Higher tacrolimus concentrations early after transplant reduce the risk of acute GvHD in reduced-intensity allogeneic stem cell transplantation.

There is significant variability in the serum concentrations of tacrolimus attained early post transplant due to drug interactions and genomic variation. We evaluated whether tacrolimus concentrations early post transplant correlated with incidence of acute GvHD in 120 consecutive patients allografted with a uniform reduced-intensity conditioning regimen. All patients received standard prophylaxis with oral tacrolimus and IV methotrexate. The primary variable of interest was mean weekly tacrolimus concentrations in the initial 4 weeks post transplant. In multivariate analysis, week 1 tacrolimus concentration was an independent predictor of acute grade 2-4 GvHD (hazard ratio (HR), 0.90; 95% confidence interval (CI), 0.84-0.97; P<0.01). This association was driven by a lower risk of acute grade 2-4 GvHD in patients with week 1 tacrolimus concentrations >12 ng/mL (HR, 0.47; 95% CI, 0.25-0.88; P=0.02). Week 1 tacrolimus concentrations were not associated with chronic GvHD, relapse or overall survival. Lower tacrolimus concentrations at weeks 2, 3 and 4 were not associated with a higher incidence of GvHD. In summary, we found that higher tacrolimus concentrations during the first week after allografting with a reduced-intensity conditioning regimen were associated with significantly reduced risk of acute grade 2-4 GvHD without increasing risk of relapse.

High-dose corticosteroids with or without etanercept for the treatment of idiopathic pneumonia syndrome after allo-SCT.

Idiopathic Pneumonia Syndrome (IPS) is a common complication after allo-SCT and results in high mortality rates. Conventional treatment for IPS typically includes supportive care and high-dose corticosteroids (CS). Data suggests that TNF-α is important in the pathogenesis of IPS and that the TNF-α inhibitor etanercept may be useful for IPS treatment. We performed a retrospective comparison of consecutive patients treated at our center for IPS with CS only from 1999 to 2003 (group 1, n=22) or CS plus etanercept from 2004 to 2007 (group 2, n=17). In all, 18% of patients in group 1 vs 53% in group 2 were successfully taken off respiratory support and discharged from the hospital (P=0.039). OS was significantly better for recipients of CS plus etanercept (P=0.003). The estimated survival at 28 days and 2 years after IPS was 36.4% (95% CI 17-56%) and 9.1% (95% CI 2-25%) for group 1 and 88.2% (95% CI 61-97%) and 18% (95% CI 4-38%) for group 2, respectively. Our retrospective comparison suggests that the addition of etanercept to CS for IPS improves response rates and OS. However, outcomes remain limited in both groups, highlighting the need for more effective interventions to treat early and late complications of IPS.

Inflammatory cytokine inhibition with combination daclizumab and infliximab for steroid-refractory acute GVHD.

Treatment options for steroid-refractory GVHD (SR-GVHD) are unsatisfactory and prognosis is poor. Inflammatory cytokines IL-2 and TNF-α are important mediators of GVHD and may be critical targets for therapy. We retrospectively reviewed our experience using combination anti-cytokine therapy of daclizumab and infliximab. Seventeen evaluable patients had a median age of 47 years (range 35-63). The conditioning regimen was myeloablative in 13 and non-myeloablative in 4 cases. GVHD occurred at a median of 49 days after transplant in 12 patients (range 21-231 days) and at a median of 46 days (range 25-119 days) after donor lymphocyte infusion in 5 patients. All patients had persistent or progressive GVHD despite 1-2 mg/kg/day of corticosteroids for a median of 7 days (range 2-26 days). They received a combination of daclizumab and infliximab for acute GVHD IBMTR severity index B (3), C (10) or D (4). Of the 17 patients analyzed, 47% responded to treatment, 24% had complete resolution of symptoms and 24% had partial responses. Survival was limited and all the patients died a median of 6.7 months (range 1.6-26) from transplant and 35 days from initiation of daclizumab/infliximab. This retrospective analysis suggests that combination anti-cytokine therapy with daclizumab/infliximab has significant activity in SR-GVHD, but outcomes remain poor. New methods to prevent and treat GVHD are urgently needed.