Background Dysfunction of regulatory T (Treg) cells has been detected in diverse inflammatory disorders, including chronic graft-versus-host disease (GVHD). Interleukin-2 is critical for Treg cell growth, survival, and activity. We hypothesized that low-dose interleukin-2 could preferentially enhance Treg cells in vivo and suppress clinical manifestations of chronic GVHD. Methods In this observational cohort study, patients with chronic GVHD that was refractory to glucocorticoid therapy received daily low-dose subcutaneous interleukin-2 (0.3×106, 1×106, or 3×106 IU per square meter of body-surface area) for 8 weeks. The end points were safety and clinical and immunologic response. After a 4-week hiatus, patients with a response could receive interleukin-2 for an extended period. Results A total of 29 patients were enrolled. None had progression of chronic GVHD or relapse of a hematologic cancer. The maximum tolerated dose of interleukin-2 was 1×106 IU per square meter. The highest dose level induced unacceptable constitutional symptoms. Of the 23 patients who could be evaluated for response, 12 had major responses involving multiple sites. The numbers of CD4+ Treg cells were preferentially increased in all patients, with a peak median value, at 4 weeks, that was more than eight times the baseline value (P<0.001), without affecting CD4+ conventional T (Tcon) cells. The Treg:Tcon ratio increased to a median of more than five times the baseline value (P<0.001). The Treg cell count and Treg:Tcon ratio remained elevated at 8 weeks (P<0.001 for both comparisons with baseline values), then declined when the patients were not receiving interleukin-2. The increased numbers of Treg cells expressed the transcription factor forkhead box P3 (FOXP3) and could inhibit autologous Tcon cells. Immunologic and clinical responses were sustained in patients who received interleukin-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60% (range, 25 to 100). Conclusions Daily low-dose interleukin-2 was safely administered in patients with active chronic GVHD that was refractory to glucocorticoid therapy. Administration was associated with preferential, sustained Treg cell expansion in vivo and amelioration of the manifestations of chronic GVHD in a substantial proportion of patients. (Funded by a Dana–Farber Dunkin' Donuts Rising Star award and others; ClinicalTrials.gov number, NCT00529035.)
A novel short-course, bortezomib-based GVHD regimen can abrogate the survival impairment of MMUD RIC HSCT, can enhance early immune reconstitution, and appears to be suitable for prospective randomized evaluation.
• Rituximab prevents steroidrequiring chronic graft-vs-host disease when given after peripheral blood stem cell transplantation.• Overall survival is improved with rituximab after allogeneic peripheral blood stem cell transplantation when compared with a control cohort.B cells are implicated in the pathophysiology of chronic graft-vs-host disease (GVHD), and phase 2 trials suggest that B cell depletion can treat established chronic GVHD. We hypothesized that posttransplantation B cell depletion could prevent the occurrence of chronic GVHD. We performed a 65-patient phase 2 trial of rituximab (375 mg/m 2 IV), administered at 3, 6, 9, and 12 months after transplantation. Rituximab administration was safe without severe infusional adverse events. The cumulative incidences of chronic GVHD and systemic corticosteroid-requiring chronic GVHD at 2 years from transplantation were 48% and 31%, respectively, both lower than the corresponding rates in a concurrent control cohort (60%, P 5 .1, and 48.5%, P 5 .015). There was no difference in relapse incidence, but treatment-related mortality at 4 years from transplantation was significantly lower in treated subjects when compared with controls (5% vs 19%, P 5 .02), and overall survival was superior at 4 years (71% vs 56%, P 5 .05). At 2 years from transplantation, the B-cell activating factor/B-cell ratio was significantly higher in subjects who developed chronic GVHD in comparison with those without chronic GVHD (P 5 .039). Rituximab can prevent systemic corticosteroid-requiring chronic GVHD after peripheral blood stem cell transplantation and should be tested in a prospective randomized trial. This trial was registered at www.clinicaltrials.gov as NCT00379587. (Blood. 2013;122(8):1510-1517
Chronic graft-versus-host disease (cGVHD) induces significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Corticosteroids are standard initial therapy despite limited efficacy and long-term toxicity. Based on our experience using bortezomib as effective acute GVHD prophylaxis, we hypothesized that proteasome-inhibition would complement the immunomodulatory effects of corticosteroids to improve outcomes in cGVHD. We undertook a single-arm phase II trial of bortezomib plus prednisone for initial therapy of cGVHD. Bortezomib was administered at 1.3 mg/m2 IV on days 1, 8, 15, 22 of each 35-day cycle for 3 cycles (15 weeks). Prednisone was dosed at 0.5-1 mg/kg/day with a suggested taper after cycle 1. All 22 enrolled participants were evaluable for toxicity, 20 were evaluable for response. Bortezomib plus prednisone therapy was well-tolerated, with one occurrence of grade 3 sensory peripheral neuropathy possibly related to bortezomib. The overall response rate at week 15 in evaluable participants was 80%, including 2 (10%) complete and 14 (70%) partial responses. The organ-specific complete response rate was 73% for skin, 53% for liver, 75% for gastrointestinal tract, and 33% for joint, muscle, or fascia involvement. The median prednisone dose decreased from 50 mg/day to 20 mg/day at week 15 (p < 0.001). The combination of bortezomib and prednisone for initial treatment of cGVHD is feasible and well-tolerated. We observed a high response rate to combined bortezomib and prednisone therapy, but, in this single-arm study, we could not directly measure the impact of bortezomib. Proteasome inhibition may offer benefit in the treatment of cGVHD and should be further evaluated
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