In:
Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 1237-1237
Abstract:
Steroid refractory GVHD is a major cause of morbidity and mortality after allogeneic transplantation. The response rates of grade III–IV GvHD to second line therapy are 20–30%, while long term survival is less than 10% (Arai et al. 2002). The monoclonal antibody Daclizumab targets the α-chain of the IL-2 receptor (CD25) , an early activation marker of TH-cells. We adminstered Daclizumab in combination with Sirolimus, an immunosuppressive agent that inhibits the signal transduction of IL-2 as second line therapy for servere acute GvHD of the gut. Thirty five patients with acute GvHD grade III and IV were evaluated. Thirteen patients had GvHD of the gut exclusively. Twenty-two patients suffered from GvHD of the gut and liver. Diagnosis of GvHD of the gut was performed by total colonoscopy including biopsy. Liver GvHD was diagnosed clinically. All patients had received and not responded to steroids (300 mg/d) for at least five days. Daclizumab (1 mg/kg) was given on days 1, 4, 8, 15, 21 and 28. Sirolimus was given orally. Sirolimus blood levels were targeted at 10–15 ng/ml. The underlying diseases were AML (18), ALL (9), CML (2), NHL and MMY (6). Twenty patients had an unrelated donor, 9 had a matched sibling donor and 6 had an haploidentical sibling donor. The stem cell source was bone marrow (6), peripheral stem cells (21) and both (6). In two patients GvHD developed after donor lymphocyte infusion. No adverse reactions related to infusion of the antibody were observed. Adverse side effects of Sirolimus included cytopenia and mucositis. These were especially observed with high Sirolimus blood levels. Viral reactivations occurred in 20 patients (8 x HHV6, 8 x EBV, 2 x CMV, 1 x Adenovirus and 1 x HSV). In four patients FACScan analysis of peripheral blood was performed to measure the CD25 expression on TH-cells. CD25/CD4 positivity ranged from 57–100% (median 69%) before the start of therapy. After the first antibody infusion CD25 was not detectable on TH-cells. Overall response to therapy was 48% (17/36) with 37% complete responders (13/35). Overall survival was significantly higher in those patients responding to Daclizumab/Sirolimus therapy (p & lt;0.00001). In addition those patients that suffered from GvHD of the gut without liver affection had a significantly better prognosis. The 2 year overall survival after transplantation of patients with isolated GvHD of the gut was 45% versus 5% of the patients with gut plus liver GvHD (p=0.0001). Overall 74% of the patients (26/35) died. Five patients died of relapsing acute leukaemia, 8 of GvHD and 13 of infective complications. Taken together this analysis demonstrates that 1) GvHD of the gut can be treated effectively with Daclizumab and Sirolimus, 2) isolated GvHD of the gut has a signifcantly higher overall survival than GvHD of the gut and liver, 3) combination of Daclizumab and Sirolimus provides potent immunosuppression and patients should be monitored cautiously for infectious complications and relapse.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V104.11.1237.1237
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2004
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1468538-3
detail.hit.zdb_id:
80069-7