title: Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases.
abstract: Myeloablative conditioning associated with hazardous immediate and late complications is considered as a mandatory first step in preparation for allogeneic blood or marrow transplantation (allogeneic BMT) for the treatment of malignant hematologic disorders and genetic diseases. Immune-mediated graft-versus-leukemia (GVL) effects constitute the major benefit of allogeneic BMT. Therefore, we have introduced the use of relatively nonmyeloablative conditioning before allogeneic BMT aiming for establishing host-versus-graft tolerance for engraftment of donor immunohematopoietic cells for induction of GVL effects to displace residual malignant or genetically abnormal host cells. Our preliminary data in 26 patients with standard indications for allogeneic BMT, including acute leukemia (n = 10); chronic leukemia (n = 8), non-Hodgkin's lymphoma (n = 2), myelodysplastic syndrome (n = 1), multiple myeloma (n = 1), and genetic diseases (n = 4) suggest that nonmyeloablative conditioning including fludarabine, anti-T-lymphocyte globulin, and low-dose busulfan (8 mg/kg) is extremely well tolerated, with no severe procedure-related toxicity. Granulocyte colony-stimulating factor mobilized blood stem cell transplantation with standard dose of cyclosporin A as the sole anti-graft-versus-host disease (GVHD) prophylaxis resulted in stable partial (n = 9) or complete (n = 17) chimerism. In 9 patients absolute neutrophil count (ANC) did not decrease to below 0.1 x 10(9)/L whereas 2 patients never experienced ANC < 0.5 x 10(9)/L. ANC > or = 0.5 x 10(9)/L was accomplished within 10 to 32 (median, 15) days. Platelet counts did not decrease to below 20 x 10(9)/L in 4 patients requiring no platelet support at all; overall platelet counts > 20 x 10(9)/L were achieved within 0 to 35 (median 12) days. Fourteen patients experienced no GVHD at all; severe GVHD (grades 3 and 4) was the single major complication and the cause of death in 4 patients, occurring after early discontinuation of cyclosporine A. Relapse was reversed by allogeneic cell therapy in 2/3 cases, currently with no residual host DNA (male) by cytogenetic analysis and polymerase chain reaction. To date, with an observation period extending over 1 year (median 8 months), 22 of 26 patients (85%) treated by allogeneic nonmyeloablative stem cell transplantation are alive, and 21 (81%) are disease-free. The actuarial probability of disease-free survival at 14 months is 77.5% (95% confidence interval, 53% to 90%). Successful eradication of malignant and genetically abnormal host hematopoietic cells by allogeneic nonmyeloablative stem cell transplantation represents a potential new approach for safer treatment of a large variety of clinical syndromes with an indication for allogeneic BMT. Transient mixed chimerism which may protect the host from severe acute GVHD may be successfully reversed postallogeneic BMT with graded increments of donor lymphocyte infusions, thus resulting in eradication of malignant or genetically abnormal progenitor cells of host origin.
authors.affiliation: Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Slavin
authors.forename: A
authors.initials: A
authors.lastname: Nagler
authors.forename: E
authors.initials: E
authors.lastname: Naparstek
authors.forename: Y
authors.initials: Y
authors.lastname: Kapelushnik
authors.forename: M
authors.initials: M
authors.lastname: Aker
authors.forename: G
authors.initials: G
authors.lastname: Cividalli
authors.forename: G
authors.initials: G
authors.lastname: Varadi
authors.forename: M
authors.initials: M
authors.lastname: Kirschbaum
authors.forename: A
authors.initials: A
authors.lastname: Ackerstein
authors.forename: S
authors.initials: S
authors.lastname: Samuel
authors.forename: A
authors.initials: A
authors.lastname: Amar
authors.forename: C
authors.initials: C
authors.lastname: Brautbar
authors.forename: O
authors.initials: O
authors.lastname: Ben-Tal
authors.forename: A
authors.initials: A
authors.lastname: Eldor
authors.forename: R
authors.initials: R
authors.lastname: Or
mesh_terms: D000293:Adolescent; D000328:Adult; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006086:Graft vs Host Disease / Q000401:mortality; D006402:Hematologic Diseases / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007938:Leukemia / Q000628:therapy; D008223:Lymphoma / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000628:therapy; D009190:Myelodysplastic Syndromes / Q000628:therapy; D016133:Polymerase Chain Reaction; D019172:Transplantation Conditioning