Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy.
The immune-mediated graft-versus-leukemia effect is important to prevent relapse after allogeneic progenitor cell transplantation. This process requires engraftment of donor immuno-competent cells. The objective of this study was to assess the feasibility of achieving engraftment of allogeneic peripheral blood or bone marrow progenitor cell after purine analog containing nonmyeloablative chemotherapy. Patients with advanced leukemia or myelodysplastic syndromes (MDS) who were not candidates for a conventional myeloablative therapy because of older age or organ dysfunction were eligible. All patients had an HLA-identical or one-antigen-mismatched related donor. Fifteen patients were treated (13 with acute myeloid leukemia and 2 with MDS). The median age was 59 years (range, 27 to 71 years). Twelve patients were either refractory to therapy or beyond first relapse. Eight patients received fludarabine at 30 mg/m2/d for 4 days with idarubicin at 12 mg/m2/d for 3 days and ara-c at 2 g/m2/d for 4 days (n = 7) or melphalan at 140 mg/m2/d (n = 1). Seven patients received 2-chloro-deoxyadenosine at 12 mg/m2/d for 5 days and ara-C 1 at g/m2/d for 5 days. Thirteen patients received allogeneic peripheral blood stem cells and 1 received bone marrow after chemotherapy. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methyl-prednisolone. Treatment was generally well tolerated, with only 1 death from multiorgan failure before receiving stem cells. Thirteen patients achieved a neutrophil count of greater than 0.5 x 10(9)/L a median of 10 days postinfusion (range, 8 to 17 days). Ten patients achieved platelet counts of 20 x 10(9)/L a median of 13 days after progenitor cell infusion (range, 7 to 78 days). Eight patients achieved complete remissions (bone marrow blasts were < 5% with neutrophil recovery and platelet transfusion independence) that lasted a median of 60 days posttransplantation (range, 34 to 170+ days). Acute GVHD grade > or = 2 occurred in 3 patients. Chimerism analysis of bone marrow cells in 6 of 8 patients achieving remission showed > or = 90% donor cells between 14 and 30 days postinfusion, and 3 of 4 patients remaining in remission between 60 and 90 days continued to have > or = 80% donor cells. We conclude that purine analog-containing nonmyeloablative regimens allow engraftment of HLA-compatible hematopoietic progenitor cells. This approach permits us to explore the graft-versus-leukemia effect without the toxicity of myeloablative therapy and warrants further study in patients with leukemia who are ineligible for conventional transplantation with myeloablative regimens either because of age or concurrent medical conditions.
Giralt
S
S
Department of Hematology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Estey
E
E
Albitar
M
M
van Besien
K
K
Rondón
G
G
Anderlini
P
P
O'Brien
S
S
Khouri
I
I
Gajewski
J
J
Mehra
R
R
Claxton
D
D
Andersson
B
B
Beran
M
M
Przepiorka
D
D
Koller
C
C
Kornblau
S
S
Kørbling
M
M
Keating
M
M
Kantarjian
H
H
Champlin
R
R
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000628:therapy; D017338:Cladribine / Q000008:administration & dosage; D003131:Combined Modality Therapy; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D005240:Feasibility Studies; D005260:Female; D000069585:Filgrastim; D006087:Graft vs Host Reaction; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000401:mortality / Q000628:therapy; D010865:Pilot Projects; D011994:Recombinant Proteins; D012074:Remission Induction; D016879:Salvage Therapy; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
D000964:Antimetabolites, Antineoplastic; D011994:Recombinant Proteins; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D017338:Cladribine; D014740:Vidarabine; C024352:fludarabine; D000069585:Filgrastim; D015255:Idarubicin