Julie-An Talano

Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicenter experience.

Chronic granulomatous disease (CGD) can be cured by allogeneic hemopoietic stem cell transplantation (HSCT). Complications include graft failure, graft-versus-host disease (GVHD), infection, and transplant-related mortality; therefore, reduced-intensity conditioning regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of treosulfan-based conditioning in HSCT for pediatric patients with CGD. The following data were collected: risk features pre-HSCT, additional conditioning agents, donor type and stem cell source, toxicity, engraftment, GVHD, chimerism, viral reactivation, post-HSCT complications, length of follow-up, and outcome. Seventy patients (median age, 107 months; interquartile range [IQR], 46-232 months) from 16 centers worldwide were transplanted between 2006 and 2015. Ninety-one percent had high-risk features. Fifty-seven HLA-matched donors, 12 HLA-mismatched donors, and 1 CD3(+)TCR αβ/CD19 depleted parental haploidentical transplants were performed. No major toxicity was reported. Median times to neutrophil and platelet engraftment were 17 (IQR, 15-35) and 16 (IQR, 13-50) days. At a median follow-up of 34 months (IQR, 13-102 months), the overall survival was 91.4%, and event-free survival was 81.4%. The cumulative incidence of acute grade III-IV GVHD was 12%. Nine patients developed chronic GVHD. When split cell chimerism was available, 95% or more myeloid donor chimerism was documented in 80% of surviving patients. Secondary graft failure occurred in 12% of patients. Treosulfan-containing conditioning regimens can be used safely in HSCT for children with CGD and high-risk clinical features, achieving excellent survival with high myeloid chimerism. Further studies are needed to compare with other regimens and evaluate the long-term outcome, particularly on fertility.

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.

Sequential myeloablative autologous stem cell transplantation and reduced intensity allogeneic hematopoietic cell transplantation is safe and feasible in children, adolescents and young adults with poor-risk refractory or recurrent Hodgkin and non-Hodgkin lymphoma

The outcome of children, adolescents and young adults (CAYA) with poor-risk recurrent/refractory lymphoma is dismal (⩽30%). To overcome this poor prognosis, we designed an approach to maximize an allogeneic graft vs lymphoma effect in the setting of low disease burden. We conducted a multi-center prospective study of myeloablative conditioning (MAC) and autologous stem cell transplantation (AutoSCT), followed by a reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (AlloHCT) in CAYA, with poor-risk refractory or recurrent lymphoma. Conditioning for MAC AutoSCT consisted of carmustine/etoposide/cyclophosphamide, RIC consisted of busulfan/fludarabine. Thirty patients, 16 Hodgkin lymphoma (HL) and 14 non-Hodgkin lymphoma (NHL), with a median age of 16 years and median follow-up of 5years, were enrolled. Twenty-three patients completed both MAC AutoSCT and RIC AlloHCT. Allogeneic donor sources included unrelated cord blood (n=9), unrelated donor (n=8) and matched siblings (n=6). The incidence of transplant-related mortality following RIC AlloHCT was only 12%. In patients with HL and NHL, 10 year EFS was 59.8% and 70% (P=0.613), respectively. In summary, this approach is safe, and long-term EFS with this approach is encouraging considering the poor-risk patient characteristics and the use of unrelated donors for RIC AlloHCT in the majority of cases.

Hematopoietic stem cell transplantation for sickle cell disease: state of the science.

Sickle cell disease (SCD) is an inherited disorder secondary to a point mutation at the sixth position of the beta chain of human hemoglobin resulting in the replacement of valine for glutamic acid. This recessive genetic abnormality precipitates the polymerization of the deoxygenated form of hemoglobin S inducing a major distortion of red blood cells (S‐RBC), which decreases S‐RBC deformability leading to chronic hemolysis and vaso‐occlusion. These processes can result in severe complications including chronic pain, end‐organ dysfunction, stroke, and early mortality. The only proven curative therapy for patients with SCD is myeloablative conditioning and allogeneic stem cell transplantation from HLA‐matched sibling donors. In this review, we discuss the most recent advances in allogeneic stem cell transplantation in patients with SCD including more novel approaches such as reduced toxicity conditioning and the use of alternative allogeneic donors, including matched unrelated donors (MUDs), unrelated cord blood donors (UCBT), and familial haploidentical (FHI) donors. The results to date are very encouraging regarding allogeneic stem cell transplantation for patients with SCD including high survival rates and enabling a greater number of patients suffering from this chronic and debilitating condition to receive curative allogeneic stem cell therapies. However, we still have several areas to investigate and barriers to overcome to successfully cure the majority of patients with severe SCD through allogeneic stem cell therapies.

Long-term follow-up of children with fever of unknown origin

came symptom-free during hospitalization or shortly after discharge and remained so.31 Eighteen patients had persistent fever for several months to years after discharge, but in ten the fevers eventually relented. Therefore, two thirds (41/61) of such cases in adults resolved spontaneously.5 Only one study concentrated solely on children with FUO in whom no diagnosis was established after an active outpatient or inpatient evaluation, all of whom were referred for rheumatologic evaluation; as with adults, at 2-year follow-up most of the children had favorable outcomes.6 Our objective was to ascertain the long-term outcome of all children at our institution with FUO in whom no diagnosis was established after initial outpatient or inpatient evaluation.

Monitoring and Prevention of Relapse after Allogeneic Hematopoietic Cell Transplantation for Myeloid Malignancies

Acute myeloid leukemia and myelodysplastic syndromes are the most common indications for allogeneic hematopoietic cell transplantation. Although this treatment can be curative, even in advanced disease, treatment failure is commonly manifested by relapse of disease, for which treatment is successful in only a minority of patients. There is a necessity for new strategies for prevention of posttransplantation relapse through early disease detection and intervention in order to improve patient outcomes. Detection of minimal residual disease in posttransplantation surveillance is felt to be a necessary component of any strategy. In chronic myeloid leukemia, assessment of the BCR-ABL1 load by quantitative real-time PCR provides an optimal guideline for posttransplantation therapeutic decisions, but in patients with acute myeloid leukemia or myelodysplastic syndromes, the situation is more complex because of the genetic heterogeneity of these disorders. Past strategies for relapse prevention have focused on use of donor lymphocyte infusions with variable success. Peritransplantation and maintenance therapies (eg, azacitidine) are under current investigation. This review summarizes the current status of minimal residual disease monitoring and prevention strategies for both pediatric and adult patients with myeloid malignancies in the transplantation setting and discusses perspectives for further improvement.

Focal nodular hyperplasia in pediatric allogeneic hematopoietic cell transplant: case series.

Focal nodular hyperplasia in pediatric allogeneic hematopoietic cell transplant: case series

The use of novel Therakos™ Cellex® for extracorporeal photopheresis in treatment of graft‐versus‐host disease in paediatric patients

Extracorporeal photopheresis (ECP) is an established second line treatment option for graft‐versus‐host disease (GVHD) post‐haematopoietic progenitor cell transplant. At our centre, the Therakos™ Cellex® has replaced the Therakos™ UVAR‐XTS™ machine for ECP since 2009. We reviewed the records of 385 procedures using the Therakos™ Cellex® for safety and tolerability. Nine patients underwent ECP for GVHD. The median age was 13·5 years (range 3·7–24) and weight was 49·2 kg (range 18·5–86·3). The mean duration per procedure was 106 min (range 60–205). Fifteen (3·9%) procedures were cancelled and 10 (2·6%) were delayed, with central venous line (CVL) issues being the most frequent problem. With the use of prophylactic tissue plasminogen activator, fewer CVL‐related occlusions were observed (4·7% vs. 2·3%). There was one episode of a CVL‐associated thrombosis and one episode of delayed bleeding. There were four episodes of viral reactivation, four CVL‐associated infections (1142 catheter days) and one episode of systemic inflammatory response syndrome. No patient experienced symptomatic hypotension. This is the first report outlining the safety and tolerability of the Therakos™ Cellex® device for ECP in children and young adults.

Allogeneic cellular and autologous stem cell therapy for sickle cell disease: ‘whom, when and how’

Sickle cell disease (SCD) is an autosomal recessive inherited hematological disorder characterized by chronic hemolysis and vaso-occlusion, resulting in multiorgan dysfunction and premature death. The only known curative therapy for patients with severe SCD is myeloablative conditioning and allo-SCT from HLA-matched sibling donors. In this state of the art review, we discuss current and future considerations including patient selection/eligibility, intensity of conditioning regimens, allogeneic graft sources, graft manipulation, mixed donor chimerism, organ function and stability and autologous gene correction stem cell strategies. Recent novel approaches to promote mixed donor chimerism have included the use of matched unrelated adult donors, umbilical cord blood donors, haploidentical familial donors and the utilization of nonmyeloablative, such as reduced intensity and reduced toxicity conditioning regimens. Future strategies will include gene therapy and autologous gene correction stem cell designs. Prospects are bright for novel stem and cellular approaches for patients with severe SCD, and we are currently at the end of the beginning for utilizing cellular therapeutics for the curative treatment of this chronic and debilitating condition.

Transplant Outcomes for Children with T Cell Acute Lymphoblastic Leukemia in Second Remission: A Report from the Center for International Blood and Marrow Transplant Research

Survival for children with relapsed T cell acute lymphoblastic leukemia (T-ALL) is poor when treated with chemotherapy alone, and outcomes after allogeneic hematopoietic cell transplantation (HCT) is not well described. Two hundred twenty-nine children with T-ALL in second complete remission (CR2) received an HCT after myeloablative conditioning between 2000 and 2011 and were reported to the Center for International Blood and Marrow Transplant Research. Median age was 10 years (range, 2 to 18). Donor source was umbilical cord blood (26%), matched sibling bone marrow (38%), or unrelated bone marrow/peripheral blood (36%). Acute (grades II to IV) and chronic graft-versus-host disease occurred in, respectively, 35% (95% confidence interval [CI], 27% to 45%) and 26% (95% CI, 20% to 33%) of patients. Transplant-related mortality at day 100 and 3-year relapse rates were 13% (95% CI, 9% to 18%) and 30% (95% CI, 24% to 37%), respectively. Three-year overall survival and disease-free survival rates were 48% (95% CI, 41% to 55%) and 46% (95% CI, 39% to 52%), respectively. In multivariate analysis, patients with bone marrow relapse, with or without concurrent extramedullary relapse before HCT, were most likely to relapse (hazard ratio, 3.94; P = .005) as compared with isolated extramedullary disease. In conclusion, HCT for pediatric T-ALL in CR2 demonstrates reasonable and durable outcomes, and consideration for HCT is warranted.