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Case Report Renal and Neurological Response with Eculizumab in A View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref Hindawi Publishing Corporation Case Reports in Hematology Volume 2015, Article ID 425410, 4 pages http://dx.doi.org/10.1155/2015/425410 Case Report Renal and Neurological Response with Eculizumab in a Patient with Transplant Associated Thrombotic Microangiopathy after Allogeneic Hematopoietic Progenitor Cell Transplantation Ömür Gökmen Sevindik, Enci AlacacJoLlu, Abdullah KatgJ, Ferife Medeni Solmaz, Celal Acar, Özden PiGkin, Mehmet Ali Özcan, Fatih Demirkan, Bülent Ündar, and Güner Hayri Özsan Department of Hematology, Dokuz Eylul¨ University, 35340 Izmir, Turkey Correspondence should be addressed to Om¨ ur¨ Gokmen¨ Sevindik; [email protected] Received 19 September 2014; Revised 30 December 2014; Accepted 30 December 2014 Academic Editor: Eduardo Arellano-Rodrigo Copyright © 2015 Om¨ ur¨ Gokmen¨ Sevindik et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Transplantation-associated thrombotic microangiopathy (TA-TMA) is a challenge after allogeneic hematopoietic progenitor cell transplantation, considering the diagnostic uncertainties and lack of established treatment. We report a 43-year-old male patient who was diagnosed as TA-TMA after allogeneic progenitor cell transplantation for a progressive ALK negative anaplastic large cell lymphoma and responded to eculizumab with dramatically improving neurological status and renal function. Rapid neurological and renal recovery achieved after eculizumab could support a possible relationship between complement activation and TA-TMA. Eculizumab should be a reasonable treatment approach in patients with TA-TMA after allogeneic hematopoietic progenitor cell transplantation. 1. Introduction uncontrolled splenic hemorrhage. Considering the aggressive nature of the disease, CHOP regimen initiated immediately Transplantation-associated thrombotic microangiopathy after diagnosis and staging procedures. After two cycles (TA-TMA) represents a challenge after allogeneic hemato- of CHOP regimen, no significant response was achieved poietic progenitor cell transplantation because of diagnostic and ESHAP regimen initiated. After two cycles of ESHAP uncertainties, lack of established treatment, and an overall regimen, a short term partial response could be achieved and poor prognosis [1]. Eculizumab, which is a monoclonal allogeneic progenitor cell transplantation was applied from antibody against terminal complement, has been used HLA matched (10/10) sibling donor of the patient because successfully in atypical hemolytic and uremic syndrome and of progressive disease [3]. Cells were collected peripherally 6 TA-TMA associated with solid organ transplantation. Data and the amount of reinfused CD34+ cells was 5.3 × 10 /kg. about its efficacy in TA-TMA associated with hematopoietic Busulfan and cyclophosphamide were used as conditioning progenitor cell transplantation lacks [2]. and cyclosporine used for the prophylaxis of graft versus host disease. At the 7th day of reinfusion, acinetobacter 2. Case Report sepsis developed and patient was put on to a broad spectrum of antibiotics. While recovering from acinetobacter sepsis, We report a 43-year-old male patient who was diagnosed as a rapid neurological and renal deterioration was observed. TA-TMA after allogeneic progenitor cell transplantation from Patient was stuporous and had a tonic-clonic epileptic HLA matched sibling donor and treated with eculizumab. seizure; he also had a severe headache and hallucinations The patient was diagnosed with stage 4 ALK negative before the onset of seizure. Meanwhile, the ldh level was anaplastic large cell lymphoma after splenectomy due to increased dramatically up to 3200 U/L and schistocytes were 2 Case Reports in Hematology Creatinine (mg/dL) LDH (U/L) 5 4500 4.5 4000 4 3500 3.5 3 3000 2.5 2500 2 2000 1.5 1500 1 1000 0.5 500 0 0 1 2 3 5 6 7 8 9 1 2 3 5 6 7 8 9 10 12 13 14 15 16 10 12 13 14 15 16 Plasma Plasma exchange exchange Day of reinf. of Day reinf. of Day 7th day of reinf. of 7th day reinf. of 7th day 1st eculizumab 4 1st eculizumab 4 1st eculizumab Day 0 of TA-TMA 0 of Day TA-TMA 0 of Day 2nd eculizumab 11 2nd eculizumab 11 2nd eculizumab Glasgow coma scale (GCS) 70 16 60 50 12 40 30 8 20 4 10 0 0 1 2 3 5 6 7 8 9 1 2 3 5 6 7 8 9 15 10 12 13 14 16 10 12 13 14 15 16 Plasma Plasma exchange exchange Day of reinf. of Day Day of reinf. of Day 7th day of reinf. of 7th day 7th day of reinf. of 7th day 1st eculizumab 4 1st eculizumab 1st eculizumab 4 1st eculizumab Day 0 of TA-TMA 0 of Day Day 0 of TA-TMA 0 of Day 2nd eculizumab 11 2nd eculizumab 2nd eculizumab 11 2nd eculizumab Hb (g/dL) 3 Thrombocyte (10 /L) Plasma 1st 2nd Day of 7th day Day 0 of exchange eculizumab eculizumab reinf. of reinf. TA-TMA 123 day 4 5 678910 day 11 12 13 14 15 16 Schistocytes − − ++ ++ ++ ++ ++ ++ ++ + + + ++ + + + − − − Seizure − − ++−−−−−−−−−−−−− − − Figure 1: Clinical and biological response to eculizumab therapy. The figure shows data indicating neurological and renal improvement after administration of monoclonal C5 antibody eculizumab in our case with TA-TMA posthematopoietic progenitor cell transplantation with central nervous syprogenitor involvement. LDH levels were decreased dramatically, but thrombocyte count did not improve, possibly related to delayed hematopoietic engraftment. detected at the peripheral blood smear (20–30/HPF). Despite coma scale (GCS) score of 4. Hemodialysis was applied due being hyponormotensive during the period of sepsis, he had to worsening renal functions and acidosis. Despite rigorous hypertensive episodes with a maximum of 180/100 mmHg plasma exchange, no response was achieved and plasma accompanying the neurological symptoms. Cranial MRI exchange was stopped after 5 consecutive cycles. Eculizumab and lumbar puncture revealed no pathological feature. CSF therapy was initiated according to atypical hemolytic and culture was negative and cytological analysis revealed no uremic syndrome dosage. With two weekly administrations malignant cells. Viral analysis of CSF and blood was negative of 900 mgs of eculizumab, neurological status got gradually regarding CMV and EBV.His Hb level has decreased from 9.5 better and patient was able to achieve a GCS score of 11. to 7.2 g/dL with an MCV of 96 fL and reticulocyte count of Hemodialysis stopped and a normal glomerular filtration rate 2.49%. Both direct and indirect coombs tests were negative could be achieved. Despite recovering renal and neurological and haptoglobulin level was slightly decreased below the status, platelet count remained below 20000/microL, possibly lower limit of normal. After ruling out an ongoing infectious related to delayed hematopoietic engraftment (Figure 1). disease, cerebrovascular event, and malignant infiltration of Patient was lost with diffuse alveolar hemorrhage at the 12th CNS with lymphoma, patient was diagnosed, as TA-TMA. day of eculizumab with a stable low platelet count, a normal ADAMTS13 activity was %37 with no detectable inhibitors. ldh level, a normal glomerular filtration rate, a GCS score of All complement levels were in normal range (C3, C4, Factor 11, and fewer schistocytes at peripheral blood smear. H, and Factor I). Urinalysis revealed a protein concentration of 120 mg/dL. Calcineurin inhibitor stopped immediately 3. Discussion after diagnosis and plasma exchange was initiated. Plasma exchange was performed on a daily basis with 1.5 plasma Hematopoietic progenitor cell transplantation- (HPCT-) volumes, using FFP as a replacement fluid. Neurological associated TA-TMA is a well-recognized and potentially status got worse and patient was intubated with a Glasgow severe complication of HPCT that can lead to a high risk Case Reports in Hematology 3 of morbidity and mortality [4]. The incidence of TA-TMA six pediatric HPCT recipients who developed TA-TMA, 67% is 10–35% as reported in the largest retrospective reviews complete remission were achieved with eculizumab, all of and studies examining renal and other tissues [1]. Jodele whom achieved complete blockade of complement activity et al. have reported a 39% incidence in 100 consecutive [15]. To our knowledge, our case is the first in the literature children and young adult patients who had hematopoietic defining the efficacy of eculizumab at thrombotic microan- progenitor cell transplantation [5]. The cause of TA-TMA giopathy which developed rapidly after reinfusion. Rapid is multifactorial. Risk factors include high-dose chemother- neurological and renal recovery achieved after eculizumab apy, radiation therapy, unrelated donor, HLA mismatch, could support a possible relationship between complement exposure to calcineurin inhibitors (CNIs), graft-versus-host activation and TA-TMA. Eculizumab should be a reasonable disease, and infections [1, 6–8]. The release of inflammatory treatment approach in patients with TA-TMA after allogeneic cytokines causes microvascular endothelial injury and acti- hematopoietic progenitor cell transplantation. vates platelets and coagulation factors, leading to thrombosis and fibrin deposition in microvasculature of organs, most Conflict of Interests commonly in the kidney [1].Recently,Jodeleetal.andLaskin et al. have suggested an involvement of the complement The authors declare that there is no conflict of interests dysregulation in the development of TA-TMA [9, 10]. Limited regarding the publication of this paper. feasibility of tissue diagnosis of HPC-associated TA-TMA has led to the development of noninvasive diagnostic criteria. Cho et al. had validated the previously described criteria and References added “probable TA-TMA” category, which did not require [1] B.L.Laskin,J.Goebel,S.M.Davies,andS.Jodele,“Smallvessels, renal and neurological findings for the diagnosis of TA-TMA. big trouble in the kidneys and beyond: hematopoietic stem Validatedcriteriaincluded(1)lactatedehydrogenase(LDH) cell transplantation-associated thrombotic microangiopathy,” elevated above the upper limit of normal for age, (2) de novo Blood,vol.118,no.6,pp.1452–1462,2011.
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