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A novel reduced-intensity conditioning regimen induces a high incidence of sustained donor-derived neutrophil and platelet engraftment after double-unit cord blood transplantation.

ABSTRACT: A preparative regimen of reduced intensity that can reliably engraft cord blood (CB) and can be used as an alternative to either high-dose myeloablative or nonmyeloablative conditioning is needed. We evaluated double-unit CB transplantation in 30 patients (median age, 56 years; range, 18 to 69) with acute leukemia or myelodysplasia using a regimen of cyclophosphamide 50 mg/kg, fludarabine 150 mg/m(2), thiotepa 10 mg/kg, and 400 cGy total body irradiation with cyclosporine-A/mycophenolate mofetil immunosuppression. Ninety-seven percent of patients engrafted at a median of 26 days (range, 13 to 43), and 93% of patients had recovered platelets by day 180. Grades II to IV acute graft-versus-host disease (GVHD) incidence was 67% at day 180, and chronic GVHD was 10% at 1 year. Transplant-related mortality was 20% at day 180, and relapse was 11% at 2 years. Overall, 2-year disease-free survival (DFS) was 60% at 2 years. A hierarchy in DFS was seen according to the Sorror comorbidity score: 11 patients (median age, 55 years) with a score of 1 had a 2-year DFS of 82% compared with 62% in 9 patients (median age, 51 years) with a score of 2 to 3 and 40% in 11 patients (median age, 58 years) with a score of 4 to 5 (P = .13). This reduced-intensity regimen combined with double-unit CB transplantation reliably facilitates sustained donor engraftment without antithymocyte globulin. Although other approaches are needed in patients with high comorbidity scores, this regimen is highly effective in patients ?50 years old who are otherwise reasonably fit. It also represents a promising alternative to high-dose conditioning in younger patients.

SUBMITTER: Ponce DM

PROVIDER: S-EPMC3673764 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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A novel reduced-intensity conditioning regimen induces a high incidence of sustained donor-derived neutrophil and platelet engraftment after double-unit cord blood transplantation.

Ponce Doris M DM Sauter Craig C Devlin Sean S Lubin Marissa M Gonzales Anne Marie AM Kernan Nancy A NA Scaradavou Andromachi A Giralt Sergio S Goldberg Jenna D JD Koehne Guenther G Perales Miguel A MA Young James W JW Castro-Malaspina Hugo H Jakubowski Ann A Papadopoulos Esperanza B EB Barker Juliet N JN

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20130214 5

A preparative regimen of reduced intensity that can reliably engraft cord blood (CB) and can be used as an alternative to either high-dose myeloablative or nonmyeloablative conditioning is needed. We evaluated double-unit CB transplantation in 30 patients (median age, 56 years; range, 18 to 69) with acute leukemia or myelodysplasia using a regimen of cyclophosphamide 50 mg/kg, fludarabine 150 mg/m(2), thiotepa 10 mg/kg, and 400 cGy total body irradiation with cyclosporine-A/mycophenolate mofetil ...[more]

PMID: 23416850

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Project description:Reduced-intensity conditioning (RIC) umbilical cord blood (UCB) transplantation is increasingly used in hematopoietic stem cell transplantation (HCT) for older and medically unfit patients. Data on the efficacy of HCT after RIC relative to myeloablative conditioning (MAC) are limited. We compared the outcomes of acute myeloid leukemia (AML) patients >18 yrs who received UCB grafts after either RIC or MAC. One hundred nineteen adult patients with AML in complete remission (CR) underwent an UCB transplant after RIC (n =74, 62%) or MAC (n = 45, 38%) between January 2001 and December 2009. Conditioning was either reduced intensity and consisted of cyclophosphamide 50 mg/kg, fludarabine 200 mg/m(2), and total-body irradiation (TBI) 200 cGy or myelablative and consisted for cyclophosphamide 120 mg/kg, fludarabine 75 mg/m(2), and TBI 1200-1320 cGy. All patients received cyclosporine (day -3 to day +180) and mycophenolate mofetil (day -3 to day +45) post-HCT immunosuppression and hematopoietic growth factor. Use of RIC was reserved for patients >45 years (n = 66, 89%) or preexisting severe comorbidities (n = 8, 11%). The 2 groups were similar except for preceding myelodysplastic syndrome (RIC = 28% versus MAC = 4%, P < .01) and age that was dictated by the treatment protocols (median, RIC = 55 years versus MAC = 33years; P < .01). The incidence of neutrophil recovery at day +42 was higher with RIC (94% versus MAC = 82%, P < .1), whereas platelet recovery at the sixth month was similar (RIC = 68% versus MAC = 67%, P = .30). Incidence of grade II-IV acute graft-versus-host disease (aGVHD) (RIC = 47% versus MAC = 67%, P < .01) was decreased with similar incidence of chronic GVHD (cGVHD) (RIC = 30% versus MAC = 34%, P = .43). Median follow-up for survivors was 3.8 and 4.5 years for RIC and MAC, respectively (P = .4). Using RIC, 3-year leukemia-free survival (LFS) was decreased (31% versus MAC = 55%, P = .02) and 3-year relapse incidence was increased (43% versus MAC = 9%, P < .01). Two-year transplant-related mortality (TRM) was similar (RIC = 19% versus MAC = 27%; P = .55). In multivariate analysis, RIC recipients and those in CR2 with CR1 duration <1 year had higher risk of relapse and poorer LFS with no independent predictors of TRM. UCB with RIC extends the use of allogeneic HCT for older and frail patients without excessive TRM with greater benefit for patients in CR1 and CR2 with longer CR1.

Project description:The high incidence of human herpesvirus-6 (HHV-6) reactivation, potentially interfering with engraftment after umbilical cord blood (UCB) hematopoietic cell transplantation (HCT), remains a major challenge. To potentially address this problem, we evaluated the effect of prophylactic foscarnet administered twice daily beginning on day +7 and continuing through engraftment in 25 patients. To determine the impact of foscarnet on HHV-6, engraftment, and other transplantation outcomes, we compared results in 61 identically treated patients with hematologic malignancies. Treatment and control groups underwent reduced-intensity conditioning UCB HCT with a conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation 200 cGy with or without antithymocyte globulin (ATG), using sirolimus plus mycophenolate mofetil immune suppression. The treatment and control groups were similar in terms of age, disease risk, use of ATG, Hematopoietic Cell Transplantation Comorbidity Index, and graft CD34 cell dose; however, foscarnet-treated patients were less likely to receive a double UCB graft and to be treated more recently (2016 to 2018). The cumulative incidence of HHV-6 reactivation by day +100 was 63% for all patients (95% confidence interval [CI], 51% to 75%) and was not significantly different between the 2 groups. HHV-6 reactivation occurred at a median of 34 days in the foscarnet group and 25.5 days in the control group. The incidence of neutrophil engraftment at day 42 was higher in the foscarnet group compared with the control group (96%; [95% CI, 83% to 100%] versus 75% [95% CI, 64% to 85%]; P< .01). The cumulative incidence of platelet engraftment by 6 months was 92% (95% CI, 69% to 100%) for the foscarnet group versus 75% (95% CI, 60% to 90%) for the control group (P= .08), and multivariate analysis identified the use of foscarnet as an independent predictor of better platelet engraftment. No patients died as a result of graft failure in recipients of foscarnet, whereas 5 patients died from graft failure in the control group. Six-month overall survival (OS) and nonrelapse mortality (NRM) were better in the foscarnet group (96% versus 72% [P= .02] and 4% versus 18% [P= .07], respectively). Even though foscarnet prophylaxis did not prevent HHV-6 viremia, we observed a delay in time to HHV-6 reactivation, a trend toward differences in engraftment, NRM, and OS compared with historical controls.

Dataset Information

A novel reduced-intensity conditioning regimen induces a high incidence of sustained donor-derived neutrophil and platelet engraftment after double-unit cord blood transplantation.

Publications

A novel reduced-intensity conditioning regimen induces a high incidence of sustained donor-derived neutrophil and platelet engraftment after double-unit cord blood transplantation.

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