Ann E. Haight

Transplantation Outcomes for Severe Combined Immunodeficiency, 2000–2009

BACKGROUND The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth. METHODS We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009). RESULTS Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival. CONCLUSIONS Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313

The role of reduced-intensity conditioning (RIC) regimens in pediatric cancer treatment is unclear. To define the efficacy of a busulfan/fludarabine/antithymocyte globulin RIC regimen in pediatric patients ineligible for myeloablative transplantation, we completed a trial at 23 institutions in the Pediatric Blood and Marrow Transplant Consortium. Forty-seven patients with hematologic malignancies were enrolled. Sustained engraftment occurred in 98%, 89%, and 90%, and full donor chimerism was achieved in 88%, 76%, and 78% of evaluable related bone marrow/peripheral blood stem cells (BM/PBSCs), unrelated BM/PBSCs, and unrelated cord blood recipients. With a median follow-up of 24 months (range, 11-53 months), 2-year event-free survival, overall survival (OS), transplantation-related mortality, and relapse were 40%, 45%, 11%, and 43%, respectively. Univariate analysis revealed an inferior outcome when patients had undergone previous total body irradiation (TBI)-containing myeloablative transplantation (2-year OS, 23% vs 63% vs 52%, previous TBI transplantation vs no TBI transplantation vs no transplantation, P = .02) and when patients not previously treated with TBI had detectable disease at the time of the RIC procedure (2-year OS, 0% vs 63%, detectable vs nondetectable disease, P = .01). Favorable outcomes can be achieved with RIC approaches in pediatric patients in remission who are ineligible for myeloablative transplantation. This study was registered at www.clinicaltrials.gov as #NCT00795132.

Unrelated cord blood transplantation in children with sickle cell disease: Review of four-center experience

Abstract:  UCBT was performed in seven children with SCD and stroke (HLA match 4/6 n = 5; 5/6 n = 2). Four received myeloablative regimens (BU, CY, ATG plus FLU in one patient). One had primary graft failure, three had sustained engraftment, two with grade III–IV GVHD (one died, one developed chronic GVHD), one with stable mixed chimerism. Three patients treated with reduced‐intensity regimens (FLU, BU or CY, ATG, TLI) failed to engraft; one engrafted after second UCBT (HU, TT, RXA, ALZ, TBI). Four patients (57%) developed viral infections. Engraftment, GVHD, and infection remain challenges.

Randomized clinical trial of therapeutic music video intervention for resilience outcomes in adolescents/young adults undergoing hematopoietic stem cell transplant: A report from the Children's Oncology Group

To reduce the risk of adjustment problems associated with hematopoietic stem cell transplant (HSCT) for adolescents/young adults (AYAs), we examined efficacy of a therapeutic music video (TMV) intervention delivered during the acute phase of HSCT to: 1) increase protective factors of spiritual perspective, social integration, family environment, courageous coping, and hope‐derived meaning; 2) decrease risk factors of illness‐related distress and defensive coping; and 3) increase outcomes of self‐transcendence and resilience.

Clinical Outcomes of Children Receiving Intensive Cardiopulmonary Support During Hematopoietic Stem Cell Transplant

Objective: We investigated the short-term and 1-year clinical outcomes of 129 children who received intensive cardiopulmonary support during hematopoietic stem cell transplant. Intensive cardiopulmonary support was defined as receiving at least one of the following interventions: continuous positive pressure ventilation, dopamine infusion greater than or equal to 10 mcg/kg/minute, or the use of any other vasoactive infusion. Duration of intensive cardiopulmonary support, survival to hospital discharge, and predictors of these outcome variables were compared with 387 hematopoietic stem cell transplant patients who did not receive intensive support during the same period. We also report the 1-year survival; presence of chronic graft-versus-host disease; and renal, cardiac, and pulmonary function for all patients. Design: A multicenter retrospective cohort study. Setting: The ICU and hematopoietic stem cell transplant unit of nine pediatric tertiary care centers. Patients: Children undergoing hematopoietic stem cell transplant who required intensive cardiopulmonary support. Interventions: None. Results: Predictors of the need for intensive support included unrelated donor allogeneic transplant, glomerular filtration rate less than 85 mL/minute/1.73 m2, and nonmalignant disease as the indication for transplant. The survival to discontinuation of intensive support for all patients was 62% and 58% for patients who received invasive mechanical ventilatory support. The duration of mechanical ventilation was not predictive of survival. Predictors of intensive support mortality included macroscopic bleeding, engraftment, and pediatric logistic organ dysfunction score greater than one in two domains. Survival to hospital discharge was 50% for the intensive support group and 99% for the nonintensive support group. Overall 1-year survival was 40% in the intensive support population and 65% in the nonintensive support group. There were no significant differences in the survival, rates of chronic graft-versus-host disease, creatinine, forced expiratory volume in 1-minute, cardiac shortening fraction, or performance status in intensive and nonintensive support patients who survived to hospital discharge. Conclusion: Intensive cardiopulmonary support plays an important and potentially life-saving role in the care of pediatric stem cell transplant patients. Survivors of intensive support do not have compromised 1-year survival or organ function compared with children who did not receive intensive support.

The ethics of a proposed study of hematopoietic stem cell transplant for children with “less severe” sickle cell disease

Hematopoietic stem cell transplant (HSCT) is the only cure for sickle cell disease (SCD). HSCT using an HLA-identical sibling donor is currently an acceptable treatment option for children with severe SCD, with expected HSCT survival >95% and event-free survival >85%. HSCT for children with less severe SCD (children who have not yet suffered overt disease complications or only had mild problems) is controversial. It is important to consider the ethical issues of a proposed study comparing HLA-identical sibling HSCT to best supportive care for children with less severe SCD. In evaluating the principles of nonmaleficence, respect for individual autonomy, and justice, we conclude that a study of HLA-identical sibling HSCT for all children with SCD, particularly hemoglobin SS and Sβ(0)-thalassemia disease, is ethically sound. Future work should explore the implementation of a large trial to help determine whether HSCT is a beneficial treatment of children with less severe SCD.

Racial/ethnic diversity in children's oncology clinical trials: ten years later.

During the past 50 years, clinical trials have led to dramatic improvement in pediatric cancer survival. Prior studies have shown that racial/ethnic and age groups have not been enrolled proportionally. Whites, Hispanics, and adolescents are under‐represented and black children are over‐represented. This study identifies the current racial/ethnic/age/sex representation in pediatric (ages birth to 19 years) cancer treatment trials.

Unmet Needs of Siblings of Pediatric Stem Cell Transplant Recipients

BACKGROUND AND OBJECTIVES: In 2010, the Bioethics Committee of the American Academy of Pediatrics issued recommendations that pediatric hematopoietic stem cell donors should have an independent advocate. Formulating appropriate guidelines is hindered by the lack of prospective empirical evidence from families about the experience of siblings during typing and donation. Our aim was to provide these data. METHODS: Families with a child scheduled to undergo hematopoietic stem cell transplant were recruited. All family members, including children aged 9 to 22 years, were eligible. Qualitative interviews were conducted within 3 time periods: pretransplant, 6 to 8, and 9 to 11 months posttransplant. Quantitative scales assessing decision satisfaction and regret were administered at time 2. RESULTS: Thirty-three families were interviewed. Of the 119 family members, 76% perceived there was no choice in the decision to HLA-type siblings; 77% perceived no choice in sibling donation; 86% had no concerns about typing other than needle sticks; and 64% had no concerns about donation. Common concerns raised were dislike of needle sticks (19%), stress before typing results (14%), and fear of donation (15%). Posttransplantation, 33% of donors wished they had been given more information; 56% of donors stated they benefited from donation. Only 1 donor expressed regret posttransplant. CONCLUSIONS: Most family members did not view sibling typing and donation as a choice, were positive about the experience, and did not express regrets. We recommend education for all siblings before typing, comprehensive education for the donor by a health care provider pretransplant, and systematic donor follow-up after transplantation.

Clinical outcomes and graft characteristics in pediatric matched sibling donor transplants using granulocyte colony-stimulating factor-primed bone marrow and steady-state bone marrow.

Abstract:  Matched sibling donor (MSD) transplant is a life‐saving procedure for children with various hematological malignancies and non‐malignancies. Traditionally, steady‐state bone marrow (S‐BM) has been used as the source of stem cells. More recently, peripheral blood stem cell (PBSC) after granulocyte‐colony stimulating factor (G‐CSF) mobilization has gained popularity. Adult studies of G‐CSF‐primed BM (G‐BM) have shown that it produces rapid white blood cell engraftment like PBSC, but with less chronic graft‐vs.‐host disease. No such study has been published in pediatric patients. We conducted a pilot clinical trial of G‐BM for pediatric patients. Ten patients were enrolled and were compared to a contemporaneous group of 12 patients who received S‐BM. Patients in the G‐BM group received a higher dose of total nucleated cells/kg (7.01 vs. 3.76 × 108, p = 0.0009), higher granulocyte–macrophage colony‐forming units (CFU‐GM)/kg (7.19 vs. 3.53 × 105, p = 0.01) and had shorter inpatient length of stay (28 vs. 40 days, p = 0.04). The engraftment, transfusion requirement and disease‐free survival between the two groups were similar. We concluded that G‐BM should be considered as an alternative graft source to S‐BM, with the benefits of larger graft cell dose, higher CFU‐GM dose and shorter length of stay.

Barriers to hematopoietic cell transplantation clinical trial participation of African American and black youth with sickle cell disease and their parents

African Americans and Blacks have low participation rates in clinical trials and reduced access to aggressive medical therapies. Hematopoietic cell transplantation (HCT) is a high-risk but potentially curative therapy for sickle cell disease (SCD), a disorder predominantly seen in African Americans. We conducted focus groups to better understand participation barriers to HCT clinical trials for SCD. Nine focus groups of youth with SCD (n=10) and parents (n=41) were conducted at 3 sites representing the Midwest, South Atlantic, and West South Central US. Main barriers to clinical trial participation included gaps in knowledge about SCD, limited access to SCD/HCT trial information, and mistrust of medical professionals. For education about SCD/HCT trials, participants highly preferred one-on-one interactions with medical professionals and electronic media as a supplement. Providers can engage with sickle cell camps to provide information on SCD/HCT clinical trials to youth and local health fairs for parents/families. Youth reported learning about SCD through computer games; investigators may find this medium useful for clinical trial/HCT education. African Americans affected by SCD face unique barriers to clinical trial participation and have unmet HCT clinical studies education needs. Greater recognition of these barriers will allow targeted interventions in this community to increase their access to HCT.