title: Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase.
abstract: Reduced-intensity or nonmyeloablative stem cell transplantation (NST) is designed to induce host-versus-graft tolerance by engraftment of donor stem cells. The rationale behind NST is to induce optimal graft-versus-leukemia (GVL) effects for elimination of all malignant cells by donor alloreactive immunocompetent cells as an alternative to standard high-dose myeloablative chemoradiotherapy. NST based on the use of fludarabine, low-dose busulfan, and anti-T-lymphocyte globulin (ATG) was employed in 24 patients aged 3 to 63 years with chronic myeloid leukemia (CML) in first chronic phase (CP). Graft-versus-host disease (GVHD) prophylaxis consisted of low-dose cyclosporine (CSP), in some cases with low-dose methotrexate. Early discontinuation of CSP was attempted in cases of mixed chimerism in an attempt to amplify GVL effects. All 24 patients showed rapid 3-lineage engraftment, mostly without complete aplasia; 6 patients did not require transfusion of any blood products. NST was associated with minimal procedure-related toxicity. The incidence of acute GVHD (grade I or higher) was 54%; however, this incidence increased following CSP withdrawal. After a follow-up of up to 70 months (median, 42 months), 21 of 24 patients remained alive and disease free. The GVL effects induced by donor immunocompetent lymphocytes eradicated all host hematopoietic cells, as evidenced by molecular testing. The Kaplan-Meier probability of survival and disease-free survival at 5 years is 85% +/- 8% (95% confidence interval, 70%-100%). NST may successfully replace myeloablative stem cell transplantation, providing a safer, well-tolerated therapeutic option for all patients with CML in first CP with a matched donor. However, this conclusion must be tested in a prospective randomized clinical trial.
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
authors.forename: Reuven
authors.initials: R
authors.lastname: Or
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Shapira
authors.forename: Igor
authors.initials: I
authors.lastname: Resnick
authors.forename: Avraham
authors.initials: A
authors.lastname: Amar
authors.forename: Aliza
authors.initials: A
authors.lastname: Ackerstein
authors.forename: Simcha
authors.initials: S
authors.lastname: Samuel
authors.forename: Memet
authors.initials: M
authors.lastname: Aker
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Naparstek
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Shimon
authors.initials: S
authors.lastname: Slavin
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000633:toxicity; D002066:Busulfan / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000633:toxicity; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000150:complications / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D012074:Remission Induction / Q000379:methods; D016019:Survival Analysis; D014184:Transplantation, Homologous / Q000379:methods; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D007166:Immunosuppressive Agents; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine