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A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases.

ABSTRACT: Reduced-intensity conditioning (RIC) regimens have the potential to decrease transplantation-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with nonmalignant diseases (NMD). Twenty-two children with a median age of 2.8 years, many with severe comorbidities and prior viral infections, were enrolled in a novel RIC protocol consisting of hydroxyurea, alemtuzumab, fludarabine, melphalan, and thiotepa followed by single UCBT. Patients underwent transplantation for inherited metabolic disorders (n = 8), primary immunodeficiencies (n = 9), hemoglobinopathies (n = 4) and Diamond Blackfan anemia (n = 1). Most umbilical cord blood (UCB) units were HLA-mismatched with median infused total nucleated cell dose of 7.9 × 10(7)/kg. No serious organ toxicities were attributable to the regimen. The cumulative incidence of neutrophil engraftment was 86.4% (95% confidence interval [CI], 65% to 100%) in a median of 20 days, with the majority sustaining > 95% donor chimerism at 1 year. Cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV by day 180 was 27.3% (95% CI, 8.7% to 45.9%) and 13.6% (95 CI, 0% to 27.6%), respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95% CI, 0% to 20.8%). The primary causes of death were viral infections (n = 3), acute GVHD (n = 1) and transfusion reaction (n = 1). One-year overall and event-free survivals were 77.3% (95% CI, 53.7% to 89.8%) and 68.2% (95% CI, 44.6% to 83.4%) with 31 months median follow-up. This is the first RIC protocol demonstrating durable UCB engraftment in children with NMD. Future risk-based modifications of this regimen could decrease the incidence of viral infections. (www.clinicaltrials.gov/NCT00744692).

SUBMITTER: Parikh SH

PROVIDER: S-EPMC3947864 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases.

Parikh Suhag H SH Mendizabal Adam A Benjamin Cara L CL Komanduri Krishna V KV Antony Jeyaraj J Petrovic Aleksandra A Hale Gregory G Driscoll Timothy A TA Martin Paul L PL Page Kristin M KM Flickinger Ketti K Moffet Jerelyn J Niedzwiecki Donna D Kurtzberg Joanne J Szabolcs Paul P

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20131201 3

Reduced-intensity conditioning (RIC) regimens have the potential to decrease transplantation-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with nonmalignant diseases (NMD). Twenty-two children with a median age of 2.8 years, many with severe comorbidities and prior viral infections, were enrolled in a novel RIC protocol consisting of hydroxyurea, alemtuzumab, ...[more]

PMID: 24296492

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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.

Project description:Allogeneic hematopoietic stem cell transplantation for patients with a hemoglobinopathy can be curative but is limited by donor availability. Although positive results are frequently observed in those with an HLA-matched sibling donor, use of unrelated donors has been complicated by poor engraftment, excessive regimen-related toxicity, and graft-versus-host disease (GVHD). As a potential strategy to address these obstacles, a pilot study was designed that incorporated both a reduced-intensity conditioning and mesenchymal stromal cells (MSCs). Six patients were enrolled, including 4 with high-risk sickle cell disease (SCD) and 2 with transfusion-dependent thalassemia major. Conditioning consisted of fludarabine (150 mg/m(2)), melphalan (140 mg/m(2)), and alemtuzumab (60 mg for patients weighing > 30 kg and .9 mg/kg for patients weighing <30 kg). Two patients received HLA 7/8 allele matched bone marrow and 4 received 4-5/6 HLA matched umbilical cord blood as the source of HSCs. MSCs were of bone marrow origin and derived from a parent in 1 patient and from an unrelated third-party donor in the remaining 5 patients. GVHD prophylaxis consisted of cyclosporine A and mycophenolate mofetil. One patient had neutropenic graft failure, 2 had autologous hematopoietic recovery, and 3 had hematopoietic recovery with complete chimerism. The 2 SCD patients with autologous hematopoietic recovery are alive. The remaining 4 died either from opportunistic infection, GVHD, or intracranial hemorrhage. Although no infusion-related toxicity was seen, the cotransplantation of MSCs was not sufficient for reliable engraftment in patients with advanced hemoglobinopathy. Although poor engraftment has been observed in nearly all such trials to date in this patient population, there was no evidence to suggest that MSCs had any positive impact on engraftment. Because of the lack of improved engraftment and unacceptably high transplant-related mortality, the study was prematurely terminated. Further investigations into understanding the mechanisms of graft resistance and development of strategies to overcome this barrier are needed to move this field forward.

Dataset Information

A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases.

Publications

A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases.

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