Pentostatin and Alemtuzumab for Allogeneic PBPCT

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date9/15/048/31/08

Funding

  • National Institutes of Health: $256,298.00
  • National Institutes of Health: $268,229.00

ASJC

  • Medicine(all)

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