-
Journal of Nephrology Sep 2023The choice of induction therapy in kidney transplantation is often non-standardized and centre-specific. Clinicians can choose between depleting and non-depleting...
BACKGROUND
The choice of induction therapy in kidney transplantation is often non-standardized and centre-specific. Clinicians can choose between depleting and non-depleting antibodies, which differ in their immunosuppressive capacity and the concomitant risk of infection. We herein present a standardized risk-stratified algorithm for induction therapy that might help to balance the risk of rejection and/or serious infection.
METHODS
Prior to kidney transplantation, patients were stratified into low-risk, intermediate-risk or high-risk according to our protocol based on immunologic risk factors. Depending on their individual immunologic risk, patients received basiliximab (low risk), antithymocyte globulin (intermediate risk) or low-dose alemtuzumab (high risk) for induction therapy. We analysed the results after 3 years of implementation of our risk-stratified induction therapy protocol at our kidney transplant centre.
RESULTS
Between 01/2017 and 05/2020, 126 patients were stratified in accordance with our protocol (low risk/intermediate risk/high risk: 69 vs. 42 vs. 15 patients). The median follow-up time was 1.9 [1.0-2.5] years. No significant difference was observed in rejection rate and allograft survival (low risk/intermediate risk/high risk: 90.07% vs. 80.81% vs. 100% after 3 years (p > 0.05)) among the groups. The median eGFR at follow-up was (low risk/intermediate risk/high risk) 47 [33-58] vs 58 [46-76] vs 44 [22-55] ml/min/1.73 m. Although the rate of viral and bacterial infections did not differ significantly, we observed a higher rate of opportunistic fungal infections with alemtuzumab induction.
CONCLUSIONS
Our strategy offers facilitated and individualized choice of induction therapy in kidney transplantation. We propose further evaluation of our algorithm in prospective trials.
Topics: Humans; Alemtuzumab; Kidney Transplantation; Antibodies, Monoclonal, Humanized; Prospective Studies; Induction Chemotherapy; Immunosuppressive Agents; Graft Rejection; Graft Survival
PubMed: 37688753
DOI: 10.1007/s40620-023-01746-1 -
Blood Mar 2024Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte...
Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% first-line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other first-line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (confidence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving first-line etoposide. Compared with the HLH-2004 study, both pre-HSCT and post-HSCT survival of patients receiving first-line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of patients with pHLH reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes.
Topics: Infant, Newborn; Humans; Etoposide; Lymphohistiocytosis, Hemophagocytic; Treatment Outcome; Hematopoietic Stem Cell Transplantation; Lymphoproliferative Disorders
PubMed: 37992218
DOI: 10.1182/blood.2023022281 -
Journal of the Endocrine Society Nov 2023To determine the rate and clinical characteristics associated with abnormal thyroid and adrenal function in recipients of nonmyeloablative hematopoietic cell...
PURPOSE
To determine the rate and clinical characteristics associated with abnormal thyroid and adrenal function in recipients of nonmyeloablative hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) and beta-thalassemia.
METHODS
We retrospectively reviewed patients who enrolled in 4 nonmyeloablative HCT regimens with alemtuzumab and total body irradiation (TBI). Baseline and annual post-HCT data were compared, which included age, sex, sickle phenotype, thyroid panel (total T3, free T4, thyroid stimulating hormone, antithyroid antibodies), cortisol level, ACTH stimulation testing, ferritin, medications, and other relevant medical history.
RESULTS
Among 43 patients in haploidentical transplant and 84 patients in the matched related donor protocols with mostly SCD, the rate of any thyroid disorder pre-HCT was 3.1% (all subclinical hypothyroidism) and post-HCT was 29% (10 hypothyroidism, 4 Grave's disease, and 22 subclinical hypothyroidism). Ninety-two (72%) patients had ferritin >1000 ng/dL, of which 33 patients (35.8%) had thyroid dysfunction. Iron overload was noted in 6 of 10 patients with hypothyroidism and 12 of 22 patients with subclinical hypothyroidism.Sixty-one percent were on narcotics for pain control. With respect to adrenal insufficiency (AI) pre-HCT, 2 patients were maintained on corticosteroids for underlying rheumatologic disorder and 8 had AI diagnosed during pre-HCT ACTH stimulation testing (total 10, 7.9%). Post-HCT, an additional 4 (3%) developed AI from corticosteroid use for acute graft vs host disease, Evans syndrome, or hemolytic anemia.
CONCLUSION
Although iron overload was common in SCD, thyroid dysfunction pre-HCT related to excess iron was less common. Exposure to alemtuzumab or TBI increased the rates of thyroid dysfunction post-HCT. In contrast, AI was more common pre-HCT, but no risk factor was identified. AI post-HCT was infrequent and associated with corticosteroid use for HCT-related complications.
PubMed: 37953902
DOI: 10.1210/jendso/bvad134 -
Ophthalmic Plastic and Reconstructive...To present 5 cases of alemtuzumab-induced thyroid eye disease (AI-TED) and review the literature to highlight the natural history, severity, and outcomes as compared... (Review)
Review
PURPOSE
To present 5 cases of alemtuzumab-induced thyroid eye disease (AI-TED) and review the literature to highlight the natural history, severity, and outcomes as compared with conventional thyroid eye disease (TED).
METHODS
A multi-institutional retrospective case series of patients with AI-TED was compiled. Chart review evaluated for clinical characteristics, imaging findings, and treatment for AI-TED. Additionally, a comprehensive review of the literature identified all previously published cases of AI-TED.
RESULTS
Five new patients with AI-TED were included in this series. The average clinical activity score on presentation was 2.8 (range 1-4) and reached an average peak of 5.0 during the active phase of the disease (4-7). Patients were treated medically with selenium (40%) or monoclonal antibodies including teprotumumab or tocilizumab (40%). Surgical treatment with orbital decompression for compressive optic neuropathy was performed on 2 (40%) patients. Combined with 11 previously reported cases, these 16 patients with AI-TED had an average clinical activity score on presentation of 3.3. The average length of the AI-TED phase was 14.0 months, and all patients were treated with medical and/or surgical interventions for their disease.
CONCLUSIONS
Clinical and imaging findings in AI-TED mirror that of conventional TED, however, AI-TED may present with greater severity. AI-TED may develop many months after Graves' disease; therefore, providers should be aware of this association and monitor patients for the development of severe TED.
Topics: Humans; Graves Ophthalmopathy; Alemtuzumab; Retrospective Studies; Graves Disease; Optic Nerve Diseases
PubMed: 36893061
DOI: 10.1097/IOP.0000000000002367 -
Neurologia 2023This article analyses the presence of gender bias in clinical trials of monoclonal antibodies used to treat multiple sclerosis. (Review)
Review
INTRODUCTION
This article analyses the presence of gender bias in clinical trials of monoclonal antibodies used to treat multiple sclerosis.
MATERIAL AND METHODS
We performed a systematic review of controlled clinical trials of 4 monoclonal antibodies used to treat multiple sclerosis (natalizumab, rituximab, alemtuzumab, and ocrelizumab). We searched the PubMed/MEDLINE database for articles published in English before March 2020. The study was conducted in accordance with the relevant international recommendations.
RESULTS
The search identified 89 articles, 55 of which met the inclusion criteria. Of all patients included in these trials, 64.6% were women. The lead authors of 10 of the studies were women. Fifteen of the 55 studies included a sex-based analysis of the primary endpoint. Only 8 articles discussed the results separately for men and for women.
CONCLUSIONS
The clinical trials of these 4 monoclonal antibodies present a significant gender bias. In most cases, the primary and secondary endpoints are not analyzed according to patient sex, despite the fact that international recommendations include this as a minimum requirement for ensuring scientific validity and obtaining appropriate results for extrapolation to the wider population.
Topics: Humans; Female; Male; Antibodies, Monoclonal; Multiple Sclerosis; Sexism; Alemtuzumab; Rituximab
PubMed: 37996214
DOI: 10.1016/j.nrleng.2021.01.008 -
Transplantation Reviews (Orlando, Fla.) Dec 2023Recommendations of the use of antibody induction treatments in kidney transplant recipients (KTR) are based on moderate quality and historical studies. This systematic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Recommendations of the use of antibody induction treatments in kidney transplant recipients (KTR) are based on moderate quality and historical studies. This systematic review aims to reevaluate, based on actual studies, the effects of different antibody preparations when used in specific KTR subgroups.
METHODS
We searched MEDLINE and CENTRAL and selected randomized controlled trials (RCT) and observational studies looking at different antibody preparations used as induction in KTR. Comparisons were categorized into different KTR subgroups: standard, high risk of rejection, high risk of delayed graft function (DGF), living donor, and elderly KTR. Two authors independently assessed the risk of bias.
RESULTS
Thirty-seven RCT and 99 observational studies were finally included. Compared to anti-interleukin-2-receptor antibodies (IL2RA), anti-thymocyte globulin (ATG) reduced the risk of acute rejection at two years in standard KTR (RR 0.74, 95%CI 0.61-0.89) and high risk of rejection KTR (RR 0.55, 95%CI 0.43-0.72), but without decreasing the risk of graft loss. We did not find significant differences comparing ATG vs. alemtuzumab or different ATG dosages in any KTR group.
CONCLUSIONS
Despite many studies carried out on induction treatment in KTR, their heterogeneity and short follow-up preclude definitive conclusions to determine the optimal induction therapy. Compared with IL2RA, ATG reduced rejection in standard-risk, highly sensitized, and living donor graft recipients, but not in high DGF risk or elderly recipients. More studies are needed to demonstrate beneficial effects in other KTR subgroups and overall patient and graft survival.
Topics: Humans; Aged; Antilymphocyte Serum; Immunosuppressive Agents; Kidney Transplantation; Alemtuzumab; Antibodies; Graft Rejection; Lymphocytes; Transplant Recipients; Graft Survival
PubMed: 37774445
DOI: 10.1016/j.trre.2023.100795 -
Multiple Sclerosis and Related Disorders Nov 2023Disease-modifying therapies (DMTs) in multiple sclerosis (MS) can be classified according to the efficacy in which they prevent inflammatory activity. To date, there are...
BACKGROUND
Disease-modifying therapies (DMTs) in multiple sclerosis (MS) can be classified according to the efficacy in which they prevent inflammatory activity. To date, there are limited data regarding the use of high-efficacy treatments (HETs) in Latin America (LATAM). We aimed to analyze the use of HETs in Argentina, focusing on the clinical and sociodemographic characteristics of the patients who use these treatments and the changes in the trend of use over the years.
METHODS
A retrospective cohort study was done using the Argentina MS patient registry, RelevarEM. Patients diagnosed with relapsing-remitting MS (RRMS) according to validated diagnostic criteria and under treatment with natalizumab, alemtuzumab, cladribine, rituximab or ocrelizumab were included.
RESULTS
Out of 2450 RRMS patients under a DMT, 462 (19%) were on HETs. One third of those patients (35%) received HETs as the first treatment. The most frequent reason for switching to HETs was treatment failure to previous DMT (77%). The time from MS diagnosis to the first HET in treatment-naive patients was less than one year (IQR: 0-1 year) and in treatment-experienced patients it was 5 years (IQR: 3-9 years). Between 2015 and 2017 (P1), 729 patients included in RelevarEM started a new treatment, of which 85 (11.65%) were HETs. Between 2018 and 2020 (P2), 961 patients included in RelevarEM started a new treatment, of which 284 (29.55%) were HETs. When comparing P2 with P1, a significant increase in the use of HETs was observed (p < 0.01). The most frequently used HETs were alemtuzumab (50.59%) in P1, and cladribine (45.20%) in P2.
CONCLUSION
The demographic and clinical characteristics of patients under HET in Argentina were identified. Based on a real-world setting, we found a significant trend towards and a rapid increase in the use of HETs in clinical practice in patients with RRMS.
Topics: Humans; Multiple Sclerosis, Relapsing-Remitting; Cladribine; Multiple Sclerosis; Alemtuzumab; Retrospective Studies; Argentina; Immunosuppressive Agents
PubMed: 37634468
DOI: 10.1016/j.msard.2023.104935 -
Journal of Biomedical Informatics Dec 2023Computational models are at the forefront of the pursuit of personalized medicine thanks to their descriptive and predictive abilities. In the presence of complex and...
OBJECTIVE
Computational models are at the forefront of the pursuit of personalized medicine thanks to their descriptive and predictive abilities. In the presence of complex and heterogeneous data, patient stratification is a prerequisite for effective precision medicine, since disease development is often driven by individual variability and unpredictable environmental events. Herein, we present GreatNectorworkflow as a valuable tool for (i) the analysis and clustering of patient-derived longitudinal data, and (ii) the simulation of the resulting model of patient-specific disease dynamics.
METHODS
GreatNectoris designed by combining an analytic strategy composed of CONNECTOR, a data-driven framework for the inspection of longitudinal data, and an unsupervised methodology to stratify the subjects with GreatMod, a quantitative modeling framework based on the Petri Net formalism and its generalizations.
RESULTS
To illustrate GreatNectorcapabilities, we exploited longitudinal data of four immune cell populations collected from Multiple Sclerosis patients. Our main results report that the T-cell dynamics after alemtuzumab treatment separate non-responders versus responders patients, and the patients in the non-responders group are characterized by an increase of the Th17 concentration around 36 months.
CONCLUSION
GreatNectoranalysis was able to stratify individual patients into three model meta-patients whose dynamics suggested insight into patient-tailored interventions.
Topics: Humans; Workflow; Computer Simulation; Precision Medicine; Cluster Analysis
PubMed: 37984546
DOI: 10.1016/j.jbi.2023.104546 -
Human Immunology May 2024Intestinal allografts are the most immunologically complex and carry the highest risk of rejection among solid organ transplantation, necessitating complex... (Review)
Review
Intestinal allografts are the most immunologically complex and carry the highest risk of rejection among solid organ transplantation, necessitating complex immunosuppressive management. We evaluated the latest information regarding induction immunosuppression, with an emphasis on established, novel, and emergent therapies. We also reviewed classic and novel induction immunosuppression strategies for highly sensitized recipients. Comparable progress has been made in intestinal transplantation clinical outcomes since the implementation of induction strategies. This review shows a clear diversity of induction protocols can be observed across different centers. The field of intestinal transplantation is still in its early stages, which is further complicated by the limited number of institutions capable of intestinal transplantation and their geographical variation, which further hinders the development of adequately powered studies in comparison to other organs. As the implementation of institution-specific induction protocols becomes more refined and results are disseminated, future research efforts should be directed towards the development of efficacious induction strategies.
Topics: Humans; Intestines; Graft Rejection; Immunosuppressive Agents; Immunosuppression Therapy; Organ Transplantation
PubMed: 38599892
DOI: 10.1016/j.humimm.2024.110800 -
Pediatric Nephrology (Berlin, Germany) Oct 2023Induction agent used at the time of kidney transplant is often based upon center practice and recipient characteristics. We evaluated outcomes across induction therapies...
BACKGROUND
Induction agent used at the time of kidney transplant is often based upon center practice and recipient characteristics. We evaluated outcomes across induction therapies among children enrolled in the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) transplant registry with data in the Pediatric Health Information System (PHIS).
METHODS
This is a retrospective study of merged data from NAPRTCS and PHIS. Participants were grouped by induction agent: interleukin-2 receptor blocker (IL-2 RB), anti-thymocyte/anti-lymphocyte globulin (ATG/ALG), and alemtuzumab. Outcomes assessed included 1-, 3-, and 5-year allograft function and survival, rejection, viral infections, malignancy, and death.
RESULTS
A total of 830 children transplanted between 2010 and 2019. At 1 year post-transplant, the alemtuzumab group had higher median eGFR (86 ml/min/1.73 m) compared to IL-2 RB and ATG/ALG (79 and 75 ml/min/1.73 m, respectively; P < 0.001); at 3 and 5 years, there was no difference. Adjusted eGFR over time was similar across all induction agents. Rejection rates were lower among the alemtuzumab group vs. IL-2RB and ATG (13.9% vs. 27.3% and 24.6%, respectively; P = 0.006). Adjusted ATG/ALG and alemtuzumab had higher hazard ratio for time to graft failure compared to IL-2 RB (HR 2.48 and HR 2.11, respectively; P < 0.05). Incidence of malignancy, mortality, and time to first viral infection was similar.
CONCLUSION
Although rejection and allograft loss rates were distinct, the incidences of viral infection and malignancy were comparable across induction agents. By 3 years post-transplant, there was no difference in eGFR. A higher resolution version of the Graphical abstract is available as Supplementary information.
Topics: Humans; Child; Alemtuzumab; Kidney Transplantation; Antibodies, Monoclonal, Humanized; Retrospective Studies; Health Information Systems; Interleukin-2; Antilymphocyte Serum; Graft Rejection; Immunosuppressive Agents; Graft Survival
PubMed: 37154962
DOI: 10.1007/s00467-023-05955-5