Low-dose interleukin-2 (IL-2) therapy for chronic graft-versus-host disease (cGVHD) generates a rapid rise in plasma IL-2 levels and CD4+CD25+CD127−Foxp3+ regulatory T-cell (CD4Treg) proliferation, but both decrease over time despite continued daily administration. To test whether IL-2 dose escalation at the time of anticipated falls in plasma levels could circumvent tachyphylaxis and enhance CD4Treg expansion, we conducted a phase 1 trial in 10 adult and 11 pediatric patients with steroid-refractory cGVHD (www.clinicaltrials.gov: NCT02318082). Daily IL-2 was initiated in children and adults (0.33 × 106 and 0.67 × 106 IU/m2 per day, respectively). Dose escalations were scheduled at weeks 2 and 4 to a maximum dose of 1 × 106 IU/m2 per day in children and 2 × 106 IU/m2 per day in adults. Patients continued at their maximum tolerated dose (MTD) until week 8. Children tolerated IL-2 dose escalation with partial responses (PRs) in 9 of 11 patients (82%) at multiple cGVHD sites, including lung. Patient-reported outcome scores for skin and lung improved significantly in pediatric patients. In contrast, 5 of 10 adults required dose reduction, and only 2 of 7 evaluable patients (29%) had PRs at week 8. CD4Tregs and natural killer cells expanded in both cohorts without significant changes in conventional CD4+ T cells (Tcons) or CD8+ T cells. Children achieved a higher median CD4Treg/Tcon ratio at week 8 (0.4 vs 0.18, P = .02) despite lower IL-2 doses. We show for the first time that low-dose IL-2 is safe and effective in children with advanced cGVHD. In adults, escalation above the previously defined MTD did not improve CD4Treg expansion or clinical response.

Background. Gut decontamination (GD) can decrease the incidence and severity of acute graftversus-host-disease (aGVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). In this pilot study, we examined the impact of GD on the gut microbiome composition and incidence of aGVHD in HCT patients.Methods. We randomized 20 pediatric patients undergoing allogeneic HCT to receive (GD) or not receive (no-GD) oral vancomycin-polymyxin B from day -5 through neutrophil engraftment.We evaluated shotgun metagenomic sequencing of serial stool samples to compare the composition and diversity of the gut microbiome between study arms. We assessed clinical outcomes in the 2 arms and performed strain-specific analyses of pathogens that caused bloodstream infections (BSI).Results. The two arms did not differ in the predefined primary outcome of Shannon diversity of the gut microbiome at two weeks post-HCT (Genus, p=0.8; Species, p=0.44) or aGVHD incidence (p=0.58). Immune reconstitution of T-cell and B-cell subsets was similar between groups. Five patients in the no-GD arm had eight BSI episodes vs one episode in the GD arm (p=0.09). The BSI-causing pathogens were traceable to the gut in seven of eight BSI episodes in the no-GD arm, including Staphylococcus species.Conclusions. While GD did not differentially impact Shannon diversity or clinical outcomes, our findings suggest that GD may protect against gut-derived BSI in HCT patients by decreasing the prevalence or abundance of gut pathogens.

CD3 + and CD3 + CD4 + T cells above 500 cells/ml were achieved by 180 and 270 days, respectively. IgA and IgM levels achieved normal values by 180 days. Conclusion: BPX-501 following ab-T and B-cell depleted haplo-HSCT represents a highly effective transplantation strategy for pediatric pts with AL. Rimiducid was an effective treatment for pts with steroid-resistant GvHD.

BackgroundGut decontamination (GD) can decrease the incidence and severity of acute graft- versus-host-disease (aGVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). Several HCT centers standardly practice GD with different antibiotic regimens. In this pilot study, we examined the impact of GD on the gut microbiome composition and incidence of aGVHD in HCT patients.MethodsWe randomized 20 pediatric patients undergoing allogeneic HCT to receive (GD) or not receive (no-GD) oral vancomycin-polymyxin B from day -5 through neutrophil engraftment. We evaluated shotgun metagenomic sequencing of serial stool samples to compare the composition and diversity of the gut microbiome between study arms. We assessed clinical outcomes in the 2 arms and performed strain-specific analyses of pathogens that caused bloodstream infections (BSI).ResultsThe two arms did not differ in Shannon diversity of the gut microbiota at two weeks post- HCT (Genus, p=0.8; Species, p=0.44) or aGVHD incidence (p=0.58). Immune reconstitution of T- cell subsets was similar, but absolute CD19+ B-cell counts were higher in the GD arm at 12 months post-HCT (p=0.02). Five patients in the no-GD arm had eight BSI episodes vs one episode in the GD arm (p=0.09). The BSI-causing pathogens were traceable to the gut in seven of eight BSI episodes in the no-GD arm, including the genus Staphylococcus.ConclusionsWhile GD did not differentially impact Shannon diversity or clinical outcomes, our findings suggest that GD may protect against gut-derived BSI in HCT patients by decreasing the prevalence or abundance of gut microbial pathogens.Key points:–In this phase 2 randomized study of gut decontamination (GD) in 20 pediatric HCT patients, neither two-week post-HCT Shannon diversity of the gut microbiome nor incidence of aGVHD differ between the GD and no-GD arms.–All bloodstream infections (BSIs) caused by pathogens traceable to the gut either temporally or via strain-specific analysis (concomitant gut colonization) occurred in patients in the no-GD arm; this suggests that GD with vancomycin-polymyxin B may decrease the incidence of gut-derived BSI in allo-HCT patients.–In contrast to prior studies, we find that non-mucosal barrier injury (MBI) pathogens, such as Staphylococcus aureus, can be found in the gut microbiome of HCT patients.

No abstract