Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children.

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.

A Feasibility Study Evaluating Extraoral Photobiomodulation Therapy for Prevention of Mucositis in Pediatric Hematopoietic Cell Transplantation.

OBJECTIVE: The objective of this study was to determine the feasibility, safety, and tolerability of providing extraoral photobiomodulation therapy (PBT) for prevention of oral mucositis (OM) in pediatric hematopoietic cell transplantation (HCT). BACKGROUND DATA: OM is a frequent complication in pediatric HCT. METHODS: Patients 4-21 years of age scheduled for myeloablative HCT were eligible to participate. PBT was delivered using a THOR Model LX2M with a 69 Diode LED Cluster Probe (34 × 660 nm 10 mW, 35 × 850 nm 30 mW; 1390 mW total power output) at an irradiance of 50 mW/cm(2). Daily treatment exposed six sites (right, left, and midline face and neck) for 60 sec each, for a total dose of 3.0 J/cm(2). Treatment was initiated on the 1st day of conditioning, through day +20. OM assessments were completed at baseline then daily, from day -1 through day +20. Feasibility assessment included both qualitative and quantitative measures and outcomes from patients and providers. RESULTS: Thirteen patients with a median age of 15 years (range, 4.8-21.6) were consented and enrolled, and completed the protocol. The incidence of severe OM [World Health Organization (WHO) Grade ≥3] was 77%, with a median duration of 4 days (range, 1-14). Of 355 attempted PBT administrations, there were six refusals, and the mean proportion of days with data submitted was 96.2% [95% confidence interval (CI): 78.5-97.2%]. The 10 trained nurses all reported that the device was accessible, maneuverable, and lightweight, and that training was effective. There was no reported toxicity attributed to the PBT. CONCLUSIONS: Daily delivery of external PBT and completion of OM evaluations is feasible in children undergoing HCT.

Safety and immunogenicity of modified vaccinia Ankara in hematopoietic stem cell transplant recipients: a randomized, controlled trial.

BACKGROUND: Modified vaccinia Ankara (MVA-BN, IMVAMUNE) is emerging as a primary immunogen and as a delivery system to treat or prevent a wide range of diseases. Defining the safety and immunogenicity of MVA-BN in key populations is therefore important. METHODS: We performed a dose-escalation study of MVA-BN administered subcutaneously in 2 doses, one on day 0 and another on day 28. Twenty-four hematopoietic stem cell transplant recipients were enrolled sequentially into the study, and vaccine or placebo was administered under a randomized, double-blind allocation. Ten subjects received vaccine containing 10(7) median tissue culture infective doses (TCID50) of MVA-BN, 10 subjects received vaccine containing 10(8) TCID50 of MVA-BN, and 4 subjects received placebo. RESULTS: MVA-BN was generally well tolerated at both doses. No vaccine-related serious adverse events were identified. Transient local reactogenicity was more frequently seen at the higher dose. Neutralizing antibodies (NAb) to Vaccinia virus (VACV) were elicited by both doses of MVA-BN and were greater for the higher dose. Median peak anti-VACV NAb titers were 1:49 in the lower-dose group and 1:118 in the higher-dose group. T-cell immune responses to VACV were detected by an interferon γ enzyme-linked immunosorbent spot assay and were higher in the higher-dose group. CONCLUSIONS: MVA-BN is safe, well tolerated, and immunogenic in HSCT recipients. These data support the use of 10(8) TCID50 of MVA-BN in this population. CLINICAL TRIALS REGISTRATION: NCT00565929.

Seroprotective titers against 2009 H1N1 influenza A virus after vaccination in allogeneic hematopoietic stem cell transplantation recipients.

Little data are available regarding the safety and immunologic response to pandemic H1N1 influenza vaccine in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). We measured serum antibody titers against A/California/7/2009 H1N1 using a hemagglutination inhibition assay in 82 allogeneic HSCT recipients who received the 2009 H1N1 vaccine between November 2009 and January 2010 after it became available at our institution. The median time between HSCT and vaccination was 19 months (range, 2.5-94 months), and the median time from vaccination to specimen collection was 56 days (range, 14-140 days). Seroprotective antibody titers (hemagglutination inhibition titer ≥1:40) against 2009 H1N1 influenza A virus were detected in 51% of patients. The presence of chronic graft-versus-host disease and type of conditioning regimen did not affect the rate of detection of seroprotective titers after vaccination. Patients were more likely to have a seroprotective titer the farther away from HSCT they were (adjusted odds ratio, 1.79 per year; 95% confidence interval, 1.12-2.85). Rituximab administration in the year before vaccination was associated with a lack of seroprotective titer (adjusted odds ratio, 0.11; 95% confidence interval, 0.01-0.97). The vaccine was safe and well tolerated. Strategies are needed to improve the influenza vaccine response in this population, especially those receiving immunotherapy.