Intraarterial catheter guided steroid administration in treatment of steroid refractory gastrointestinal GVHD after HSCT

Transcription

1 Intraarterial catheter guided steroid administration in treatment of steroid refractory gastrointestinal GVHD after HSCT Poster No.: C-1041 Congress: ECR 2013 Type: Authors: Keywords: DOI: Scientific Exhibit D. Bürgler, C. Bucher, J. Passweg, A. Fischmann; Basle/CH Interventional vascular, Gastrointestinal tract, Hematologic, Catheter arteriography, Outcomes analysis, Catheters, Arterial access /ecr2013/C-1041 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. Page 1 of 8

2 Purpose Hematopoietic stem cell transplantation (HSCT) is the standard treatment for high risk leukemia and lymphoma. Acute graft-versus-host disease (agvhd) is the single most important cause for morbidity and mortality post HSCT. AGvHD is caused by donor T-cells that are activated by host antigen presenting cells, migrate to target tissues (skin, gut, liver) and cause target organ dysfunction. AGvHD with clinically relevant gastrointestinal involvement (GI agvhd) occurs in 30-75% of patients [1]. Standard first line treatment of agvhd is high dose steroids. However, about 50% of patients do not fully respond to first line treatment. Once steroid resistance occurs, 11-14% of patients achieve complete remission of agvhd symptoms [2], for patients not responding completely mortality is 30-70% [3]. Unfortunately, there is no established second line treatment for steroid refractory agvhd. Clinical observation suggests, that some agvhd in some patients is amenable to mega dose steroid treatment, albeit with high treatment related mortality. Therefore, the concept of local dose intensification that can easily applied for skin agvhd has been expanded to GI agvhd. Shapira et al. [4] (in 2002) and Weintraub et al. [5] (in 2010) described their experience in small uncontrolled single center patient's series of 11 and 15 patients. However, the patients described in these reports were mostly pediatric and intraarterial treatment was often administered after multiple other lines of therapy. Therefore we sought to investigate the applicability of intraarterial steroid administration (IASA) in a setting of adult PBSCT. We also hypothesized that if IASA were given early after systemic treatment failure, the response rate would be favorable compared with the published datasets. Methods and Materials Patient selection and inclusion criteria Patients were eligible for inclusion if they developed GI agvhd. All included patients were not responding to intravenous methylprednisolone administered at 2 mg / kg body weight within 14 days after onset of GI agvhd; and had a GI agvhd clinical stage of 2-4. The diagnosis and severity of agvhd was graded according to the 1994 consensus conference on acute GvHD grading by Przepiorka et al [1]. An infectious cause of the gastrointestinal symptoms was excluded. Page 2 of 8

3 Treatment procedure Catheter guided intraarterial steroid administration (IASA) was performed using standard sterile technique and local anesthesia. By accessing the right or left common femoral artery a 4 Fr angiography catheter was used to locate and select the superior (SMA) and inferior mesenteric artery (IMA) and, in patients with upper gastrointestinal symptoms into the celiac trunk (7 patients) and the left gastric artery (2 patients) Fig. 1 on page 3. Drug infusion into each artery was performed over 3 minutes per artery. The median total dose of methylprednisolone was 182 mg ( mg). In 7 patients with persistent or recurring symptoms, IASA was repeated within 14 days. Treatment response and follow-up Treatment response was evaluated: Non-response was defined as persisting symptoms and death during hospitalization after onset of GI agvhd. Partial response was defined as patients with improved gastrointestinal symptoms after IASA but remaining symptoms at discharge. Complete response was defined as patients with complete resolution of gastrointestinal symptoms at discharge from hospital. All patients received follow-up in post transplant consultation at our institution or by medical chart reviews of further hospitalization. There was a follow-up 100 days after initial IASA, re-evaluating patient's GvHD grade. Overall Survival All patients still alive at September 2012 were defined as survivors. All other patients had documented times of death in their medical charts. The time was measured form initial IASA and HSCT to death. Images for this section: Page 3 of 8

4 Fig. 1: Proof of correct catheter placement during intraarterial steroid application: Superior mesenteric artery (right), inferior mesenteric artery (left). Page 4 of 8

5 Results Between January 2010 and June 2012, 12 patients with steroid refractory GI agvhd received IASA at our institution. The mean patient's age was 53 years (range 30-69), 9 were male and 3 female. Underlying diagnosis and patient characteristics are shown in Table 1 on page 6. All 12 patients showed GI agvhd with a median grade of 3 (grade 2-4), in 6 patients the skin (grade 1-3) and in 4 patients the liver (grade 1-3) were involved. The median overall peak grade of agvhd was 3 (range 2-4). The median time from HSCT to onset of GI agvhd was 20 days (range 6-278). The median time from onset of GI agvhd to initial IASA was 19 days (range 9-41). 7 patients not responding to the first IASA received a second IASA (median period of time between IASA was 13 days, range 6-14). No technical complications occurred. There was one duodenal ulcer described in one patient two days after second IASA. Six out of 12 patients (50%) could be discharged from the hospital at a median of 32 days (15-116) post IASA. Four patients (33%) had a complete response without symptoms. Two patients (17%) showed a partial response with improved symptoms. Details are displayed in Table 2 on page 6. In the latter, symptoms decreased from initial GI agvhd grade of 3 to 1 and 2 respectively (overall agvhd grade remained between 2-3 due to mucocutaneous involvement). All patients with response were discharged on oral diet and medication. 3 out of 6 responders not responding to initial IASA received a second IASA. Two complete responders showed improved symptoms thereafter. One partial responder did not respond to second IASA. All 6 responders were alive at follow-up 100 days after initial IASA, 2 patients without any symptoms, 2 patients with mild mucocutaneous involvement and 2 patients with mucocutaneous (grade 2) and gastrointestinal (grade 1-2) involvement (overall agvhd grade 2-3). Five of six responders were still alive at a median time of 217 days ( ) after IASA and 281 days ( ) after HSCT. One responder died 560 days after HSCT due to pre-existing comorbidity. Six out of 12 patients died during hospitalization due to IASA refractory- and steroid refractory GI agvhd. All 6 patients not responding to IASA died due to agvhd related reasons within the hospitalization at a median of time of 40 days (range 17-47). Page 5 of 8

6 Images for this section: Table 1 Table 2 Page 6 of 8

7 Conclusion Catheter guided intraarterial steroid administration (IASA) is a feasible and seems to be an effective second line treatment option for systemic steroid refractory GI agvhd. GI agvhd is characterized by both a reduction in the number of steroid receptors in diseased tissue and a decrease in the receptors' affinity for steroids [6, 7]. Further and higher doses of systemic steroids have failed to improve symptoms of GI agvhd and furthermore cause profound immunosuppression associated with increased risk of infection and tumor recurrence. IASA delivers treatment directly to the diseased gastrointestinal tissue. High concentrations of steroids can be applied locally, thereby overcoming the underlying unresponsiveness without further depressing the already incompetent immune system in these patients. Two small previous reports enrolling 11 and 15 patients reported the effect of IASA in steroid refractory GI agvhd. Shapira et al enrolled 15 patients with liver and / or GI agvhd [4]. Another report of Weintraub et al enrolled 11 patients with GI agvhd. They used a study protocol comparable to ours. Partial response was defined as improved symptoms at discharge and complete response was defined as complete resolution of symptoms at discharge [5]. In our cohort 33% of our patients showed a complete response, while Shapira et al. reported a complete response in 82% and Weintraub et al. in 36% of the patients. Contrary to Shapira et al, who also included responders who died in hospital, we and Weinberg et al. evaluated death in hospital as non-response. This possibly explains the slight difference in the response rate. We found a lower response rate (50%) compared to Weintraub et al, who reported improved symptoms at discharge in 72% of patients. However both studies only enrolled a small number of patients, with single cases affecting the results. This is also visible in the long-term survival rate of 50% compared to 43% and 27% at a median of one year in Shapira and Weintraub's data respectively. However, our study has a limitation in the fact, that 3 patients currently only completed a followup of 64, 72 and 98 days respectively, and can therefore not be evaluated in the one year survival rate. No complications occurred during IASA. One patient developed a duodenal ulcer two days after the second IASA during which we administrated higher doses of methylprednisolone (200 mg). There is a high probability that this ulceration was related to IASA. These data are encouraging and should promote further investigation. Page 7 of 8

8 References 1. Przepiorka D, Weisdorf D, Martin P, et al consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15(6): Weisdorf D, Haake R, Blazar B, Miller W, McGlave P, Ramsay N, Kersey J. & Filipovich A. (1990) Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome. Blood, 75, Pietryga D. (1993) Prevention and treatment of acute graft-vs-host disease. American Journal of Pediatric Hematology and Oncology, 15, Shapira MY, Bloom AI, Or R, et al. Intraarterial catheter directed therapy for severe graft-versus-host disease. Br J Haematol 2002; 119(3): Weintraub JL, Belanger AR, Sung CC, Stangl PA, Nowakowski FS, Lookstein RL. Intraarterial methylprednisolone infusion in treatment-resistant graft-versus-host dis ease. Cardiovasc Intervent Radiol 2010; 33(3): Rogler G, Meinel A, Lingauer A, et al. Glucocorticoid receptors are down-regulated in infl amed colonic mucosa but not in peripheral blood mononuclear cells from patients with infl ammatory bowel disease. Eur J Clin Invest 1999; 29(4): Schottelius A, Wedel S, Weltrich R, et al. Higher expression of glucocorticoid receptor in peripheral mononuclear cells in infl amatory bowel disease. Am J Gastroenterol 2000; 95(8): Personal Information David Bürgler 1, Christoph Bucher 2, Jokob Passweg 2, Arne Fischmann 1 1 Clinic of Radiology & Nuclear Medicine, University of Basel Hospital, Switzerland 2 Department of Hematology, University of Basel Hospital, Switzerland dbuergler@uhbs.ch Page 8 of 8