cycles. We employed the TLD approach in 111 patients (40 females/71 males) with median age of 50 years (range 19-71) with advanced hematologic malignancies (45% chemotherapy refractory; 60% high risk of relapse by Seattle Criteria (Kahl C et al Blood 2007). Median CD3⁺, CD4⁺, and CD8⁺counts at enrollment were 673 cells/μl (5-3953), 286 cells/μl (5-3888), and 277 cells/μl (1-1763) respectively. Following TLD chemotherapy, median CD3⁺,CD4⁺, and CD8⁺counts were 164 cells/μl (1-1496), 82 cells/μl (0-508) and 52 cells/μl (1-1195) respectively. All patients then received an identical reduced intensity conditioning regimen (fludarabine/cyclophosphamide) followed by T-cell replete HLA-matched sibling peripheral blood stem cell allografts and cyclosporine-based graft versus host disease (GVHD) prophylaxis. 109 evaluable patients demonstrated 100% engraftment; there were no late graft failures. At Day+14, median lymphocyte chimerism was 99% and median myeloid and whole blood chimerism were 100%. Patients were able to maintain chimerism as evidenced by 100% median chimerism in the myeloid, lymphoid and whole blood compartments at Day+28 and 100% median whole blood chimerism at Day +100. The cumulative incidence of grades II-IV and grades III-IV acute GVHD was 46% and 23% respectively. The cumulative incidence of chronic GVHD was 59% (15% limited, 44% extensive). One and 5-year TRM was 15% and 21% respectively. At Day +28, 38 patients had achieved a complete remission (CR) and 44 achieved partial remission (PR). Twelve additional CRs were observed at Day +100 without withdrawal of immunosuppression or donor lymphocyte infusion. Event free survival (EFS) and overall survival (OS) at one year were 49% and 66% respectively. EFS and OS at five years were 31% and 47% respectively. Of those patients alive at one year (n=73), 66% were in CR. Of those patients in CR, 58% had high risk of relapse by Seattle Criteria and 92% had not been in CR at the time of transplant (31% had stable or progressive disease). At median follow-up of 5.4 years, 65% of this subset of patients were alive and still in CR. By univariate analysis, the age of the recipient and presence of an ABO minor mismatch were significantly associated with OS (p<0.05); number of prior therapies, disease status at the time of transplant, and relapse risk by Seattle criteria were significantly associated with EFS and OS (p<0.05). The strategy of TLD provides a personalized approach to pre-transplant host immune status resulting in early full donor chimerism. Using TLD prior to RIST resulted in a high percentage of sustained complete remissions in patients with advanced hematologic malignancies.