Calcineurin Inhibitor Withdrawal Research Articles

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome after hematopoietic stem cell transplantation for thalassemia major: incidence, management, and outcome

Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present prospective study, we aimed to investigate the incidence, management, and outcome of VOD/SOS in patients with thalassemia major (TM) who received allo-HSCT. VOD/SOS was diagnosed and classified based on the modified Seattle criteria. The prophylactic regimen for VOD/SOS was a combination treatment of dalteparin and lipo-PGE1. VOD/SOS was managed through an approach consisting of adequate supportive measures, short-term withdrawal of calcineurin inhibitors (CNIs), and the use of methylprednisolone and basiliximab for graft-versus-host disease prophylaxis. VOD/SOS was found in 54 of 521 patients (10.4%) at a median time of 12 days after allo-HSCT. The cumulative incidence of all-grade and moderate VOD/SOS was 10.4% and 4.2%, respectively. Among the 54 VOD/SOS patients, no patient developed severe grade and died from VOD/SOS. Besides, the cumulative incidence of transplant-related mortality on day 100 for patients with or without VOD/SOS was 0% vs. 4.0% (P = 0.187), respectively, and the 3-year overall survival rates were 94.3% vs. 93.2% (P = 0.707), respectively. Collectively, we concluded that appropriate symptomatic therapy and short-term withdrawal of CNIs safely mitigated the mortality of VOD/SOS in TM patients who underwent allo-HSCT.

Comparison of two strategies based on mammalian target of rapamycin inhibitors in secondary prevention of non-melanoma skin cancer after kidney transplantation, a pilot study.

After kidney transplantation, withdrawal of calcineurin inhibitors (CNI) and conversion to sirolimus (SRL) may reduce the occurrence of new non-melanoma skin cancer (NMSC). Conversely, a reduced CNI exposure with everolimus (EVR) is an alternative strategy that has not been thoroughly evaluated. We retrospectively compared the occurrence of newly diagnosed NMSCs in two cohorts of kidney transplant recipients (KTR) with at least one NMSC: 35 patients were converted to EVR with reduced CNI exposure (CNI/EVR group), whereas 46 patients were converted to SRL in association with mycophenolic acid (MPA) (SRL/MPA group). Two years after conversion, survival free of new NMSC was similar between the two cohorts (p=.37), with 19 KTR (54.3%) in the CNI/EVR group and 22 (47.8%) in the SRL/MPA group being diagnosed of at least one new NMSC. Half of the KTR from both groups showed adverse events, leading to mTORi discontinuation for 37.1% of KTR in the CNI/EVR group and 21.7% in the SRL/MPA group (p=.09). The incidence of rejections was similar between the two groups. In a retrospective cohort of KTR with at least one post-transplant NMSC, the outcome of the patients converted to a CNI/EVR regimen was not different from those converted to a SRL/MPA regimen.

Optimal blood levels of (extended-release) tacrolimus in living donor kidney transplantation to prevent de novo donor-specific antibody production: A retrospective cohort study

Chronic antibody-mediated rejection, caused by de novo donor-specific antibody (dnDSA) production, results in poor graft survival. To prevent dnDSA production, optimal blood levels of immunosuppressive drugs in living donor kidney transplant recipients were determined. A total of 772 recipients underwent living donor kidney transplantation between January 2008 and December 2017. Graft survival and risk factors for dnDSA production were investigated in 647 recipients. Optimal blood levels of tacrolimus (TAC) and extended-release TAC (TACER) were measured in recipients receiving steroids and mycophenolate mofetil, combined with TAC (n = 53) or TACER (n = 135). Receiver operating characteristic (ROC) curve analysis and comparisons between dnDSA-negative and dnDSA-positive recipients were carried out. The Kaplan-Meier method revealed significantly poor graft survival in dnDSA-positive recipients (P < 0.001). Cox regression models indicated calcineurin inhibitor withdrawal as a significant risk for dnDSA production (P < 0.001; hazard ratio 6.637; 95% confidence interval 2.667–6.517). Average trough levels of TAC and TACER in dnDSA-negative recipients were significantly higher than those in dnDSA-positive recipients (4.88 vs 3.69 ng TAC/ml, P = 0.023, and 4.60 vs 3.85 ng TACER/ml, P = 0.001). ROC curve analysis indicated 4.325 and 3.990 ng/ml as the best trough levels under TAC- and TACER-based regimens, respectively, to prevent dnDSA production (areas under the curve: 0.788 and 0.813, respectively). Maintenance of the trough levels of TAC > 4.325 ng/ml and TACER > 3.990 ng/ml may prevent dnDSA production.

5-Year outcomes of the prospective and randomized CISTCERT study comparing steroid withdrawal to replacement of cyclosporine with everolimus in de novo kidney transplant patients.

Withdrawal of either steroids or calcineurin inhibitors are two strategies to reduce treatment-related side effects and improve long-term outcomes of kidney transplantation. The CISTCERT study compared the efficacy and safety of these two strategies. In this multicenter, randomized controlled trial, 151 incident kidney transplant recipients received cyclosporine (CsA), mycophenolic acid (MPA), and steroids during three months, followed by either steroid withdrawal (CsA/MPA) or replacement of cyclosporine with everolimus (EVL) (EVL/MPA/steroids). 5-year patient survival (89% vs. 86%; P=NS) and death-censored graft survival (95% vs. 96%; P=NS) were comparable in the CsA/MPA and EVL/MPA/steroids arm, respectively. 51 CrEDTA clearance was comparable in the intention-to-treat analysis, but in the on-treatment population, the EVL/MPA/steroids arm exhibited a superior 51 CrEDTA clearance at 1 and 5years after transplantation (61.6 vs. 52.4, P=0.05 and 59.1 vs. 46.2ml/min/1.73m2 , P=0.042). Numerically more and more severe rejections were observed in the EVL/MPA/steroids arm, which also experienced a higher incidence of posttransplant diabetes (26% vs. 6%, P=0.0016) and infections. No significant differences were observed in cardiovascular outcomes and malignancy. Both regimens provide an excellent long-term patient survival and graft survival. Regarding graft function, EVL/MPA/steroids is an attractive strategy for patients with good tolerability who remain free of rejection. (ClinicalTrials.gov number: NCT00903188; EudraCT Number 2007-005844-26).

Time to Conversion to an Everolimus-Based Regimen: Renal Outcomes in Liver Transplant Recipients From the EVEROLIVER Registry.

Longterm use of a calcineurin inhibitor (CNI)-based regimen is one of the major reasons for chronic renal failure in liver transplantation recipients (LTRs). The Everolimus Liver registry (EVEROLIVER) evaluated renal function in LTRs who were converted to everolimus (EVR). This observational registry included all LTRs receiving EVR across 9 centers from France. Data are being collected in an electronic database over 10 years (12 visits/patient) to evaluate efficacy, renal function (estimated glomerular filtration rate [eGFR]), and safety of EVR use in clinical practice, and the current analysis is reporting up to 60months of findings. Until September 2017, 1045 patients received EVR after a mean time of 3.6±5.1years. CNI withdrawal was feasible in 57.7% of patients as of month 60. Mean eGFR improved in patients with baseline eGFR <60mL/minute/1.73m2 and was maintained in those with baseline eGFR ≥60mL/minute/1.73m2 . Among patients with chronic kidney disease (CKD; baseline eGFR <60mL/minute/1.73m2 ), 55% converted to EVR within 3 months (early conversion) and 39.4% converted between 4 and 12months after transplantation (mid-conversion) experienced improvement in eGFR (≥60mL/minute/1.73m2 ) at month 36. Only 20.9% and 17.4% among those converted beyond 12months (late conversion) experienced improvement respectively at month 36 and 60. A logistic regression analysis in patients with CKD stage ≥3 demonstrated that late conversion, age, and female sex were associated with nonimprovement of eGFR (≥60mL/minute/1.73m2 ). Data from this real-life use of EVR indicate that renal function was maintained from the preconversion period until month 36 even in patients with advanced CKD. However, early rather than late conversion appears to be a safe approach to preserve longterm renal function in LTRs.

A noninferiority design for a delayed calcineurin inhibitor substitution trial in kidney transplantation.

Improving long‐term kidney transplant outcomes requires novel treatment strategies, including delayed calcineurin inhibitor (CNI) substitution, tested using informative trial designs. An alternative approach to the usual superiority‐based trial is a noninferiority trial design that tests whether an investigational agent is not unacceptably worse than standard of care. An informative noninferiority design, with biopsy‐proven acute rejection (BPAR) as the endpoint, requires determination of a prespecified, evidence‐based noninferiority margin for BPAR. No such information is available for delayed CNI substitution in kidney transplantation. Herein we analyzed data from recent kidney transplant trials of CNI withdrawal and “real world” CNI‐ based standard of care, containing subjects with well‐documented evidence of immune quiescence at 6 months posttransplant—ideal candidates for delayed CNI substitution. Our analysis indicates an evidence‐based noninferiority margin of 13.8% for the United States Food and Drug Administration's composite definition of BPAR between 6 and 24 months posttransplant. Sample size estimation determined that ~225 randomized subjects would be required to evaluate noninferiority for this primary clinical efficacy endpoint, and superiority for a renal function safety endpoint. Our findings provide the basis for future delayed CNI substitution noninferiority trials, thereby increasing the likelihood they will provide clinically implementable results and achieve regulatory approval.

LONG-TERM RESULTS OF EVEROLIMUS ON RENAL FUNCTION AND REJECTION AFTER HEART TRANSPLANTATION IN A REAL-LIFE SCENARIO

Introduction: Clinical study results are still controversial about the start of everolimus (ERL) with and without calcineurin inhibitor (CNI) after heart transplantation (HTx). Thus, we analyzed long-term data of the effect of ERL on renal function and the incidence of biopsy proven acute cellular rejection (BPACR) apart from clinical studies in a real-life scenario. Methods: 105 patients, who received HTx between 2005 and 2015, were divided into three groups (Gs) according to the time of ERL start; G1≤ 3 months (mo) after HTx (n=46), G2 4-12 mo after HTx (n=33) or G3 >12 mo after HTx (n=26). Additionally, we analyzed patients either with CNI withdrawal ≤3mo (sub-group, SG1, n=25) after ERL start, or with concomitant CNI therapy >12mo (SG2, n=71) after ERL start. Renal function was calculated using the MDRD formula for the glomerular filtration rate (GFR) in relation of baseline value before ERL, and at 12 and 60mo after ERL start (ΔGFR mL/min). Iincidence of BPACR (≥2R) was compared between the study groups at 12 and 60mo after HTx. Results: At 12mo after ERL start ΔGFR was a significant better in patients of G2 compared to patients of G3 (G2: +3.98 vs G3: -4.98, p=0.04). Furthermore, CNI withdrawal did not further improved renal function compared to concomitant CNI therapy at this early time point. However, patients of G1 had a higher ΔGFR at 60mo after ERL start compared to patients of either G2 or 3 (G1: +1.59, G2: -12.71, G3: -6.26, p1vs2=0.035 and p1vs3=0.27). In all three Gs, patients with early CNI withdrawal had a higher ΔGFR than patients with concomitant CNI therapy at 60mo (SG1: G1: +5.53; G2: +0.36; G3: -22.26, p1vs3=0.01, p1vs2=0.02; SG2: G1 -0.83, G2: -22.12, G3: -6.73, p1vs3=0.045; p1vs2=0.02). Incidence of BPACR at 12mo after HTx was not different between the study groups (G1: 15.2%, G2: 19.1%, G3: 19.2%, p=0.72). However, CNI-free patients of G1 had a higher incidence of BPACR than patients with concomitant CNI therapy of G1 at 12mo (SG1: 33,3% vs SG 2: 6,9%, p=0.03) and at 60mo (SG1: 22% vs. SG2: 0%, p=0.049). All BPACR were without hemodynamic compromise. Conclusion: We showed that an early ERL therapy within 3mo of HTx had a long-term beneficial effect on renal function in a real-life scenario. Early CNI withdrawal enhanced the nephroprotective effect further. While the incidence of BPACR was increased by early CNI-withdrawal, graft function, however, was not severely impaired.

COVID-19 and kidney transplantation: Results from the TANGO International Transplant Consortium.

Kidney transplant recipients may be at a high risk of developing critical coronavirus disease 2019 (COVID‐19) illness due to chronic immunosuppression and comorbidities. We identified hospitalized adult kidney transplant recipients at 12 transplant centers in the United States, Italy, and Spain who tested positive for COVID‐19. Clinical presentation, laboratory values, immunosuppression, and treatment strategies were reviewed, and predictors of poor clinical outcomes were determined through multivariable analyses. Among 9845 kidney transplant recipients across centers, 144 were hospitalized due to COVID‐19 during the 9‐week study period. Of the 144 patients, 66% were male with a mean age of 60 (±12) years, and 40% were Hispanic and 25% were African American. Prevalent comorbidities included hypertension (95%), diabetes (52%), obesity (49%), and heart (28%) and lung (19%) disease. Therapeutic management included antimetabolite withdrawal (68%), calcineurin inhibitor withdrawal (23%), hydroxychloroquine (71%), antibiotics (74%), tocilizumab (13%), and antivirals (14%). During a median follow‐up period of 52 days (IQR: 16‐66 days), acute kidney injury occurred in 52% cases, with respiratory failure requiring intubation in 29%, and the mortality rate was 32%. The 46 patients who died were older, had lower lymphocyte counts and estimated glomerular filtration rate levels, and had higher serum lactate dehydrogenase, procalcitonin, and interleukin‐6 levels. In sum, hospitalized kidney transplant recipients with COVID‐19 have higher rates of acute kidney injury and mortality.

P1636THE IMPACT OF CALCINEURIN INHIBITOR WITHDRAWAL ON DE NOVO DSA PRODUCTION IN LIVING DONOR KIDNEY TRANSPLANTATION

Abstract Background and Aims Chronic antibody mediated rejection caused by de novo donor specific antibody (dnDSA) is one of the biggest reasons for graft failure. At present, because it is difficult to treat CAMR, prevention of de novo DSA production is important. We investigated the risk factor for dnDSA production in living donor kidney transplantation. Method 807 patients underwent living donor kidney transplantation between January 2008 and December 2016. 159 recipients were excluded because of preformed DSA (58 recipients), pediatric transplantation (35 recipients), pancreas transplantation after kidney transplantation (4 recipients), and insufficient data on DSA after transplantation (62 recipients). 648 recipients were enrolled in this study. In 84 out of 648 recipients, dnDSA were detected until December 2018. With cox regression analysis, the risk factors for de novo DSA production were investigated between dn DSA positive and negative groups. The impact of donor characteristics including age and sex, and recipient characteristics including age, sex, hemodialysis vintage, cold ischemic time, past history of transfusion, pregnancy, and transplantation, HLA mismatch, pre-operative Flow PRA results, ABO incompatibility, rituximab induction, splenectomy, pre-operative plasmapheresis, transplantation from first-degree relatives, conversion of calcineurin inhibitor (CNI), conversion of mycophenolate mofetil, mizoribin, and everolimus, CNI used for induction, induction with mycophenolate mofetil, mizoribin, and everolimus, CNI withdrawal, withdrawal of mycophenolate mofetil, mizoribin, and everolimus, and rejection within 6 months after transplantation were investigated. Results In the univariate analysis, male recipient, male donor, and CNI withdrawal were the significant risk factors (P=0.020, HR 1.795, 95%CI 1.095-2.942; P=0.027, HR 0.568, 95%CI 0.344-0.938; P&amp;lt;0.001, HR 6.346, 95%CI 2.560-15.730, respectively). In the multivariate analysis, calcineurin inhibitor withdrawal was significant risk factor with P&amp;lt;0.001, HR 6.374, 95%CI 2.567-15.828. Conclusion Calcineurin inhibitor withdrawal was the significant risk factor for de novo DSA production in living donor kidney transplantation

COVID-19 and Calcineurin Inhibitors: Should They Get Left Out in the Storm?

COVID-19 and Calcineurin Inhibitors: Should They Get Left Out in the Storm?

Quadritherapy vs standard tritherapy immunosuppressant regimen after heart transplantation: A propensity score-matched cohort analysis.

After heart transplant, adding everolimus (EVL) to standard immunosuppressive regimen mostly relies on converting calcineurin inhibitors (CNIs) into EVL. The aim of this study was to describe the effects of combining low-dose EVL and CNIs in maintenance immunosuppression regimen (quadritherapy) and compare it with standard tritherapy associating standard-dose CNIs, mycophenolate mofetil, and corticosteroids. In the 3-year registry cohort of heart transplanted patients, those who received quadritherapy were compared with those who received tritherapy. EVL was added after 3months posttransplant. Three analyses were performed to control for confounders: propensity score matching, multivariable survival, and inverse probability score weighting analyses. Among 213 patients who were included (75 with quadritherapy), propensity score matching selected 64 unique pairs of patients with similar characteristics. In the matched cohort (n=128), quadritherapy was associated with fewer deaths (3 [4.7%] vs 17 [21.9%], P=.007) and biopsy-proven acute rejections (15 [23.4%] vs 31 [48.4%], P=.002). These results were confirmed in the overall cohort (n=213), after multivariable and inverse probability score weighting analyses. Renal function and donor-specific HLA-antibodies remained similar in both groups. Low-dose combination quadritherapy was associated with fewer deaths and rejections, compared with standard immunosuppression tritherapy.

Long-Term Results of Everolimus on Renal Function and Rejection after Heart Transplantation in a Real-Life Scenario

Clinical study results are still controversial about the start of everolimus (ERL) with and without calcineurin inhibitor (CNI) after heart transplantation (HTx). Thus, we analyzed long-term data of the effect of ERL on renal function and the incidence of biopsy proven acute cellular rejection (BPACR) apart from clinical studies in a real-life scenario. 105 patients, who received HTx between 2005 and 2015, were divided into three groups (Gs) according to the time of ERL start; G1≤ 3 months (mo) after HTx (n=46), G2 4-12 mo after HTx (n=33) or G3 >12 mo after HTx (n=26). Additionally, we analyzed patients either with CNI withdrawal ≤3mo (sub-group, SG1, n=25) after ERL start, or with concomitant CNI therapy >12mo (SG2, n=71) after ERL start. Renal function was calculated using the MDRD formula for the glomerular filtration rate (GFR) in relation of baseline value before ERL, and at 12 and 60mo after ERL start (ΔGFR mL/min). Iincidence of BPACR (≥2R) was compared between the study groups at 12 and 60mo after HTx. At 12mo after ERL start ΔGFR was a significant better in patients of G2 compared to patients of G3 (G2: +3.98 vs G3: -4.98, p=0.04). Furthermore, CNI withdrawal did not further improved renal function compared to concomitant CNI therapy at this early time point. However, patients of G1 had a higher ΔGFR at 60mo after ERL start compared to patients of either G2 or 3 (G1: +1.59, G2: -12.71, G3: -6.26, p1vs2=0.035 and p1vs3=0.27). In all three Gs, patients with early CNI withdrawal had a higher ΔGFR than patients with concomitant CNI therapy at 60mo (SG1: G1: +5.53; G2: +0.36; G3: -22.26, p1vs3=0.01, p1vs2=0.02; SG2: G1 -0.83, G2: -22.12, G3: -6.73, p1vs3=0.045; p1vs2=0.02)Incidence of BPACR at 12mo after HTx was not different between the study groups (G1: 15.2%, G2: 19.1%, G3: 19.2%, p=0.72). However, CNI-free patients of G1 had a higher incidence of BPACR than patients with concomitant CNI therapy of G1 at 12mo (SG1: 33,3% vs SG 2: 6,9%, p=0.03) and at 60mo (SG1: 22% vs. SG2: 0%, p=0.049). All BPACR were without hemodynamic compromise. We showed that an early ERL therapy within 3mo of HTx had a long-term beneficial effect on renal function in a real-life scenario. Early CNI withdrawal enhanced the nephroprotective effect further. While the incidence of BPACR was increased by early CNI-withdrawal, graft function, however, was not severely impaired.

Survival in Lung Transplant Recipients on a Calcineurin Free Regimen: Is It Possible?

Calcineurin inhibitors (CNI) are the cornerstone of immunosuppression in lung transplantation. The International Heart and Lung Transplant registry data estimates that almost 99% of patients are on a CNI-based immunosuppression regimen. The population of lung transplant (LTx) recipients not on a calcineurin inhibitor is exceedingly rare and their outcomes have not been previously examined in a systematic way. An IRB-approved, retrospective, observational, cohort study of LTx recipients who received CNI-free, everolimus (EVR)-based immunosuppression at the University of Colorado from January 1, 1995 - October 1, 2019. The health system's electronic medical records was queried to identify and collect data on eligible LTx recipients. All continuous variables are presented as median(range). Seven of 12 were single LTx (ILD, COPD), five were bilateral LTx,(ILD, COPD, CF) and one was a re-transplant. The majority (8/12) of patients were transitioned to CNI-free, EVR-based immunosuppression due to renal insufficiency, 3/12 due to metastatic cancer, and 1/12 due to both renal failure and cancer. Five of 12 were maintained on three agents (EVR, corticosteroid, and either methotrexate or azathioprine) and the others were on corticosteroids with EVR alone. The median time to transition to CNI-free immunosuppression was 8.8 (2.3 to 21.3) years. Median age at CNI cessation was 67 years old (40-72 years old). Median survival on CNI-free immunosuppression for all comers was 1.6 years with median survival in the deceased cohort (n=8) of 1 year (4 days to 4.6 years) and median survival in the living cohort (n=4) of 2.1 years (1.2 years to 8.2 years). At least three patients were treated with high dose steroids for presumed acute rejection after stopping the CNI. This review demonstrates that in certain situations withdrawal of CNI and transition to CNI-free, EVR- based immunosuppression may result in durable patient survival. Larger multicenter cohort analysis may be the next step in understanding the safety, efficacy and role of CNI-free immunosuppression, as equipoise would be impossible to achieve in a randomized controlled trial.

Long-Term Effects of the Replacement of Calcineurin Inhibitors With Everolimus and Mycophenolate in Patients With Calcineurin Inhibitor–Related Nephrotoxicity

BackgroundThere is little evidence on the long-term effects of calcineurin inhibitor (CNI) withdrawal and substitution with everolimus and mycophenolate mofetil in maintenance therapy of patients who have received heart transplants and have concurrent CNI nephrotoxicity. Aims of this study were to evaluate the progression of renal dysfunction after discontinuation of CNIs and to monitor for major adverse events after therapy change. MethodsData from 41 patients who underwent heart transplant and have different degrees of renal dysfunction (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), without evidence of proteinuria, and in whom CNI therapy was replaced by everolimus, were analyzed. At the time of CNI withdrawal, clinical parameters, echocardiographic data, blood tests of renal function, and monitoring of adverse events were recorded. The median follow-up period was 5 years ± 28 months. ResultsIn 52% of patients, there was a clear improvement in renal function (10.5 mL/min/1.73 m2 of extra eGFR on average). The former were characterized by less advanced age and a short time from the heart transplant. The echocardiographic parameters showed a significant reduction in septum thickness (11.58 ± 2 mm vs 10.29 ± 2 mm; P = .0001) and in left ventricle posterior wall thickness (10.74 ± 1 mm vs 9.74 ± 1 mm; P = .0004). The incidence of late acute rejection and cardiac allograft vasculopathy was similar in our population compared to literature data. ConclusionsA therapeutic switch from CNIs to everolimus and mycophenolate mofetil can improve renal function in patients with CNI nephrotoxicity, especially in those with a shorter time period from transplantation, without exposing them to a higher incidence of late acute rejection and cardiac allograft vasculopathy.

Invasive haemodynamics in de novo everolimus vs. calcineurin inhibitor heart transplant recipients.

AimsInvasive haemodynamic profiles at rest and during exercise after heart transplantation (HTx) have never been described in a randomized trial where de novo everolimus (EVR)‐based therapy with early calcineurin inhibitor (CNI) withdrawal has been compared with conventional CNI treatment. We report central invasive haemodynamic parameters at rest and exercise during a 3 year follow‐up after HTx in a sub‐study of the SCandiavian Heart transplant Everolimus De novo stUdy with earLy calcineurin inhibitor avoidancE trial. We hypothesized that the nephroprotective properties, the less development of cardiac allograft vasculopathy (CAV), and the antifibrotic properties of EVR, in comparison with CNI‐based immunosuppression, would demonstrate favourable invasive haemodynamic profiles in patients at rest and during exercise.Methods and resultsNinety of 115 HTx recipients randomized to EVR or CNI treatment performed right heart catheterization at rest and 68 performed right heart catheterization at exercise up to 3 years after HTx. Haemodynamic profiles were compared between EVR and CNI treatment groups. Resting haemodynamics improved in both groups from pre‐HTx to the first follow‐up at 7–11 weeks post‐HTx and thereafter remained unchanged up to 3 years of follow‐up. During follow‐up, cardiac reserve during exercise increased with higher levels of maximum heart rate (118 to 148 b.p.m., P < 0.001), mean arterial pressure (103 to 128 mmHg, P < 0.001), and cardiac output (10.3 to 12.2 l/min, P < 0.001). No significant differences in haemodynamic parameters were observed between the EVR and CNI groups at rest or exercise. Isolated post‐capillary pulmonary hypertension (mean pulmonary arterial pressure > 20 mmHg, pulmonary arterial wedge pressure ≥ 15 mmHg, and pulmonary vascular resistance <3) were measured in 11% of the patients at 7–11 weeks, 5% at 12 months, and 6% at 36 months after HTx. The EVR group had significantly better kidney function (76 mL/min/1 vs. 60 mL/min/1, P < 0.001) and reduced CAV (P < 0.01) but an increased rate of early biopsy‐proven treated rejections (21.2% vs 5.7%, P < 0.01) compared with the CNI group at any time point. The differences in renal function, CAV, or early biopsy‐proven treated acute rejections were not associated with altered haemodynamics.Conclusions De novo EVR treatment with early CNI withdrawal compared with conventional CNI therapy did not result in differences in haemodynamics at rest or during exercise up to 3 years after HTx despite significant differences in renal function, reduced CAV, and number of early biopsy‐proven treated rejections.

Study Design of an Open-Label, Single-Arm, Multicenter, Phase 2 Study to Evaluate the Safety and Efficacy of Defibrotide in Adult Patients with Transplant-Associated Thrombotic Microangiopathy

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is an uncommon, but well-recognized, hematopoietic cell transplant (HCT) complication associated with high morbidity and mortality. TA-TMA may result from microvascular endothelial cell (EC) damage induced by HCT conditioning regimens, immunosuppressive drugs, and infections, and it may be mediated by complement activation in some cases. Although there is no consensus on optimal TA-TMA treatment, common interventions include withdrawal, replacement, or dose modification of calcineurin inhibitors (CI) and/or mammalian target of rapamycin (mTOR) inhibitors (ie, CI/mTORi changes). When increased complement activity is present, terminal complement cascade inhibition has been used. Defibrotide (DF) is approved for adult and pediatric patients (pts) with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal or pulmonary dysfunction post-HCT in the US and Canada and for pts aged &gt;1 month with severe hepatic VOD/SOS post-HCT in the EU. DF reduces EC activation, promotes fibrinolysis, and may be a novel therapy for TA-TMA. This prospective, open-label, single-arm, multicenter, phase 2 study (EUDRACT: 2018-001101-90) is designed to assess the efficacy and safety of DF for treating pts with high-risk TA-TMA (defined as definite TMA per Postalcioglu M, et al. Biol Blood Marrow Transplant. 2018;24(11):2344-2353) who have failed to respond to CR/mTORi changes. Study Design and Methods: Diagnostic criteria for "definite" TA-TMA include lactate dehydrogenase (LDH) &gt;2 × the upper limit of normal, thrombocytopenia (platelet count &lt;50 × 109/L or ≥50% decrease from peak platelets post-HCT), schistocytes ≥2 per high-power field in peripheral blood, serum creatinine increase &gt;50% from baseline, and a negative Coombs test. Allogeneic HCT pts (aged ≥18 years) who have definite TA-TMA with persistent or progressive disease after 7 or 3 days, respectively, following CI/mTORi changes are eligible (Figure). Pts will be excluded if they relapse after HCT, have grade 4 acute graft-versus-host disease or VOD/SOS, or clinically significant bleeding within 24 hours of enrollment. Planned enrollment is 30 to 40 pts. Pts will receive a 2-hour intravenous infusion of DF 25 mg/kg/day (6.25 mg/kg every 6 hours) for a recommended duration of 21 days (up to 60 days). Pts will be followed for 180 days from DF start (Day 1). The study has 2 co-primary efficacy endpoints: hematologic response by Day 45 (relative to DF start) and renal response by Day 45. Hematologic response is defined as normalization of LDH and platelet count ≥50 × 109/L without platelet transfusion for 7 days (if baseline count was &lt;50 × 109/L) or ≥50% increase in platelet count (if baseline count was ≥50 × 109/L). Renal response is defined as &lt;25% increase or decrease in serum creatinine versus baseline at DF start (renal function stabilization) or ≥25% decrease in serum creatinine versus baseline at DF start or independence from dialysis (if pt was dialysis dependent at baseline or started dialysis after baseline) (renal function improvement). Secondary efficacy endpoints are overall survival, duration of hematologic or renal response, proportion of pts achieving hematologic or renal (measured by serum creatinine or estimated glomerular filtration rate) response by Days 60, 90, and 180, independence from dialysis at Days 60, 90, and 180 for pts with dialysis dependence, and neurologic improvement (defined as any increase in Mini-Mental Status Examination score versus baseline or resolution of TA-TMA seizure activity) at Days 7, 14, 21, and 45. Safety endpoints include incidence of treatment-emergent adverse events (AEs), treatment-emergent serious AEs, and AEs of interest (eg, hemorrhage and hypotension) occurring up to 30 days after the last DF dose. Analysis of the co-primary efficacy endpoints will be evaluated in pts who receive ≥1 DF dose. For each co-primary endpoint, a reference background rate, based upon data from literature and/or registries or research databases, will be established to represent the Day 45 hematologic and renal response rates in a similar pt population in the setting of currently available therapy without DF treatment. A clinically meaningful benefit from DF will be inferred if the lower bounds of the 95% confidence interval of the co-primary endpoints are greater than their respective reference background rates. Disclosures Ho: Jazz Pharmaceuticals: Consultancy. Keshelava:Jazz Pharmaceuticals: Employment, Equity Ownership. Swann:Jazz Pharmaceuticals: Employment, Equity Ownership. Tappe:Jazz Pharmaceuticals: Employment, Equity Ownership. OffLabel Disclosure: The abstract contains a description of off-label product use. Defibrotide is approved for treatment of hepatic VOD/SOS post-HCT (as described in the background) and this study is evaluating its use in patients with TA-TMA.

Interventions to Prevent Nonmelanoma Skin Cancers in Recipients of a Solid Organ Transplant: Systematic Review of Randomized Controlled Trials.

Organ transplant recipients are at high risk of developing skin cancer. The benefits and harms of interventions to prevent nonmelanoma skin cancer in solid organ transplant recipients have not been summarized. We searched MEDLINE, Embase, and CENTRAL through April 2018. Risk of bias was assessed using the Cochrane tool, and evidence certainty was evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation process. Prespecified outcomes were nonmelanoma skin cancer, clearance and prevention of keratotic skin lesions, and intervention-specific adverse events. Ninety-two trials (20 012 participants) were included. The evaluated treatments were cancer-specific interventions (acitretin, imiquimod, photodynamic therapy, nicotinamide, topical diclofenac, and selenium) and immunosuppression regimes (azathioprine, mycophenolate mofetil, calcineurin inhibitors, mammalian target of rapamycin [mTOR] inhibitors, belatacept, induction agents, and withdrawal of calcineurin inhibitors or corticosteroids). Effects on nonmelanoma skin cancer were uncertain for photodynamic therapy (3 trials, 93 participants, risk ratio [RR] 1.42 [95% confidence interval (CI), 0.65-3.11]; low certainty evidence), nicotinamide (2 trials, 60 participants), acitretin (2 trials, 61 participants), and imiquimod (1 trial, 20 participants) compared to control. mTOR inhibitors probably reduced skin cancer compared to calcineurin inhibitors (12 trials, 2225 participants, RR 0.62 [95% CI, 0.45-0.85]; moderate certainty evidence). Photodynamic therapy may cause pain at the treatment site (4 trials, 95 patients, RR 17.09 [95% CI, 4.22-69.26]; low certainty evidence). There is limited evidence for the efficacy and safety of specific treatments to prevent nonmelanoma skin cancers among solid organ transplant recipients.

Clinical analysis of 9 patients with transplant-related thrombotic microangiopathy

Objective: To analyze the clinical features, efficacy and outcomes in patients with transplantation associated thrombotic microangiopathy (TA-TMA). Methods: The clinical data of 9 patients who developed TA-TMA after allogeneic hematopoietic stem cell transplantation (allo-HSCT) were retrospectively analyzed from January 2011 to August 2018 in Affiliated Tumor Hospital of Zhengzhou University. Results: There were 6 male and 3 female patiens with a median age of 31 (12-38) years. The median time from transplantation to TA-TMA was 76 (24-155) days. The baseline blood and biochemical parameters at diagnosis of TA-TMA included median hemoglobin (Hb) 66 (58-77) g/L,platelet (PLT) count 22 (4-38) × 10(9)/L,serum lactic dehydrogenase (LDH) 655 (305-4 238) U/L,blood urine nitrogen (BUN) level 15.9 (4.8-26.2) mmol/L,blood creatinine (Cr) level 118 (24-380) μmol/L. The proportion of median peripheral blood schistocytes was 2.6%(1.2%-9%). All patients had positive urinary occult blood tests,and urinary protein was seen in 4 patients. Three patients had mental symptoms. Coombs tests were all negative. The main treatments of TA-TMA composed of reduction and withdrawal of calcineurin inhibitor,steroids and plasma exchange. Response was seen in 4 patients. Patients who did not response to the treatment had a higher proportion of schistocytes,more severe acute graft-versus-host disease (aGVHD),more elevated serum LDH and other transplant-related complications. Conclusions: TA-TMA after allo-HSCT is a serious complication with high mortality rate. The proportion of schistocytes in peripheral blood, serum LDH level and comorbidities are prognostic factors of clinical outcome.

Pre-Transplant Genetic Susceptibility in Adult Allogeneic Hematopoietic Cell Transplant Recipients: Incidence and Clinical Relevance in Transplant-Associated Thrombotic Microangiopathy

Introduction: Transplant-associated thrombotic microangiopathy (TA-TMA) is a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (HCT). In light of encouraging results by complement inhibition treatment, a few studies and case series have reported complement-related genetic variants in patients with TA-TMA. However, several issues remain undisclosed, regarding both the incidence of such variants and the clinical importance of pre-transplant genetic profiling. Within this context, we hypothesized that pre-transplant genetic susceptibility is evident in adult TA-TMA patients but not in their donors or control transplanted patients and also investigated the association of genetic variants with response to treatment and survival.Methods:To this end, we enrolled consecutive adult allogeneic HCT recipients diagnosed with TA-TMA according to the International Working Group criteria between 2014-2017. Patients were managed based on institutional policy with conventional treatment including withdrawal of calcineurin or mTOR inhibitors, steroid administration and/or plasma infusion/plasma exchange. To test our hypothesis, we also studied donors of the enrolled patients with available samples and age- and sex-matched control HCT recipients. Genomic DNA was extracted from pre-transplant peripheral blood samples of TA-TMA patients, donors and controls. Probes were designed using the Design studio (Illumina). The amplicons cover the exonic regions of complement regulatory genes (complement factor H/CFH, CFH-related, CFI, CFB, CFD, C3, CD55, C5, CD46, thombomodulin/THBD) and TMA-associated ADAMTS13, spanning 15 bases into the intronic regions. After quality assessment, each sample was treated independently in order to produce the appropriate mapping of the reads against the human reference genome hg19. Variant calling was performed using the Genome Annotation Toolkit and variant annotation using annovar together with supplemental databases. Variants with minor allele frequency lower than 1% were considered rare.Results:We studied 30 patients that presented TA-TMA at median + 73 (9-540) days with full hematopoietic constitution, 18 donors of our patients and 30 controls, without significant differences in transplant characteristics (Table).Donors of patients presented significantly lower number of detected (p=0.039) and rare (p=0.049) variants per sample, as well as variants in exonic, splicing or UTR regions (p=0.025) compared to TA-TMA patients. In control patients, we also observed a significantly lower number of rare variants in ADAMTS13 (p=0.002), CD46 (p=0.001), CFH (p=0.010), CFI (p=0.031) and CFB (p=0.016) compared to TA-TMA patients (Graph). Variants previously reported to be pathogenic in TMAs were found in ADAMTS13 and CFB. While heterozygous pathogenic mutations were present in both TA-TMA and control samples, homozygous pathogenic mutations were evident only in 4 TA-TMA patients (p=0.038).Regarding clinical outcomes, 21 of 30 TA-TMA patients (70%) were refractory to conventional treatment. Refractory patients presented a significantly increased incidence of variants in exonic, splicing or UTR regions (p=0.045) compared to responders. 12 patients received eculizumab based on institutional policy. Despite initial laboratory response to eculizumab treatment, only 4 of 12 survived. 19 out of 30 patients succumbed to treatment-related mortality, which was also associated with significantly increased number of variants in exonic, splicing or UTR regions (p=0.012).Conclusions:Increased incidence of pathogenic, rare and exonic variants in TA-TMA patients supports a relevant role for genetic susceptibility that is not evident in control HCT recipients or patients' donors. This, combined with the finding that exonic variants were associated with refractoriness to treatment and increased mortality, indicates that pre-transplant genetic profiling may be useful to intensify monitoring and early intervention in high-risk patients. In this complex setting, the functional and clinical role of genetic variants needs to be further investigated in prospective studies. [Display omitted] DisclosuresGavriilaki:European Hematology Association: Research Funding. Stamatopoulos:Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

Effects of late cyclosporine withdrawal on renal graft function and survival.

Attempts to discontinue calcineurin inhibitors (CNIs) early after renal transplantation without conversion to an alternative immunosuppressive have failed due to high rates of acute rejection. Data on "late" CNI withdrawal are lacking so far. We carried out a matched case-control study on the effects of CNI withdrawal on graft loss and mortality in 90 patients (1500 screened) with advanced graft dysfunction (serum creatinine > 3.5mg/dl) and a cyclosporine-based triple immunosuppressive regimen at the Charité University Hospital, Berlin. Cyclosporine was withdrawn at a mean of 54.0 ± 32.8months post-transplant in 45 subjects. Whereas estimated glomerular filtration rate (eGFR) did not significantly differ between the groups at this time (12.4 ± 2.7 vs. 14.7 ± 8.9 in the control group, p = 0.08), it was significantly higher in subjects undergoing withdrawal after 120months (Δ 4.1ml/min; p < 0.001). In a Cox regression analysis adjusted for age, gender and eGFR, patients with CNI withdrawal showed better survival rates for the combined endpoint death/graft loss (hazard ratio, HR [95% confidence interval]: 0.19 [0.12-0.33], p = 0.001) compared to matched controls. The survival benefit was significant for the endpoints death (p = 0.01) and graft loss (p = 0.001). CNI withdrawal was associated with improved survival rates in patients with advanced graft dysfunction in this retrospective analysis.