Browsing by Author "Page, Kristin"

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    A Phase II Randomized Clinical Trial of the Safety and Efficacy of Intravenous Umbilical Cord Blood Infusion for Treatment of Children with Autism Spectrum Disorder.
    (The Journal of pediatrics, 2020-07) Dawson, Geraldine; Sun, Jessica M; Baker, Jennifer; Carpenter, Kimberly; Compton, Scott; Deaver, Megan; Franz, Lauren; Heilbron, Nicole; Herold, Brianna; Horrigan, Joseph; Howard, Jill; Kosinski, Andrzej; Major, Samantha; Murias, Michael; Page, Kristin; Prasad, Vinod K; Sabatos-DeVito, Maura; Sanfilippo, Fred; Sikich, Linmarie; Simmons, Ryan; Song, Allen; Vermeer, Saritha; Waters-Pick, Barbara; Troy, Jesse; Kurtzberg, Joanne

    Objective

    To evaluate whether umbilical cord blood (CB) infusion is safe and associated with improved social and communication abilities in children with autism spectrum disorder (ASD).

    Study design

    This prospective, randomized, placebo-controlled, double-blind study included 180 children with ASD, aged 2-7 years, who received a single intravenous autologous (n = 56) or allogeneic (n = 63) CB infusion vs placebo (n = 61) and were evaluated at 6 months postinfusion.

    Results

    CB infusion was safe and well tolerated. Analysis of the entire sample showed no evidence that CB was associated with improvements in the primary outcome, social communication (Vineland Adaptive Behavior Scales-3 [VABS-3] Socialization Domain), or the secondary outcomes, autism symptoms (Pervasive Developmental Disorder Behavior Inventory) and vocabulary (Expressive One-Word Picture Vocabulary Test). There was also no overall evidence of differential effects by type of CB infused. In a subanalysis of children without intellectual disability (ID), allogeneic, but not autologous, CB was associated with improvement in a larger percentage of children on the clinician-rated Clinical Global Impression-Improvement scale, but the OR for improvement was not significant. Children without ID treated with CB showed significant improvements in communication skills (VABS-3 Communication Domain), and exploratory measures including attention to toys and sustained attention (eye-tracking) and increased alpha and beta electroencephalographic power.

    Conclusions

    Overall, a single infusion of CB was not associated with improved socialization skills or reduced autism symptoms. More research is warranted to determine whether CB infusion is an effective treatment for some children with ASD.
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    A risk factor analysis of outcomes after unrelated cord blood transplantation for children with Wiskott-Aldrich syndrome.
    (Haematologica, 2017-06) Shekhovtsova, Zhanna; Bonfim, Carmem; Ruggeri, Annalisa; Nichele, Samantha; Page, Kristin; AlSeraihy, Amal; Barriga, Francisco; de Toledo Codina, José Sánchez; Veys, Paul; Boelens, Jaap Jan; Mellgren, Karin; Bittencourt, Henrique; O'Brien, Tracey; Shaw, Peter J; Chybicka, Alicja; Volt, Fernanda; Giannotti, Federica; Gluckman, Eliane; Kurtzberg, Joanne; Gennery, Andrew R; Rocha, Vanderson; Eurocord, Cord Blood Committee of Cellular Therapy and Immunobiology Working Party of the EBMT, Federal University of Parana, Duke University Medical Center and Inborn Errors Working Party of the EBMT
    Wiskott-Aldrich syndrome is a severe X-linked recessive immune deficiency disorder. A scoring system of Wiskott-Aldrich syndrome severity (0.5-5) distinguishes two phenotypes: X-linked thrombocytopenia and classic Wiskott-Aldrich syndrome. Hematopoietic cell transplantation is curative for Wiskott-Aldrich syndrome; however, the use of unrelated umbilical cord blood transplantation has seldom been described. We analyzed umbilical cord blood transplantation outcomes for 90 patients. The median age at umbilical cord blood transplantation was 1.5 years. Patients were classified according to clinical scores [2 (23%), 3 (30%), 4 (23%) and 5 (19%)]. Most patients underwent HLA-mismatched umbilical cord blood transplantation and myeloablative conditioning with anti-thymocyte globulin. The cumulative incidence of neutrophil recovery at day 60 was 89% and that of grade II-IV acute graft-versus-host disease at day 100 was 38%. The use of methotrexate for graft-versus-host disease prophylaxis delayed engraftment (P=0.02), but decreased acute graft-versus-host disease (P=0.03). At 5 years, overall survival and event-free survival rates were 75% and 70%, respectively. The estimated 5-year event-free survival rates were 83%, 73% and 55% for patients with a clinical score of 2, 4-5 and 3, respectively. In multivariate analysis, age <2 years at the time of the umbilical cord blood transplant and a clinical phenotype of X-linked thrombocytopenia were associated with improved event-free survival. Overall survival tended to be better in patients transplanted after 2007 (P=0.09). In conclusion, umbilical cord blood transplantation is a good alternative option for young children with Wiskott-Aldrich syndrome lacking an HLA identical stem cell donor.
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    Decreased Mortality in 1-Year Survivors of Umbilical Cord Blood Transplant vs. Matched Related or Matched Unrelated Donor Transplant in Patients with Hematologic Malignancies.
    (Transplant Cell Ther, 2021-05-12) Bohannon, Lauren; Tang, Helen; Page, Kristin; Ren, Yi; Jung, Sin-Ho; Artica, Alexandra; Britt, Anne; Islam, Prioty; Siamakpour-Reihani, Sharareh; Giri, Vinay; Lew, Meagan; Kelly, Matthew; Choi, Taewoong; Gasparetto, Cristina; Long, Gwynn; Lopez, Richard; Rizzieri, David; Sarantopoulos, Stefanie; Chao, Nelson; Horwitz, Mitchell; Sung, Anthony
    BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HCT) has the potential to cure hematologic malignancies, but is associated with significant morbidity and mortality. While deaths during the first year after transplant are often attributable to treatment toxicities and complications, death after the first year may be due to sequelae of accelerated aging caused by cellular senescence. Cytotoxic therapies and radiation used in cancer treatments and conditioning regimens for HCT can induce aging at the molecular level; HCT patients experience time-dependent effects, such as frailty and aging-associated diseases, more rapidly than people who have not been exposed to these treatments. Consistent with this, recipients of younger cells tend to have decreased markers of aging and improved survival, decreased GVHD, and lower relapse rates. OBJECTIVES: Given that umbilical cord blood (UCB) is the youngest donor source available, we studied the outcomes after the first year of UCB transplant vs. matched related donor (MRD) and matched unrelated donor (MUD) transplant in patients with hematologic malignancies over a 20-year period. STUDY DESIGN: In this single center, retrospective study, we examined the outcomes of all adult patients who underwent their first allogeneic HCT through the Duke Adult Bone Marrow Transplant (ABMT) program from January 1, 1996 to December 31, 2015, to allow for at least 3 years of follow-up. Patients were excluded if they died or were lost to follow-up before day 365 post-HCT; received an allogeneic HCT for a disease other than a hematologic malignancy; or received cells from a haploidentical or mismatched adult donor. RESULTS: UCB recipients experienced a better unadjusted overall survival than MRD/MUD recipients (log rank p=0.03, Figure 1, median OS: UCB not reached, MRD/MUD 7.4 years). After adjusting for selected covariates, UCB recipients who survived at least 1 year after HCT had a hazard of death that was 31% lower than that of MRD/MUD recipients (HR: 0.69, 95% CI: 0.47-0.99, p=0.049). This trend held true in a subset analysis of subjects with acute leukemia. UCB recipients also experienced lower rates of moderate or severe chronic graft-versus-host disease (GVHD) and non-relapse mortality, and slower time to relapse. UCB and MRD/MUD recipients experienced similar rates of grade 2-4 acute GVHD, chronic GHVD, secondary malignancy, and subsequent allogeneic HCT. CONCLUSIONS: UCB is already widely used as a donor source in pediatric HCT; however, adult outcomes and adoption have historically lagged behind in comparison. Recent advancements in UCB transplantation such as the implementation of lower-intensity conditioning regimens, double unit transplants, and ex-vivo expansion have improved early mortality, making UCB an increasingly attractive donor source for adults; furthermore, our findings suggest that UCB may actually be a preferred donor source for mitigating late effects of HCT.
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    Development and validation of a rapid, aldehyde dehydrogenase bright-based cord blood potency assay.
    (Blood, 2016-05-12) Shoulars, Kevin; Noldner, Pamela; Troy, Jesse D; Cheatham, Lynn; Parrish, Amanda; Page, Kristin; Gentry, Tracy; Balber, Andrew E; Kurtzberg, Joanne
    Banked, unrelated umbilical cord blood provides access to hematopoietic stem cell transplantation for patients lacking matched bone marrow donors, yet 10% to 15% of patients experience graft failure or delayed engraftment. This may be due, at least in part, to inadequate potency of the selected cord blood unit (CBU). CBU potency is typically assessed before cryopreservation, neglecting changes in potency occurring during freezing and thawing. Colony-forming units (CFUs) have been previously shown to predict CBU potency, defined as the ability to engraft in patients by day 42 posttransplant. However, the CFU assay is difficult to standardize and requires 2 weeks to perform. Consequently, we developed a rapid multiparameter flow cytometric CBU potency assay that enumerates cells expressing high levels of the enzyme aldehyde dehydrogenase (ALDH bright [ALDH(br)]), along with viable CD45(+) or CD34(+) cell content. These measurements are made on a segment that was attached to a cryopreserved CBU. We validated the assay with prespecified criteria testing accuracy, specificity, repeatability, intermediate precision, and linearity. We then prospectively examined the correlations among ALDH(br), CD34(+), and CFU content of 3908 segments over a 5-year period. ALDH(br) (r = 0.78; 95% confidence interval [CI], 0.76-0.79), but not CD34(+) (r = 0.25; 95% CI, 0.22-0.28), was strongly correlated with CFU content as well as ALDH(br) content of the CBU. These results suggest that the ALDH(br) segment assay (based on unit characteristics measured before release) is a reliable assessment of potency that allows rapid selection and release of CBUs from the cord blood bank to the transplant center for transplantation.
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    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 K
    The 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.
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    Early and late outcomes after cord blood transplantation for pediatric patients with inherited leukodystrophies.
    (Blood Adv, 2018-01-09) van den Broek, Brigitte TA; Page, Kristin; Paviglianiti, Annalisa; Hol, Janna; Allewelt, Heather; Volt, Fernanda; Michel, Gerard; Diaz, Miguel Angel; Bordon, Victoria; O'Brien, Tracey; Shaw, Peter J; Kenzey, Chantal; Al-Seraihy, Amal; van Hasselt, Peter M; Gennery, Andrew R; Gluckman, Eliane; Rocha, Vanderson; Ruggeri, Annalisa; Kurtzberg, Joanne; Boelens, Jaap Jan
    Leukodystrophies (LD) are devastating inherited disorders leading to rapid neurological deterioration and premature death. Hematopoietic stem cell transplantation (HSCT) can halt disease progression for selected LD. Cord blood is a common donor source for transplantation of these patients because it is rapidly available and can be used without full HLA matching. However, precise recommendations allowing care providers to identify patients who benefit from HSCT are lacking. In this study, we define risk factors and describe the early and late outcomes of 169 patients with globoid cell leukodystrophy, X-linked adrenoleukodystrophy, and metachromatic leukodystrophy undergoing cord blood transplantation (CBT) at an European Society for Blood and Marrow Transplantation center or at Duke University Medical Center from 1996 to 2013. Factors associated with higher overall survival (OS) included presymptomatic status (77% vs 49%;P= .006), well-matched (≤1 HLA mismatch) CB units (71% vs 54%;P= .009), and performance status (PS) of >80 vs <60 or 60 to 80 (69% vs 32% and 55%, respectively;P= .003). For patients with PS≤60 (n = 20) or 60 to 80 (n = 24) pre-CBT, only 4 (9%) showed improvement. Of the survivors with PS >80 pre-CBT, 50% remained stable, 20% declined to 60 to 80, and 30% to <60. Overall, an encouraging OS was found for LD patients after CBT, especially for those who are presymptomatic before CBT and received adequately dosed grafts. Early identification and fast referral to a specialized center may lead to earlier treatment and, subsequently, to improved outcomes.
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    Ethical considerations of using a single minor donor for three bone marrow harvests for three HLA-matched siblings with primary immunodeficiency.
    (Pediatric blood & cancer, 2019-04) Parikh, Suhag H; Pentz, Rebecca D; Haight, Ann; Adeli, Mehdi; Martin, Paul L; Driscoll, Timothy A; Page, Kristin; Kurtzberg, Joanne; Prasad, Vinod K; Barfield, Raymond C
    Allogeneic hematopoietic stem cell transplantation is curative for primary immunodeficiencies. Bone marrow from an unaffected human leukocyte antigen (HLA)-identical sibling donor is the ideal graft source. For minor donors, meaningful consent or assent may not be feasible, and permission from parents or legal guardians is considered acceptable. Adverse events, albeit extremely small, can be associated with bone marrow harvest in pediatric donors. Donor safety concerns potentially increase with multiple bone marrow harvests. Very little is known about multiple bone marrow harvests from pediatric donors. We describe the ethical considerations and clinical decision-making in an unusual clinical situation where three patients with the same primary immunodeficiency were HLA identical to one another and their younger sibling, who underwent bone marrow harvests three times between 1.3 and 4 years of age, resulting in successful transplantation for all three patients. We hope that this experience will provide guidance to providers and families in a similar situation.
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    Human leukocyte antigen supertype matching after myeloablative hematopoietic cell transplantation with 7/8 matched unrelated donor allografts: a report from the Center for International Blood and Marrow Transplant Research.
    (Haematologica, 2016-10) Lazaryan, Aleksandr; Wang, Tao; Spellman, Stephen R; Wang, Hai-Lin; Pidala, Joseph; Nishihori, Taiga; Askar, Medhat; Olsson, Richard; Oudshoorn, Machteld; Abdel-Azim, Hisham; Yong, Agnes; Gandhi, Manish; Dandoy, Christopher; Savani, Bipin; Hale, Gregory; Page, Kristin; Bitan, Menachem; Reshef, Ran; Drobyski, William; Marsh, Steven Ge; Schultz, Kirk; Müller, Carlheinz R; Fernandez-Viña, Marcelo A; Verneris, Michael R; Horowitz, Mary M; Arora, Mukta; Weisdorf, Daniel J; Lee, Stephanie J
    The diversity of the human leukocyte antigen (HLA) class I and II alleles can be simplified by consolidating them into fewer supertypes based on functional or predicted structural similarities in epitope-binding grooves of HLA molecules. We studied the impact of matched and mismatched HLA-A (265 versus 429), -B (230 versus 92), -C (365 versus 349), and -DRB1 (153 versus 51) supertypes on clinical outcomes of 1934 patients with acute leukemias or myelodysplasia/myeloproliferative disorders. All patients were reported to the Center for International Blood and Marrow Transplant Research following single-allele mismatched unrelated donor myeloablative conditioning hematopoietic cell transplantation. Single mismatched alleles were categorized into six HLA-A (A01, A01A03, A01A24, A02, A03, A24), six HLA-B (B07, B08, B27, B44, B58, B62), two HLA-C (C1, C2), and five HLA-DRB1 (DR1, DR3, DR4, DR5, DR9) supertypes. Supertype B mismatch was associated with increased risk of grade II-IV acute graft-versus-host disease (hazard ratio =1.78, P=0.0025) compared to supertype B match. Supertype B07-B44 mismatch was associated with a higher incidence of both grade II-IV (hazard ratio=3.11, P=0.002) and III-IV (hazard ratio=3.15, P=0.01) acute graft-versus-host disease. No significant associations were detected between supertype-matched versus -mismatched groups at other HLA loci. These data suggest that avoiding HLA-B supertype mismatches can mitigate the risk of grade II-IV acute graft-versus-host disease in 7/8-mismatched unrelated donor hematopoietic cell transplantation when multiple HLA-B supertype-matched donors are available. Future studies are needed to define the mechanisms by which supertype mismatching affects outcomes after alternative donor hematopoietic cell transplantation.
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    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, Joanne
    Infants 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.
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    Long-Term Functional Outcomes following Hematopoietic Stem Cell Transplant for Early Infantile Krabbe Disease.
    (Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2018-06-19) Allewelt, Heather; Taskindoust, Mahsa; Troy, Jesse; Page, Kristin; Wood, Susan; Parikh, Suhag; Prasad, Vinod K; Kurtzberg, Joanne
    Allogeneic hematopoietic stem cell transplantation (HSCT) can retard the progression of early infantile Krabbe disease (EIKD). Superior outcomes are achieved if HSCT is performed prior to the onset of symptoms, however little information is available about the long-term outcomes in surviving patients. We now describe functional outcomes in pre-symptomatic infants who underwent HSCT for EIKD at ≤2 months of life. Records of the 19 patients who underwent HSCT for EIKD at ≤2 months of age from 1996-2010 were reviewed. Long-term functional outcomes were compared between those transplanted at <30 days and ≥30 days of life. Median age at transplant was 27 days (range 19-61). Median follow-up of the cohort was 12.6 years. Overall survival at 5 and 10 years post-transplant was 84.2% (95% CI:58.7-94.6%) and 78.6% (95% CI:52.5-91.4%), respectively. More favorable outcomes were seen in patients who underwent HSCT at <30 days of age, particularly in domains of mobility (p=0.01), communication (p=0.02), and feeding (p=0.008). Improved functional outcomes were observed when HSCT was performed in the first month of life, defining a critical period for intervention. These results support the implementation of newborn screening to enable rapid diagnosis and early treatment of infants with EIKD.
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    Umbilical cord blood transplantation to treat Pelizaeus-Merzbacher Disease in 2 young boys.
    (Pediatrics, 2014-11) Wishnew, Jessica; Page, Kristin; Wood, Susan; Galvin, Leo; Provenzale, James; Escolar, Maria; Gustafson, Kathryn; Kurtzberg, Joanne
    Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive leukodystrophy caused by mutations in the proteolipid protein 1 gene on the Xq22 chromosome. PMD is a dysmyelinating disorder characterized by variable clinical presentation and course. Symptoms range from mild motor deficits to progressive spasticity and neurologic decline resulting in death at an early age. There is no definitive curative treatment. This report presents the clinical course of 2 young boys with PMD who are the first known patients to receive umbilical cord blood transplantation as a therapeutic intervention to stabilize disease progression. Pretransplantation evaluation revealed that both patients had significant motor deficits as well as delayed cognitive function as compared with age-matched peers. Brain imaging revealed varying degrees of hypomyelination. Both patients received myeloablative chemotherapy followed by an unrelated donor umbilical cord blood infusion, which they tolerated well with no major transplantation-related complications. At 7-years and 1-year posttransplantation, respectively, both boys are making slow neurocognitive improvements and show no evidence of functional decline. Imaging results show stable or improving myelination. Although the results of unrelated donor umbilical cord blood transplantation in these 2 boys with PMD are encouraging, longer-term follow-up will be necessary to assess the effect of this treatment on the variable natural disease course.