The regimen relies on graft vs tumor effects to cure cancer and consists of fludarabine and a low dose of total body irradiation before HCT and a course of immunosuppression with mycophenolate mofetil and a calcineurin inhibitor after HCT. This regimen has allowed extension of allogeneic HCT to a previously unserved population of older or medically infirm patients. Use of this regimen also has contributed to improving allogeneic HCT outcomes over the past decade. Herein, we describe outcomes among 372 patients aged 60 years or older with advanced hematologic malignancies who underwent allogeneic HCT in prospective clinical trials. Between March 4, 1998, and December 24, 2008, 372 patients aged 60 to 75 years underwent allogeneic HCT for advanced hematologic malignancies after nonmyeloablative conditioning per multi institutional protocols executed at 18 centers coordinated through the Fred Hutchinson Cancer Research Center, Seattle, Washington.
The primary differences between protocols were the addition of fludarabine to 2 Gy total body irradiation, the EKB-569 use of HLA matched related or unrelated or HLA mismatched grafts, variations in the duration and intensity of posttransplantation immunosuppressive medications, and disease specific protocols. These changes were aimed at reducing the risks of graft vs host disease and graft rejection. All protocols were approved by the institutional review boards of the Fred Hutchinson Cancer Research Center and the collaborating sites. All patients provided written informed consent using forms approved by the local institutional review boards.
Inclusion criteria included diagnoses SNX-5422 of hematologic malignancy with disease specific high risk features favoring allogeneic HCT, older than 55 to 60 years, younger than 55 to 60 years but at high risk for nonrelapse mortality due to failed prior high dose HCT or preexisting comorbid conditions, failure of 1 or more front line therapies for Bcell malignancies, and morphologic remission for acute myeloid leukemia or myelodysplastic syndrome. Exclusion criteria included older than 75 years, pregnancy, cardiac ejection fraction less than 40% for related recipients and less than 35% for unrelated recipients, pulmonary diffusion capacity less than 35%, decompensated liver disease, Karnofsky Performance Status Scale values less than 50% to less than 70%, and serologic evidence of infection with the human immunodeficiency virus.
Three hundred fifty one patients were conditionedwith2 ZM-447439 Gytotal bodyirradiation aloneonday?1beforeHCT or with 2 Gy total body irradiation with fludarabine, 30 mg/mper day, on days ?4, ?3, and ?2 before HCT. Twenty one patients received 3 Gy or 4 Gy total body irradiation in addition to fludarabine. Postgrafting immunosuppression included mycophenolate mofetil plus a calcineurin inhibitor in different schedules. Patients and their donors were matched for HLA A, HLA B, andHLA Cby at least intermediate resolutionDNAtyping, and for HLA DRB1 and HLA DQB1 by highresolution techniques. All but 3 patients, who had marrow grafts, received peripheral blood mononuclear cells. Infection prophylaxis and treatment were performed according to each institutions standard practice guidelines.
Complete remission was defined as complete disappearance of disease. Progression was defined as 50% or greater increase in disease burden compared with pretransplant status, while relapse was defined as emergence of minimal residual disease after achievement of complete remission. Pretransplant comorbid conditions were HDAC-42 evaluated and scored by a single investigator per the HCTspecific comorbidity index. Physical functions before and afterHCT were assessed prospectively by clinicians using the KPS. Scores for risk of relapse were classified retrospectively according to the published categorization for patients receiving the nonmyeloablative conditioning regimen. The peak severity of acute GVHD was graded by protocol principal investigators.
Chronic GVHD was diagnosed and staged according to published criteriaand NSCLC was labeled as extensive if treated with systemic steroids in addition to continuation of the study immunosuppressive medications. Thirty days after last use of any immunosuppressive medication was designated as date of resolution of chronic GVHD. Outcome data were determined as of June 23, 2010. Overall and progressionfree survivals were estimated by the Kaplan Meier method. Cumulative incidence estimates were calculated for acute and chronic GVHD, graft rejection, toxicity, complete remission, relapse or progression, nonrelapse mortality, and discontinuation of immunosuppression. Prevalence of chronic GVHD was estimated by methods previously described. Hazard ratios were estimated from Cox regression models.
Rate ratios for infection were estimated from Poisson regression models. Deaths were treated as competing events in analyses of graft rejection, GVHD, complete remission, toxicity, discontinuation of immunosuppression, and disease progression. Progression and nonrelapse mortality were the components of progressionfree survival and were treated as competing events. The association of age with time to event outcomes was based on a Cox regression analysis using age as a continuous variable. Comparisons of infection rates were performed similarly using Poisson regression. Comparison of rates of hospitalization was based on the _test. Comparison of CD3 and CD34 chimerism was based on the Kruskal Wallis test.
Factors tested in univariate models prior to inclusion in the multivariate model included recipient age, donor age, recipient/ donor sex combinations, recipient/ donor ABO matching degree, recipient/ donor cytomegalovirus serostatus, donor type, HCT CI scores,pretransplant KPS percentages, interval between diagnosis and HCT, number of prior regimens, prior radiation treatment, prior HCT, relapse risk,graft CD3 cell dose, graft CD34 cell dose, and dose of total body irradiation.