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 transplant-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with non-malignant 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 were transplanted for inherited metabolic disorders (N=8), primary immunodeficiencies (N=9), hemoglobinopathies (N=4) and Diamond Blackfan anemia (N=1). Most UCB units were HLA-mismatched with median infused total nucleated cell dose of 7.9 × 107/kg. No serious organ toxicities were attributable to the regimen. The cumulative incidence of neutrophil engraftment was 86.4% (95% confidence interval [CI], 65%–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–IV and III–IV by day 180 was 27.3% (95% CI, 8.7%–45.9%) and 13.6% (95 CI, 0%–27.6%), respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95% CI, 0%–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%–89.8%) and 68.2% (95% CI, 44.6%–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)

Optimal Outcomes in Young Class 3 Patients With Thalassemia Undergoing HLA-Identical Sibling Bone Marrow Transplantation

“…Engraftment was likely enhanced by the potent myelosuppressive and immunosuppressive potential of TT, which promotes engraftment in murine transplantation models, 36 and in genetic diseases, 37 T cell-depleted hematopoietic stem cell transplants, 38 and umbilical cord blood transplantation. 39 Increasing Flu dose alone was not sufficient to enhance engraftment in class 3 patients treated with the original protocol. A recent study treated 7 patients following the original protocol with the Flu dose increased to 125 mg/m 2 during cytoreduction, and reported a 14% incidence of rejection.…”

Thalassemia 2016: Modern medicine battles an ancient disease

“…Traditionally, fully matched HLA identical sibling donors were used but improved outcome was reported with matched unrelated [53] and with single locus mismatch related (not sibling) donors [58]. Recently, success has even been reported using unrelated cord blood, including with reduced intensity conditioning [59]. The ability to use unrelated cord blood considerably enlarges the donor pool available for each patient.…”

Decreases in thymopoiesis of astronauts returning from space flight

“…Multiple clinical settings, including primary immunodeficiency states, HIV-1 infection (1,(10)(11)(12), and that after allogeneic hematopoietic stem cell transplantation (13)(14)(15)(16), are characterized by deficiencies in human thymopoiesis and are associated with an increased risk of death due to infections normally controlled by a broad TCR repertoire. The recovery of thymopoiesis following chemotherapy and therapy of infection-related immunodeficiency is age dependent and governs diverse and functional TCR reconstitution (11,(13)(14)(15).…”