Effect of Conditioning Regimen Intensity on Acute Myeloid Leukemia Outcomes after Umbilical Cord Blood Transplantation

Department of Medicine, University of Minnesota Blood and Marrow Transplantation Program, Minneapolis, Minnesota 55455, USA.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation (Impact Factor: 3.4). 09/2011; 17(9):1327-34. DOI: 10.1016/j.bbmt.2011.01.007
Source: PubMed


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.

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    • "Rodriguez et al. (2006) noted higher risk of relapse in adults with non-Hodgkin lymphoma following RTC vs. MAC prior to AlloSCT. Most recently, a report from the University of Minnesota noted significantly higher 3-year risk of relapse among adults with AML receiving RTC (44%) than among those receiving MAC (9%) prior to UCBT (Oran, et al 2011). The Paediatric Blood and Marrow Transplant Consortium reported 43% cumulative incidence of in 47 paediatric patients with haematological malignancies following RTC and AlloSCT, similar to the 43% risk of relapse observed in the present study (Pulsipher, et al 2009). "
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    ABSTRACT: Immune reconstitution appears to be delayed following myeloablative conditioning (MAC) and umbilical cord blood transplantation (UCBT) in paediatric recipients. Although reduced toxicity conditioning (RTC) versus MAC prior to allogeneic stem cell transplantation is associated with decreased transplant-related mortality, the effects of RTC versus MAC prior to UCBT on immune reconstitution and risk of graft-versus-host disease (GVHD) are unknown. In 88 consecutive paediatric recipients of UCBT, we assessed immune cell recovery and immunoglobulin reconstitution at days +100, 180 and 365 and analysed risk factors associated with acute and chronic GVHD. Immune cell subset recovery, immunoglobulin reconstitution, and the incidence of opportunistic infections did not differ significantly between MAC versus RTC groups. In a Cox model, MAC versus RTC recipients had significantly higher risk of grade II-IV acute GVHD [Hazard Ratio (HR) 6·1, P = 0·002] as did recipients of 4/6 vs. 5-6/6 HLA-matched UCBT (HR 3·1, P = 0·03), who also had significantly increased risk of chronic GVHD (HR 18·5, P = 0·04). In multivariate analyses, MAC versus RTC was furthermore associated with significantly increased transplant-related (Odds Ratio 26·8, P = 0·008) and overall mortality (HR = 4·1, P = 0·0001). The use of adoptive cellular immunotherapy to accelerate immune reconstitution and prevent and treat opportunistic infections and malignant relapse following UCBT warrants further investigation.
    Full-text · Article · Aug 2011 · British Journal of Haematology
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    • "In RIC-CBT, it was reported that leukemia-free survival was decreased, and relapse incidence was increased compared to those observed in myeloablative CBT. The patients who underwent RIC-CBT with acute myeloid leukemia in the second complete remission or the first complete remission duration <1 year had higher risk of relapse and poorer leukemia-free survival with similar incidence of chronic GVHD [50]. In Japan, our study group, the Nagoya Blood and Marrow Transplantation Group, carried out a small-scale study [20] on the clinical features of post-CBT chronic GVHD using an NIH criteria [51] which is originally developed for bone marrow transplantation and peripheral blood SCT. "
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    ABSTRACT: Cord blood transplantation (CBT) is an attractive alternative therapy in adult patients with advanced hematological malignancies in whom matched donors are unavailable. However, the risk of complications, especially infections, post-CBT increases the mortality rates in these patients. Although the incidence of acute and chronic graft versus host disease (GVHD) post-CBT is lower than that following bone marrow transplantation and peripheral blood stem cell transplantation (SCT), the additional immunosuppressive therapy required to treat it could increase the mortality in these patients. Further, chronic GVHD following CBT is milder and responds better to treatment than that occurring after bone marrow transplants. Unlike bone marrow transplantation, the onset of GVHD is a positive prognostic indicator of overall survival in patients receiving CBT, due to the graft versus malignancy (GVM) effect. This paper focuses on the immune reactions following CBT and aims to elucidate a management strategy for acute and chronic GVHD.
    Full-text · Article · Jun 2011

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