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Treatment of steroid-resistant acute GVHD with OKT3 and high-dose steroids results in better disease control and lower incidence of infectious complications when compared to high-dose steroids alone: a randomized multicenter trial by the EBMT Chronic Leukemia Working Party

Leukemia volume 21, pages 1830–1833 (2007)Cite this article

Acute graft-versus-host disease (GVHD) following allogeneic stem cell transplantation has an adverse prognosis despite novel approaches with respect to both conditioning regimens and immunosuppression. Methylprednisolone (MP) 2 mg/kg body weight is generally used as an initial treatment; however, achievement of durable response to steroids widely varies with both the extent of human leukocyte antigen (HLA) disparity between donor and recipient and disease severity.1, 2, 3 Failure of adequate response to MP represents refractory GVHD that is difficult to manage. Numerous approaches and agents have, often retrospectively, been evaluated. Besides significant escalation in steroid doses and some approaches using extracorporeal photopheresis mainly monoclonal antibodies (or equivalent constructs) have attracted special attention.4, 5 Response to second-line treatment is often of transient nature and due to either secondary complications of intensified immunosuppression or progressing GVHD mortality remains discouragingly high. Our experience with monoclonal antibody directed against CD3 (OKT3 muromonab) as second-line and subsequent treatment in refractory GVHD6 provided basis for a prospective, randomized trial in patients with steroid-resistant acute GVHD following transplantation of allogeneic hematopoietic cells. The study was approved by the Institutional Review Boards of all participating centers.

Patients with acute GVHD of grades II–IV developing until day 100 after transplantation were eligible to undergo randomization to either monoclonal antibody OKT3 (Orthoclone, Janssen-CILAG, Neuss, Germany) 5 mg intravenously once daily plus MP 10 mg/kg BW (HD-MP) versus HD-MP alone. Concomitant immunosuppression was to be continued. Primary end point was a trend for better response of acute GVHD at study day 100. Secondary end points included survival at 1 year after allogeneic hematopoietic cell transplantation, incidence of infectious complications and side effects of treatment. For both groups, reduction of steroids was scheduled for the first 8 days and then subject to decision of the local investigator. Assessment of overall severity of GVHD was performed on the day of registration and then daily; on the day of randomization and then daily until day 10 and on days 30 and 100 after the first dose of study drug, and 1 year from transplantation if a patient was alive. The survival analysis was performed on all patients who had received at least one dose of study medication. Response was evaluated on an intent-to-treat basis, thus excluding subjects requiring third-line therapy before study day 100. Data were prospectively registered and analyzed. Kaplan–Meier analysis was used to analyze survival, and differences in (event-free) survival between treatment subgroups were compared with the use of the log-rank test. Proportions in the study subgroups were compared with the use of the χ2-test or Fisher's exact test (categorical variables). Mann–Whitney U-test and Student's t-test were applied as appropriate to test for group differences of ordinal or continuous variables. P<0.05 was considered to indicate statistical significance. Binary logistic regression analysis was used to assess the effect of age, HLA disparity, sex mismatch, onset of any infectious complications, initiation of third-line treatment and treatment modality (for example, MP alone vs OKT3 and HD-MP) on survival.

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Authors and Affiliations

  1. Department of Hematology and Oncology, University Hospital, Wuerzburg, Germany

    S Knop, A Schaefer & H Einsele

  2. Department of Hematology and Oncology, University Hospital, Tuebingen, Germany

    H Hebart & C Faul

  3. Department of Hematology, University Hospital, Basel, Switzerland

    A Gratwohl

  4. Department of Hematology, University Hospital, Regensburg, Germany

    E Holler

  5. Department of Hematology, Imperial College, Hammersmith Hospital Campus, London, UK

    J Apperley

  6. Department of Hematology and Oncology, Grosshadern University Hospital, Munich, Germany

    H J Kolb

  7. Department of Hematology and Oncology, University Hospital, Leipzig, Germany

    C Kliem & D Niederwieser

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  1. S Knop
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Correspondence to H Einsele.

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Knop, S., Hebart, H., Gratwohl, A. et al. Treatment of steroid-resistant acute GVHD with OKT3 and high-dose steroids results in better disease control and lower incidence of infectious complications when compared to high-dose steroids alone: a randomized multicenter trial by the EBMT Chronic Leukemia Working Party. Leukemia 21, 1830–1833 (2007). https://doi.org/10.1038/sj.leu.2404731

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