Patients Receiving Calcineurin Inhibitors Research Articles

Soluble LAG3: A Potential Marker for the Development and Activity of Acute Graft-Versus-Host Disease

Acute graft-versus-host disease (aGVHD), usually developing within 100 days after hematopoietic stem cell transplantation (HSCT), is mainly attributed to donor T cell pro-inflammatory responses against mismatched host histocompatibility antigens. The persistence of increased effector T cell responses following HSCT is partially related to an altered function of T regulatory cells (Tregs) and their failure to prevent GVHD. Certain immune checkpoint molecules, such as cytotoxic T-lymphocyte antigen 4, programmed cell death protein 1 (PD1) and lymphocyte activation gene-3 (LAG3), highly expressed on Tregs, are involved in maintaining immune tolerance and preventing immune-mediated inflammation. LAG3 is a newly identified inhibitory receptor, found on most immune cells, including CD4+ and CD8+ T cells, Tregs, and dendritic cells. Previous studies have demonstrated a role of LAG3 expression on T cells in GVHD suppression. Its soluble isoform sLAG3, released from the cell membrane, has been recently reported to also contribute to enhanced immune-mediated responses in solid tumors and autoimmune diseases, such as anti-PD1-resistant melanoma, rheumatoid arthritis (RA), and ANCA-associated vasculitis. Given this evidence, the current study aimed to explore a potential role of sLAG3 in GVHD development. Serum samples of 25 patients (≥18 years old) who underwent allogeneic HSCT at Rambam from 01.2021 to 01.2023 were drawn on days -7, +100, +180 of transplant. Twelve serum samples obtained from the Biobank were used as healthy control (HC). All samples were assessed for the sLAG3 levels using a commercial ELISA kit. The median level measured in HC (56pg/mL) was considered a cutoff to define the “low and high level sLAG3 groups”. Twenty-three patients were included in the analysis [median age at transplant - 59.5 years (range 19-75); 52% males]. Seventeen patients had acute myeloid leukemia, 3 - myelodysplastic syndrome, 2 - acute lymphoblastic leukemia and 1 had primary myelofibrosis. Fourteen patients had a matched unrelated donor, 6- matched related donors, and 3 - haploidentical donors. Nineteen patients received calcineurin inhibitor (CNI) and methotrexate-based GVHD prophylaxis (13 with ATG); 4 patients received post-transplant cytoxan-based prophylaxis, with CNI and mycophenolate-mofetil. Overall, 17/23 (74%) patients developed GVHD: 9 - aGVHD and 8 - chronic GVHD (cGVHD). A low pre-transplant sLAG3 level (<56pg/mL) was found in 8/23 patients, while it was high (>56pg/mL) in 15/23. Notably, 9/15 (60%) patients in the “high sLAG3 group”, but none in the “low sLAG3 group” were diagnosed with aGVHD, suggesting a high sLAG3 level as a possible indicator for patient-pre-transplant susceptibility to aGVHD development, irrespective of transplant factors, such as conditioning regimen, donor type, etc. Four patients in each group developed cGVHD. Furthermore, there was a significant increase in sLAG3 levels between the baseline and GVHD diagnosis in patients who developed aGVHD (mean: from 156.1±172.8, to 323.9±201.3), but not in those who either had cGVHD (mean: from 119.71±90.5 to 150.1±147.1) or did not have GVHD (mean: from 49.7±36 to 52.1±22.2). Overall, 11/23 patients were in complete remission (CR) at the time of HSCT; 9/11 were in the high-sLAG3 group and 6 of them developed aGVHD. In the low-sLAG3 group, most patients (6/8) had some degree of active disease (persistent disease or minimal-residual disease). These findings may reflect high T-effector cell and/or low Treg activity, possibly contributing to both anti-leukemic effect and GVHD development. In conclusion: The current study demonstrates, for the first time, that the pre-transplant sLAG3 level is significantly increased and continues to further increase in patients who develop aGVHD following HSCT compared to those who don't. These findings suggest a potential role of sLAG3 as a predicting factor for aGVHD development as well as a marker of treatment response that could guide therapeutic decisions in this patient setting.

A fragment of type VI collagen alpha-6 chain is elevated in serum from patients with atopic dermatitis, psoriasis, hidradenitis suppurativa, systemic lupus erythematosus and melanoma

Extracellular matrix (ECM) remodeling of the skin is a continuous process necessary for maintaining tissue homeostasis. Type VI collagen (COL6) is characterized as a beaded filament, located in the dermal ECM, where COL6-α6-chain has been demonstrated upregulated in atopic dermatitis. The aim of this study was to develop and validate a competitive ELISA, targeting the N-terminal of COL6-α6-chain, named C6A6, and evaluate its associations with the dermatological condition’s atopic dermatitis, psoriasis, hidradenitis suppurativa, systemic lupus erythematosus, systemic sclerosis, urticaria, vitiligo, and cutaneous malignant melanoma in comparison, to healthy controls. A monoclonal antibody was raised and employed in an ELISA assay. The assay was developed, technically validated, and evaluated in two independent patient cohorts. Cohort 1 showed C6A6 was significantly elevated in patients with atopic dermatitis (p < 0.0001), psoriasis (p < 0.0001), hidradenitis suppurativa (p = 0.0095), systemic lupus erythematosus (p = 0.0032) and melanoma (p < 0.0001) compared to healthy donors. Cohort 2 confirmed C6A6 being upregulated in atopic dermatitis compared to healthy controls (p < 0.0001), but also associated with disease severity (SCORAD, p = 0.046) and lowered in patients receiving calcineurin inhibitors (p = 0.014). These findings are hypothesis generating, and the utility of the C6A6 biomarker for disease severity and treatment response needs to be validated in larger cohorts and longitudinal studies.

Clinico-biochemical Profile of Biopsy-proven Minimal Change Disease in Adults from a Tertiary Care Center in South India.

Minimal change disease (MCD) is the most common cause of nephrotic syndrome (NS) in children, and in adults, it contributes to 10%-25% of NS. MCD in adults follows a slightly different course associated with increased incidence of steroid resistance, hematuria, and HTN. This is a prospective-record analysis study aimed to analyze the profile of MCD in adults, response to treatment, and relapse rates. A retrospective observational study was carried out and data were collected retrospectively from all biopsy-proven MCD patients between 2012 and 2018. A total of 86 adults were diagnosed to have biopsy-proven MCD. Of these, 32 were excluded due to insufficient data/lost for follow-up. The IBM SPSS Statistics version 22.0 was used for the statistical analysis. Descriptive analysis includes expression of all the explanatory and outcome variables in terms of frequency and proportions for categorical variables whereas in terms of mean ± standard deviation for continuous variables. Chi-square test was used to compare the age, gender, remission, renal failure and response of different drugs, treatment durations, comorbidity conditions, relapse episodes, and different types of infections based on the degree of proteinuria among study patients. A total of 54 biopsy-proven adult MCD patients were analyzed. The mean age of the patients studied was 36.67 years, with the oldest patient being 76 years. In the study group, 37 (68.5%) patients were male and 14 (31.5%) were female. In the study population, 20 (37%) were hypertensive, 3 (5.6%) were diabetic, and 10 (18.5%) had renal failure at presentation. On treatment, 52 out of 54 patients received steroids, of which 41 (75.9%) were steroid responsive, 6 (11.1%) steroid dependent, and 7 (13%) steroid resistant. The mean time for remission in steroidsensitive patients was 8.8 weeks. Among the steroid-dependent and steroid-resistant patients, 11 patients received calcineurin inhibitors (CNIs), of which 3 were CNI resistant. In the study Group 1 patient received cyclophosphamide and two received rituximab. In the study population, two patients failed to achieve remission and one patient was initiated on hemodialysis and later lost for follow-up. Minimal change NS is a type of NS which is highly responsive to steroids with good prognosis in children. Adult MCD patients require a higher and prolonged course of steroid when compared to children. CNIs and rituximab form a promising second-line drug in patients who are steroid resistant/dependent. However, CNI dependency or relapse after stopping steroids is a concern.

Does mtori base immunosuppression offer survival advantage after liver transplantation for hepatocellular carcinoma? Systematic review and meta-analysis of randomized controlled trials.

Recurrence is still a problem after liver transplant for hepatocellular carcinoma (HCC). We performed an updated systematic review and meta-analysis of randomized controlled trials comparing tumor recurrence of mammalian target of rapamycin inhibitors (mTORi) versus Calcineurin inhibitor-based immunosuppression after liver transplantation for HCC. A systematic search was conducted in the following databases: MEDLINE, EMBASE, and Cochrane Central Register of Control Trials databases. The Medical Subject Headings used in the search included: "sirolimus," "everolimus," "mTORi," "HCC," "mTORi," "hepatic transplantation" "randomized controlled trials," and "liver transplantation (LT)". Seven randomized controlled trials were included for meta-analysis. There were a total of 1,365 patients, with 712 of these patients receiving calcineurin inhibitors (CNIs) while 653 had received mTORi. Our meta-analysis revealed that patients that received mTORi-based immunosuppression had superior recurrence-free survival (RFS) at 1 year and 3 years with a hazard ratio of 2.02 and 1.36, respectively. Meta-analysis also showed that within the first 3 years after LT for HCC, patients receiving CNIs-based immunosuppression have a higher recurrence than those receiving mTORi-based immunosuppression. Our meta-analysis revealed that recipients of mTORi-based immunosuppression had a superior OS at 1 year and 3 years. mTORi-based immunosuppression is associated with decreased early recurrence and improved RFS and overall survival.

Indirectly Recognizable Epitopes Derived from Recipient Mismatched HLA-B Are Associated with Adverse Prognosis in Single-Unit Cord Blood Transplantation

Backgrounds Despite cord blood is an important alternative stem cell source for the patients without HLA matched donors, engraftment failure is the most significant obstacle in cord blood transplantation (CBT). Donor-specific anti-HLA antibody and hemophagocytic syndrome (HPS) after severe pre-engraftment immune reaction are the major causes of engraftment failure. However, the allo-immunity associated with graft rejection has not been fully understood. In HLA-mismatched transplantation, mismatched HLA is an important target for allo-immunity but the immunogenicity is different depending on the mismatched HLA pair of donor and recipient. Therefore, we hypothesized that by evaluating the antigenicity of mismatched HLA, we could improve donor selection criteria for CBT. Methods: We performed a retrospective analysis of clinical data on 4,100 single-unit CBT in Japan between 2001 and 2017 deposited in Transplant Registry Unified Management Program (TRUMP). Using the PIRCHE algorithm (PIRCHE AG, Berlin), the number of mismatched HLA-derived epitopes to be presented by HLA was predicted. PIRCHE was quantified separately for the mismatched recipient loci (HLA-A, -B, -C, -DRB1) and the presenting donor-HLA (ClassI or ClassII, matched or mismatched HLA). Specifically, we evaluated binding affinities of peptides that could be made from recipient mismatched HLA to donor HLA using netMHCpan and netMHCIIpan. Epitopes with IC50 < 500 nM for Class I and < 1000 nM for Class II were defined as PIRCHE-I and PIRCHE-II, respectively. Results: The death-censored median observation period was 2.7 years (0.5-17.1), median age at transplantation was 53 years (16-75), and 96.4% of patients were infused with HLA-mismatched cord blood. The present cohort includes patients with AML (49.6%), ALL (14.0%), Lymphoma (12.9%), MDS (10.8%), CML (2.2%), and other diseases (10.5%). Full-intensity conditioning was performed in 50.4% of patients. All patients received calcineurin inhibitors (CNI) for graft-versus-host disease (GvHD) prophylaxis, 1410 (34.5%) of them received MMF and 2110 (51.5%) received MTX in combination with CNI. The number of PIRCHEs derived from each HLA-loci showed zero-inflated distributions. Patients with PIRCHE-I derived from recipient mismatched HLA-B (rB-PIRCHE-I) had a higher non-relapse mortality (NRM, Hazard ratio [HR] = 1.19, p = 0.004) and lower progression free survival (PFS, HR = 1.12, p = 0.002). They tended to have higher risk for engraftment failure and infection was leading cause of death. rB-PIRCHE-I was not associated with incidence of acute and chronic GvHD. Interestingly, rB-PIRCHE-I on matched HLA (rB-PIRCHE-I on match) was significantly associated with prognosis (PFS, HR = 1.11, p = 0.005), but those presented on mismatched HLA were not (PFS, HR = 1.07, p = 0.1). The numbers of infused nucleated cells and CD34+ cells in the graft were higher in the patients with rB-PIRCHE-I on match, but there was no difference in other patient backgrounds with or without rB-PIRCHE-I on match. In patients transplanted with HLA-B mismatched cord blood, rB-PIRCHE-I on match was prognostic. In patients who received MMF, rB-PIRCHE-I on match was associated with engraftment failure (Figure 1) and poor prognosis (NRM, HR = 1.48, p < 0.001; PFS, HR = 1.26, p < 0.001), whereas there was no prognostic impact in the patients with MTX. In order to elucidate the mechanism by which rB-PIRCHE-I increases engraftment failure in patients with MMF, we performed a detailed analysis of 100 patients who underwent CBT with MMF in the cohort of Kyushu University Hospital. As a result, we found that the frequency of HPS was significantly higher in patients with rB-PIRCHE-I on match (HR = 5.75, p = 0.001) Discussion: In the early period after CBT, donor antigen-presenting cells (APCs) are not reconstituted and donor T-cell is restricted to donor HLA. Therefore, we speculate that recipient APCs are inducing severe allo-immune reaction by presenting rB-PIRCHE-I on matched HLAs which are recognizable to donor T-cells. Furthermore, NK cells in the graft have been reported to prevent GvHD via suppression of recipient APCs, and MMF has the ability to suppress NK cells; it is possible that MMF enhanced the allo-immune response induced by recipient APCs. (Figure 2) Conclusion: HLA-mismatched cord blood without rB-PIRCHE-I is more desirable as a donor; when selecting a donor with rB-PIRCHE-I, it may be better to use MTX instead of MMF. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effect of mammalian-target-of-rapamycin inhibitors on the cancer risk in patients receiving calcineurin inhibitors: Data mining of a spontaneous reporting database.

Calcineurin inhibitors (CNIs), including cyclosporine and tacrolimus, are associated with an increased cancer risk. However, whether mammalian target of rapamycin inhibitors (mTORis), including sirolimus and everolimus, decrease the cancer risk in patients receiving CNIs remains uncertain. We aimed to determine whether mTORis are associated with a decreased cancer risk in patients receiving CNIs using data mining of a spontaneous adverse reaction database. Disproportionality analysis was conducted using the U.S. Food and Drug Administration Adverse Event Reporting System database (2004-2019) with reporting odds ratio and information component being used to indicate a signal. Data subset analyses indicated that sirolimus and everolimus were not associated with a decreased cancer risk in patients receiving cyclosporine or tacrolimus but were associated with an increased risk of nonmelanoma skin cancer (NMSC) and Kaposi's sarcoma. mTORis are not associated with a decreased cancer risk but are associated with a further increase in the risk of NMSC and Kaposi's sarcoma in patients receiving CNIs. Further studies are necessary to clarify the mechanism underlying the association between mTORis and NMSC or Kaposi's sarcoma.

MO163: Mycophenolate Mofetil Superior to Azathioprine and as Effective as Calcineurin Inhibitors in Lupus Nephritis Maintenance Therapy: Data from a Single Centre Prospective Study

Abstract BACKGROUND AND AIMS Systemic lupus erythematosus is the prototype of a multiorgan, multisystemic autoimmune disease. It has relatively frequent renal involvement (prevalence of 15–60%). A total of 19–25 patients develop end-stage renal disease after 10 years of disease onset. We studied the efficiency of mycophenolate mofetil compared to azathioprine and calcineurin inhibitors as maintenance therapy. We analysed a population of 67 patients with biopsy-proven lupus nephritis. We compared the groups for rates of achievement and maintaining remission at 18 months after the induction therapy, renal flares and rates of ESRD at the end of the study. METHOD We concluded a single-centre longitudinal study to assess the efficacy of mycophenolate mofetil as maintenance therapy in patients with biopsy-proven lupus nephritis: clinical remission rates, renal flares, renal function at the end of the follow-up period. We used SPSS version 16 for the statistics. Clinical data were taken from the electronic health records of the hospital (Hipocrate Informational System). RESULTS We included in the study patients diagnosed with systemic lupus erythematosus, who underwent renal biopsy between January 2008 and December 2018, followed-up until May 2020. Patients were assessed using proteinuria, anti-DNA double-strand antibodies, serum creatinine and eGFR-CKD-EPI measurements, C3, C4 levels and urinary sediment. In our study group, 58 patients were female, 9 were male, with a median age at diagnosis of 29 years, and median duration of the disease of 10 years. Median duration of corticosteroid treatment was 10.1 years. The most frequent classes of lupus nephritis were class IV (47.76%), class III (17.91%) and class V (17.91%) (ISN classification). At the moment of the kidney biopsy, 77.61% patients had nephrotic syndrome, and 22.39% nephritic syndrome. Patients underwent induction therapy with standard regimens (NIH 55.22%, Euro-Lupus 19.4%, mycophenolate 25.37%, CNI 1.49%). Maintenance therapy during the study period was as follows (all patients had corticosteroids in standard dose): 5 had mycophenolate, 27 azathioprine, 26 had both mycophenolate and azathioprine during the study period (treatment switches form one immunosuppressant to another were necessary during the study period due to adverse effects, occurring pregnancies, patient preference, costs of treatment), and 9 had calcineurin inhibitors. Of the 67 patients, at 18 months after the first induction regimen, 3 had no therapeutic response, and required a second course of induction, 25 maintained partial remission and 39 maintained total remission. A total of 21/67 patients had no renal flare, 46/67 patients had renal flares. At the end of the study, 13/67 patients were ESRD and 54/67 were non-ESRD. We obtained the following results (Kruskal–Wallis and Bonferroni tests): maintaining remission at 18 months following induction therapy for mycophenolate mofetil—15.4% complete remission, 2.6% partial remission; in the azathioprine group—52.6% partial remission, 26.9% complete remission; in patients who received both mycophenolate and azathioprine (required a switch in therapy)—36.8% partial remission, 42.3% complete remission; in patients receiving calcineurin inhibitors—7.9% partial remission, 15.4% complete remission (P = .02). Renal flare rates were 7.1% for calcineurin inhibitors, 11.9% for mycophenolate mofetil, 28.6% for azathioprine, 52.4% for azathioprine and mycophenolate (Kruskal–Wallis, P = .002). At the end of the study, the frequency of ESRD was lowest in patients receiving mycophenolate or calcineurin inhibitors: 7.1% mycophenolate, 7.1% calcineurin inhibitors, 14.3% azathioprine, 71.4% mycophenolate and azathioprine (P = .039). CONCLUSION We identified that mycophenolate mofetil therapy led to better renal outcomes compared to azathioprine (higher clinical remission rates and fewer ESRD patients) and proved the same efficiency as calcineurin inhibitors.

Incidence rates for hospitalized infections, herpes zoster, and malignancies in patients with ulcerative colitis in Japan: an administrative health claims database analysis.

Patients with ulcerative colitis (UC) are at an increased risk of certain infections and malignancies compared with the general population. Incidence rates (IRs) of hospitalized infections, herpes zoster (HZ), and malignancies in patients with UC, stratified by treatment, in Japan were estimated. This retrospective study identified patients with UC treated with corticosteroids, immunosuppressants, or tumor necrosis factor inhibitors (TNFi) from 2 administrative databases (Japan Medical Data Center [JMDC] and Medical Data Vision [MDV]). IRs (unique patients with events per 100 patient-years) were estimated for hospitalized infections, HZ, and malignancies, between June 2010 and May 2018. Among 6,033 MDV patients with UC receiving corticosteroids, immunosuppressants, or TNFi, IRs (95% confidence intervals) were: hospitalized infections, 1.73 (1.52-1.93); HZ, 1.00 (0.85-1.16), and malignancies, 1.48 (1.29-1.66). Among 958 JMDC patients with UC receiving corticosteroids, immunosuppressants, or TNFi, IRs (95% confidence intervals) were: HZ, 1.82 (1.27-2.37) and malignancies, 1.35 (0.87-1.82). In both cohorts, IRs of malignancies were generally similar among patients receiving immunosuppressants, TNFi, or combination therapy (immunosuppressants and TNFi); this was also true for IRs of hospitalized infections and HZ in the MDV cohort. IRs of hospitalized infections, HZ, and malignancies were higher in patients receiving calcineurin inhibitors compared with immunosuppressants or TNFi, in both cohorts. IRs of hospitalized infections, HZ, and malignancies among patients with UC were generally similar regardless of UC treatment, except for calcineurin inhibitors.

Post-Transplantation Immunosuppression After TCRΑβ/CD19 Graft Depletion Does Not Improve HSCT Outcomes in Primary Immunodeficiency

We recently demonstrated that TCRαβ+/CD19+ graft depletion successfully prevents severe acute and chronic graft-versus-host disease (GVHD) in pediatric patients with primary immunodeficiencies (PID) receiving transplants from both matched unrelated and mismatched related donors. However, in all patients, short-term post-hematopoietic stem cell transplantation (HSCT) immunosuppressive therapy (IST) was used. There are limited data on TCRαβ+/CD19+ graft depletion with no post-HSCT IST implementation. In the current study 74 PID patients who underwent first HSCT from matched unrelated (n=51) or mismatched related donors (n=23) with TCRαβ+/CD19+ graft depletion were included. All received as a conditioning regimen a combination of treosulfan with fludarabine and either melphalan or thiotepa. In all, thymoglobulin 5 mg/kg (days −5, −4, −3) and rituximab at day −1 were used. In 48 patients, various approaches to short-term post-transplantation IST were used, and 26 patients received no post-HSCT IST. The rates of engraftment, acute and chronic GVHD, survival, and mortality were similar in those who received and did not receive IST, with a slightly higher incidence of graft rejection in patients not receiving IST: 19% in the non-IST group against 13% in the IST group (P = .41). The incidence of cytomegalovirus reactivation was 50% and 39% (P = .50) and Epstein-Barr virus reactivation 10% and 0 (P = .20) in the IST and non-IST groups, respectively. No grade 4 adverse events were seen in both groups, although in 19 of 40 (47.5%) patients receiving calcineurin inhibitors, the therapy was discontinued before day 45. More robust immune recovery with both T- and B-lymphocytes was observed in the non-IST group. To conclude, TCRαβ+/CD19+ in combination with particular serotherapy effectively prevents severe acute and chronic GVHD in PID. Regarding remaining risks of infectious complications and additional drug-related toxicity, there are no benefits to post-HSCT IST use in these patients.

Risk of Renal Recovery Post Dialysis-Requiring AKI in Critically Ill Transplant Patients Receiving Calcineurin Inhibitors

Risk of Renal Recovery Post Dialysis-Requiring AKI in Critically Ill Transplant Patients Receiving Calcineurin Inhibitors

Impact of pre-transplant use of antibiotics on the graft-versus-host disease in adult patients with hematological malignancies

ABSTRACT Objectives Changes in fecal microbiota affect the incidence and extent of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Most patients with hematological malignancies receive antibiotics for the treatment of febrile neutropenia prior to allogeneic HSCT, and pre-transplant use of antibiotics may influence the fecal microbiota and GVHD. Methods We retrospectively analysed consecutive adult patients with hematological malignancies who received allogeneic HSCT at Chungnam National University Hospital between 2007 and 2018. Pre-transplant use of antibiotics was defined as the use of antibiotics before conditioning chemotherapy. Results This study included 131 patients with a median age of 46 (range, 18–71) years: 76 (58%) patients were AML, 28 (21.4%) with ALL, 23 (17.6%) with MDS, and 4 (3.1%) with CML. All patients received calcineurin inhibitors with short-course methotrexate for GVHD prophylaxis. A total of 31 (23.7%) patients received anti-thymocyte globulin. All patients received antibiotics prior to HSCT: 70 (53.4%) patients received glycopeptide, 114 (87.0%) received cefepime, 87 (66.4%) received piperacillin/tazobactam, and 51 (38.9%) received carbapenem. Patients who received glycopeptide had more frequently extensive chronic GVHD (cGVHD) than those who did not (51.1% vs. 28.1% at 5 years) and had more frequently cGVHD of the lung (34.8% vs. 15.8% at 5 years). Pre-transplant use of glycopeptide did not affect the overall survival (OS) or GVHD- and relapse-free survival (GRFS) (median OS; 49 months in glycopeptide group vs. not reached in non-glycopeptide group, p=0.475; median GRFS; 9 months in glycopeptide group vs. 16 months in non-glycopeptide group, p=0.092). Conclusion Pre-transplant use of glycopeptide tends to increase the incidence of extensive cGVHD.

What Do Data Tell Us About Patients Receiving Calcineurin Inhibitors (CNIs) and Contracting a Coronavirus

What Do Data Tell Us About Patients Receiving Calcineurin Inhibitors (CNIs) and Contracting a Coronavirus

New-Onset Post-Transplant Diabetes Mellitus after Allogeneic Hematopoietic Cell Transplant Is Initiated by Insulin Resistance, Not Immunosuppressive Medications.

New-onset post-transplant diabetes mellitus (PTDM) occurs frequently after allogeneic hematopoietic cell transplant (HCT). Although calcineurin inhibitors and corticosteroids are assumed to be the cause for hyperglycemia, patients developing PTDM have elevated fasting C-peptide levels before HCT and before immunosuppressive medications. To determine if PTDM results from established insulin resistance present before transplant, we performed oral glucose tolerance tests (OGTTs) and measured whole body, peripheral, and hepatic insulin sensitivity with euglycemic hyperinsulinemic clamps before and 90 days after HLA-identical sibling donor HCT in 20 patients without pretransplant diabetes. HCT recipients were prospectively followed for the development of new-onset PTDM defined as a weekly fasting blood glucose ≥ 126 mg/dL or random blood glucose ≥ 200 mg/dL. During the first 100 days all patients received calcineurin inhibitors, and 11 individuals (55%) were prospectively diagnosed with new-onset PTDM. PTDM diagnosis preceded corticosteroid treatment. During the pretransplant OGTT, elevated fasting (87 mg/dL versus 101 mg/dL; P = .005) but not 2-hour postprandial glucose levels predicted PTDM diagnosis (P = .648). In response to insulin infusion during the euglycemic hyperinsulinemic clamp, patients developing PTDM had lower whole body glucose utilization (P = .047) and decreased peripheral/skeletal muscle uptake (P = .031) before and after transplant, respectively, when compared with non-PTDM patients. Hepatic insulin sensitivity did not differ. Survival was decreased in PTDM patients (2-year estimate, 55% versus 100%; P = .039). Insulin resistance before HCT is a risk factor for PTDM independent of immunosuppression. Fasting pretransplant glucose levels identified PTDM susceptibility, and peripheral insulin resistance could be targeted for prevention and treatment of PTDM after HCT.

Safety Analysis of Patients Who Received Ruxolitinib for the Treatment of Steroid-Refractory Acute Graft-Vs-Host Disease in Expanded Access Programs

Introduction Graft-vs-host disease (GVHD) is a serious, potentially fatal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ruxolitinib (RUX), a Janus kinase (JAK)1/JAK2 inhibitor, is in phase 3 development for patients with steroid-refractory (SR) acute and chronic GVHD. Outside of clinical trials, access to RUX is provided to patients with GVHD through Incyte- and Washington University (WU)–sponsored expanded access programs (EAPs) and single-patient investigational new drug (IND) applications. Objective To report pooled safety data from a subset of patients with SR acute GVHD (aGVHD) enrolled in these programs. Methods Eligible patients were ≥12 years of age, developed SR acute or chronic GVHD after allo-HSCT, and were not eligible for Incyte-sponsored GVHD clinical trials. Patients enrolled in the 2 EAPs received oral RUX at a starting dose of 5 mg twice daily (BID; maximum dose 10 mg BID); those on single-patient INDs received RUX as agreed to by Incyte and the treating physician. Concurrent therapy with other treatments for GVHD was permitted. Serious adverse events (SAEs) were assessed. Data from patients with aGVHD were pooled across the 3 programs; summary statistics are reported. Results At data cutoff (02 Apr 2018), 28 patients with SR aGVHD (Incyte EAP, n=13; WU EAP, n=9; single-patient IND, n=6) and 104 patients with SR chronic GVHD (Incyte EAP, n=33; WU EAP, n=31; single-patient IND, n=40) had enrolled in the programs. Mean (range) age of patients with SR aGVHD was 48 (13–73) years; 71.4% of patients were male. aGVHD was reported in the gastrointestinal (GI) tract (57.1%), skin (53.6%), liver (17.9%), lungs (7.1%), and eyes (3.6%). Most patients (75.0%) received ≥3 prior treatments for GVHD, including corticosteroids; 71.4% of patients received calcineurin inhibitors, and 28.6% of patients received prior RUX. Most patients (n=25) initially received 5 mg RUX BID; 1 patient received 10 mg RUX BID, and 2 patients received RUX 5 mg once daily. Five patients (17.9%) received 10 mg RUX BID as their last dose. Treatment was ongoing in 13 patients (46.4%) at data cutoff; discontinuations were due to death (n=7), withdrawn consent (n=3), disease progression (n=2), primary disease relapse (n=2), or drug refusal (n=1). The mean (range) duration of treatment was 79.6 (1–326) days. SAEs were reported in 13 patients (46.4%). There were no cytopenia, fungal infection, or cytomegalovirus SAEs. Respiratory failure (n=3) and GVHD (n=2) were the only SAEs reported in >1 patient. Ten patients had fatal outcomes following an SAE. Sepsis (n=1) was the only fatal SAE suspected to be related to RUX; no others SAEs were considered related to RUX. Conclusion Patients in the RUX EAPs were heavily pretreated, and more than half of the patients reported GI GVHD. SAEs were reported in almost half of the patients (46.4%), but no new or unexpected SAEs have been reported.

A Step Forward Towards Cytomegalovirus Free Hematopoietic Stem Cell Transplantation

Introduction: Cytomegalovirus (CMV) reactivation remains one of the most serious complications after allogeneic hematopoietic stem cell transplantation (HSCT) occurring in up to 30-50% of HSCT recipients. CMV reactivation can lead to adverse outcomes including end-organ damage and graft failure. Prevention of CMV infection may improve outcomes of HSCT recipients; however, CMV reactivation can still occur in HSCT recipients despite receiving prophylactic acyclovir. In this study, we used prophylactic ganciclovir pre-transplant to reduce the incidence of CMV reactivation and CMV disease.Methods: To reduce the incidence of CMV reactivation and disease, ganciclovir was administered before transplantation (5 mg/kg twice daily intravenously from day −8 to day −2) for all donor and recipient seropositive allogeneic HSCT. This was followed by high dose valacyclovir or acyclovir starting day 0 until one year post-transplant. Patients were monitored weekly with serum CMV PCR through Day 100 post transplantation. Preemptive therapy was started for an elevated CMV viral load. CMV reactivation was defined as a CMV viral load of more than 135 IU/ml. Over the course of the analysis period, two different PCR methods were used for CMV viral load; since 2015 Roche Cobas AmpliPrep/Cobas TaqMan CMV test was implicated. CMV disease was defined as detection of CMV by one of the following diagnostic tests including: culture, immunohistochemistry staining, or histopathology examination accompanied by documentation of disease signs and symptoms of the affected organ. Statistical analysis was performed using SAS version 9.4. Logistic regression models were explored to assess the association of age, graft source, and disease type on CMV reactivation. We performed a retrospective analysis of all recipient or donor CMV seropositive patients who received their first allogeneic HSCT at the University of Virginia between 2012 and 2017.Results: Seventy-nine consecutive patients were treated. The median age was 58 years (range 20 to 72). The most common diagnoses were acute myeloid leukemia (n=39, 49%) and acute lymphocytic leukemia (n=11, 14% ). Graft sources were matched related donor, (n=24, 30%), matched unrelated donor, (n=28, 35%), haploidentical (n=4, 5%) and cord blood (n=23, 29%). 43 patients (55%) received myeloablative (CyTBI, BuCy and FluBu) conditioning. 36 patients (45%) received reduced intensity/nonmyeloablative conditioning (Flu/Cy/TBI+/- ATG, Flu/Cy/ATG ,Flu Mel, Flu Bu and Cy ATG). All patients received calcineurin inhibitor based prophylactic immunosuppressive therapy for GVHD prevention.24 patients (30%) had CMV reactivation with median time of reactivation of 47 days post-transplant (range 27 to 229). 22 out of the 24 (88%) patients required treatment for CMV reactivation with a median treatment duration of 37 days (range 14 to 315). Patients were treated with either ganciclovir or foscarnet, as clinically indicated. The cumulative incidence of CMV reactivation at day 100 post-transplant was 27% with a 95% CI (18%-37%). The median highest viral load was 2130 copies/ml (range 151 to 3,250,000 copies/ml). There were no patients with biopsy proven CMV disease. There were no deaths attributed to CMV reactivation or disease.The median time-to neutrophil recovery (ANC > 500 k/uL) was 18 days and the median time to platelet count greater than 20,000 k/ul unsupported was 19 days. The incidence of acute GVHD (Grades II-IV) was 25 %. The incidence of significant acute kidney injury defined by serum creatinine of more than 2.5 mg/dL was 2.4 %. 1 year overall survival estimate was 54% with 95% CI (42-65%). In multivariate analysis, patients who received cord blood transplants, were approximately 4 times more likely to have a CMV reactivation (Odds Ratio 3.9 with a 95% CI(1.4-10.9)), p= 0.01, than those who did not.Conclusions:The incidence of CMV reactivation by day 100 of 27% with pre-transplant ganciclovir may be improved compared to historical controls of 30-50%.The use of pre-transplant ganciclovir was associated with no CMV disease, in this single center study.The use of pre-transplant ganciclovir is safe, with low incidence of kidney damage.These data suggest that pre-transplant ganciclovir with Preemptive therapy for viral reactivation should be considered regardless of graft source. Future prospective randomized trials are needed to evaluate strategies for CMV prophylactic regimens. DisclosuresNo relevant conflicts of interest to declare.

Post-Transplant Lymphoproliferative Disorders (PTLDs) After Heart Transplantation

Objective Post-transplant lymphoproliferative disorders (PTLDs) are one of most important cause of morbidity and mortality after heart transplantation (HTx), especially in children. Although Rituximab therapy combined with chemotherapy and reduced immunosuppression has been reported to be effective to suppress B cell type PTLD (B-PTLD), PTLDs relapse frequently and the outcome is still poor. Everolimus (EVL) has been reported to inhibit growth of human EBV-transformed B lymphocytes in vitro and in vivo. In this report, we described 4 adults and 4 children of PTLD after HTx. Material and Methods All 8 cases were suffered from B-PTLD and one concomitantly had leiomyoma. Duration between HTx and onset of PTLD in children was shorter than that in adults [a mean 20.0 (6 to 38) months vs 65.5 (18 to 104) months]. In all patients, final diagnosis was made by histological examination (lymph nodes in 4, tumors in 3 and ulcer in 1). All patients received calcineurin inhibitor (CNI) (cyclosporine in 3 and tacrolimus in 5) and 7 received mycophenolate mofetil and one received EVL prior to PTLD. Results All 4 children and 3 adult showed elevation of Epstein Barr virus (EBV) DNA. In children, chief complaints were fever and/or abdominal pain, but no adults showed abdominal pain. All patients were given Rituximab and chemotherapy with reduced. EVL was started to be given after chemotherapy to keep a trough level within 3-8 ng/ml. A girl showed relapse of PTLD in the trachea, but she was cured after Rituximab treatment and withdrawal of CNI. One adult showed relapse of T-PTLD 7 years after the onset of B-PTLD. One adult shoed relapse of PTLD in the chest and died 15 months after the onset of PTLD. One boy showed complete remission of B-PTLD but still had multiple leiomyoma in the intestine. Other 4 patients showed no relapse. Conclusion All patients had B-PTLD but showed different histology and clinical findings. Most patients were associated with EBV and combination therapy with Rituximab may be useful. However, to manage PTLD, individual strategy might be required, and histological examination is essential to decide treatment strategy. the Practical Research Project for Allergic Diseases and Immunology (Research on Technology of Medical Transplantation) from the Japan Agency for Medical Research and Development, AMED (Grant No. 17ek0510017h0002).

Retrospective Cohort Analysis of Liposomal Amphotericin B Nephrotoxicity in Patients with Hematological Malignancies.

We retrospectively examined the incidence, onset, risk factors, and outcomes of renal injury during 103 treatment courses of liposomal amphotericin B (L-AMB) in 97 adult patients with hematological malignancies. All the patients were analyzed before, during, and after the administration of L-AMB, and renal injury was graded according to the RIFLE criteria (risk, injury, failure, loss of function, end-stage renal disease). Most patients (87.3%) received L-AMB at 3 mg/kg of body weight/day. Nearly two-thirds (61.7%) of the treatment courses did not meet any RIFLE category for renal injury, while 19.4% of patients were classified at risk, 13.6% met an injury classification, and 5.8% were categorized as developing renal failure. However, 15% of the patients developed renal injury within 48 h of the onset of multiorgan failure associated with sepsis, bleeding, or progressing malignancy. When these patients were analyzed as a competing risk for L-AMB-associated renal injury (RIFLE category I or above) in a multivariate Cox regression model, receipt of cyclosporine (subhazard ratio [SHR], 2.62; 95% confidence interval [CI], 1.10 to 6.27; P = 0.03), cyclosporine plus furosemide at ≥40 mg/day (SHR, 5.46; 95% CI, 1.89 to 15.74; P = 0.002), or cyclosporine plus foscarnet (SHR, 9.03; 95% CI, 3.68 to 22.14; P < 0.0001) were the only comedications significantly associated with increased rates of renal injury. The cumulative incidence of L-AMB renal injury during the first 10 days of therapy was 7% overall but only 3% in patients who were not receiving cyclosporine. Hence, the renal risk of L-AMB therapy may be lessened if patients are switched to alternative agents after 7 to 10 days or if aggressive diuresis and/or foscarnet is avoided, especially among patients receiving calcineurin inhibitors.

Calcineurin and mTOR inhibitors have opposing effects on regulatory T cells while reducing regulatory B cell populations in kidney transplant recipients

BackgroundRegulatory B (Breg) and T (Treg) cells represent a biomarker for tolerance in transplant patients. Despite the importance of Treg and Breg in transplantation and the suggested crosstalk between both suppressive cell populations, little is known on how they are influenced by long-term immunosuppressive treatment. The aim of the present study was to investigate the effect of different immunosuppressive drugs used in routine clinical practice on Treg and Breg cell numbers. MethodsThirty-six kidney transplant recipients with stable graft function were recruited and classified according to their concomitant therapy: 22 patients received calcineurin inhibitors (CNI) and 14 patients received mammalian target of rapamycin (mTOR) inhibitors. A group of 8 healthy untreated subjects was included as control. Absolute numbers of peripheral blood-derived IL10-producing B cells (CD19+IL10+), CD19+CD24hiCD38hi transitional B cells and Treg cells (CD4+CD25+FOXP3+) were quantified in all KT patients and controls by flow cytometry. ResultsCD19+CD24hiCD38hi transitional B cells increased over time and seem to be related with long-term therapeutic graft survival irrespective of the treatment regimen. CNI and mTOR inhibitors significantly reduced numbers of Breg cells when compared with healthy individuals, whereas mTOR inhibitors expanded Treg cells in comparison with CNI drugs. ConclusionsBridging the drug-mediated reduction of Breg cell numbers in vivo with the requirements of Breg cells for long-term transplant success remains an as yet unresolved task for therapeutic intervention. Further larger cohort studies that evaluate the effect of different treatment regimen on defined lymphocyte subpopulations are warranted.

A Single Institution Study of Allogeneic Hematopoietic Stem Cell Transplant for MDS and AML in Patients 60 Years of Age and Older: Impact of Disease Risk Index and Secondary Disease

Background: Allogeneic Hematopoietic cell transplantation (HCT) is potentially curative therapy for MDS and AML. Although the median age at presentation is >65 years, most patients receiving HCT for these disorders are young (<60years). With the availability of Reduced Intensity Conditioning (RIC) many older patients are able to undergo HCT. The older age group is the most rapidly increasing cohort in CIBMTR registry. We analyzed the outcomes of AML and MDS patients' ≥ 60 years who received allogeneic sibling or unrelated donor HCT at our institution between 2009 and 2014. We also evaluated the influence of patient-, disease-, and transplant related factors on outcomes.Methods: Prospectively collected data available in the BMT databases at Mayo Clinic Florida, Arizona and Rochester as well as individual patient charts were reviewed after IRB approval. Patients with MDS or AML in complete remission at the time of transplant were included; those with active disease, induction failure, or prior transplant were excluded. HCT-specific comorbidity index (HCT-CI) and the disease risk index (DRI- Armand et al. Blood 2012) was noted. Survival estimates were calculated using the Kaplan Meier method. Associations with survival were explored using single variable Cox-regression modeling and log-rank tests.Results: 80 patients were included; 68 AML and 12 MDS. 31 (39%) were male. Median age 66 years (range 60-75). 33%, 52%, and 13% patients had ECOG status of 0, 1, >2, respectively. Thirty-seven patients (46%) had low or intermediate DRI and 43(54%) had high DRI. Twenty-two (28%), 24 (30%), and 34 (43%) patients had HCT-CI of 0, 1, or >2. There were equal number of sibling and unrelated donors; 85% were full HLA match and 15% with 1 or 2 mismatches; mean age of the donors was 52years (range18-74). Transplant conditioning was fludarabine-containing reduced intensity regimens in 78 (97%), 2 patients received myeloablative conditioning. The source of stem cells was peripheral blood in all patients. A median of 5.87 x10^6 CD34/kg donor cells were infused (range 1.58-10.92 X10^6). All patients received calcineurin inhibitor based GVHD prophylaxis (tacrolimus 56%, cyclosporine 44%); 6 patients also received ATG.The median follow up of survivors was 13 months. Kaplan Meier estimate of overall survival at 100 days, 1 year, and 2 years was 90%, 64%, and 55%. Cumulative incidence of relapse at 6 months, 1 year, and 2 years was 19.5%, 22.3%, and 27.1%. Relapse free survival at 2 years was 50%. The non-relapse/ treatment related mortality at 6 months, 1 year and 2 years was 11.7%, 15.9% and 15.9%. The rate of acute grade 2-4 GVHD was 30% and chronic GVHD was 39%. Univariate analysis identified secondary disease (compared to de novo) and high DRI(compared to low/intermediate) to be associated with worse mortality - HR 2.54 (1.31-4.93; P = 0.006), and 2.31 (1.13-4.73; P = 0.021), respectively. Probability of overall survival at 6 months, 1 year, and 2 years for patients with de novo disease (n=57) vs. secondary disease (n=23) was 87.1% vs. 64.5%, 71.1 vs. 45.6%, and 63.2 vs. 32.6%, respectively; P= 0.006. There was no effect of donor age, donor type or degree of mis-match on the survival.Conclusion: Allogeneic HCT is feasible in older patients with MDS and AML utilizing reduced intensity conditioning regimens with acceptable outcomes that are comparable to published results in younger patients. Patients with high DRI and secondary disease have poorer overall survival as compared to those with de novo disease and low/intermediate disease risk index. These data support other studies that age alone does not negatively influence transplant outcomes. DisclosuresNo relevant conflicts of interest to declare.

Twelve-month efficacy and safety of the conversion to everolimus in maintenance heart transplant recipients.

To determine the clinical reasons for conversion to everolimus (EVL) and long-term outcomes in heart transplant (HT) recipients. A retrospective 12-mo study has been carried out in 14 Spanish centres to assess the efficacy and safety of conversion to EVL in maintenance HT recipients. Two hundred and twenty-two patients were included (mean age: 53 ± 10.5 years; mean time from HT: 8.1 ± 4.5 years). The most common reasons for conversion were nephrotoxicity (30%), chronic allograft vasculopathy (20%) and neoplasms (17%). The doses and mean levels of EVL at baseline (conversion to EVL) and after one year were 1.3 ± 0.3 and 1.2 ± 0.6 mg/d and 6.4 ± 3.4 and 5.6 ± 2.5 ng/mL, respectively. The percentage of patients receiving calcineurin inhibitors (CNIs) at baseline and on the final visit was 95% and 65%, respectively. The doses and mean levels of CNIs decreased between baseline and month 12 from 142.2 ± 51.6 to 98.0 ± 39.4 mg/d (P < 0.001) and from 126.1 ± 50.9 to 89.2 ± 47.7 ng/mL (P < 0.001), respectively, for cyclosporine, and from 2.9 ± 1.8 to 2.6 ± 1.9 mg/d and from 8.3 ± 4.0 to 6.5 ± 2.7 ng/mL (P = 0.011) for tacrolimus. In the subgroup of patients converted because of nephrotoxicity, creatinine clearance increased from 34.9 ± 10.1 to 40.4 ± 14.4 mL/min (P < 0.001). There were 37 episodes of acute rejection in 24 patients (11%). The most frequent adverse events were oedemas (12%), infections (9%) and gastrointestinal problems (6%). EVL was suspended in 44 patients (20%). Since the database was closed at the end of the study, no further follow-up data is available. Conversion to EVL in maintenance HT recipients allowed minimisation or suspension of the CNIs, with improved kidney function in the patients with nephrotoxicity, after 12 mo.