Treatment of Steroid-Resistant Acute GvHD with OKT3 and High-Dose Steroids Versus High-Dose Steroids Alone.

Despite new conditioning regimens and introduction of novel immunosuppressants in hematopoietic cell transplantation (HCT), acute graft-versus-host disease (aGvHD) remains an often life threatening complication. Methylprednisolone (MP) 2 mg/kg body weight (BW) per day is the initial standard treatment with escalation to high-dose MP (10 mg/kg BW per day) for non-responders. Recently, we demonstrated OKT3 muromonab to be an effective second-line and subsequent salvage treatment. Response duration, however, was frequently short-lived in those extensively pretreated patients and inversely correlated with duration from allografting. In the current randomized multicenter trial we investigated high-dose MP (HD-MP) versus OKT3 5 mg per day plus HD-MP. Primary endpoints were response to treatment after 100 days and survival at one year from HCT. Secondary endpoints were side effects and incidence of infectious complications. Patients with resistant °II to IV aGvHD on standard MP following allogeneic HCT were randomized to HD-MP or OKT3 + HD-MP after exclusion of other severe HCT-related complications. Eighty patients from 6 transplant centers were enrolled. Median age for the 40 patients who received OKT3 + HD-MP was 40 (range, 19 – 65) years and for the 40 patients who received HD-MP 39 (range, 19 – 56) years. There was no statistical significant difference between the groups for severity of aGvHD (°II vs. °III/IV); stem cell source (bone marrow vs. peripheral blood progenitor cells); GvHD prophylaxis (CSA vs. ATG+CSA); and conditioning regimen (TBI/Cy vs. Bu-Cy). However, significantly fewer HCTs in the OKT3 + HD-MP group were from HLA-identical siblings. Currently, 62 subjects are evaluable for response. In both arms, reduction of severe and proportional increase of moderately-severe aGvHD was observed with resolution of all °IV cases until day +30. However, significantly more patients in the OKT3 + HD-MP became disease-free (°0) by day +100 when compared to patients treated with HD-MP alone: 39.3 % vs. 20.6 % (p=0.03). In the OKT3 + HD-MP group relative increase of disease-free patients was higher for all organ systems at all time points when compared to patients on HD-MP treatment without reaching statistical. With respect to infectious complications, the incidence of both bacterial and viral infections was slightly and for invasive aspergillosis significantly higher in the HD-MP when compared to the OKT3 + HD-MP group (20.6 vs. 10.7 %; p=0.025). Treatment related mortality was higher in the HD-MP group when compared to the OKT3 + HD-MP group by days +30 (32.3 vs. 10.7 %) and +100 (55. 9 vs. 39.3 %). However, this did not translate into a significantly better one-year survival with the currently evaluable patients: one-year survival for the HD-MP group was 32.4 % and for the OKT3 + HD-MP group 46.4 %. (p=0.72). We conclude that OKT3 + HD-MP results in higher response rates for patients with steroid-resistant aGvHD and thus leads to a better immune reconstitution after HCT what is reflected by reduced incidence and mortality of infectious complications. Final results of the trial will be presented.