Ex vivo purging of allogeneic marrow with L-Leucyl-L-leucine methyl ester. A phase I study.
L-Leucyl-L-leucine methyl ester (LLME) is a lysosomatropic compound that is converted by dipeptidyl peptidase I to metabolites that are membranolytic for cytotoxic T cells, NK cells, and LAK cells. Ex vivo treatment of murine marrow with LLME ameliorates acute graft-versus-host-disease (GVHD), which led to consideration of a clinical study. A phase I study design was initiated to evaluate the effects of ex vivo purging of allogeneic marrow on engraftment, since LLME also suppresses human progenitor cells. All patients received a preparative regimen of cyclophosphamide plus total body irradiation. GVHD prophylaxis consisted of cyclosporine +/- corticosteroids. This study included 19 patients with high risk disease undergoing allogeneic transplantation from an HLA-identical sibling (n = 12) or a partially HLA-matched family donor (n = 7). Marrow mononuclear cells were treated ex vivo in a dosage escalation study with LLME concentrations of 0.25 mM, 0.375 mM, and 0.5 mM. Marrow NK and LAK activities were essentially eliminated at concentrations > or = 0.375 mM LLME. CD8+ cells were also reduced. Granulocyte macrophage colony-forming unit recovery was 3% at 0.5 mM LLME. The median time to an absolute neutrophil count of 500/microliters was 17 days after transplantation (95% confidence interval = 14-18 days). One patient that received marrow treated with 0.5 mM LLME died of secondary graft failure. Complete donor chimerism was documented in each evaluable case. NK recovery was delayed at LLME concentrations > or = 0.375 mM LLME. Grade II/IV GVHD occurred in 4/18 evaluable patients. Ex vivo treatment of human marrow with LLME diminishes NK activity, LAK activity, CD8+ cells, and granulocyte macrophage colony-forming units, but does not totally prevent acute GVHD.
Rosenfeld
C S
CS
Texas Oncology, P.A., Stem Cell Transplant Unit, University of Texas Southwestern Medical Center, Dallas 75235-8887, USA.
Thiele
D L
DL
Shadduck
R K
RK
Zeigler
Z R
ZR
Schindler
J
J
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D016465:Bone Marrow Purging; D016026:Bone Marrow Transplantation / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004151:Dipeptides; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000276:immunology; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents; D007938:Leukemia / Q000628:therapy; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000628:therapy; D008297:Male; D008875:Middle Aged; D012307:Risk Factors
D004151:Dipeptides; D007166:Immunosuppressive Agents; C045139:leucyl-leucine-methyl ester