Standard Immunosuppression Research Articles

Successful Transplantation of 96 Hepatitis C-positive Donor Hearts in the Era of Direct-Acting Antiviral Therapies

For patients awaiting heart transplantation (HT), hepatitis C virus (HCV)-positive donors offer to expand the donor pool, shorten wait times and decrease wait list mortality. While early reported outcomes have been promising, knowledge of 1-year outcomes in larger cohorts of patients remains unclear. Between September 2016 and September 2019, 96 patients underwent HT from HCV-positive donors, 83 of whom were viremic at time of organ recovery. All patients were treated with standard immunosuppression and, for those who developed donor-derived HCV (dd-HCV), with a course of direct-acting antiviral (DAA) therapy. Data collection and analysis were performed after obtaining IRB approval and informed patient consent. Baseline characteristics: Mean age of recipients at time of HT was 52 ± 12 years (72% male, 68% Caucasian, 44% on left ventricular assist device support). Mean age of donors was 32 ± 7 years. Among donors, results of HCV antibody (Ab) and nucleic acid testing (NAT) were: 80 Ab+/NAT+, 13 Ab+/NAT-, 3 Ab-/NAT+. Time to transplant: Among all patients, median active waitlist time from consent to acceptance of HCV-positive donors was 4 days (IQR 1, 17). Hepatitis C testing and treatment: No recipients of NAT- donor hearts developed HCV infection. Of 83 patients who received NAT+ donor hearts, 80 (96.4%) developed dd-HCV. Treatment with DAA therapy was well tolerated and yielded sustained virologic responses in 100% of treated patients (n=52, to date). Survival: Among 80 patients with dd-HCV, survival at 30-days and 1-year post-HT was 91.2% and 88.3%, respectively, not significantly different when compared to patients transplanted with HCV-negative donors during the same time frame (30-day survival 96%, p=0.10; 1-year survival 91.6%, p=0.27). In the era of direct-acting antiviral therapies, hepatitis C-positive donors are a viable strategy to expand the donor pool, potentially reducing waitlist duration and mortality.

Efficacy and Tolerability of Isavuconazole versus Posaconazole for Fungal Prophylaxis after Lung Transplantation

Azole antifungals are commonly prescribed for fungal prophylaxis (ppx) following lung transplant, but have many side effects and drug interactions. Isavuconazole, a new broad-spectrum azole antifungal, may obviate these issues. We retrospectively reviewed all lung transplant recipients (LTR) from February 2018 through September 2019 who received either ISA or POS for fungal ppx for 3 months post-transplant. Prior to February 2019 all patients received POS for ppx. Starting February 2019, POS was replaced by ISA at standard dosing. All patients received basiliximab induction and standard triple immunosuppression post-transplant. Surveillance bronchoscopies were performed at 1, 3, 6, and 12 months post-transplant. In total, we reviewed 24 LTR who received ISA and 29 who received POS. Baseline characteristics were similar between groups. Median duration of follow-up was significantly shorter for the ISA group (137 vs. 340 days, p<0.01). Breakthrough fungal infections occurred in 3 (13%) and 2 (7%) patients in the ISA and POS groups, respectively (p=0.65). All ISA patients developed oropharyngeal candidiasis; in the POS group there was one each of candida empyema and mold colonization. Post-ppx fungal infections occurred in 1 (4%) and 5 (17%) patients in the ISA and POS groups, respectively (p=0.20). All of these were mold colonization except for one case of oropharyngeal candidiasis. There was no difference between fungal-infection free survival based on Kaplan-Meier analysis (p=0.69). POS was held in two cases and discontinued in 1 patient due to a drug interaction causing hepatotoxicity compared to zero patients receiving ISA (p=0.24). Breakthrough fungal infections were similar between LTR receiving ISA or POS for fungal ppx. Longer follow-up of ISA patients is needed for definitive comparison of long-term infection risk. POS was discontinued in more patients due to drug interactions. ISA is a reasonable choice for primary fungal ppx in LTR.

Blood Eosinophilia Predicts Poor Outcome in Lung Transplant Recipients

Eosinophils are associated with the onset of chronic respiratory diseases like asthma and COPD. In lung transplantation, patients with increased bronchoalveolar lavage eosinophils demonstrated a worse chronic lung allograft dysfunction (CLAD)-free survival and overall survival. We investigated the association between blood eosinophilia, graft survival and CLAD-free survival after lung transplantation. A retrospective analysis was performed including all transplanted patients within our center between 2011 and 2016 (n=376). Blood eosinophils were measured as part of the routine clinical follow-up including all measurements prior to 01/06/2019. A ROC analysis was performed to define cut-offs for blood eosinophilia and patients were subsequently divided in those with high blood eosinophilia vs. those with lower eosinophilia based on the defined cut-off. All patients received oral steroids as part of their standard immunosuppressive drug regimen. ROC analysis revealed that the optimal threshold for blood eosinophilia is >7.85% (p=0.0026) for overall survival and >7.75% (p=0.001) for CLAD-free survival. Using a threshold of >8%, 112 patients had high blood eosinophilia and 264 had low eosinophilia (16 patients developed high eosinophilia after CLAD). Patients with blood eosinophilia >8% demonstrated worse graft survival (p=0.004) and CLAD-free survival (p=0.0076) compared to those with lower blood eosinophilia. Within the high eosinophilia group, 65 (58%) patients were diagnosed with CLAD, of which 42 (37.5%) patients had BOS and 23 (20.5%) had RAS. In the group with lower eosinophilia, 80 (30.3%) patients developed CLAD with 71 (26.9%) BOS and 9 (3.4%) RAS (p<0.0001). Lung transplant recipients with high blood eosinophilia (>8%) demonstrate inferior graft survival and CLAD-free survival, specifically RAS. These findings require further research and may lead to the development of an easy to use, non-invasive marker for poor transplant outcome.

Prevalence of Acute Cellular Rejection and Its Impact on Survival Post Heart Transplantation in the Contemporary Era

Identify the prevalence and associates of ISHLT grade ≥2R acute cellular rejection (≥2CR) and its impact on survival post heart transplantation in a well-phenotyped, modern era Irish cohort all of whom receive induction therapy. Retrospective analysis of 88 patients who underwent heart transplantation between 2014 and 2019 (mean age 49.8 ± 13.02 years; female 29.5%). Data was collected on recipient and donor anthropometrics, HLA profile, panel reactive antibodies (PRAs) ischaemia time, cytomegalovirus (CMV) serostatus and endomyocardial biopsy results over a median follow up of 2.04 years (IQR 3.18). Kaplan Meier survival, univariate and multivariate cox regression analysis were performed. Standard immunosuppression was with basiliximab induction, a calcineurin inhibitor, steroid and antimetabolite. All-cause mortality at 1 year was 14%. In those patients surviving to first biopsy (n=82), 55% experienced at least 1 episode of ≥2CR at a median time of 53.5 days (IQR 149) and cumulative survival was reduced in this group (p=0.04). More than 1 episode of ≥2CR was not associated with an incremental mortality risk. Intermediate-high risk CMV serostatus was independently associated with increased mortality on multivariate analysis (HR 3.16; 95%CI 1.04-9.65; p=0.04) but not with an increased risk of ≥2CR. There was no association between ischaemic time, PRAs, other recipient/donor matching characteristics, number of HLA mismatches or mismatches confined to any of the 6 HLA subclasses on survival or development of ≥2CR. In a modern era Irish cohort where induction therapy is standard, patients who experienced ≥1 episode of ≥2CR post transplant had reduced survival. Intermediate-high risk CMV serostatus was the only independent associate of increased mortality but not for ≥2CR. Further work in an extended cohort will focus on understanding the mechanisms underpinning rejection in this contemporary population and its consequences.

Low-dose Thymoglobulin vs Basiliximab Induction Therapy in Low-Risk Living Related Kidney Transplant Recipients: A Prospective Randomized Trial

ContextThymoglobulin is used effectively as induction agent in kidney transplantation but the optimal dose is not well established. ObjectiveDemonstrate that low-dose thymoglobulin (3 mg/kg) has similar efficacy and safety compared to basiliximab induction in low-risk kidney transplantation under standard maintenance immunosuppression Design, Setting, ParticipantsProspective randomized study in kidney transplant patients (12/2016-05/2018). Inclusion criteria: Recipients > 18 years, first living donor transplant. Exclusion criteria: Second and multiorgan transplant, ABO incompatibility, positive cross-match, panel reactive antibodies (PRA) > 30%, positive donor-specific antibody, human immunodeficiency virus, hepatitis B surface antigen, hepatitis C virus positive, white blood cells < 2000 cells/mm3, platelets < 75,000 cells/mm3 and malignancy. InterventionGroup A: basiliximab (20 mg D0 and D4). Group B: thymoglobulin (3 mg/kg total). Maintenance immunosuppression: tacrolimus, mycophenolate mofetil, and steroids. Main Outcome MeasuresBiopsy-proven acute rejection (BPAR), delayed graft function, slow graft function, leukopenia, infections, adverse events, graft loss, estimated glomerular filtration rate, and death within 12 months. Results100 patients (basiliximab, n = 53) (thymoglobulin, n = 47) were included. Donor and recipient characteristics were similar except for longer dialysis (basiliximab), PRA class I (1.2% basiliximab, 4.5% thymoglobulin), HLA match (basiliximab 2.8, thymoglobulin 2.2), and cytomegalovirus status. BPAR rate was basiliximab 3.8% and thymoglobulin 6.4% (P = ns). Delayed graft function (basiliximab 3.8%; thymoglobulin 4.3%), slow graft function, and 12-month leukopenia (basiliximab 11.3%, thymoglobulin 21.3%) were similar between groups (P = ns). There was no difference in infections and adverse events between groups. Patient and graft survival were as follows: basiliximab 98.1% and 92.5%, thymoglobulin 100% and 93.6% (P = ns). ConclusionLow-dose thymoglobulin induction (3 mg/kg) can be used effectively and safely in low-risk kidney transplantation with good results during the first year post-transplant.

SAT-400 RITUXIMAB IN THE TREATMENT OF COLLAPSING FOCAL SEGMENTAL GLOMERULOSCLEROSIS- A CASE SERIES

Collapsing focal segmental glomerulosclerosis (cFSGS) is an aggressive disease presenting with a severe form of nephrotic syndrome that progresses rapidly to end-stage renal disease (ESRD) and is unresponsive to standard immunosuppression. We report here 7 cases of HIV- negative collapsing FSGS treated with rituximab. This was a retrospective study conducted at a tertiary care centre in India. The clinical data of patients with cFSGS treated with rituximab was retrieved from the FSGS registry at our centre. Complete remission was defined as 24 urinary protein of < 0.3 g/d accompanied by a normal serum albumin concentration, and a normal serum creatinine. Partial remission was defined as 24 hours urinary protein excretion < 3.5 g/d and a 50% or greater reduction from peak values; accompanied by an improvement or normalization of the serum albumin concentration and stable serum creatinine. A total of 7 patients of the 50 cFSGS received rituximab. The median age the patients was 30 years (IQR-24-30), out of which 5 were males and 2 female. The median serum creatinine, serum albumin, 24 hours urinary protein at presentation was 2.5(IQR 2-3.4) mg/dl, 2.8 (IQR 1.8-3.9) mg/dl and 6.3(IQR 4.9-7,8) g respectively. Two patients were steroid-resistant, 1 was steroid dependant, 2 were steroid and tacrolimus resistant, and one was steroid-resistant and tacrolimus dependant before starting rituximab. Five patients received CD-19 targeted rituximab, two received four doses of 375 mg/m2, and one patient received two doses of 375 mg/m2. The median cumulative dose of rituximab in CD-19 targeted therapy (after an initial dose of 375 mg/m2, patients having CD-19 levels (on monthly monitoring) >5/µL or>1% received additional low-dose (100 mg) of rituximab) and weekly regimen was 750 mg and 2000 mg, respectively. At the end of follow-up (median 18 months), four (57.14 %) patients went into remission (two partial, two complete remissions) and 2(28.5 %) were resistant to therapy, and 1(14.2 %) progressed to ESRD. Rituximab achieved remission in 60% of the cFSGS cases.

Rapid reduction of high-level pre-formed donor-specific antibodies after simultaneous liver-kidney transplantation: a report of two cases

BackgroundKidney transplantation performed in the presence of high-titre donor-specific antibodies (DSA) may result in hyper-acute or accelerated antibody-mediated rejection and rapid allograft loss. Previous studies have shown that this risk may be mitigated with simultaneous liver-kidney transplantation (SLKT); however, the mechanisms are not well defined. Here we report the evolution of pre-formed, high-level DSAs in two highly sensitised SLKT recipients peri-operatively and describe a profound sustained depletion of all DSAs from the time of liver anastomosis with no extra desensitisation therapy required.Case presentationTwo patients underwent SLKT and received our centre’s standard renal transplant immunosuppression with basiliximab and methylprednisolone for induction therapy and prednisolone, mycophenolate and tacrolimus for maintenance therapy. HLA antibody samples were collected pre-operatively, and immediately post-liver and post-kidney revascularisation, and then regularly in the post-transplant period. Complement Dependant Cytotoxicity (CDC) crossmatches were also performed. Both patients were highly sensitised with a PRA over 97%. One patient had a positive B- and T-cell crossmatch pre-transplant. These positive CDC crossmatches became negative and the level of pre-formed DSAs reduced profoundly and rapidly, within 3 h post-liver revascularisation. The reduction in pre-formed DSAs, regardless of subclass, was seen immediately post-liver revascularisation, before implantation of the renal allografts. No significant reduction in non-donor specific HLA-antibodies was observed. Both patients maintained good graft function with no rejection on kidney allograft protocol biopsies performed at 10-weeks post-transplant.ConclusionsThese cases support the protective immunoregulatory role of the liver in the setting of SLKT, with no extra desensitisation treatment given pre-operatively for these highly sensitised patients.

A Phase 2 Study of F-652, a Novel Tissue-Targeted Recombinant Human Interleukin-22 (IL-22) Dimer, for Treatment of Newly Diagnosed Acute Gvhd of the Lower GI Tract

Background IL-22 has been shown to support intestinal mucosa after damage through multiple mechanisms, including promotion of epithelial survival and regeneration as well as induction of innate antimicrobial molecules such as REG3. In experimental murine models, aGVHD resulted in elimination of host-derived IL-22-producing cells, IL-22 deficiency increased GVHD mortality and GI pathology, and early initiation of treatment with exogenous IL-22 reduced GI pathology and improved survival. We thus tested if the addition of IL-22 to corticosteroids could promote healing of GI tract injury and improve treatment response in patients with lower GI aGVHD. Methods We conducted a 27-patient open-label, single-cohort, multicenter prospective phase 2 study between 05/16 and 05/19. Eligible pts were ≥ 18 yrs old and had new onset biopsy-proven grade II-IV lower GI aGVHD following an allo-HCT. Pts received F-652 once weekly at a dose of 45 μg/kg x 4 weeks in combination with standard corticosteroid treatment. Primary endpoints included PK, safety, and day 28 lower GI aGVHD response. Additional endpoints included day 56 treatment response, evaluation of changes in gut microbiota by 16S sequencing, and plasma GVHD biomarkers. The study was powered to distinguish between an unpromising response rate of 35% and a promising response rate of 60%. Results The 27 pts (median age 55 yrs, mostly PBSC recipients) had predominantly stage 2-4 lower GI GVHD (17/27, 63%), with 6/27 (22%) pts having stage 3 and 6/27 (22%) pts having stage 4 disease. All pts had detectable F-652 levels. Overall, 19/27 achieved a day 28 response (70%, 90%CI: 56-79, Fig 1A). Response to treatment based on Ann Arbor Risk, evaluable in 20 pts, was 7/12 (58%) with high, 3/4 (75%) with intermediate, and 4/4 (100%) with low risk biomarkers (Fig 1B). At day 56, 16 pts (59%) remained treatment responders. 3 pts had repeat GI biopsy after treatment and demonstrated improvement in GI epithelial injury (Fig 2). Additionally, in a subset of 17 pts with stool samples collected, microbial diversity and relative abundance of protective commensal Blautia appeared increased in pts with a clinical response to F-652 (p = 0.082 and 0.048, respectively, Fig 3A-B). Serious TEAEs were observed in 11 pts (40%) including enterocolitis (n = 1), pyrexia (n = 1), infection (2 sepsis, 1 device-related, 1 pneumonia, 1 sinusitis), musculoskeletal (n = 2), and respiratory (n = 1). One patient was diagnosed with squamous cell carcinoma 8 months after F-652 treatment. Conclusion IL-22 in combination with corticosteroids was well tolerated and the 70% lower GI aGVHD response rate met the primary efficacy endpoint. These findings support further development of this approach and provide a proof-of-concept for combining standard immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa, promote microbial health, and improve GVHD treatment response.

Post Renal Transplant Collapsing Glomerulopathy is Associated with Poor Outcomes.

Introduction:Collapsing glomerulopathy (CG) is a distinct morphologic pattern of proliferative renal parenchymal injury. It differ from focal segmental glomerulosclerosis (FSGS) by clinicopathologic pattern and its adverse outcome. The clinical significance of CG in renal allograft biopsies is not yet clear due to scant data and less occurrence of CG in renal transplant recipients. We conducted this single-center retrospective study to evaluate the prevalence, clinicopathological features, and outcome of post renal transplant CG.Subjects and Methods:We studied 127 renal allograft biopsies performed over a period of 45 months (Jan 2015–Oct 2018). A diagnosis of CG was made if at least one glomerulus demonstrated global or segmental collapse of the glomerular capillary walls, associated marked hyperplasia, and hypertrophy of the overlying visceral epithelial cells. We analyzed clinical, biochemical, and pathological characteristics and its impact on renal allograft outcome. Statistical analysis was performed and continuous variables were expressed as means ± standard deviation (SD) or medians (interquartile range and noncontinuous data were expressed in percentage and numerical values.Results:The prevalence of CG was 5.3% (7/127) of allograft biopsies. Out of the seven patients, six patients had undergone live donor transplant and one patient had undergone deceased donor renal transplant. The native kidney disease was unknown in these patients except one (IgA nephropathy). The median duration of diagnosis for CG was 17 months after transplantation (range 5–132months). Presenting symptoms were pedal edema and hypertension in 71.4% (5) patients each. All patients had proteinuria of more than 1 gm and renal allograft dysfunction and median serum creatinine of 3.05 mg/dl (1.5–4.8 mg/dl). All patients received standard triple immunosuppression. Over a period of 2–20 months, 57.14% (4) patients developed a graft failure and 43% (3) of the other patients had functioning grafts with serum creatinine of 1.5–4.2 mg/dl.Conclusions:CG presents with moderate to severe proteinuria and may lead to rapid graft dysfunction and subsequent graft failure in most of the patients.

Preformed donor-reactive T cells that persist after ABO desensitization predict severe T cell-mediated rejection after living donor kidney transplantation - a retrospective study.

Preformed donor-reactive T cells are relatively resistant to standard immunosuppression and account for an increased incidence of T cell-mediated rejection (TCMR) and inferior kidney allograft outcomes. We analyzed 150 living donor kidney transplant recipients (KTRs) of a first kidney allograft. Ninety-eight ABO-compatible (ABOc) and 52 ABO-incompatible (ABOi) KTRs were included. Samples were collected at 6 time points, before rituximab, before immunoadsorption and pretransplantation, at +1, +2, and +3months posttransplantation, and donor-reactive T cells were measured by interferon-γ ELISPOT assay. Twenty of 98 ABOc (20%) and 12 of 52 ABOi KTRs (23%) showed positive pretransplant ELISPOT. Eight of 20 ABOc-KTRs (40%) with positive pretransplant ELISPOT showed TCMR, whereas 17 of 78 ABOc-KTRs (22%) with negative pretransplant ELISPOT did (P=0.148). Seven of 12 ABOi KTRs (57%) with positive pretransplant ELISPOT showed TCMR, whereas only 3 of 40 ABOi KTRs (8%) with negative pretransplant ELISPOT did (P<0.001). Interestingly, 6 of 7 ABOi KTRs with positive pretransplant ELISPOT that persists after ABO desensitization developed TCMR. Among 118 KTRs with negative pretransplant ELISPOT, 10 of 72 ABOc-KTRs (14%), but 0 of 46 ABOi KTRs, developed positive posttransplant ELISPOT (P=0.006). Preformed donor-reactive T cells that persist despite ABO desensitization identify KTRs at highest risk of TCMR. Less de-novo donor-reactive T cells after ABO desensitization may account for less TCMR. Both, the use of rituximab and early initiation of calcineurin inhibitor-based maintenance immunosuppression may contribute to these findings.

Alcohol-Related Liver Disease as a New Risk Factor for Post-transplant Diabetes After Liver Transplantation

IntroductionPost-transplant diabetes mellitus (PTDM) is a serious and frequent metabolic complication after the transplantation of solid organs. PTDM incidence 12 months after the transplantation is 2.5%-25%. Materials and MethodsIt is a retrospective analysis with 6-month follow-up of patients after liver transplantation without diabetes mellitus type 1 or 2 at the time of transplantation. We recorded all known risk factors for PTDM; however, only patients with tacrolimus in standard immunosuppression protocol were included in the analysis. ResultsThe PTDM incidence in the group of 102 patients was 18.6%. We identified following independent risk factors for PTDM: alcohol-related liver disease (Hazard Ratio 1.8261 [1.2246-2.723], P = .0031) and average level of tacrolimus ≥ 10 ng/mL (2.5482 [1.1592-5.6019], P = .0199). PTDM was diagnosed in average 2.5 months after the liver transplantation. ConclusionPTDM leads to infections, cardiovascular disease, and decreased survival. The mechanism by which alcohol-related liver disease influences the development of PTDM remains unclear.

Time-Restricted Versus Standard Duration Immunosuppression after Allogeneic Hematopoietic Stem Cell Transplantation: Results from the Prospective Randomized Phase III HOVON-96 Trial

Background Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been established as a powerful treatment modality for patients with hematological malignancies. The graft-versus-leukemia effect, however, is strongly associated with the occurrence of graft-versus-host disease (GVHD) and subsequent transplant-related mortality. The current standard Dutch regimen for prevention of GVHD in T-cell replete (TCR) alloHSCT following reduced intensity conditioning (RIC) consists of mycophenolic acid (MA) and cyclosporine A (CyA) for three and six months post-transplant, respectively. However, as approximately 30% of patients will never develop GVHD, immunosuppressive overtreatment is of concern and might impair outcome. Aims In the present prospective randomized, multicenter, phase III trial we set out to compare time-restricted immunosuppression versus a standard immunosuppressive regimen. The primary objective was to increase the proportion of patients with non-severe GVHD (either acute GVHD grades I-II without gut involvement or chronic GVHD not requiring systemic treatment) within 180 days after transplantation and to reduce the relapse rate, without increasing severe GVHD. Secondary endpoints included time to acute and chronic GVHD, progression-free survival (PFS), GVHD-free/relapse-free survival (GRFS), overall survival (OS), and adverse events. Methods Hematological patients planned to undergo TCR alloHSCT with a related or unrelated 8/8 HLA matched donor were included. The trial randomized patients between three treatment arms. The current analysis includes all patients randomized between arms A and B. Immunosuppression consisted of CyA twice daily aiming for serum trough levels of 250-350 µg/L and MA 16 mg/kg twice daily with a maximum dose of 2160 mg a day. The standard regimen (arm A) prescribed to discontinue MA at day 84 post-transplant and CyA was continued until day +120 followed by tapering until day +180. In those randomized for the time-restricted regimen (arm B) MA was discontinued at day 28 post-transplant and CyA was continued until day +84 followed by tapering. Results A total of 389 patients were randomized 1:1 between arms A and B, of whom 95% (184 in arm A versus 185 in arm B) proceeded to transplant. The median age was 55 (range: 18-71), 57% were male. Fifty-one patients received myeloablative conditioning and 318 (86%) patients RIC. Donors were matched siblings for 135 patients and matched unrelated donor (MUD) for 233 patients. The majority of patients received peripheral blood stem cells, consisting of median 6.46x106/kg CD34+ cells/kg (range: 0.94-26.3) and median 230x106/kg CD3+ T cells (range: 0-936). Baseline patient and transplantation characteristics were equally distributed between the treatment arms. The proportion of patients developing non-severe GVHD within 180 days post-alloHSCT was 24% in both treatment arms, with an odds ratio (OR) of 1.01 (95% confidence interval 0.61-1.67, p 0.98). The cumulative incidence (CI) of grade II-IV and grade III-IV acute GVHD at 6 months post-alloHSCT was not significantly different between the two arms (47% and 15% versus 52% and 18%), nor was the maximum grade or organ involvement of acute GVHD. In addition, no difference was seen in the two-year CI of chronic extensive GVHD between the two treatment arms (51% versus 49%). The three-year estimate of PFS was 51% (44-59%) versus 52% (44-59%), respectively. The three-year CI of progression/relapse was 28% in arm A versus 27% in arm B. OS at three years was 59% (0.51-0.66%) versus 57% (0.50-0.64%). The one-year estimate of the composite endpoint GRFS was 14% (9-19%) in arm A, and 17% (12-22%) in arm B. Incidences and nature of adverse events were comparable in both arms. Conclusion A time-restricted combination of MA and CyA did not increase the proportion of patients with non-severe GVHD within 180 days after transplantation and resulted in similar outcome as compared to standard immunosuppression following alloHSCT using sibling and well-matched unrelated donors. Given the observed high CI of acute grade II-IV and chronic extensive GVHD and low GRFS for both the time-restricted and standard regimen, recipients of TCR RIC alloHSCT should be considered for more intensive immunosuppression. Figure Disclosures Nur: Novartis: Consultancy. Deeren:Alexion, Amgen, Janssen, Roche, Sunesis, Takeda, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Outcomes in Pediatric Patients with Severe Aplastic Anemia Treated with Standard Immunosuppression and Eltrombopag

Background: Immune aplastic anemia (SAA) disproportionally affects children and young adults. Immunosuppression (IST) remains the treatment of choice for patients less than 40 years of age without a fully human leukocyte antigen (HLA) matched sibling. In the pediatric population (aged &amp;lt;18 years), from NIH historic studies, horse antithymocyte globulin (h-ATG) and cyclosporine(CSA) regimes have produced good results, with an overall response rate (ORR) of 74% at 6 months, a relapse rate of 33% at 10 years, and an overall survival (OS) of 80% at 10 years (Scheinberg P, J Pediatrics 2008), generally better outcomes than in adults. Eltrombopag (EPAG) is an oral thrombopoietin-receptor agonist that has been shown to significantly improve response rates when combined with h-ATG and CSA for treatment-naïve patients (Townsley D, NEJM 2017). We report here a pediatric subgroup analysis of our clinical trial (NCT01623167) to assess whether the addition of EPAG to IST improved ORR in children with SAA. Methods: Between 2012 and 2018 a total of 39 patients &amp;lt;18 years of age with SAA were treated with front line EPAG in combination with h-ATG and CSA. We assessed ORR at 6 months, relapse rate, rate of clonal evolution, and OS. Additionally, we monitored for the development of clonal evolution and for the emergence of somatic clones. Germline testing for inherited marrow failure was performed in all patients. Response was defined by blood counts no longer satisfying criteria for SAA. Outcomes were compared to two treatment-naive cohorts: adult patients aged 18 years and older who received EPAG in combination with immunosuppression (adult EPAG group), and a historical cohort (from 1989 to 2010) of 87 pediatric patients aged &amp;lt;18 years who were treated with immunosuppression (pediatric IST group). The pediatric IST group included all patients treated with a h-ATG based regimen including h-ATG with CSA, and h-ATG with CSA and additional immunosuppression (either mycophenolate mofetil or sirolimus). A historical adult group (Adult IST group) of 322 patients treated from 1989 to 2010 with the same IST regimens as the pediatric IST group was also used as a comparator. Analyses were based on intention-to-treat. Results: Median age in the pediatric EPAG group was 15 years and in the pediatric IST group 11 years. Thirty-two patients (of an initial 39) were evaluable for response at 6 months. Seven patients (18%) were taken off study prior to 6 months to undertake bone marrow transplant, due to either failure to respond by 3 months or clinical urgency in count recovery. Overall, 28 (72%) of all treated patients achieved a response at 6 months, by comparison, responses were observed in 74% of the pediatric IST group (p=0.836) and in 83% in the adult EPAG group (p=0.143). In contrast, patients in the adult EPAG group had a significant difference in 6 month ORR compared with the adult IST group (83% versus 58%, p= &amp;lt;0.0001). The PK analysis of EPAG suggested comparable exposure in pediatric (6-17 years) and adult population. Of the 28 patients who achieved a response at 6 months, 43% relapsed, compared to 28% in the pediatric IST group (p=0.252). Median time to relapse in the pediatric EPAG group was 565 days from IST. There was no significant difference in survival between the pediatric EPAG group and either the pediatric IST group or the adult EPAG group. Clonal evolution occurred in 3 (8%) of patients (monosomy 7, del 5q, and translocation 5:12); 7% of patients evolved in the pediatric IST group. Somatic mutation testing was performed in 36 patients at baseline and was negative in all. At the 6 month timepoint, 5 patients had developed new somatic mutations (2 ASXL1, 2 ATRX, 1 BCOR), three clones appeared in responders and two in non-responders. Germline testing did not reveal any pathogenic variants. Conclusion: Eltrombopag added to immunosuppression did not improve ORR at 6 months in pediatric patients with SAA compared to our historical cohort of pediatric IST patients. In contrast, adults had much improved responses with EPAG. Some patients were taken off study prior to 6 month evaluation (18% compared to 6% in the pediatric IST group) to pursue BMT, likely reflecting recent improvements in outcomes and donor availability. In our study the addition of eltrombopag to IST did not provide any obvious therapeutic benefit to pediatric patients with severe aplastic anemia. This research was supported in part by the Intramural Research Program of the NIH and NHLBI. Disclosures No relevant conflicts of interest to declare.

Facilitating Resolution of Life-Threatening Acute Graft-vs-Host Disease with Human Chorionic Gonadotropin and Epidermal Growth Factor

Background: Acute graft-versus-host disease (aGVHD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation that fails to improve with intense immunosuppression in some patients. We hypothesized that urinary-derived human chorionic gonadotropin [uhCG] could help facilitate resolution of life-threatening aGVHD when added as supportive care via two potential mechanisms: immunomodulation (akin to its role in pregnancy) and supplementation of epidermal growth factor (EGF, to aid in epithelial repair). Methods: In phase I, 26 participants received subcutaneous injections of uhCG in addition to standard immunosuppression (13 initial therapy for Minnesota high risk aGVHD and 13 receiving 2nd line therapy). Participants underwent serial blood testing for biomarkers of hormone response, immune modulation, and aGVHD activity on study. Findings: UhCG was well tolerated, with no dose-limiting toxicities. Sixty-two percent of patients in the high-risk cohort and 54% of patients in the 2nd line cohort had a complete response at study day 28. Plasma EGF was elevated 6-fold (from 4 to 24 pg/ml, p=0.02) at 6 hours post-dose in the high risk cohort, in contrast to no peak in plasma EGF in the more severe 2nd line cohort. After 1 week of uhCG, patients demonstrated a 2-fold increase in regulatory T cell to conventional T cell ratio, suggesting immune modulation despite high dose steroids. Responding patients showed significantly lower plasma amphiregulin and higher plasma butyrate at study completion, suggesting improvement in mucosal damage over time. Interpretation: hCG is a novel, safe supportive therapy, proceeding to phase II testing at 2,000 units/m2 in high-risk aGVHD. Trial Registration: This study is registered at ClinicalTrials.gov (NCT02525029). Funding Statement: This study was funded by the BMT Fund for the Future (SGH), a Regenerative Medicine Minnesota clinical trial award (SGH), and R01 HL11879, R01 HL56067 and R37 AI34495 (BRB). SGH is a University of Minnesota Women’s Early Research Career (WERC) award recipient and conducted this study during her time as a WERC scholar. Declaration of Interests: The authors have no relevant financial conflicts of interest to disclose. SGH has provided consulting services for Incyte, Bristol Myers Squibb, Janssen, and CSL Behring. BRB receives remuneration as an advisor to Kadmon Pharmaceuticals, Inc, Five Prime Therapeutics Inc, Regeneron Pharmaceuticals, Magenta Therapeutics, BlueRock Therapeuetics and consulting services for Bristol-Myers-Squibb, Incyte, Equillium, Regimmune, Dr. Reddy, GT Biopharma and Incyte Corp; research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences, Inc, Abbvie Inc., Leukemia and Lymphoma Society, Childrens' Cancer Research Fund, and KidsFirst Fund, and is a co-founder of Tmunity. Ethics Approval Statement: This study was approved by the University of Minnesota Institutional Review Board, and all participants signed written, informed consent.

Impact of immunosuppressive therapy on brain derived cytokines after liver transplantation

BackgroundWhile acute neurotoxic side effects of calcineurin inhibitors (CNI) are well-known, data upon long-term effects on brain structure and function are sparse. We hypothesize that long-term CNI therapy affects the neuroimmune system, thereby, increasing the risk of neurodegeneration. Here, we measured the impact of CNI therapy on plasma levels of brain- and T cell-derived cytokines in a cohort of patients after liver transplantation (LT). MethodsLevels of T cell-mediated cytokines (e.g. Interferon-γ (IFN-γ)) and brain-derived cytokines (e.g. brain derived neurotrophic factor (BDNF), platelet derived growth factor (PDGF)) were measured by multiplex assays in plasma of 82 patients about 10 years after LT (17 with CNI free, 35 with CNI low dose, 30 with standard dose CNI immunosuppression) and 33 healthy controls. Data were related to psychometric test results and parameters of cerebral magnetic resonance imaging. ResultsIFN-γ levels were significantly higher in the CNI free LT patient group (p=0.027) compared to healthy controls. BDNF levels were significantly lower in LT patients treated with CNI (CNI low: p<0.001; CNI standard: p=0.016) compared to controls. PDGF levels were significantly lower in the CNI low dose group (p=0.004) and for PDGF-AB/BB also in the CNI standard dose group (p=0.029) compared to controls. BDNF and PDGF negatively correlated with cognitive function and brain volume (p<0.05) in the CNI low dose group. ConclusionOur results imply that long-term treatment with CNI suppresses BDNF and PDGF expression, both crucial for neuronal signaling, cell survival and synaptic plasticity and thereby may lead to cognitive dysfunction and neurodegeneration.

SUCCESSFUL SINGLE LUNG TRANSPLANT OF A HEPATITIS C POSITIVE DONOR TO AN HIV SEROPOSITIVE RECIPIENT WITH PULMONARY FIBROSIS

SESSION TITLE: Pulmonary Pathology SESSION TYPE: Fellow Case Reports PRESENTED ON: 10/20/2019 1:00 PM - 2:00 PM INTRODUCTION: With the successful medical management of HIV, seropositivity is no longer a contraindication to solid-organ transplantation. Extrapolation from the experience of liver and kidney transplants with seropositive HIV patients over the past decade has laid the early foundation for heart and lung transplantation. Additionally, the development of Direct Acting Antivirals (DAAs) has made hepatitis C positive organ donation possible. CASE PRESENTATION: We describe the case of a 60 year old male with HIV, hypertension and progressive pulmonary fibrosis on supplemental oxygen who presented to our institution for lung transplant evaluation. He was diagnosed with HIV in 2003 and has been compliant on antiretrovirals with an undetectable viral load and high CD4 count. He denies a history of opportunistic infections or prior malignancies. His pre-transplant evaluation shows he is HCV negative, but is CMV and EBV positive. Latent Tuberculosis screening with Quantiferon Gold was positive, with no prior history of tuberculosis infection or treatment for LBTI. In preparation for transplant, his antiretrovirals were optimized to avoid drug-drug interactions with tacrolimus. He was consented to join our institution’s single center pilot study using Mavyret for 8 weeks as treatment for Lung Transplant Recipients with HCV positive donors. He was listed and received a single left lung transplant from a hepatitis C positive donor (also EBV+/CMV+). He was started on standardized transplant immunosuppression and prophylaxis, as well as Mavyret 3 tablets daily for treatment of Hepatitis C per our research protocol. His hospital course was overall uncomplicated. He is currently two months post -transplant with a stable FEV1, continued control of HIV with undetectable viral load with normal CD4 counts, and has completed his HCV treatment. He is now HCV antibody positive but with undetectable viral load. DISCUSSION: The experience from liver and kidney transplant in HIV positive persons has helped optimize patient selection characteristics, as well as, immunosuppressive and HAART regimen for post-transplant medical management. However, data for efficacy of lung transplantation in HIV seropositive patients is limited to a few published case studies worldwide. Furthermore, while hepatitis C donors represent a potential viable means to meaningfully increase donor availability, transplants from hepatitis C donors to seronegative recipients represents only a very small proportion of all lung transplants. CONCLUSIONS: Our case is unique, as it is the first case report, to our knowledge, of lung transplant from a hepatitis C positive donor to an HIV seropositive recipient. This case illustrates the clinical viability of using hepatitis C donors for lung transplantation in HIV recipients. Reference #1: Young KA, Dilling DF. The Future of Lung Transplantation. Chest. 2019;155(3):465-473. Reference #2: Koval C., Malinis M., Mueller N., Krisl J., Hannan M., Grossi P., Huprikar S. Heart and Lung Transplantation Outcomes in HIV-Positive Recipients Am J Transplant. 2017;17 (suppl 3). Reference #3: Kern RM, Seethamraju H, Blanc PD, Sinha N, Loebe M, Golden J, et al. The feasibility of lung transplantation in HIV-seropositive patients. Ann Am Thoracic Soc. 2014;11(6):882. DISCLOSURES: No relevant relationships by Luis Angel, source=Web Response No relevant relationships by Sangita Goel, source=Web Response No relevant relationships by Melissa Lesko, source=Web Response

Retraction: Comprehensive Comparison of Three Different Immunosuppressive Regimens for Liver Transplant Patients with Hepatocellular Carcinoma: Steroid-Free Immunosuppression, Induction Immunosuppression and Standard Immunosuppression.

Retraction: Comprehensive Comparison of Three Different Immunosuppressive Regimens for Liver Transplant Patients with Hepatocellular Carcinoma: Steroid-Free Immunosuppression, Induction Immunosuppression and Standard Immunosuppression.

Renal Outcomes of Liver Transplantation Recipients Receiving Standard Immunosuppression and Early Renal Sparing Immunosuppression: A Retrospective Single Center Study.

Background.New-onset stage 4–5 chronic kidney disease (CKD) after liver transplantation (LT) is associated with high morbidity, mortality, and economic burden. In 2010, we instituted an early renal sparing immunosuppression (RSI) protocol for LT recipients with severe renal dysfunction (pre-LT dialysis/estimated glomerular filtration rate (eGFR)<30mL/min/1.73 m2 or post-LT acute kidney injury) consisting of 2 doses of basiliximab for induction and delaying tacrolimus to post-LT day 4–7. We examined the effect of early RSI on post-LT renal outcomes.Methods.Data on all adults who had LT between January 1, 2010, and December 12, 2014 were collected. We calculated the renal risk index (RRI) score for each LT recipient (https://rri.med.umich.edu). Primary outcome was new-onset post-LT stage 4–5 CKD.Results.Of 214 LT recipients, 121 (57%) received early RSI and 93 (43%) received standard immunosuppression. Cumulative incidence of new-onset stage 4–5 CKD was higher in early RSI compared with standard immunosuppression (P = 0.03). Female sex and RRI score were the significant risk factors for development of post-LT stage CKD in the entire study cohort as well as the LT recipients with RRI ≥ sixth decile (high-risk group).Conclusions.Delaying tacrolimus initiation combined with basiliximab induction did not have a durable effect on long-term renal outcomes in high-risk LT recipients. Further studies are needed to identify the effective strategies to preserve renal function by targeting patients at high risk for CKD progression.

Eltrombopag in Immune Thrombocytopenia, Aplastic Anemia, and Myelodysplastic Syndrome: From Megakaryopoiesis to Immunomodulation.

Eltrombopag is an orally available thrombopoietin receptor agonist indicated for the treatment of immune thrombocytopenia (ITP). Beyond the effect on megakaryopoiesis, the drug also showed a stimulating effect on the hematopoietic stem cell with consistent clinical efficacy in aplastic anemia (AA) and myelodysplastic syndromes (MDS). Eltrombopag is highly effective in ITP and less so in AA and MDS. This observation underlines the importance of residual normal hematopoiesis, which is maximal in ITP, minimal/absent in AA, and dysregulated in MDS. In ITP, the drug at 50-75mg daily induced up to 85% responses both in clinical trials and real-life studies, with the possibility of tapering and discontinuation. In AA, eltrombopag at 150mg daily was effective in about 40% of cases relapsed/refractory to standard immunosuppression or ineligible for bone marrow transplant. In MDS, the drug seems less effective, with responses in about a quarter of patients at various schedules. The efficacy of eltrombopag in ITP, AA, and MDS suggests the existence of common immune-pathological mechanisms in these diseases, including autoimmunity against peripheral blood cells and bone marrow precursors, as well as a possible evolution of one condition into the other. Additional mechanisms of action emerging from the clinical use of eltrombopag include modulation of T-regulatory cells, restoration of Fc-γ receptor balance in phagocytes, and an iron-mobilizing effect. In this review, we analyzed the most recent literature on eltrombopag use and efficacy in patients with ITP, AA, and MDS, exploring the basis for different dosing, combined treatments, and discontinuation in each context.

230.6: Multivisceral Transplant without an ostomy – 5-year experience

Introduction: Strides continue to be made in the care of patients following Intestinal Transplantation (ITx) yet, rejection continues to be a threat to its’ success. A temporary ostomy to assess the mucosa and easily perform a biopsy remains the diagnostic gold standard. However, patients with an ostomy may have high output and decreased renal function. A change in intestinal flora, as stool and mucosa are exposed to air, may trigger rejection. Methods: We retrospectively reviewed 101 primary ITx performed from Jan 2013 to Dec 2018. 27 Isolated Intestine-Colon transplants and 7 Modified MVT were excluded. 67 patients underwent a MVT. 4 died in OR from bleeding and 1 within 72 hours thus excluded as abdominal closure was not performed. Standard immunosuppression was induction with antithymoglobulin/rituximab and maintenance with tacrolimus/mTOR inhibitor. Results: Of 62 patients, 50 had 1-year follow up. 26 were pediatric (1-15yr) and 24 adult (19–68 yr). In 54% (27/50), no ostomy was performed. In 46%, an ostomy was performed- ileostomy in 12% (6/23), colostomy in 32% (16/23), hybrid colon ostomy in 2% (1/23). There was no difference between groups (Ostomy/No Ostomy) in length of stay (LOS) or admissions within the first year. LOS was 79 days with Ostomy(13–232) and 80 days (14–360) in No Ostomy. There was a trend for earlier discontinuation of parenteral nutrition in No Ostomy(32 days) vs. Ostomy(53 days). Initial endoscopy occurred earlier in Ostomy at 10 vs. 27 days in No Ostomy[F (1,48) = 15.99, p=0.0002]. Number of scopes performed in the 1st year were significantly less in patients with No Ostomy(mean = 6) vs. Ostomy(mean = 11) [F (1,48) = 15.17, p=0.0003] (Fig 2). Despite this, there was no significant difference in rejection. There was a trend toward increased rejection in patients with Ostomy(35%, 8/23) vs. No Ostomy(19%, 5/27). There was no difference in creatinine pre-transplant (non-renal) nor at 1-year post. However, the majority of patients with an ostomy (colostomy + hybrid colon) had colon in continuity making dehydration less likely. Patient 1-year survival did not differ at 82% (4/23) for those with Ostomy and 78% (6/27) with No Ostomy. Conclusion: MVT without an ostomy continues to be feasible and safe without an increased risk of rejection nor death. Postop care seems to be easier and preservation of kidney function may impact long term ITx outcomes. Lack of ostomy greatly adds to patient satisfaction and quality of life.