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Journal of Neurology Jun 2024The COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could...
BACKGROUND
The COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic onset.
METHODS
A multi-centre longitudinal study with 8,771 participants from MSBase was conducted. Two time periods were defined: pre-pandemic (March 11 2018-March 10 2020) and post-pandemic onset (March 11 2020-11 March 2022). The association between time and prescribing trends was analysed using multivariable mixed-effects logistic regression. DMT initiation refers to first initiation of any DMT, whilst DMT switches indicate changing regimen within 6 months of last use.
RESULTS
Post-pandemic onset, there was a significant increase in DMT initiation/switching to natalizumab and cladribine [(Natalizumab-initiation: OR 1.72, 95% CI 1.39-2.13; switching: OR 1.66, 95% CI 1.40-1.98), (Cladribine-initiation: OR 1.43, 95% CI 1.09-1.87; switching: OR 1.67, 95% CI 1.41-1.98)]. Anti-CD20mAb initiation/switching decreased in the year of the pandemic, but recovered in the second year, such that overall odds increased slightly post-pandemic (initiation: OR 1.26, 95% CI 1.06-1.49; Switching: OR 1.15, 95% CI 1.02-1.29. Initiation/switching of fingolimod, interferon-beta, and alemtuzumab significantly decreased [(Fingolimod-initiation: OR 0.55, 95% CI 0.41-0.73; switching: OR 0.49, 95% CI 0.41-0.58), (Interferon-gamma-initiation: OR 0.48, 95% CI 0.41-0.57; switching: OR 0.78, 95% CI 0.62-0.99), (Alemtuzumab-initiation: OR 0.27, 95% CI 0.15-0.48; switching: OR 0.27, 95% CI 0.17-0.44)].
CONCLUSIONS
Post-pandemic onset, clinicians preferentially prescribed natalizumab and cladribine over anti-CD20 mAbs and fingolimod, likely to preserve efficacy but reduce perceived immunosuppressive risks. This could have implications for disease progression in pwMS. Our findings highlight the significance of equitable DMT access globally, and the importance of evidence-based decision-making in global health challenges.
PubMed: 38935148
DOI: 10.1007/s00415-024-12518-7 -
Experimental and Clinical... Oct 2023Alemtuzumab is a monoclonal antibody against CD52 that is being increasingly used in renal transplantation as a lymphocyte-depleting agent. Data on alemtuzumab use in...
Alemtuzumab is a monoclonal antibody against CD52 that is being increasingly used in renal transplantation as a lymphocyte-depleting agent. Data on alemtuzumab use in resistant rejection episodes are scarce, especially in children. Here, we present a 14-year-old renal transplant patient with acute cellular and humoral rejection who was treated with pulse steroids, plasmapheresis, and intravenous immunoglobulin with no success. He had 2 previous rejection episodes that were treated with antithymocyte globulin. In the third episode, alemtuzumab was given as a rescue therapy, and the patient benefited from the treatment. No complications were observed. Alemtuzumab can be a treatment option in pediatric patients with refractory rejection episodes.
Topics: Male; Humans; Child; Adolescent; Alemtuzumab; Kidney Transplantation; Immunosuppressive Agents; Antibodies, Monoclonal, Humanized; Immunosuppression Therapy; Graft Rejection
PubMed: 30806200
DOI: 10.6002/ect.2018.0203 -
Annals of Clinical and Translational... Jun 2024Observational real-world study to analyze the clinical effects of alemtuzumab (ALEM) and subsequent disease-modifying therapy (DMT) usage in multiple sclerosis (MS). (Observational Study)
Observational Study
BACKGROUND/OBJECTIVE
Observational real-world study to analyze the clinical effects of alemtuzumab (ALEM) and subsequent disease-modifying therapy (DMT) usage in multiple sclerosis (MS).
METHODS
Data retrieved from the Austrian MS treatment registry (AMSTR) included baseline (BL) characteristics (at ALEM start), annualized relapse rate (ARR), 6-month confirmed progression independent of relapse activity (PIRA; ≥ 0.5-point Expanded Disability Status Scale (EDSS) score increase), 6-month confirmed disability improvement (CDI; ≥ 0.5-point EDSS decrease), and safety outcomes until initiation of a subsequent DMT. The EDSS was re-baselined at 30 days from ALEM start (BL EDSS).
RESULTS
Eighty-seven ALEM-treated patients (median age: 32 years, 72% female, 14% treatment-naïve) were followed for a median of 55 (interquartile range 31-68) months. We found significant reductions in the ARR from 1.16 before ALEM to 0.15 throughout Years 1-9 (p < 0.001). Subsequent DMTs were initiated in 19 patients (22%, 74% anti-CD20 monoclonal antibodies). At Year 5 (n = 53), more patients achieved CDI (58%, 95% confidence interval (CI) 45%-71%) than had experienced PIRA (14%, CI 7.5%-24%), and 58% remained relapse-free. Shorter MS duration (p < 0.001, hazard ratio (HR) 0.86 (CI 0.80-0.93)) and no previous high-efficacy treatment (p < 0.001, HR 5.16 (CI 2.66-10.0)) were the best predictors of CDI, while PIRA was associated with a higher number of previous DMTs (p = 0.04, HR 3.06, CI 1.05-8.89). We found no new safety signals.
INTERPRETATION
ALEM had long-lasting beneficial effects on the ARR and disability improvement, especially when initiated early in the course of the disease. Only a subset of patients received subsequent DMTs.
Topics: Humans; Female; Alemtuzumab; Male; Austria; Adult; Multiple Sclerosis; Immunologic Factors; Registries; Multiple Sclerosis, Relapsing-Remitting; Treatment Outcome; Middle Aged; Disease Progression
PubMed: 38715245
DOI: 10.1002/acn3.52056 -
Journal of the European Academy of... Jan 2024
Topics: Humans; Alemtuzumab; Antibodies, Monoclonal; Antineoplastic Agents; Sezary Syndrome; Skin Neoplasms; Treatment Outcome
PubMed: 37595960
DOI: 10.1111/jdv.19441 -
American Journal of Kidney Diseases :... Jun 2024Kidney transplant patients with glomerulonephritis (GN) as their native disease commonly have received pretransplant immunosuppression (PTI). This may contribute to the...
RATIONALE & OBJECTIVE
Kidney transplant patients with glomerulonephritis (GN) as their native disease commonly have received pretransplant immunosuppression (PTI). This may contribute to the immunosuppression burden potentially increasing the risk for infections after transplantation.
STUDY DESIGN
Single-center, retrospective cohort study.
SETTING & PARTICIPANTS
Recipients of a kidney transplant from January 2005 until May 2020 at a tertiary care university teaching hospital.
EXPOSURE
Patients with GN as their native kidney disease who received PTI for treatment of GN (n=184) were compared with nondiabetic recipients of kidney transplants who did not receive PTI (n = 579).
OUTCOME
First occurrence after transplantation of an infection outcome, either viral (BK or cytomegalovirus [CMV] infection) or bacterial.
ANALYTICAL APPROACH
Cox regression analysis adjusted for age at transplant, sex, race, donor type, year of transplant surgery, dialysis vintage, receipt of T-cell depleting induction, and CMV transplant status.
RESULTS
Over a median follow-up period of 5.7 years, patients with GN PTI were not at an increased risk for developing any first viral infection compared with controls (adjusted HR [AHR] 0.69 [95% CI, 0.52-0.91]) nor at increased risk for specific viral infections: BK infection 19.6% vs 26.3% (AHR 0.72 [95% CI, 0.50-1.05]) or CMV infection, 24.5% vs 29.0% (AHR, 0.76 [95% CI, 0.54-1.07]), respectively. There was also no increased risk of developing a first bacterial infection: 54.5% vs 57.5% (AHR, 0.90 [95% CI, 0.71-1.13]). These findings of no increased risk for infection were independent of the type of PTI used (cyclophosphamide, rituximab, mycophenolate mofetil, or calcineurin inhibitor) or the type of T-cell depleting induction therapy (alemtuzumab or antithymocyte globulin) administered.
LIMITATIONS
Single-center study, no data on methylprednisone use for PTI, unmeasured confounding.
CONCLUSIONS
Use of PTI for the treatment of GN was not associated with an increased risk of viral (BK or CMV) or bacterial infection after transplantation. Additional surveillance for infection after transplantation for patients who received PTI may not be necessary.
PLAIN-LANGUAGE SUMMARY
Many kidney transplant patients have glomerular disease as the cause of kidney failure. These patients may be exposed to immunosuppression before transplantation, which could increase the risk for infections after receipt of a transplanted kidney. We identified kidney transplant recipients at a university teaching hospital who received immunosuppression before transplant for the treatment of glomerular kidney disease. We examined their risk for infection after transplantation by comparing it with the risk among transplant patients who were not exposed to immunosuppression before transplant. We observed no increased risk for infection after exposure to prior immunosuppression. Therefore, patients exposed to significant amounts of immunosuppression before transplantation may not require special surveillance or medication adjustment for fear of infection after their receipt of a kidney transplant.
Topics: Humans; Kidney Transplantation; Male; Female; Glomerulonephritis; Retrospective Studies; Middle Aged; Immunosuppressive Agents; Adult; Cytomegalovirus Infections; Immunosuppression Therapy; Bacterial Infections; Postoperative Complications
PubMed: 38160700
DOI: 10.1053/j.ajkd.2023.10.016 -
Pediatric Transplantation May 2024Alemtuzumab is a lymphocyte depleting agent used for induction in kidney transplant, but long-term information on its use in pediatric recipients remains sparse.
BACKGROUND
Alemtuzumab is a lymphocyte depleting agent used for induction in kidney transplant, but long-term information on its use in pediatric recipients remains sparse.
METHODS
We performed a single-center retrospective cohort study of 57 pediatric kidney transplant recipients receiving alemtuzumab 20 mg/m/dose ×2 doses for induction immunosuppression. All patients underwent surveillance biopsies, and 91.3% underwent steroid withdrawal by day 4 post-transplant. Outcomes of interest included graft survival, development of donor specific antibodies (DSA), incidence of viremia and PTLD, and duration of lymphopenia.
RESULTS
Median follow-up time was 7.9 years (IQR 5-13.6 years). Median graft survival was 16.5 years (95% CI 11.6-unknown). DSA developed in 36.5% at a median of 944 days (IQR 252-2113 days). Incidences of BK polyomavirus DNAemia (BKPyV-DNAemia), CMV DNAemia, and EBV DNAemia were 38.6%, 22.8%, and 14%, respectively; one patient developed PTLD at 13.3 years post-transplant. Median duration of lymphopenia was 365 days (IQR 168-713 days); 19.3% of patients remained lymphopenic at 3 years post-transplant. There was no association between duration of lymphopenia and graft survival, rejection, DSA detection, or viremia.
CONCLUSIONS
A two-dose alemtuzumab induction protocol can have excellent outcomes with a steroid-free maintenance immunosuppression regimen. More comprehensive, multicenter, comparative studies of pediatric kidney transplant are needed to improve long-term outcomes.
Topics: Child; Humans; Alemtuzumab; Graft Rejection; Graft Survival; Immunosuppressive Agents; Kidney Transplantation; Lymphopenia; Retrospective Studies; Steroids; Viremia
PubMed: 38623881
DOI: 10.1111/petr.14753 -
American Journal of Hematology May 2024Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low...
Azathioprine/hydroxyurea preconditioning prior to nonmyeloablative matched sibling donor hematopoietic stem cell transplantation in adults with sickle cell disease: A prospective observational cohort study.
Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19-49], 13 females) were transplanted. Median follow-up was 46.0 months (IQR 21.8-57.9). One-year overall survival and event-free survival (graft failure or death) were both 95% (95% confidence interval 86-100). Mean donor myeloid and T-cell chimerism 1-year post-transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid-responsive grade II intestinal acute graft-versus-host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event-free survival and robust donor T-cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov: NCT05249452.
PubMed: 38733340
DOI: 10.1002/ajh.27360 -
Transplantation and Cellular Therapy Jan 2024Alemtuzumab, fludarabine, and melphalan containing-reduced intensity conditioning (RIC) is commonly used in patients undergoing allogeneic hematopoietic cell...
Age Impacts Risk of Mixed Chimerism Following Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Non-Severe Combined Immune Deficiency Inborn Errors of Immunity.
Alemtuzumab, fludarabine, and melphalan containing-reduced intensity conditioning (RIC) is commonly used in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for definitive treatment of high-risk inborn errors of immunity (IEI). Although survival is favorable, there is an increased risk of mixed chimerism leading to secondary graft failure. This study evaluated factors associated with the risk of developing mixed chimerism, particularly the influence of age in patients undergoing allogeneic HCT for non-severe combined immune deficiency (SCID) IEI who received a uniform RIC regimen that included intermediate schedule alemtuzumab, fludarabine, and melphalan. We hypothesized that age would impact the incidence of mixed chimerism. We retrospectively reviewed records of patients who underwent HCT for non-SCID IEI with a uniform RIC regimen that included intermediate schedule alemtuzumab (1 mg/kg divided over days -14 to -10), fludarabine (150 mg/m or 5 mg/kg if weight <10 kg divided over days -9 to -4), and melphalan (140 mg/m or 4.7 mg/kg if weight <10 kg on day -3) between 2010 and 2020 at our institution. Mixed chimerism was defined as <95% donor chimerism on 2 or more consecutive occasions in whole blood. Ninety-three patients who underwent RIC-HCT for non-SCID IEI using intermediate schedule alemtuzumab, fludarabine, and melphalan were categorized into 3 groups: age <1 year, age 1 to 5 years, and age >5 years. Forty-nine patients (52.7%) developed mixed chimerism, at a median of 34 days post-HCT (range, 10 to 1396 days). Mixed chimerism developed in 88.9% (n = 16/18) of the age <1 year group, in 57.1% (n = 20/35) of the age 1 to 5 years group, and in 35% (n =14/40) of the age >5 years group. Patients age <5 years were significantly more likely to develop mixed chimerism (χ (3, N = 93) = 14.8; P = .001). We observed a significantly increased cumulative incidence of developing mixed chimerism associated with age <1 year (P = .0002). Competing risk regression analysis showed a 3-fold higher risk of developing mixed chimerism for age <1 year (subdistribution hazard ratio (HR), 3.05; 95% confidence interval [CI], 1.11 to 8.38; P = .031,) compared to age >5 years and a significantly decreased risk of mixed chimerism in patients who developed acute GVHD prior to any intervention (OR, .24; 95% CI, .09 to .65; P = .005) There were no significant associations between mixed chimerism and graft source, graft type, CD34 or CD3 cell dose, HLA match, or underlying disease (hemophagocytic lymphohistiocytosis [HLH] versus non-HLH). Additionally, the need for secondary intervention was evaluated; 27 patients (29.0%) required 1 or more secondary interventions (donor lymphocyte infusion, CD34 boost, or second HCT). Patients age <1 year with mixed chimerism were significantly more likely than patients age >5 years to require secondary intervention for mixed chimerism (P = .004). Our study demonstrates that age <5 years, especially age <1 year, is associated with an increased risk of developing mixed chimerism in patients undergoing RIC-HCT for non-SCID IEI using intermediate-schedule alemtuzumab, fludarabine, and melphalan. Our data suggest tailoring regimen intensity based on age to reduce the incidence of mixed chimerism. Children age <5 years, particularly those age <1 year, require a higher-intensity regimen. Possible strategies include adding thiotepa or using a busulfan-based reduced toxicity regimen.
Topics: Child; Humans; Infant; Child, Preschool; Alemtuzumab; Melphalan; Chimerism; Retrospective Studies; Transplantation Conditioning; Hematopoietic Stem Cell Transplantation; Lymphohistiocytosis, Hemophagocytic; Antigens, CD34
PubMed: 37821080
DOI: 10.1016/j.jtct.2023.09.024 -
Hematology (Amsterdam, Netherlands) Dec 2023T-prolymphocytic leukemia (T-PLL) is an aggressive hematologic malignancy. A portion of patients can be cured with alemtuzumab induction followed by allogeneic...
T-prolymphocytic leukemia (T-PLL) is an aggressive hematologic malignancy. A portion of patients can be cured with alemtuzumab induction followed by allogeneic hematopoietic stem cell transplant, but patients who relapse after transplant have a poor prognosis, and there is no standard of care. We report a case of a 64-year-old man with relapsed JAK3-mutant T-PLL following allogeneic transplant who was treated with ruxolitinib and venetoclax. Treatment with ruxolitinib and venetoclax resulted in a partial response including stabilization of the peripheral lymphocyte count, improvement in thrombocytopenia, decrease in splenomegaly, and a numerical reduction in the percentage of bone marrow involved by T-PLL. The combination was well tolerated with the exception of neutropenic infections. This case adds to the growing body of literature supporting venetoclax and rituximab as a viable treatment option for relapsed/refractory T-PLL with JAK-STAT alterations.
Topics: Male; Humans; Middle Aged; Leukemia, Prolymphocytic; Nitriles; Pyrimidines; Leukemia, Prolymphocytic, T-Cell
PubMed: 37485976
DOI: 10.1080/16078454.2023.2237342 -
Actas Dermo-sifiliograficas Feb 2024The use of disease-modifying therapies (DMT) has led to a paradigm shift in the management of multiple sclerosis. A comprehensive narrative review was conducted through...
The use of disease-modifying therapies (DMT) has led to a paradigm shift in the management of multiple sclerosis. A comprehensive narrative review was conducted through an extensive literature search including Medline and Google Scholar to elucidate the link between DMT and the propensity of cutaneous malignancies. Sphingosine-1-phosphate receptor modulators, such as fingolimod and siponimod are associated with a higher risk of basal cell carcinoma (BCC), but not squamous cell carcinoma, or melanoma. The associated physiopathological mechanisms are not fully understood. Alemtuzumab and cladribine show isolated associations with skin cancer. Regarding other DMT, no increased risk has ever been found. Given the evidence currently available, it is of paramount importance to advocate for necessary dermatological assessments that should be individualized to the risk profile of each patient. Nonetheless, additional prospective studies are still needed to establish efficient dermatological follow-up protocols.
PubMed: 38307166
DOI: 10.1016/j.ad.2024.01.022