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As Treatment for Refractory Acute Graft-Versus-Host Disease

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As Treatment for Refractory Acute Graft-Versus-Host Disease View metadata, citation and similar papers at core.ac.uk brought to you by CORE Biology of Blood and Marrow Transplantation 12:1135-1141 (2006) provided by Elsevier - Publisher Connector ᮊ 2006 American Society for Blood and Marrow Transplantation 1083-8791/06/1211-0001$32.00/0 doi:10.1016/j.bbmt.2006.06.010 Encouraging Results with Inolimomab (Anti-IL-2 Receptor) as Treatment for Refractory Acute Graft-versus-Host Disease Jose Luis Piñana, David Valcárcel, Rodrigo Martino, M. Estela Moreno, Anna Sureda, Javier Briones, Salut Brunet, Jorge Sierra Division of Clinical Hematology, Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Barcelona, Spain Correspondence and reprint requests: David Valcárcel, Division of clinical Hematology, Hospital de la Santa Creu i Sant Pau, St Antoni Ma Claret 167, Barcelona 08021, Spain (e-Mail: [email protected]). Received September 16, 2005; accepted June 21, 2006 ABSTRACT Enlimomab, an anti-interleukin-2 receptor (anti-IL-2R) monoclonal antibody, may be useful in the treatment of steroid-refractory acute graft-versus-host disease (aGVHD) by inhibiting 1 of its putative immunopatho- genic pathways. We retrospectively analyzed 40 consecutive patients who received enlimomab as salvage treatment for steroid refractory aGVHD at a single institution between June 1999 and December 2004. Enlimomab was given intravenously at a dose of 11 mg/d for 3 consecutive days, followed by 5.5 mg/d for 7 consecutive days and then 5.5 mg every other day for 5 doses. No infusion-related side effects were noted. Twenty-three patients (58%) responded, including 15 (38%) complete and 8 (20%) partial responses. Median overall survival was 294 days (58-996 days) for responders versus 14 days for nonresponders (P < .001), with a 1 year probability of 59% vs 0% for overall survival (P < .0001). Patients without gastrointestinal (GI) involvement showed a higher response rate (100% versus 50% for those without versus with GI involvement, In addition, patients who showed some response by day 15 had a higher overall survival (73 ؎ 12% vs (03. ؍ P The results of this study suggest that enlimomab may be an effective salvage .(02. ؍ respectively, P ,12% ؎ 24 therapy for patients with steroid-refractory aGVHD, particularly for those without GI disease, and supports further studies with this agent in prospective controlled trials. © 2006 American Society for Blood and Marrow Transplantation KEY WORDS Acute graft-versus-host disease ● Anti-interleukin-2R ● Enlimomab ● Allogeneic stem cell transplantation INTRODUCTION (MMF) and tacrolimus, also seem to have limited effi- cacy [5,6]. Refractory acute graft-versus-host disease (aGVHD) With the recent advances in the understanding of remains an important cause of morbidity and mortality the immune-pathophysiology of aGVHD it has been after allogeneic hematopoietic stem cell transplantation. possible to identify several potential new therapeutics Steroids are first-line treatment for aGVHD [1], but targets [7]. Monoclonal-antibodies against cytokines they fail to obtain a good response in up to 50% of such as interleukin (IL)-2 and IL-1, tumor necrosis fac- patients [2,3]. Antithymocyte globulin (ATG) has been tor ␣, and interferon ␥ are being used to block T cell widely used in steroid refractory aGVHD [4], but the activation and as a consequence to prevent or treat results with this second-line therapy are poor, mainly GVHD [1,8]. Treatment of aGVHD using anti-IL-2 due to high mortality from opportunistic infections. receptor (anti-IL-2R) is justified by the fact that this Other salvage regimens, such as mycophenolate mofetil receptor is crucial in the effector phase of aGHVD [7-9]. IL-2 promotes the expansion and differentiation Jose Luis Piñana and David Valcárcel contributed equally to the elabo- of T cells [7]. Therefore, blockage of IL-2-induced ration of this study. T cell activation may prevent or revert aGVHD. 1135 1136 J. L. Pin˜ana et al. IL-2R is a heterodimeric molecule with 3 polypep- Ն1 other organ were considered to show progression tide chain subunits (␣, ␤, ␥) [10]. Most T cells express 2 of aGVHD. subunits, conforming intermediate-affinity IL-2R. Ex- pression of the ␣-subunit (CD25) conforms the high- Therapy affinity receptor for IL-2. This high-affinity IL-2R is Patients received enlimomab according to the expressed on activated T cells, whereas resting T cells manufacturer’s instructions; the drug was adminis- lack this receptor. Selective inhibition of activated T cells trated intravenously at 11 mg/d for 3 days, 5.5 mg/d could theoretically favor immunologic recovery by acti- for 7 days, and 5.5 mg every other day for 5 doses. vating T cells that do not express CD25 by blocking Thirty patients received 1 course of enlimomab, 8 IL-2. patients received 2 courses, and 2 patients received 3 ␬ Enlimomab is a murine immunoglobulin G1 courses due to absence of response or relapse after ␣ monoclonal antibody directed against the -chain of response to the first course of the drug. Cyclosporine IL-2R. Anti-Il-2R has shown beneficial effects in the A (CsA) and/or MMF was maintained during enli- treatment of aGVHD [11-14]. In contrast, there are momab treatment, but those patients who were on also experiences showing a poor efficacy of anti-IL-2R ATG treatment stopped this drug before enlimomab as prevention or treatment for this complication [15- treatment. After enlimomab was started, steroids were 17]. These discrepancies may be explained in part by tapered, although most patients continued with low different patient selections and by the fact that there doses of steroids (0.2-0.5 mg/kg per day of prednisone are several anti-IL-2R antibodies with different phar- or an equivalent) while on enlimomab. macokinetic profiles and possibly different affinities to IL-2R and soluble IL-2R, which may lead to variable Statistical Analysis degrees of inactivation and to different results. Differences in response rate according to the or- During a 5-year period, we used an anti-IL-2R gans involved, number of salvage therapies, cycles of antibody, enlimomab, as treatment for steroid-refrac- enlimomab, and onset of aGVHD were assessed by tory aGVHD and for treatment of aGVHD resistant chi-square test and Student t test. Survival was esti- to steroids and ATG. mated by the Kaplan-Meier method and comparisons of actuarial curves were made by log-rank and Taron- Ware tests. In the comparison of responders with METHODS nonresponders and the comparison of day-15 re- Patients sponders, we excluded those patients who died before day 15 after the start of enlimomab. Nonrelapse mor- In this study we retrospectively analyze all 40 tality was calculated by using cumulative incidence, consecutive patients who received enlimomab as sal- with relapse of neoplastic disorders as a competitive vage therapy for aGVHD between June 1999 and variable. Follow-up and overall survival (OS) were December 2004. All patients gave their written in- calculated since the start of enlimomab treatment. formed consent and the drug was administered as Response was analyzed with respect to the first cycle compassionate use after approval from our institu- of enlimomab even in those patients who received Ͼ1 tional and national health authorities. cycle of the drug. GVHD Diagnosis and Response Assessment RESULTS Diagnosis of aGVHD was based mainly on classic Patient Characteristics clinical presentation with confirmatory pathologic findings in all but 1 patient. The characteristics of the 40 patients who were Resistant aGVHD was defined as disease progres- treated are listed in Tables 1 and 2. sion in the first 3 days or if there was no improvement All patients showed a clinical picture compatible after 7 days of initial or second-line treatment. Max- with aGVHD and all had histopathologic findings imum staging of aGVHD was defined according to compatible with aGVHD in the organs biopsied. Only established criteria [18] and was assessed the day be- 1 patient had no histologic proof of aGVHD, but he fore beginning enlimomab. developed a typical rash plus liver abnormalities. The Response to treatment was defined as follows: skin rapidly improved with steroids but the liver dis- complete response (CR) was the clinical and labora- ease progressed, and the liver subsequently showed tory disappearance of aGVHD features, partial re- PR with enlimomab. sponse (PR) was a decrease of Ն1 grade in overall There were 29 men (73%) and 11 women (27%), stage of aGVHD, and no response included stable and with a median age of 47 years (range, 17-63 years). progressive disease. Those patients who showed im- Follow-up for the entire group was 58 days (range, provement in 1 organ but whose disease progressed in 4-996 days) and that for survivors was 351 days (range, Enlimomab (Anti-IL-2R) for Steroid Refractory aGVHD Table 1. Clinical Characteristic of Patients Who Received Enlimomab as Salvage Therapy for Acute GVHD Relapse of Onset Dehy GVHD- aGVHD/ Pt. Age Cond GVHD GVHD Affected Inolimomab Surv Chronic Cause N Sex Disea DO Reg Prophylaxis (d) Grade Organ Prior Therapies (d)* N°Cycles Resp (days) GVHD of Death F AA MMU SC CsA, MTX, ATG 14 III S, GI PDN ؉ ATG‡ 74 1 NR 24 –/– aGVHD/34 1 F AA MU SC MTX, Tc, ATG 13 IV S, L, GI PDN ؉ ATG† 21 1 NR 4 –/– IFI/34 2 M CLL IS SC CsA 21 IV S, L, GI PDN ؉ MMF 39 1 NR 8 –/– aGVHD/48 3 M NHL IS RIC CsA, MTX 50 III S, L, GI PDN ؉ MMF ؉ ATG 4 1 NR 19 –/– aGVHD/47 4 F ALL IS SC CsA, MTX 88 IV L, GI PDN ؉ ATG 21 1 PR 24 No/Ext cGVHD/35 5 F CML MMU SC CsA, MTX 10 III S, L, GI PDN ؉ ATG 24 1 CR 65
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