Pentostatin and Alemtuzumab for Allogeneic PBPCT

DESCRIPTION (provided by applicant): Reduced-intensity nonmyeloablative (NM) allogeneic hematopoietic cell transplantation (HCT; transplantation of bone marrow or peripheral blood progenitor cells [PBPCs]) may be therapeutic in patients at unacceptably high risk of mortality from conventional myeloablative HCT. Preparative regimens for NMHCT incorporate immunosuppressive and reduced-dose myelosuppressive agents to allow donor cell engraftment. However, all reported NMHCT regimens are associated with post-HCT neutropenia, with or without other cytopenias. No studies have yet examined a purely immunosuppressive regimen for NMHCT. Pentostatin (2'-deoxycoformycin; PENTO) is a purine nucleoside analog that exerts lymphocytotoxicity by irreversible inhibition of adenosine deaminase (ADA). Alemtuzumab (Campath l-H; ALEM) is a humanized IgG1 kappa anti-CD52 monoclonal antibody that exerts lymphocytoxicity by antibody-dependent cellular cytotoxicity, complement-mediated lysis and/or induction of apoptosis. Neither PENTO nor ALEM has intrinsic myelotoxicity. The proposed studies will test and explore the hypothesis that pre-HCT immunosuppression with PENTO plus ALEM will allow sustained engraftment of donor cells and not induce myelosuppression. The first specific aim will be a phase II trial of continuous-infusion i.v. PENTO (total dose 12 mg/m 2 over 72 hr, days -8 through -6) and i.v. ALEM (20 mg/day, days -5 through -1) followed by HLA-matched related or unrelated allogeneic PBPC transplantation (PBPCT) in high-risk subjects (age 18-75 years) with hematologic malignancies or renal cell carcinoma. The primary efficacy and safety endpoints will be donor chimerism and non-relapse mortality, respectively, at day +100. Hematologic reconstitution, graft-versus-host disease (GVHD), regimen-related toxicities, event-free survival and other outcome measures will also be assessed in these subjects. The second specific aim will evaluate pharmacodynamic and immunologic effects of PENTO and ALEM by: determination of kinetics and mechanisms of loss of recipient T cells and myeloid cells, including assays of apoptosis and mitochondal injury; post-PBPCT humoral and cellular reconstitution; and quantified thymic output by T-cell receptor excision circle (TREC) analyses. The proposed complementary clinical and laboratory research studies will provide new knowledge for the rational development of and understanding of mechanisms in NMHCT.