Browsing by Subject "Transplantation Conditioning"
Now showing 1 - 20 of 28
Results Per Page
Sort Options
Item Open Access A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2014-03) Parikh, Suhag H; Mendizabal, Adam; Benjamin, Cara L; Komanduri, Krishna V; Antony, Jeyaraj; Petrovic, Aleksandra; Hale, Gregory; Driscoll, Timothy A; Martin, Paul L; Page, Kristin M; Flickinger, Ketti; Moffet, Jerelyn; Niedzwiecki, Donna; Kurtzberg, Joanne; Szabolcs, PaulReduced-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).Item Open Access Allogeneic stem cell transplantation with omidubicel in sickle cell disease.(Blood advances, 2021-02) Parikh, Suhag; Brochstein, Joel A; Galamidi, Einat; Schwarzbach, Aurélie; Kurtzberg, JoanneMany patients with sickle cell disease (SCD) do not have HLA-matched related donors for hematopoietic stem cell transplantation (HSCT). Unrelated cord blood (UCB) is an alternative graft option but is historically associated with high graft failure rates, with inadequate cell dose a major limitation. Omidubicel is a nicotinamide-based, ex vivo-expanded UCB product associated with rapid engraftment in adults with hematologic malignancies. We hypothesized that increasing the UCB cell dose with this strategy would lead to improved engraftment in pediatric patients undergoing myeloablative HSCT for SCD. We report the outcomes of a phase 1/2 study in 13 patients with severe SCD who received omidubicel in combination with an unmanipulated UCB graft and 3 who received a single omidubicel graft. Grafts were minimally matched with patients at 4 of 6 HLA alleles. Median age at transplant was 13 years. A median CD34+ expansion of ∼80-fold was observed in omidubicel and led to rapid neutrophil engraftment (median, 7 days). Long-term engraftment was derived from the unmanipulated graft in most of the double cord blood recipients. Two of the 3 single omidubicel recipients also had sustained engraftment. Incidence of acute graft-versus-host disease (GVHD) was high, but resolved in all surviving patients. Event-free survival in the double cord group was 85% (median follow-up 4 years). All 3 patients in the single cord group were alive at 1 year after transplantation. Ex vivo expansion of UCB with omidubicel supports engraftment in patients with SCD. This approach to decreasing the incidence of GVHD should be optimized for general use in patients with SCD. This study was registered at www.clinicaltrials.gov as #NCT01590628.Item Open Access Cell therapy for diverse central nervous system disorders: inherited metabolic diseases and autism.(Pediatric research, 2018-01) Sun, Jessica M; Kurtzberg, JoanneThe concept of utilizing human cells for the treatment of medical conditions is not new. In its simplest form, blood product transfusion as treatment of severe hemorrhage has been practiced since the 1800s. The advent of hematopoietic stem cell transplantation (HSCT) began with the development of bone marrow transplantation for hematological malignancies in the mid-1900s and is now the standard of care for many hematological disorders. In the past few decades, HSCT has expanded to additional sources of donor cells, a wider range of indications, and the development of novel cell products. This trajectory has sparked a rapidly growing interest in the pursuit of innovative cell therapies to treat presently incurable diseases, including neurological conditions. HSCT is currently an established therapy for certain neurologically devastating inherited metabolic diseases, in which engrafting donor cells provide lifelong enzyme replacement that prevents neurological deterioration and significantly extends the lives of affected children. Knowledge gained from the treatment of these rare conditions has led to refinement of the indications and timing of HSCT, the study of additional cellular products and techniques to address its limitations, and the investigation of cellular therapies without transplantation to treat more common neurological conditions, such as autism spectrum disorder.Item Open Access Consensus opinion on immune-mediated cytopenias after hematopoietic cell transplant for inherited metabolic disorders.(Bone marrow transplantation, 2021-06) Gupta, Ashish O; Jan Boelens, Jaap; Ebens, Christen L; Kurtzberg, Joanne; Lund, Troy C; Smith, Angela R; Wagner, John E; Wynn, Robert; Blazar, Bruce R; Orchard, Paul JHematopoietic stem cell transplantation (HCT) has been increasingly used for patients with inherited metabolic disorders (IMD). Immune mediated cytopenias (IMCs) after HCT, manifesting as hemolytic anemia, thrombocytopenia, and/or neutropenia, are recognized as a significant complication in this patient population, yet our understanding of the incidence, risk factors, and pathophysiology is currently limited. Review of the published literature demonstrates a higher incidence in younger patients who undergo HCT for a nonmalignant disease indication. However, a few reports suggest that the incidence is even higher among those with IMD (incidence ranging from 10 to 56%). This review summarizes the literature, provides an approach to better understanding of the possible etiology of IMCs, and proposes a diagnostic and management plan for patients with IMD who develop single or multi-lineage cytopenias after HCT.Item Open Access Durable Chimerism and Long-Term Survival after Unrelated Umbilical Cord Blood Transplantation for Pediatric Hemophagocytic Lymphohistiocytosis: A Single-Center Experience.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2017-10) Patel, Sachit A; Allewelt, Heather A; Troy, Jesse D; Martin, Paul L; Driscoll, Timothy A; Prasad, Vinod K; Kurtzberg, Joanne; Page, Kristin M; Parikh, Suhag HHemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune dysregulation characterized by fever, hepatosplenomegaly, cytopenias, central nervous system disease, increased inflammatory markers, and hemophagocytosis. Currently, allogeneic hematopoietic stem cell transplantation is the only curative approach for patients with HLH, with reported survival ranging from 50% to 70% with myeloablative conditioning (MAC) regimens. However, donor availability and transplantation-related mortality associated with conventional MAC are major barriers to success. Unrelated umbilical cord blood transplantation (UCBT) provides a readily available alternative donor source for patients lacking matched related donors. Accordingly, we report the results of UCBT in 14 children treated between 1998 and 2016. All children received standard HLH chemotherapy before UCBT. The median age at diagnosis was 2.7 months (range, .8 to 10.4) and at transplantation was 7.5 months (range, 3.8 to 17). Ten patients received MAC with busulfan/cyclophosphamide/etoposide /antithymocyte globulin (ATG) (n = 5), busulfan/cyclophosphamide /ATG (n = 4), or busulfan /melphalan/ATG (n = 1). Four patients received reduced-toxicity conditioning (RTC) with alemtuzumab/fludarabine/melphalan/hydroxyurea ± thiotepa. Cord blood units were mismatched at either 1 (n = 9) or 2 (n = 5) loci and delivered a median total nucleated cell dose of 11.9 × 107/kg (range, 4.6 to 27.9) and CD34+ dose of 3.1 × 105/kg (range, 1.1 to 6.8). The cumulative incidence of neutrophil engraftment by day 42 was 78.6% (95% confidence interval [CI], 42.9% to 93.4%) with a median of 19 days (range, 13 to 27), and that for platelet (50,000) engraftment by day 100 was 64.3% (95% CI, 28.2% to 85.7%) with a median of 51 days (range, 31 to 94). Six patients developed either grade II (n = 5) or grade IV (n = 1) acute graft-versus-host disease (GVHD); no extensive chronic GVHD was seen. Ten patients (71.4%) are alive and well at a median of 11.2 years after transplantation (range, .85 to 18.25), 9 of whom maintain sustained full donor chimerism after a single UCBT, whereas 1 patient with autologous recovery after first UCBT with RTC has achieved full donor chimerism after a second UCBT with MAC. This series demonstrates that, in combination with standard HLH therapy, UCBT after MAC or RTC conditioning can provide long-term survival with durable complete donor chimerism comparable to that of conventional donors. UCBT should be considered for patients with HLH lacking a fully matched related or unrelated adult donor.Item Open Access Durable engraftment and correction of hematological abnormalities in children with congenital amegakaryocytic thrombocytopenia following myeloablative umbilical cord blood transplantation.(Pediatric transplantation, 2015-11) Mahadeo, Kris M; Tewari, Priti; Parikh, Suhag H; Driscoll, Timothy A; Page, Kristin; Martin, Paul L; Kurtzberg, Joanne; Prasad, Vinod KThe use of HSCT is the only potentially curative treatment for CAMT, but access is limited by the availability of suitable donors. We report five consecutive patients with CAMT who received MAC and partially HLA-mismatched, UCBT (unrelated, n = 4). Median times to neutrophil (>500/μL) and platelet (≥20 000 and ≥50 000/μL) engraftment were 19, 57, and 70 days, respectively. Acute GvHD, grade II, developed in one patient, who subsequently developed limited chronic GvHD. At median follow-up of 14 yr, all patients are alive with sustained donor cell engraftment. To our knowledge, this is the largest single-center series of UCBT for patients with this disease and suggests that UCBT is a successful curative option for patients with CAMT.Item Open Access Effect of cord blood processing on transplantation outcomes after single myeloablative umbilical cord blood transplantation.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2015-04) Ballen, Karen K; Logan, Brent R; Laughlin, Mary J; He, Wensheng; Ambruso, Daniel R; Armitage, Susan E; Beddard, Rachel L; Bhatla, Deepika; Hwang, William YK; Kiss, Joseph E; Koegler, Gesine; Kurtzberg, Joanne; Nagler, Arnon; Oh, David; Petz, Lawrence D; Price, Thomas H; Quinones, Ralph R; Ratanatharathorn, Voravit; Rizzo, J Douglas; Sazama, Kathleen; Scaradavou, Andromachi; Schuster, Michael W; Sender, Leonard S; Shpall, Elizabeth J; Spellman, Stephen R; Sutton, Millicent; Weitekamp, Lee Ann; Wingard, John R; Eapen, MaryVariations in cord blood manufacturing and administration are common, and the optimal practice is not known. We compared processing and banking practices at 16 public cord blood banks (CBB) in the United States and assessed transplantation outcomes on 530 single umbilical cord blood (UCB) myeloablative transplantations for hematologic malignancies facilitated by these banks. UCB banking practices were separated into 3 mutually exclusive groups based on whether processing was automated or manual, units were plasma and red blood cell reduced, or buffy coat production method or plasma reduced. Compared with the automated processing system for units, the day 28 neutrophil recovery was significantly lower after transplantation of units that were manually processed and plasma reduced (red cell replete) (odds ratio, .19; P = .001) or plasma and red cell reduced (odds ratio, .54; P = .05). Day 100 survival did not differ by CBB. However, day 100 survival was better with units that were thawed with the dextran-albumin wash method compared with the "no wash" or "dilution only" techniques (odds ratio, 1.82; P = .04). In conclusion, CBB processing has no significant effect on early (day 100) survival despite differences in kinetics of neutrophil recovery.Item Open Access Eighth Annual International Umbilical Cord Blood Transplantation Symposium, San Francisco, California, June 3-5, 2010.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2011-02) Laughlin, Mary; Kurtzberg, Joanne; McMannis, John; Petz, LawrenceItem Open Access Factors Associated with Long-Term Risk of Relapse after Unrelated Cord Blood Transplantation in Children with Acute Lymphoblastic Leukemia in Remission.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2017-08) Page, Kristin M; Labopin, Myriam; Ruggeri, Annalisa; Michel, Gerard; Diaz de Heredia, Cristina; O'Brien, Tracey; Picardi, Alessandra; Ayas, Mouhab; Bittencourt, Henrique; Vora, Ajay J; Troy, Jesse; Bonfim, Carmen; Volt, Fernanda; Gluckman, Eliane; Bader, Peter; Kurtzberg, Joanne; Rocha, VandersonFor pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared with other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GVHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (<18 years) with ALL in first complete remission (CR1; n = 257, 40%) or second complete remission (CR2; n = 383, 60%) who received myeloablative conditioning followed by a single-unit UCBT from 2000 to 2012. Most received antithymocyte globulin (88%) or total body irradiation (TBI; 69%), and cord blood grafts were primarily mismatched at 1 (50%) or 2+ (34%) HLA loci. Considering patients in CR1, the rates of 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GVHD (grades II to IV) and TBI protected against relapse. In patients in CR2, rates of 5-year OS, LFS, and the cumulative incidence of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (≥30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GVHD and less relapse but also demonstrated an increased risk of nonrelapse mortality. In conclusion, the impact of GVHD as a graft-versus-leukemia marker is evident in pediatric ALL after UCBT. Strategies that promote graft-versus-leukemia while harnessing GVHD should be further investigated.Item Open Access Gene expression signatures that predict radiation exposure in mice and humans.(PLoS Med, 2007-04) Dressman, Holly K; Muramoto, Garrett G; Chao, Nelson J; Meadows, Sarah; Marshall, Dawn; Ginsburg, Geoffrey S; Nevins, Joseph R; Chute, John PBACKGROUND: The capacity to assess environmental inputs to biological phenotypes is limited by methods that can accurately and quantitatively measure these contributions. One such example can be seen in the context of exposure to ionizing radiation. METHODS AND FINDINGS: We have made use of gene expression analysis of peripheral blood (PB) mononuclear cells to develop expression profiles that accurately reflect prior radiation exposure. We demonstrate that expression profiles can be developed that not only predict radiation exposure in mice but also distinguish the level of radiation exposure, ranging from 50 cGy to 1,000 cGy. Likewise, a molecular signature of radiation response developed solely from irradiated human patient samples can predict and distinguish irradiated human PB samples from nonirradiated samples with an accuracy of 90%, sensitivity of 85%, and specificity of 94%. We further demonstrate that a radiation profile developed in the mouse can correctly distinguish PB samples from irradiated and nonirradiated human patients with an accuracy of 77%, sensitivity of 82%, and specificity of 75%. Taken together, these data demonstrate that molecular profiles can be generated that are highly predictive of different levels of radiation exposure in mice and humans. CONCLUSIONS: We suggest that this approach, with additional refinement, could provide a method to assess the effects of various environmental inputs into biological phenotypes as well as providing a more practical application of a rapid molecular screening test for the diagnosis of radiation exposure.Item Open Access Late Effects after Umbilical Cord Blood Transplantation in Very Young Children after Busulfan-Based, Myeloablative Conditioning.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2016-09) Allewelt, Heather; El-Khorazaty, Jill; Mendizabal, Adam; Taskindoust, Mahsa; Martin, Paul L; Prasad, Vinod; Page, Kristin; Sanders, Jean; Kurtzberg, JoanneInfants and young children who undergo allogeneic cord blood transplantation (CBT) are at increased risk for late effects because of exposure of developing organs to chemotherapy and radiation therapy typically used in transplant conditioning regimens. Busulfan (Bu)-based myeloablative regimens were developed to eliminate radiation exposure in these young children with the hope that late effects would be minimized. We now describe the late effects in 102 consecutive patients surviving a minimum of 5 years (median follow-up, 12.9 years) post-CBT. Patients were conditioned with high-dose chemotherapy using Bu-containing regimens. No patient received total body irradiation. The median age at transplant was 1 year (range, .1 to 2). Diagnoses included inherited metabolic diseases (59.8%), leukemia (17.6%), congenital immune deficiency (20.2%), bone marrow failure/myelodysplastic syndrome (3.9%), and hemoglobinopathy (2%). Among patients surviving 5 years, the overall survival rate at 10 years post-CBT was 93% (95% CI, 84.9 to 96.8). Virtually all patients (98%) experienced at least 1 significant late effect. Most (83.3%) experienced 2 or more late effects, and more than half of the patients (64.7%) experienced 3 or more late effects. The most commonly observed late effects included dental problems (92.2%), short stature (55.9%), cognitive deficits (53.6%), pulmonary dysfunction (18.6%), and abnormal pubertal development (27.9%). This is the first report of late effects of Bu-based conditioning in a cohort of very young patients at the time of transplant. These results will inform clinical care guidelines for long-term follow-up and add to the growing information regarding outcomes of hematopoietic stem cell transplantation.Item Open Access Long-term survival and late deaths after hematopoietic cell transplantation for primary immunodeficiency diseases and inborn errors of metabolism.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2012-09) Eapen, Mary; Ahn, Kwang Woo; Orchard, Paul J; Cowan, Morton J; Davies, Stella M; Fasth, Anders; Hassebroek, Anna; Ayas, Mouhab; Bonfim, Carmem; O'Brien, Tracey A; Gross, Thomas G; Horwitz, Mitchell; Horwitz, Edwin; Kapoor, Neena; Kurtzberg, Joanne; Majhail, Navneet; Ringden, Olle; Szabolcs, Paul; Veys, Paul; Baker, K ScottIt is uncertain whether late mortality rates after hematopoietic cell transplantation for severe combined immunodeficiency (SCID), non-SCID primary immunodeficiency diseases (non-SCID PIDD), and inborn errors of metabolism (IEM) return to rates observed in the general population, matched for age, sex, and nationality. We studied patients with SCID (n = 201), non-SCID PIDD (n = 405), and IEM (n = 348) who survived for at least 2 years after transplantation with normal T cell function (SCID) or >95% donor chimerism (non-SCID PIDD and IEM). Importantly, mortality rate was significantly higher in these patients compared with the general population for several years after transplantation. The rate decreased toward the normal rate in patients with SCID and non-SCID PIDD beyond 6 years after transplantation, but not in patients with IEM. Active chronic graft-versus-host disease at 2 years was associated with increased risk of late mortality for all diseases (hazard ratio [HR], 1.87; P = .05). In addition, late mortality was higher in patients with non-SCID PIDD who received T cell-depleted grafts (HR 4.16; P = .007) and in patients with IEM who received unrelated donor grafts (HR, 2.72; P = .03) or mismatched related donor grafts (HR, 3.76; P = .01). The finding of higher mortality rates in these long-term survivors for many years after transplantation confirms the need for long-term surveillance.Item Open Access Myeloablative transplantation using either cord blood or bone marrow leads to immune recovery, high long-term donor chimerism and excellent survival in chronic granulomatous disease.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2012-09) Tewari, Priti; Martin, Paul L; Mendizabal, Adam; Parikh, Suhag H; Page, Kristin M; Driscoll, Timothy A; Malech, Harry L; Kurtzberg, Joanne; Prasad, Vinod KThe curative potential of hematopoietic stem cell transplantation in patients with chronic granulomatous disease depends on availability of a suitable donor, successful donor engraftment, and maintenance of long-term donor chimerism. Twelve consecutive children (median age, 59.5 months; range, 8-140 months) with severe chronic granulomatous disease (serious bacterial/fungal infections pretransplantation; median, 3; range, 2-9) received myeloablative hematopoietic stem cell transplantation using sibling bone marrow ([SibBM]; n = 5), unrelated cord blood (UCB; n = 6), and sibling cord blood (n = 1) at our center between 1997 and 2010. SibBM and sibling cord blood were HLA matched at 6/6, whereas UCB were 5/6 (n = 5) or 6/6 (n = 1). Recipients of SibBM were conditioned with busulfan and cyclophosphamide ± anti-thymocyte globulin (ATG), whereas 6 of 7 cord blood recipients received fludarabine/busulfan/cyclophosphamide/ATG. Seven patients received granulocyte-colony stimulating factor-mobilized granulocyte transfusions from directed donors. The first 2 UCB recipients had primary graft failure but successfully underwent retransplantation with UCB. Highest acute graft-versus-host disease was grade III (n = 1). Extensive chronic graft-vs-host disease developed in 3 patients. All patients are alive with median follow-up of 70.5 months (range, 12-167 months) with high donor chimerism (>98%, n = 10; 94%, n = 1; and 92%, n = 1). Myeloablative hematopoietic stem cell transplantation led to correction of neutrophil dysfunction, durable donor chimerism, excellent survival, good quality of life, and low incidence of graft-vs-host disease regardless of graft source.Item Open Access Myelodysplastic syndrome evolving from aplastic anemia treated with immunosuppressive therapy: efficacy of hematopoietic stem cell transplantation.(Haematologica, 2014-12) Kim, Sung-Yong; Le Rademacher, Jennifer; Antin, Joseph H; Anderlini, Paolo; Ayas, Mouhab; Battiwalla, Minoo; Carreras, Jeanette; Kurtzberg, Joanne; Nakamura, Ryotaro; Eapen, Mary; Deeg, H JoachimA proportion of patients with aplastic anemia who are treated with immunosuppressive therapy develop clonal hematologic disorders, including post-aplastic anemia myelodysplastic syndrome. Many will proceed to allogeneic hematopoietic stem cell transplantation. We identified 123 patients with post-aplastic anemia myelodysplastic syndrome who from 1991 through 2011 underwent allogeneic hematopoietic stem cell transplantation, and in a matched-pair analysis compared outcome to that in 393 patients with de novo myelodysplastic syndrome. There was no difference in overall survival. There were no significant differences with regard to 5-year probabilities of relapse, non-relapse mortality, relapse-free survival and overall survival; these were 14%, 40%, 46% and 49% for post-aplastic anemia myelodysplastic syndrome, and 20%, 33%, 47% and 49% for de novo myelodysplastic syndrome, respectively. In multivariate analysis, relapse (hazard ratio 0.71; P=0.18), non-relapse mortality (hazard ratio 1.28; P=0.18), relapse-free survival (hazard ratio 0.97; P=0.80) and overall survival (hazard ratio 1.02; P=0.88) of post-aplastic anemia myelodysplastic syndrome were similar to those of patients with de novo myelodysplastic syndrome. Cytogenetic risk was independently associated with overall survival in both groups. Thus, transplant success in patients with post-aplastic anemia myelodysplastic syndrome was similar to that in patients with de novo myelodysplastic syndrome, and cytogenetics was the only significant prognostic factor for post-aplastic anemia myelodysplastic syndrome patients.Item Open Access One-unit versus two-unit cord-blood transplantation for hematologic cancers.(The New England journal of medicine, 2014-10) Wagner, John E; Eapen, Mary; Carter, Shelly; Wang, Yanli; Schultz, Kirk R; Wall, Donna A; Bunin, Nancy; Delaney, Colleen; Haut, Paul; Margolis, David; Peres, Edward; Verneris, Michael R; Walters, Mark; Horowitz, Mary M; Kurtzberg, Joanne; Blood and Marrow Transplant Clinical Trials NetworkBackground
Umbilical-cord blood has been used as the source of hematopoietic stem cells in an estimated 30,000 transplants. The limited number of hematopoietic cells in a single cord-blood unit prevents its use in recipients with larger body mass and results in delayed hematopoietic recovery and higher mortality. Therefore, we hypothesized that the greater numbers of hematopoietic cells in two units of cord blood would be associated with improved outcomes after transplantation.Methods
Between December 1, 2006, and February 24, 2012, a total of 224 patients 1 to 21 years of age with hematologic cancer were randomly assigned to undergo double-unit (111 patients) or single-unit (113 patients) cord-blood transplantation after a uniform myeloablative conditioning regimen and immunoprophylaxis for graft-versus-host disease (GVHD). The primary end point was 1-year overall survival.Results
Treatment groups were matched for age, sex, self-reported race (white vs. nonwhite), performance status, degree of donor-recipient HLA matching, and disease type and status at transplantation. The 1-year overall survival rate was 65% (95% confidence interval [CI], 56 to 74) and 73% (95% CI, 63 to 80) among recipients of double and single cord-blood units, respectively (P=0.17). Similar outcomes in the two groups were also observed with respect to the rates of disease-free survival, neutrophil recovery, transplantation-related death, relapse, infections, immunologic reconstitution, and grade II-IV acute GVHD. However, improved platelet recovery and lower incidences of grade III and IV acute and extensive chronic GVHD were observed among recipients of a single cord-blood unit.Conclusions
We found that among children and adolescents with hematologic cancer, survival rates were similar after single-unit and double-unit cord-blood transplantation; however, a single-unit cord-blood transplant was associated with better platelet recovery and a lower risk of GVHD. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00412360.).Item Open Access Outcome of transplantation for acute lymphoblastic leukemia in children with Down syndrome.(Pediatric blood & cancer, 2014-06) Hitzler, Johann K; He, Wensheng; Doyle, John; Cairo, Mitchell; Camitta, Bruce M; Chan, Ka Wah; Diaz Perez, Miguel A; Fraser, Christopher; Gross, Thomas G; Horan, John T; Kennedy-Nasser, Alana A; Kitko, Carrie; Kurtzberg, Joanne; Lehmann, Leslie; O'Brien, Tracey; Pulsipher, Michael A; Smith, Franklin O; Zhang, Mei-Jie; Eapen, Mary; Carpenter, Paul A; CIBMTR Pediatric Cancer Working CommitteeWe report on 27 patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) who received allogeneic hematopoietic cell transplantation (HCT) between 2000 and 2009. Seventy-eight percent of patients received myeloablative conditioning and 52% underwent transplantation in second remission. Disease-free survival (DFS) was 24% at a median of 3 years. Post-transplant leukemic relapse was more frequent than expected for children with DS-ALL (54%) than for non-DS ALL. These data suggest leukemic relapse rather than transplant toxicity is the most important cause of treatment failure. Advancements in leukemia control are especially needed for improvement in HCT outcomes for DS-ALL.Item Open Access Outcomes after hematopoietic stem cell transplantation for children with I-cell disease.(Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2014-11) Lund, Troy C; Cathey, Sara S; Miller, Weston P; Eapen, Mary; Andreansky, Martin; Dvorak, Christopher C; Davis, Jeffrey H; Dalal, Jignesh D; Devine, Steven M; Eames, Gretchen M; Ferguson, William S; Giller, Roger H; He, Wensheng; Kurtzberg, Joanne; Krance, Robert; Katsanis, Emmanuel; Lewis, Victor A; Sahdev, Indira; Orchard, Paul JMucolipidosis type II (MLII), or I-cell disease, is a rare but severe disorder affecting localization of enzymes to the lysosome, generally resulting in death before the 10th birthday. Although hematopoietic stem cell transplantation (HSCT) has been used to successfully treat some lysosomal storage diseases, only 2 cases have been reported on the use of HSCT to treat MLII. For the first time, we describe the combined international experience in the use of HSCT for MLII in 22 patients. Although 95% of the patients engrafted, overall survival was low, with only 6 patients (27%) alive at last follow-up. The most common cause of death post-transplant was cardiovascular complications, most likely due to disease progression. Survivors were globally delayed in development and often required complex medical support, such as gastrostomy tubes for nutrition and tracheostomy with mechanical ventilation. Although HSCT has demonstrated efficacy in treating some lysosomal storage disorders, the neurologic outcome and survival for patents with MLII were poor. Therefore, new medical and cellular therapies should be sought for these patients.Item Open Access Outcomes of transplantation using various hematopoietic cell sources in children with Hurler syndrome after myeloablative conditioning.(Blood, 2013-05) Boelens, Jaap Jan; Aldenhoven, Mieke; Purtill, Duncan; Ruggeri, Annalisa; Defor, Todd; Wynn, Robert; Wraith, Ed; Cavazzana-Calvo, Marina; Rovelli, Attilio; Fischer, Alain; Tolar, Jakub; Prasad, Vinod K; Escolar, Maria; Gluckman, Eliane; O'Meara, Anne; Orchard, Paul J; Veys, Paul; Eapen, Mary; Kurtzberg, Joanne; Rocha, Vanderson; Eurocord; Inborn Errors Working Party of European Blood and Marrow Transplant group; Duke University Blood and Marrow Transplantation Program; Centre for International Blood and Marrow ResearchWe report transplantation outcomes of 258 children with Hurler syndrome (HS) after a myeloablative conditioning regimen from 1995 to 2007. Median age at transplant was 16.7 months and median follow-up was 57 months. The cumulative incidence of neutrophil recovery at day 60 was 91%, acute graft-versus-host disease (GVHD) (grade II-IV) at day 100 was 25%, and chronic GVHD and 5 years was 16%. Overall survival and event-free survival (EFS) at 5 years were 74% and 63%, respectively. EFS after HLA-matched sibling donor (MSD) and 6/6 matched unrelated cord blood (CB) donor were similar at 81%, 66% after 10/10 HLA-matched unrelated donor (UD), and 68% after 5/6 matched CB donor. EFS was lower after transplantation in 4/6 matched unrelated CB (UCB) (57%; P = .031) and HLA-mismatched UD (41%; P = .007). Full-donor chimerism (P = .039) and normal enzyme levels (P = .007) were higher after CB transplantation (92% and 98%, respectively) compared with the other grafts sources (69% and 59%, respectively). In conclusion, results of allogeneic transplantation for HS are encouraging, with similar EFS rates after MSD, 6/6 matched UCB, 5/6 UCB, and 10/10 matched UD. The use of mismatched UD and 4/6 matched UCB was associated with lower EFS.Item Open Access Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo With Nicotinamide.(Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2019-02) Horwitz, Mitchell E; Wease, Stephen; Blackwell, Beth; Valcarcel, David; Frassoni, Francesco; Boelens, Jaap Jan; Nierkens, Stefan; Jagasia, Madan; Wagner, John E; Kuball, Jurgen; Koh, Liang Piu; Majhail, Navneet S; Stiff, Patrick J; Hanna, Rabi; Hwang, William YK; Kurtzberg, Joanne; Cilloni, Daniela; Freedman, Laurence S; Montesinos, Pau; Sanz, GuillermoPurpose
Increasing the number of hematopoietic stem and progenitor cells within an umbilical cord blood (UCB) graft shortens the time to hematopoietic recovery after UCB transplantation. In this study, we assessed the safety and efficacy of a UCB graft that was expanded ex vivo in the presence of nicotinamide and transplanted after myeloablative conditioning as a stand-alone hematopoietic stem-cell graft.Methods
Thirty-six patients with hematologic malignancies underwent transplantation at 11 sites.Results
The cumulative incidence of neutrophil engraftment at day 42 was 94%. Two patients experienced secondary graft failure attributable to viral infections. Hematopoietic recovery was compared with that observed in recipients of standard UCB transplantation as reported to the Center for International Blood and Marrow Transplant Research (n = 146). The median time to neutrophil recovery was 11.5 days (95% CI, 9 to 14 days) for recipients of nicotinamide-expanded UCB and 21 days (95% CI, 20 to 23 days) for the comparator ( P < .001). The median time to platelet recovery was 34 days (95% CI, 32 to 42 days) and 46 days (95% CI, 42 to 50 days) for the expanded and the comparator cohorts, respectively ( P < .001). The cumulative incidence of grade 2 to 4 acute graft-versus-host disease (GVHD) at day 100 was 44%, and grade 3 and 4 acute GVHD at day 100 was 11%. The cumulative incidence at 2 years of all chronic GVHD was 40%, and moderate/severe chronic GVHD was 10%. The 2-year cumulative incidences of nonrelapse mortality and relapse were 24% and 33%, respectively. The 2-year probabilities of overall and disease-free survival were 51% and 43%, respectively.Conclusion
UCB expanded ex vivo with nicotinamide shortens median neutrophil recovery by 9.5 days (95% CI, 7 to 12 days) and median platelet recovery by 12 days (95% CI, 3 to 16.5 days). This trial establishes feasibility, safety, and efficacy of an ex vivo expanded UCB unit as a stand-alone graft.Item Open Access Plerixafor (a CXCR4 antagonist) following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery.(J Hematol Oncol, 2018-03-04) Green, Michael MB; Chao, Nelson; Chhabra, Saurabh; Corbet, Kelly; Gasparetto, Cristina; Horwitz, Ari; Li, Zhiguo; Venkata, Jagadish Kummetha; Long, Gwynn; Mims, Alice; Rizzieri, David; Sarantopoulos, Stefanie; Stuart, Robert; Sung, Anthony D; Sullivan, Keith M; Costa, Luciano; Horwitz, Mitchell; Kang, YubinBACKGROUND: The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation. METHODS: We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis. RESULTS: Thirty patients received plerixafor following peripheral blood stem cell (n = 28) (PBSC) or bone marrow (n = 2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04) and platelet recovery >20 K (p = 0.04) compared to the controls. CONCLUSIONS: Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01280955.