Course Of Immunosuppressive Therapy Research Articles

The case of Kinsburn’s Encephalopathy in a child with neuroblastoma of posterior mediastinum

Opsoclonus-myoclonus-ataxia syndrome (OMAS) is an autoimmune rare disease of the central nervous system with lesion of the cerebellum and its ligaments. Purpose - to present a case of the rare Kinsburn’s Encephalopathy - OMAS and to attract the attention to its timely diagnosis. Clinical case. A child at the age of 1 year and 9 months was observed in the neurological department of the National Children’s Specialized Hospital “OKHMATDYT”. Neurological status: eyes opsoclonus, truncal tremor, ataxia of the cerebellum. There were also changes in behavior and a sleep disorder. She became sick in 1 month after acute respiratory infection. True diagnosis was made: Kinsburn’s Encephalopathy - opsoclonus-myoclonus syndrome. A study of the child’s immune status was made and, most importantly, computerized tomography (CT) of the whole body. Mediastinal neuroblastoma was diagnosed. In addition to the diagnosis, the child receive adequate therapy - intravenous immunoglobulin at a dose of 2 g/kg for a 5-day course. On the background of the received therapy, the child was marked with positive dynamics, she began to walk by herself, the atactic syndrome diminished, opsoclonus remained unchanged. Consequently, the main cause of autoimmune defeat of the nervous system was detected and the child was directed to the further examination and treatment to the Cancer Institute of the National Academy of Medical Science of Ukraine. Radical removal of the left hemopleura neuroblastoma was made. According to the results of morphological and immunohistochemistry tests, the phenotype obtained in the material of the operation is characteristic of the neuroblastoma (ICD-O code 9500/3), pT1bpN0M0, negative form. In the future, the child continued to receive courses of immunosuppressive therapy. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Comparison of Hematopoietic Stem Cell Transplantation and Repeated Immunosuppressive Therapy As Second-Line Treatment for Relapsed/Refractory Severe Aplastic Anemia

The optimal treatment for patients with severe aplastic anemia (SAA) who fail or have relapse after an initial course of immunosuppressive therapy (IST) has not been established. We conducted a retrospective study to compare the effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) (n = 36) with repeated IST (n = 33) as salvage therapy for relapsed/refractory SAA between 2007 and 2022. In the repeated IST group, patients were treated with antithymocyte globulin (ATG) (n = 16) or high-dose cyclophosphamide (HD-CTX) (n = 17). The overall response rate was 42.4% at 6 months, and 60.6% at 12 months. In the HSCT group, 6 were matched sibling donor (MSD), 7 were matched unrelated donor (MUD), and 23 were haploidentical donor (HID). All patients achieved neutrophil engraftment and no primary graft failure was observed. The rate of platelet engraftment was 88.9%, with a median time of 16 days. The cumulative incidences of grade II-IV, III-IV acute GVHD was 36.1% ± 0.7%, 13.9% ± 0.3% at day +100, and chronic GVHD was 36.2% ± 0.7% at 5 years. Compared with IST, HSCT recipients showed much higher hematologic recovery rate at 3-, 6- and 12-months post treatment (63.9%, 83.3% and 86.1%, respectively, P < 0.001). The estimated 5-year overall survival (OS) (79.8% ± 6.8% vs. 80.0% ± 7.3%, p = 0.957) were similar; however, the estimated 5-year failure-free survival (FFS) was significantly better in the HSCT group (79.8% ± 6.8% vs. 55.2% ± 9.2%, p = 0.049). In multivariate analysis, age ≤ 35 years at salvage HSCT was the only favorable factor for OS and FFS ( p = 0.019, 95% CI 0.019-0.706). These results suggest that HSCT and repeated IST are both effective for refractory/relapsed SAA in the salvage setting. Considering the superior FFS in the HSCT cohort, especially in younger patients (age ≤ 35 years), we recommend HSCT instead of a second IST for these patients.

Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia.

We compared the efficacy and safety of eltrombopag (ELTR) combined with immunosuppressive therapy (IST) and IST alone in treatment-naïve children with severe (SAA)and very severe (vSAA) aplastic anemia. Ninety-eight pediatric patients were randomized to receive horse antithymocyte globulin (hATG) and cyclosporin A (CsA) with (n=49) or without (n= 49) ELTR. The primary endpoint was the overall response rate (ORR) at 4months. After 4 months, nonresponders were crossed over to the alternative group. In all patients, the ORR in ELTR+ IST and IST groups was similar (65% vs 53%; P= .218); however, the complete response (CR) rate was significantly higher in the ELTR+ IST group (31% vs 12%; P=.027). In severity subgroups, the ORR was 89% vs 57% (P= .028) in favor of IST+ ELTR in SAA, but it did not differ in patients with vSAA (52% vs 50%; P= .902). At 6 months after the crossover, 61% of initial ELTR(-) patients achieved a response compared with 17% of initial ELTR(+) patients (P= .016). No significant difference in ELTR+ IST and IST groups was observed in the 3-year overall survival (OS) (89% vs 91%; P= .673) or the 3-year event-free survival (EFS) (53% vs 41%; P=.326). There was no unexpected toxicity related to ELTR. Adding ELTR to standard IST was well tolerated and increased the CR rate. The greatest benefit from ELTR combined with IST was observed in patients with SAA but not in those with vSAA. The second course of IST resulted in a high ORR in initial ELTR(-) patients who added ELTR and had limited efficacy among patients who received ELTR upfront. This trial was registered at Clinicaltrials.gov as #NCT03413306.

Reactivaion of immune-related colitis during targeted therapy in a patient with metastatic cutaneous melanoma

Background. The development of unique immune-related adverse events (irAEs) is a known hallmark of immunotherapy. Generally, such complications occur during the first 3–6 months of immunotherapy, however, the experience with immune checkpoint inhibitors (ICIs) shows that irAEs can also occur after completion of ICI therapy, as well as during other anticancer treatment regimens. Description of the clinical case. We present a clinical case of a patient with metastatic cutaneous melanoma, who had recurrent events of grade 2 immune-mediated diarrhea during the 2ndline of therapy. After completion of the course of immunosuppressive therapy with systemic glucocorticoids, irAE resumed, and mesalazine and budesonide (local steroid) with subsequent dose reduction were prescribed. Maintenance anti-inflammatory therapy and re-induction of targeted therapy with BRAF- and MEK-inhibitors due to the progression of the disease resulted in the reactivation of immune-mediated colitis. The complication was successfully managed by increasing dose of local steroid to full dose. Anticancer therapy was continued at the same regime without recurrent episodes of irAEs. Conclusion. When changing the anticancer treatment regimen, the recurrence of irAEs dictates careful monitoring of toxicity and the importance of timely selection of the optimal treatment algorithm to improve the quality and longevity of cancer patients.

Controversial Interactions of Tacrolimus with Dietary Supplements, Herbs and Food

Tacrolimus is an immunosuppressive calcineurin inhibitor used to prevent rejection in allogeneic organ transplant recipients, such as kidney, liver, heart or lung. It is metabolized in the liver, involving the cytochrome P450 (CYP3A4) isoform CYP3A4, and is characterized by a narrow therapeutic window, dose-dependent toxicity and high inter-individual and intra-individual variability. In view of the abovementioned facts, the aim of the study is to present selected interactions between tacrolimus and the commonly used dietary supplements, herbs and food. The review was based on the available scientific literature found in the PubMed, Scopus and Cochrane databases. An increase in the serum concentration of tacrolimus can be caused by CYP3A4 inhibitors, such as grapefruit, pomelo, clementine, pomegranate, ginger and turmeric, revealing the side effects of this drug, particularly nephrotoxicity. In contrast, CYP3A4 inducers, such as St. John’s Wort, may result in a lack of therapeutic effect by reducing the drug concentration. Additionally, the use of Panax ginseng, green tea, Schisandra sphenanthera and melatonin in patients receiving tacrolimus is highly controversial. Therefore, since alternative medicine constitutes an attractive treatment option for patients, modern healthcare should emphasize the potential interactions between herbal medicines and synthetic drugs. In fact, each drug or herbal supplement should be reported by the patient to the physician (concordance) if it is taken in the course of immunosuppressive therapy, since it may affect the pharmacokinetic and pharmacodynamic parameters of other preparations.

T-cell receptor diversity in minimal change disease in the NEPTUNE study.

Minimal change disease (MCD) is the major cause of childhood idiopathic nephrotic syndrome, which is characterized by massive proteinuria and debilitating edema. Proteinuria in MCD is typically rapidly reversible with corticosteroid therapy, but relapses are common, and children often have many adverse events from the repeated courses of immunosuppressive therapy. The pathobiology of MCD remains poorly understood. Prior clinical observations suggest that abnormal T-cell function may play a central role in MCD pathogenesis. Based on these observations, we hypothesized that T-cell responses to specific exposures or antigens lead to a clonal expansion of T-cell subsets, a restriction in the T-cell repertoire,and anelaboration of specific circulating factors that trigger disease onset and relapses. To test these hypotheses, we sequenced T-cell receptors in fourteen MCD, four focal segmental glomerulosclerosis (FSGS), and four membranous nephropathy (MN) patients with clinical data and blood samples drawn during active disease and during remission collected by the Nephrotic Syndrome Study Network(NEPTUNE). We calculated several T-cell receptor diversity metrics to assess possible differences between active disease and remission states in paired samples. Median productive clonality did not differ between MCD active disease (0.0083; range: 0.0042, 0.0397) and remission (0.0088; range: 0.0038, 0.0369). We did not identify dominant clonotypes in MCD active disease, and few clonotypes were shared with FSGS and MN patients. While these data do not support an obvious role of the adaptive immune system T-cells in MCD pathogenesis, further study is warranted given the limited sample size. A higher resolution version of the Graphical abstract is available as Supplementary information.

Трансплантация аллогенных гемопоэтических стволовых клеток от гаплоидентичного донора больной диффузной В-клеточной крупноклеточной лимфомой, развившейся на фоне иммуносупрессивной терапии после трансплантации почки

Трансплантация аллогенных гемопоэтических стволовых клеток от гаплоидентичного донора больной диффузной В-клеточной крупноклеточной лимфомой, развившейся на фоне иммуносупрессивной терапии после трансплантации почкиA case report of haploidentical hematopoietic stem cell transplantation for diffuse large B-cell lymphoma developing in the course of immunosuppressive therapy after kidney transplantation

Combination of tuberculosis of the intra thoracic lymph nodes and acute lymphoblastic leukemia in a child

According to scientific research, malignant neoplasms in children are biomedical risk factors for the development of tuberculosis (TB). On the contrary, the occurrence of oncological disease in a child against the background of an existing tuberculous process is extremely rare. The combination of malignant neoplasm and tuberculosis creates difficulties in differential diagnosis, treatment of diseases, prevention of exacerbations and relapses. This article presents a clinical observation the development of acute lymphoblastic leukemia (ALL) in a 6-year-old child against the background of TB of the intrathoracic lymph nodes during treatment. TB proceeded favorably despite multiple family contact in the child and resistance of Mycobacterium tuberculosis to anti-tuberculosis drugs in adult relatives of the patient. At the onset of ALL, bilateral pulmonary infiltrates and pleural effusion were observed, which were not associated with TB. Specific polychemotherapy for ALL and continued chemotherapy for TB led to the cure of two diseases. Supportive cytostatic and immunosuppressive therapy for ALL required periodic courses of anti-relapse anti-tuberculosis therapy for 5 years. After 10 years of observation, the child is healthy. Thus, the possibility of a rare in clinical practice combination of TB and ALL in children should be taken into account in the diagnosis and treatment of these diseases. During courses of immunosuppressive therapy for ALL, there is a risk of reactivation of TB. It is necessary to recommend long-term observation of such children by a phthisiatrician and an oncologist to prevent recurrence of both diseases.

Селективный дефицит иммуноглобулина А в отдаленном периоде после терапии ритуксимабом

Objective of the Paper: To demonstrate the possibility of developing late-onset hypoimmunoglobulinemia after a course of immunosuppressive therapy. Key points. A clinical observation is presented when a selective immunoglobulin A deficiency gradually developed in a patient with Sjögren's disease and MALT-lymphoma, who received rituximab for several years. It was associated with increased frequency of acute respiratory infections. The molecular mechanisms of secondary antibody deficiencies followed by immunisupressive therapy are virtually unknown and are likely to be heterogenous. It is necessary to carry out a differential diagnosis with primary immunodeficiencies. Conclusion. This clinical observation confirms that when choosing rituximab or other anti-B-cell drugs as basic therapy, one should be aware of the possible development of hypoimmunoglobulinemia both during treatment and in the long-term period. Before starting treatment with rituximab, one must determine the initial levels of serum immunoglobulins to assess the risk of infectious complications and identify primary immunodeficiencies and monitor them even after discontinuation of the drug, particularly in patients with infections. Keywords: rituximab, antibody deficiency, immunoglobulin A, Sjogren’s syndrome, lymphoma.

Response of Eltrombopag in immune thrombocytopenia and acquired idiopathic aplastic anemia: A single-center experience

Eltrombopag has been used in ITP and found its use in AA armamentarium recently.We retrospectively analyzed 61 patients at a tertiary care center in Pakistan from January 2015 to January 2021. They included patients with severe AA who were refractory to at least one course of immunosuppressive therapy and persistent/chronic ITP who have received at least one previous treatment for ITP. Responses to Eltrombopag in our population were comparable to real-world experiences while tolerable hepatotoxicity and GI issues were notable.We found Eltrombopag to be a safe and efficacious agent for treating patients with ITP and AA.

New Onset Aplastic Anemia after a COVID-19 Infection: A Case Report

Aplastic anemia (AA) is a potentially life-threatening acquired bone marrow failure syndrome which leads to central pancytopenia. Although the exact pathogenesis of this disorder is yet to be fully understood, it is thought to be primarily caused by auto-immunity. Unlike other viruses, the association between SARS CoV-2 and AA remains insufficiently explored in current literature. Based on the few cases of COVID-19-induced central pancytopenia and the available literature on virus-induced AA, we propose that the development of AA in COVID-19 patients may be attributable to SARS CoV-2. We report the case of a 29-year-old female that developed AA after being hospitalized for COVID-19. She had a favorable clinical outcome after several courses of immunosuppressive therapy.

Neurological presentations of inflammatory bowel diseases

The aim. To characterize the main types of neurological manifestations in inflammatory bowel diseases – Crohn’s disease and ulcerative colitis.Main concepts. Neurological disorders represent an important aspect of extraintestinal inflammatory bowel diseases (IBD) manifestations. According to publications, the incidence of psycho-neurological syndromes varies from 0.25% to 47.50% that apparently depends on the patient’s selection in studies. Neurological signs are not always associated with IBD activity and may precede the manifestation of intestinal inflammation. The most typical include cerebral thromboembolism, peripheral and cranial neuropathies, demyelinating disorders, and cerebral vasculitis. The incidence of ischemic stroke in IBD can reach 6.4%, with approx. 20% of affected persons under 17 y.o. Hemiparesis is the predominant consequence. The risk of intracranial venous thrombosis is increased depending on the activity of intestinal inflammation; this complication can precede manifestation of IBD. Fifty per cent increased risk of multiple sclerosis in IBD patients was shown. The types of peripheral nerves involvement include mononeuropathy, plexopathy, multiple mononeuropathy, compression neuropathy, polyneuropathy and cranial neuropathy. Peripheral neuropathy may be found in 32–37% of IBD patients with a special examination. Demyelinating type, sensory axonal polyneuropathy with thin and thick fibers damage, and motor axonal polyneuropathy with thick fibers damage are observed approximately in equal proportions. It is important to differentiate ‘primary’ neuropathy with vitamin B12 and folic acid deficient, alcoholic, diabetic and drug-induced neuropathy. Clinical improvement is usually seen in the course of immunosuppressive therapy. Cranial neuropathy (mostly of II, VI, VII, VIII of cranial nerves) is described in IBD. Neurological disorders associated with administration of metronidazole, sulfasalazine, cyclosporin A, antibodies to TNF-α and integrins α4 and α4ß7 continue to be highly actual.Conclusion. There is a variety of neurologic syndromes in IBD which represents an important part of extraintestinal manifestations. Mild psychoneurological disorders may be not recognized in time. The majority of symptoms and signs may regress in the course of treatment of IBD and nutrients deficiency correction. The special attention should be paid to neurological status control while the biologic and immunosuppressor agents and metronidazole are administered.

Outcome of Severe Aplastic Anemia Treated with Low Dose Immunosuppression in Resource Limited World during Pandemic: Single Center Experience from Myanmar

Background Like other Asian countries, acquired Aplastic Anaemia (AA) is prevalent in Myanmar and severe aplastic anaemia (SAA) is one of the leading cause of mortality among haematological disorders, particularly from infectious complications. As there is no health insurance system, patients with SAA who are mainly from poor socio-economic class, have to rely on government supply of immunosuppressive therapy (IST) with anti-thymocyte globulin and ciclosporin. During pandemic, new cases are provided individually tailored treatment to minimize the risk while the patients already treated with IST are followed-up by telecommunication. Under such limited setting, outcome of SAA who received IST are reviewed to provide balanced care between risk and benefit amid pandemic in this referral center of the country. Methods In our center, SAA and very severe aplastic anaemia (VSAA) classified according to the modified Camitta criteria were treated with Anti-thymocyte globulin -Equine (Thymogam) 250mg/5ml, Bharat Serums and Vaccines ltd., India, in a total dose ranged between (depend on availability of supply) 40 to 160mg/kg divided into 4 or 5 days of intravenous infusion with oral ciclosporin A (CsA) at a dose of 5 mg/kg/day. During Covid-19 pandemic, new cases of VSAA and cases refractory to previously received IST have been offered Eltrombopag (EPAG) 100mg/day for 8 weeks and tapered depend on response. Results Between January, 2018 to July, 2020, 11 cases of SAA and 9 cases of VSAA, 19 in total, at median age 24 years (range 14-57 years) with female to male ratio of 1:5.3 received IST. Of 19, only one patient had evidence of paroxysmal nocturnal hemoglobinuria. Nine of 19 (47.4%) received lower dose of ATG ranged between 40-60 mg/kg while 5 (26.3%) had 60-80 mg/kg and another 5 (26.3%) had standard dose of 160 mg/kg. Eltrombopag was added to IST in two non-responder VSAA and up-front therapy combined with CsA in two without ATG. However, due to inadequate response, ATG has to be added later. Mortality rate during initial 12 weeks was 3/19 (15.8%) from bleeding and sepsis before achieving response, two of whom were from lower dose range group. Overall response was observed in 15 (78.9%) as early as 2nd month and all became transfusion independent although complete remission was not achieved. One without response received second course of IST at a higher dose followed by addition of EPAG. Among responder, one relapsed after one year despite having standard dose of ATG and one lost to follow-up. To date, during median follow-up of 16 months (range 3 to 30 months) except one who relapsed, 14 (73.7%) remained alive and free from SARS-COV-2 infection as well as transformation to myelodysplasia. Conclusion This is the first report from Myanmar on response to ATG supporting immune mediated aetiology underlying AA similar to other regions from Asia. This limited experience on minimum immunosuppression with low- dose ATG even at 40-60mg/kg had helped SAA and VSAA to keep transfusion independent and stay safe during pandemic. Disclosures No relevant conflicts of interest to declare.

Luna stain: a simple and cost-effective diagnostic tool helps in detecting eosinophilic granules deposition of flame figures and aids in diagnosing eosinophilic cellulitis Wells Syndrome

ABSTRACT We report a rare case of Wells syndrome in which a 61-year-old Caucasian male presented with three distinct skin lesions including a cutaneous bulla, an erythematous plaque, and a linear streak located on the patient’s left anterior thigh, left dorsal wrist, and left anterior forearm, respectively. Histologic examination revealed diffuse and interstitial eosinophilic infiltrate admixed with lymphocytes and macrophages that predominantly involve the dermis. Nodular aggregates of eosinophils surrounding dermal collagen fibers suggestive of ‘flame figures’ were identified. Luna histochemical stain was used and highlighted the deposition of eosinophilic granules over the collagen bundles confirming the presence of flame figures. Laboratory workup revealed peripheral eosinophilia, but a comprehensive clinical evaluation failed to reveal a systemic disease and ultimately the diagnosis of eosinophilic cellulitis ‘Wells Syndrome’ was rendered. After a short course of immunosuppressive therapy, the patient experienced a complete resolution of the skin lesions on his last follow-up visit several weeks from the initial diagnosis. This case highlights the various clinical forms that Wells syndrome may present with and may serve as a good example for the use of Luna stain as a simple and cost-effective diagnostic tool that can help to arrive at the accurate diagnosis and inform therapy.

Retreatment with immunosuppression for 23 patients with refractory or relapsed severe aplastic anemia

目的分析难治/复发重型再生障碍性贫血（SAA）患者二次免疫抑制治疗（IST）的疗效和安全性。方法回顾性分析23例IST难治或复发SAA患者应用二次IST[包括抗胸腺/淋巴细胞球蛋白（ATG/ALG）+环孢素A或大剂量环磷酰胺（HD-CTX）方案]的临床资料及疗效。结果共23例患者纳入研究，男11例，女12例，进行二次IST时的年龄为21（11~62）岁。难治SAA共10例，两次IST间隔时间为7（6~12）月。复发SAA患者13例，初次IST至复发时间为36（9~50）个月，复发至二次IST时间为1（0.5~24）个月，两次IST间隔时间为39（14~51）个月。6个月总体血液学反应率为69.5%（16/23）；二次IST开始1周内早期死亡2例，均为两次IST应用相同剂型ATG/ALG患者。分组疗效：难治SAA 60%（6/10），复发SAA 77%（10/13）；二次IST药物选择ATG/ALG组64%（7/11），HD-CTX组75%（9/12）。获得血液学反应的患者中2例患者再次复发，均为复发组患者，第三次应用IST后再次获得治疗反应。结论二次IST是难治与复发SAA患者安全有效的治疗手段；应用相同剂型ATG/ALG进行二次IST时应注意早期血清病反应，更换ATG/ALG剂型或换用其他IST方案可减少相关风险；二次复发患者应用第三次IST仍有机会获得治疗反应。

The Path to Cure: Using Haploidentical (haplo) Donors and High-Dose Post-Transplant Cyclophosphamide (PTCy) for Treatment-Naïve and Refractory Severe Aplastic Anemia (SAA)

SAA is a life-threatening hematopoietic stem cell disorder that is often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis and eliminate clonality. Our group has shown that PTCy after related HLA-haplo BMT can facilitate engraftment and yield low rates of relapsed and refractory (R/R) SAA. Given the risk of relapse or secondary clonal disease following immunosuppressive therapy (IST) is > 50% at five years, we decided to implement this treatment paradigm in untreated SAA. Here, we review the haplo outcomes in SAA, with an update in R/R SAA patients and new results in treatment-naïve (TN) SAA patients using haplo donors and PTCy. Patients were eligible with SAA. Fanconi anemia and short telomere patients were excluded. R/R patients had ≥ one course of IST. The conditioning regimen included standard published haplo backbone of antithymocyte globulin, low dose CY, and total body irradiation (TBI). All R/R patients received 200cGy. The TBI dose for the TN cohort was modified after 3 graft failures (GF) in initial 7 patients treated at 200cGy; thus, the last 8 TN patients received 400cGy. After the marrow graft was infused on day 0, cyclophosphamide 50mg/kg/day IV on days +3,+4 post-transplant was administered. All received mycophenolate mofetil beginning day +5 through 35 and tacrolimus day +5 to 365. Engraftment definitions include: absolute neutrophil count >1.0 x10E9/L for three consecutive days; days from last red blood cell transfusion for hemoglobin and platelet count >50,000 for 7 days without transfusion. Thirty-five SAA patients received haplo BMT: 20 R/R and 15 TN. The median follow-up is 31 months (90% CI: 26.0, 45.4). The median age was 25 (range, 4-69) years, with 23 patients > age 20 and 57% were males. The median related haplo donor age was 34 years (range, 19-57), including three non-first degree relatives. Table 1 shows data by cohort. Median time to neutrophil recovery was 17 days (range 15-88), to red cell recovery 23 days (range 6-58) and to platelet recovery 28 days (range 15-108). At the time of BMT, 25 of 35 patients had evidence of clonality (mostly PNH clones). Four of 35 patients (11.4%) (95% CI: 3.2, 26.7%) experienced GF. There was one GF out of 20 patients in the R/R group (5%) (95% CI: 0.1, 24.9%) and 3 of 15 in the TN group 20% (95% CI: 4.3,48.1%, p= 0.20). OS for all patients (Figure 1) is 94% (90% CI: 88,100%) at one and two years, 100% in the R/R group and 86% (90% CI: 72, 100%) in the TN group. The cumulative incidence of grade II-IV aGVHD at day 100 is 9% (90% CI: 1, 17%). The cumulative incidence of chronic GVHD at 2 years is 9% (90% CI: 1,17%). All R/R patients are alive and well, and fully engrafted with 100% donor chimerism; patient with primary GF is 100% chimeric after 2nd transplant from different haplo donor. One patient has extensive cGVHD. Of the first 7 TN patients who received 200cGy TBI, 4 are fully engrafted and well; of the 3 with GF, 2 died from infection and one is now 100% chimeric using second haplo donor. After increasing the TBI dose to 400cGy, the subsequent 8 patients are alive with full donor chimerism. Nonmyeloablative haplo BMT with PTCy represents a potential cure in SAA, with all 20 R/R currently alive, disease-free (including eradication of clonal diseases), and no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates. Perhaps this is not surprising given that the potential beneficial effect of front-line IST on engraftment is absent. The increase in TBI dose to 400cGy in TN patients appears to achieve more durable engraftment without early greater toxicity (infection, delayed engraftment, GVHD); more patients and longer follow up are required to understand rates of fertility and other survivorship issues. Alternative donor BMT (including haplo donors) should be offered to all SAA patients with R/R SAA who are fit enough to tolerate non-myeloablative conditioning. A potential advantage of haplo donors over unrelated donors is that the transplant center has full control and oversight of allograft quality, which can be especially important with the use of the preferred allograft source for SAA, bone marrow. Non-myeloablative haplo BMT in TN SAA could lead to a paradigm-shift in the field, such that essentially all children and fit adults can proceed quickly to a relatively safe, curative BMT. Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Cooke:Jazz pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Association of Urinary Plasminogen-Plasmin with Edema and Epithelial Sodium Channel Activation in Patients with Nephrotic Syndrome

Background: Previous animal experiments and small human studies suggest that urinary plasmin can activate the epithelial sodium channel (ENaC) and contribute to sodium retention in nephrotic syndrome (NS), but this however is not well studied in clinical settings, and its relevance to edema formation is not well characterized in humans. We have investigated the association between urinary plasmin and clinical phenotypes in a large group of patients with NS from multiple etiologies, aiming to assess the role of urinary plasmin in sodium handling and edema formation. Methods: Two hundred and three NS patients with urine and blood samples were divided into mild and severe symptom groups based on their edema severity. Twenty six of them had serial samples collected during the course of immunosuppressive therapy. The plasminogen-plasmin level and other key parameters were assayed, and their association with clinical manifestations were analyzed. Results: One hundred and one of the 203 patients had renal biopsies performed, the results of which had included all the common types of primary NS and various types of secondary NS. Quantitative comparison and multivariate logistic regression analysis identified urinary plasminogen-plasmin to creatinine ratio (uPLG-PL/C), serum albumin, D-Dimer, and cardiac dysfunction history, but not albuminuria or 24-h urine protein, as independent risk factors for edema (p < 0.01). In patients who were treated and had serial samples, a decrease in uPLG-PL/C was identified as an independent influencing factor of edema remission (p < 0.01). Finally, the urinary fractional excretion of sodium (FENa) in patients was inversely correlated with the fractional excretion of potassium (FEK; p< 0.001), and FEK/FENa ratio was positively correlated with uPLG-PL/C (p < 0.001), suggesting a close association between uPLG-PL and ENaC activation. Conclusions: Our study identifies uPLG-PL abundance as an independent influencing factor of edema in adult NS patients, and supports the conclusion that plasmin-dependent ENaC activation is an important pathophysiological mechanism of sodium retention and edema formation in humans with NS.

A CASE OF LATE DIAGNOSIS OF FAMILIAL MEDITERRANEAN FEVER COMPLICATED BY AA-AMYLOIDOSIS

The aimof study was to describe a clinical case of a hereditary disease with autosomal recessive type of inheritance – familial Mediterranean fever (FMF).Materials and methods.Patient A., 19 years old, Armenian, was hospitalized in the Department of rheumatology of the clinical hospital with complaints of periodic temperature rises to 39 °C, paroxysmal pain in the abdomen, ankle and hip joints, legs edema. In anamnesis from 8 months of age there were attacks of 1–2 day abdominal pain in combination with febrile fever; from 2 years there were arthralgia of the ankle joints, followed by knee and hip. Attacks of fever and joint syndrome recurred 3–4 times a year, lasted for 2–3 days, and disappeared spontaneously. Treatment with nonsteroidal anti-inflammatory drugs and small doses of prednisone was carried out. The examination in the hospital revealed nephrotic syndrome without impaired renal function, increasing of erythrocyte sedimentation rate (up to 62 mm/h), C-reactive protein (up to 60 mg/dl), leukocytosis (up to 16.7 × 109/L). The immunological examination revealed no abnormalities. Bacteriological and serological studies have ruled out the possibility of infectious diseases. Electrocardiography, echocardiography, ultrasound of abdomen and kidneys, multispiral computed tomography of kidneys and retroperitoneum, magnetic resonance imaging of the sacroiliac joints, nephrobiopsy were performed.Results.During the examination, a wide differential diagnosis with infectious and rheumatic diseases was carried out. Taking into account the polysyndromicity of clinical manifestations, systemic lupus erythematosus was suggested. An induction course of immunosuppressive therapy was conducted, that was ineffective. The diagnosis of systemic lupus erythematosus was doubtful and to clarify the nature of kidney morphological changes nephrobiopsy was performed that revealed the presence of kidneys AA-amyloidosis. Given these data in conjunction with clinical manifestations, the patient»s nationality, FMF was diagnosed and colchicine 2 mg/day was appointed. It was possible to stop the clinical symptoms of inflammation in FMF, but the nephrotic syndrome due to amyloidosis persists.Conclusion.The presented observation demonstrates the complexity of FMF diagnosis that verified 18 years after the appearance of the first disease symptoms. The diagnosis was helped by the presence of disease clinical manifestations and kidneys morphological study that revealed the development of a serious complication of periodic disease – AA-amyloidosis. Treatment with colchicine allowed to stop the symptoms of periodic disease.

PSY90 - Health Resource Burden Among Patients with Severe Aplastic Anemia who Have Had Insufficient Response to Immunosuppressive Therapy: A Retrospective Chart Review Study

To examine healthcare resource utilization (HRU) among patients with severe aplastic anemia (SAA) with insufficient response to immunosuppressive therapy (IST) in real-world practice. A retrospective chart review was conducted at Dana-Farber Cancer Institute, US (DFCI) and Hôpital Saint-Louis, France (HSL). Eligible patients were ≥18 years old, diagnosed with acquired SAA between 1/1/2006-7/31/2016, had insufficient response to ≥1 course of IST, and had ≥12 months follow-up post diagnosis. SAA-related HRU was summarized with incidence rates. Among the 40 patients (NDFCI=20; NHSL=20), mean age at diagnosis was 44.1 years and 52.5% of patients were women. During follow-up, 25.0% of patients died; median follow-up time after SAA diagnosis was 48.3 months. 95.0% of patients received antithymocyte globulin (ATG) in combination with cyclosporine or tacrolimus as primary therapy prior to hematopoietic stem cell transplant (HSCT). The most common secondary SAA therapies prior to HSCT were eltrombopag (27.5%) and androgens (15.0%). 75% of patients received ≥1 HSCT with a median time of 15.7 months after first IST. Prior to HSCT, the mean frequency of transfusions per patient per month (PPPM) was 2.7 red blood cell (RBC) and 3.3 platelet transfusions. The mean SAA-related HRU rates per patient per year (PPPY) were 0.9 hospitalizations, 0.4 emergency room visits, and 12.8 office visits. Among patients treated with eltrombopag (N=11), the mean number of RBC transfusions PPPM was reduced from 2.2 to 1.3 and platelet transfusions from 2.9 to 2.1 after eltrombopag treatment. Similarly, SAA-related HRU rates appeared lower after eltrombopag initiation (∆hospitalizations: -0.5; ∆emergency room visits: -1.0; ∆office visits: -10.2 PPPY). This study is among the first to quantify the transfusion and healthcare resource burden of SAA. In a subgroup of patients receiving eltrombopag, there was a trend toward a reduction in transfusion frequency and HRU following eltrombopag initiation.

Role for primary immunosuppression with everolimus after pulmonary transplantation

PurposeEverolimus is a proliferation signal inhibitor used for triple immunosuppressive therapy following solid organ transplantation. Its positive benefits, such as reduction of acute rejection episodes and reduced nephrotoxicity have been shown in kidney- as well as heart transplantation. However the role of everolimus is less well defined in lung transplantation. We thus wished to study the effect of primary immunosuppression with everolimus in a preclinical large animal lung transplantation model. MethodsLeft-sided single lung transplantation from MHC-mismatched donors was performed in 11 adult minipigs. Intravenous pharmacologic immunosuppression was maintained for 28 days with 1.5 mg/kg/d methylprednisolone, 1.0 mg/kg/d azathioprine and cyclosporine A (blood levels 300-500 ng/ml; CsA group; n = 5). A further group (CsA + Ev; n = 6) received methylprednisolone, CsA (200–300 ng/ml) and Everolimus (5–10 ng/ml). Immunosuppression was discontinued on postoperative day (POD) 28. Graft survival was monitored by sequential chest X-rays, bronchoscopies and transbronchial biopsy histology. ResultsAll animals survived the 28 day course of immunosuppressive therapy and showed healthy grafts on POD 28. Median allograft survival in the CsA group was 55 ± 15 days. CsA + Ev grafts showed median survival of 49 ± 86 days (p = 0.37). ConclusionWhereas everolimus might be advantageous as maintenance immunosuppressive agent, this data does not support an important role for everolimus in the immunosuppressive induction phase following lung transplantation.