title: Impact of postgrafting immunosuppressive regimens on nonrelapse mortality and survival after nonmyeloablative allogeneic hematopoietic stem cell transplant using the fludarabine and low-dose total-body irradiation 200-cGy.
abstract: The development of nonmyeloablative (NM) hematopoietic cell transplantation (HCT) has extended the potential curative treatment option of allografting to patients in whom it was previously contraindicated because of advanced age or comorbidity. Acute and chronic graft versus host disease (GVHD) and its consequent nonrelapse mortality (NRM), remains the major limitation of NM HCT. In this report, we analyzed the outcome of 67 patients (median age, 45 years) with hematologic diseases receiving NM conditioning with fludarabine 90 mg/m(2) and total body irradiation (TBI) 200-cGy, followed by filgrastim-mobilized peripheral blood stem cell transplant from HLA identical (n = 61), 5/6 antigen-matched related (n = 1), 6/6 antigen-matched unrelated (n = 3), and 5/6 antigen-matched unrelated (n = 2) donors. The first cohort of 21 patients were given cyclosporine (CSP) and mycophenolate mofetil (MMF) as postgrafting immunosuppression, whereas the subsequent cohort was given additional methotrexate (MTX) and extended duration of CSP/MMF prophylaxis in an attempt to reduce graft-versus-host disease (GVHD). Sixty-four (95%) patients engrafted and 3 (5%) had secondary graft failure. Myelosuppression was moderate with neutrophil counts not declining below 500/microL in approximately 25% of patients, and with more than half of the patients not requiring any blood or platelet transfusion. The 2-year cumulative interval (CI) of grade II-IV, grade III-IV acute GVHD and chronic GVHD were 49%, 30%, and 34%, respectively. The 2-year probability of NRM, overall (OS), and progression-free (PFS) survival were 27%, 43%, and 28%, respectively. GVHD-related death accounted for 85% of NRM. Compared with patients receiving CSP/MMF, patients receiving extended duration of CSP/MMF with additional MTX in postgrafting immunosuppression had a significantly lower risk of grade III-IV acute GVHD (CI 20% versus 52%; P = .009) and NRM (CI at 2 years: 11% versus 62%; P < .001), without any significant adverse impact on the risk of relapse (CI at 2 years: 59% versus 33%; P = .174) Subgroup analysis of a cohort of patients given MTX/CSP/MMF showed that patients with "standard risk" diseases (n = 21) had a 3-year OS and PFS of 85% and 65%, respectively. This compares favorably to the 41% (P = .02) and 23% (P = .03) OS and PFS, respectively, in patients with "high-risk" diseases (n = 25). In conclusion, the addition of MTX onto the current postgrafting immunosuppression regimen with extended CSP/MMF prophylaxis duration provides more effective protection against severe GVHD, and is associated with more favorable outcome in patients receiving NM fludarabine/TBI conditioning than in patients receiving fludarabine/TBI conditioning with CSP and MMF without MTX.
authors.affiliation: Bone Marrow Transplant Program, Department of Haematology, Singapore General Hospital, Singapore. liangpiu@yahoo.com.sg <liangpiu@yahoo.com.sg>
authors.forename: Liang-Piu
authors.initials: LP
authors.lastname: Koh
authors.forename: Chien-Shing
authors.initials: CS
authors.lastname: Chen
authors.forename: Bee-Choo
authors.initials: BC
authors.lastname: Tai
authors.forename: William Y K
authors.initials: WY
authors.lastname: Hwang
authors.forename: Lip-Kun
authors.initials: LK
authors.lastname: Tan
authors.forename: Hong-Yen
authors.initials: HY
authors.lastname: Ng
authors.forename: Yeh-Ching
authors.initials: YC
authors.lastname: Linn
authors.forename: Mickey B C
authors.initials: MB
authors.lastname: Koh
authors.forename: Yeow-Tee
authors.initials: YT
authors.lastname: Goh
authors.forename: Belinda
authors.initials: B
authors.lastname: Tan
authors.forename: Shan
authors.initials: S
authors.lastname: Lim
authors.forename: Yee-Mei
authors.initials: YM
authors.lastname: Lee
authors.forename: Kar-Wai
authors.initials: KW
authors.lastname: Tan
authors.forename: Te-Chih
authors.initials: TC
authors.lastname: Liu
authors.forename: Heng-Joo
authors.initials: HJ
authors.lastname: Ng
authors.forename: Yvonne S M
authors.initials: YS
authors.lastname: Loh
authors.forename: Benjamin M F
authors.initials: BM
authors.lastname: Mow
authors.forename: Daryl C L
authors.initials: DC
authors.lastname: Tan
authors.forename: Patrick H C
authors.initials: PH
authors.lastname: Tan
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018572:Disease-Free Survival; D005260:Female; D019337:Hematologic Neoplasms / Q000401:mortality* / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007165:Immunosuppression Therapy / Q000401:mortality; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D012189:Retrospective Studies; D015996:Survival Rate; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014916:Whole-Body Irradiation
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D014740:Vidarabine; C024352:fludarabine