Bone Marrow Transplantation (2011) 46, 430–435 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11 www.nature.com/bmt ORIGINAL ARTICLE Inflammatory cytokine inhibition with combination daclizumab and infliximab for steroid-refractory acute GVHD A Rager, N Frey, SC Goldstein, R Reshef, EO Hexner, A Loren, SM Luger, A Perl, D Tsai, J Davis, M Vozniak, J Smith, EA Stadtmauer and DL Porter Division of Hematology-Oncology, Blood and Marrow Transplant Program, University of Pennsylvania Medical Center, Philadelphia, PA, USA Treatment options for steroid-refractory GVHD (SR- Introduction GVHD) are unsatisfactory and prognosis is poor. Inflammatory cytokines IL-2 and TNF-a are important Acute GVHD (aGVHD) results in significant mortality and mediators of GVHD and may be critical targets for remains a major limitation to successful allogeneic hema- therapy. We retrospectively reviewed our experience using topoietic SCT (HSCT). Corticosteroids are typical first-line combination anti-cytokine therapy of daclizumab and therapy for aGVHD, but only 25–35% of patients achieve infliximab. Seventeen evaluable patients had a median age a complete response (CR) with another 15–20% achieving of 47 years (range 35–63). The conditioning regimen was partial responses.1–4 Antithymocyte globulin has been the myeloablative in 13 and non-myeloablative in 4 cases. most common therapy for steroid-refractory GVHD (SR- GVHD occurred at a median of 49 days after transplant GVHD) and leads to overall clinical improvement in in 12 patients (range 21–231 days) and at a median of 46 31–40% of patients. Unfortunately, this results in a median days (range 25–119 days) after donor lymphocyte infusion survival of only 2–4 months from initiation of treatment.5,6 in 5 patients. All patients had persistent or progressive Regardless of the treatment for SR-GVHD, only 5–30% of GVHD despite 1–2 mg/kg/day of corticosteroids for a patients who fail initial therapy survive long term, median of 7 days (range 2–26 days). They received a compared with 50–60% of those with stable response or combination of daclizumab and infliximab for acute better.7,8 Given the dismal prognosis for patients with GVHD IBMTR severity index B (3), C (10) or D (4). SR-GVHD, there is an immediate need for more effective Of the 17 patients analyzed, 47% responded to treatment, treatment approaches. 24% had complete resolution of symptoms and 24% There is compelling rationale for incorporating anti- had partial responses. Survival was limited and all the cytokine therapy into GVHD management. aGVHD patients died a median of 6.7 months (range 1.6–26) pathogenesis is a multistep process, initiated in part by from transplant and 35 days from initiation of daclizumab/ cytokine release from tissue damaged during cytotoxic infliximab. This retrospective analysis suggests that preparative regimens, resulting in donor T-cell activation combination anti-cytokine therapy with daclizumab/ and subsequent release of IL-2, TNF-a and IFN-g. infliximab has significant activity in SR-GVHD, but These molecules cause expansion and activation of outcomes remain poor. New methods to prevent and treat cytotoxic T cells and other inflammatory cells, creating GVHD are urgently needed. the characteristic tissue damage of the liver, gut and Bone Marrow Transplantation (2011) 46, 430–435; skin seen in aGVHD.9 Daclizumab and infliximab can doi:10.1038/bmt.2010.117; published online 24 May 2010 block T-cell activation mediated by IL-2 and TNF-a, Keywords: daclizumab; GVHD; infliximab; cytokines; respectively; daclizumab binds CD25 (IL-2 receptor steroid refractory a chain) and infliximab can bind the soluble subunit and the membrane-bound precursor of TNF-a. These Abs have shown modest success independently in achieving durable responses against SR-GVHD.10–14 Concurrent use of these agents was evaluated in a small number of patients receiving non-myeloablative hematopoietic cell transplantation and resulted in superior survival of patients compared with those on Correspondence: Dr A Rager, Division of Hematology-Oncology, an antithymocyte globulin-based regimen.14,15 In an University of Pennsylvania Medical Center, Blood and Marrow attempt to enhance response and improve prognosis, we Transplant Program, 3400 Civic Center Boulevard, PCAM 2 West have used a combination anti-cytokine therapy and Pavilion, Philadelphia, PA 19104, USA. E-mail: [email protected] reported our experience in treating 17 patients with Received 13 January 2010; revised and accepted 7 April 2010; published SR-GVHD using a combination of daclizumab and online 24 May 2010 infliximab. Daclizumab and infliximab for steroid-refractory GVHD A Rager et al 431 Methods including GVHD severity and the number of doses of therapy. The threshold for significance was a P-value of 0.05. Patient population All patients treated with a combination of daclizumab and infliximab for SR-GVHD after allogeneic HSCT at the Results Hospital of the University of Pennsylvania were identified through query of the hospital pharmacy database and then Patient characteristics confirmed through retrospective chart review. We identified Between June 2001 and May 2008, 354 patients underwent 22 patients from a total of 354 recipients of an allogeneic allogeneic HSCT. During this time period, 55% of patients HSCT between June 2001 and May 2008. This report is developed aGVHD. Grade I/II aGVHD developed in 29% limited to the 17 patients whose records contained sufficient of patients and grade III/IV aGVHD developed in 26% of information regarding presentation, treatment and re- patients. Among this group, we identified 22 patients who sponse to GVHD therapy for analysis. This retrospective study was approved by and conducted in accordance with Table 1 Characteristics of patients treated with combined daclizumab and infliximab the requirements of the institutional review board of the Hospital of the University of Pennsylvania. Characteristics Median age, years (range) 47 (35–63) Treatment Male, n (%) 10 (59) aGVHD was defined as both classic aGVHD and late Female, n (%) 7 (41) GVHD occurring beyond 100 days post transplant but Diagnosis, n (%) without features characteristic of chronic GVHD. Initial Acute leukemia 9 (53) steroid doses of 1–2 mg/kg/day were used to treat aGVHD. Chronic leukemia 2 (12) GVHD was refractory to steroids in all cases and initiation Lymphoma 5 (29) of daclizumab and infliximab was at the discretion of the Multiple myeloma 1 (6) treating physician. Daclizumab was intended to be given at Stem cell source, n (%) 1.5 mg/kg on day 1 and 1 mg/kg on days 4, 8, 15 and 22. BM 7 (41) Infliximab was intended to be given at 10 mg/kg on days 1, PBSC 9 (53) 8, 15 and 22. Cord 1 (6) Conditioning regimen intensity, n (%) Evaluation of response Myeloablative 13 (76) Responses were assessed weekly until death or date of last Reduced intensity 4 (24) follow-up. Data were collected regarding dose and duration Therapy before GVHD, n (%) of steroids, time of steroid failure, additional immunosup- Transplantation 12 (71) pressant agents given following therapy with daclizumab DLI 5 (29) and infliximab as well as the ability to reduce the steroid dose. aGVHD was graded using either modified Glucks- Donor source, n (%) 16 HLA-identical, sibling 5 (29) berg criteria or International Bone Marrow Transplant HLA-matched, unrelated 9 (53) Registry (IBMTR) severity index.17 For consistency, for all HLA-mismatched, unrelated 2 (12) patients included in this analysis, we determined the stage Cord blood 1 (6) of GVHD for each organ group and overall clinical grade GVHD prophylaxis: n (%) was assigned using the IBMTR severity index. CR was MTX/tacrolimus 14 (82) defined as resolution of GVHD in all organ systems. PR MTX/CsA 2 (12) signified improvement in at least one organ system by at CsA/steroids 1 (6) least one grade without deterioration in another. A mixed response was used to describe improvement in one organ IBMTR severity index grade acute GVHD, n (%) B 3 (18) system with worsening of another and progression of C 10 (59) disease describes worsening of at least one organ system D 4 (24) without improvement in others. Patients without improve- ment or deterioration during treatment with daclizumab Organs involved, n (%) Skin 9 (53) and infliximab were described as no change. Patients were Liver 9 (53) considered refractory to corticosteroids if they did not have Gut 15 (88) a CR or PR. Cause of death was assessed in all patients on the basis of chart review. Infectious complications during Days treatment to aGVHD, median (range) treatment with daclizumab and infliximab were noted. From transplant (n ¼ 12 patients) 49 (21–231) From DLI (n ¼ 5 patients) 46 (25–119) Statistical analysis Days of steroids to daclizumab/infliximab, median (range) 7 (2–26) The Kaplan–Meier method18 was used to estimate OS from No. of doses daclizumab, median (range) 5 (2–5) No. of doses infliximab, median (range) 4 (1–4) the time of transplant, donor lymphocyte infusion or onset 19 of GVHD. Fisher’s exact test was used to determine the Abbreviations: DLI ¼ donor lymphocyte infusion; IBMTR ¼ International impact on response and survival of several outcomes Bone Marrow Transplant Registry. Bone Marrow Transplantation Daclizumab and infliximab for steroid-refractory GVHD A Rager et al 432 received a combination of daclizumab and infliximab for doses, range 1–4). Reasons for failure to deliver the full SR-aGVHD; sufficient data were available for 17 of these treatment course included death, sepsis or lack of response. patients for a detailed review of outcomes. GVHD grade in Seven patients were given additional therapies for aGVHD, these patients was reassigned using the IBMTR severity including alemtuzumab, mycophenolate mofetil, rituximab index. Patient characteristics are summarized in Table 1. and pentostatin at a median of 27 days after starting All patients underwent allogeneic HSCT for hematologic daclizumab and infliximab (range 6–43 days).