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Cancer Chemotherapy and Pharmacology Dec 2020Alemtuzumab is a humanized monoclonal antibody against CD52 which is predominantly present on T and B lymphocytes. Alemtuzumab has been used as part of conditioning...
PURPOSE
Alemtuzumab is a humanized monoclonal antibody against CD52 which is predominantly present on T and B lymphocytes. Alemtuzumab has been used as part of conditioning regimens for prophylaxis against rejection and GVHD. While the mechanism of action is well understood, the pharmacokinetics of this drug in children needed to be studied in more detail especially in the setting of ex vivo T-cell-depleted hematopoietic cell transplantation (HCT).
METHODS
Serum alemtuzumab levels were measured at various time points in 13 patients who underwent haploidentical HCT utilizing ex vivo donor T-cell depletion. Alemtuzumab was administered subcutaneously at a cumulative dose of 45 mg/m from days - 13 to - 11. A one-compartmental model was used to fit the data using non-linear mixed effects modeling.
RESULTS
We determined the median half-life to be 11 days. Alemtuzumab clearance increased with increasing baseline lymphocyte count (p = 0.008). Additionally, clearance increased with weight and age (p ≤ 0.035). AUC of alemtuzumab did not have any significant relationship with type of leukemia, overall survival, engraftment, immune reconstitution, mixed chimerism or GVHD, although the number of subjects in this pilot study was limited.
CONCLUSION
Absolute lymphocyte count and body weight affect alemtuzumab clearance. We also demonstrate feasibility of body-surface area-based dosing of alemtuzumab in pediatric HCT patients. Further studies are needed to evaluate the role of monitoring alemtuzumab serum concentrations to balance the prevention of graft rejection and GVHD with the promotion of rapid donor immune reconstitution.
Topics: Adolescent; Alemtuzumab; Body Surface Area; Child; Child, Preschool; Drug Dosage Calculations; Drug Monitoring; Feasibility Studies; Female; Follow-Up Studies; Graft Rejection; Graft vs Host Disease; Half-Life; Hematopoietic Stem Cell Transplantation; Humans; Injections, Subcutaneous; Leukemia; Lymphocyte Count; Lymphocyte Depletion; Male; Metabolic Clearance Rate; Pilot Projects; T-Lymphocytes; Transplantation Conditioning; Transplantation, Haploidentical; Young Adult
PubMed: 33037919
DOI: 10.1007/s00280-020-04160-7 -
Multiple Sclerosis (Houndmills,... Aug 2019
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Humans; Incidence; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting
PubMed: 31368417
DOI: 10.1177/1352458519851219 -
Neurology Mar 2021To assess safety outcomes for the induction therapies alemtuzumab and autologous hematopoietic stem cell transplantation (AHSCT) compared to noninduction...
OBJECTIVE
To assess safety outcomes for the induction therapies alemtuzumab and autologous hematopoietic stem cell transplantation (AHSCT) compared to noninduction disease-modifying therapies.
METHODS
We performed a population-based cohort study linking the Swedish Multiple Sclerosis Register to national health care registers. Alemtuzumab, AHSCT, and a matched reference group of noninduction therapies (natalizumab, dimethyl fumarate, rituximab, fingolimod) were included if started between 2008 and 2017. Main outcomes were death, thyroid disease, nonthyroid autoimmune disease, and infection.
RESULTS
We identified 132 alemtuzumab-treated and 139 AHSCT-treated (68% high-dose cyclophosphamide and anti-thymocyte globulin [ATG], 32% BCNU, etoposide, cytosine-arabinoside, and melphalan/ATG) patients, together with 2,486 matched patients treated with noninduction therapies. Four patients in the alemtuzumab group died (incidence rate [IR] per 1,000 person-years 8.6, 95% confidence interval [CI] 2.3-22.0) compared to 1 patient in the AHSCT group (IR 1.7, 95% CI 0.0-9.6), and the mortality rate in the reference group was 0.7 (95% CI 0.3-1.3). Thyroid disease was most frequent in the alemtuzumab group (IR 109, 95% CI 75-154) but also occurred more often for AHSCT (IR 34, 95% CI 18-56) compared to the reference (IR 5.3 95% CI 3.9-7.1). The incidence of nonthyroid autoimmune disease was similar in all groups. IR for infection diagnosed ≥6 months from therapy initiation was 53 (95% CI 30-87) for alemtuzumab, 108 (95% CI 75-150) for AHSCT, and 51 (95% CI 46-57) for the reference.
CONCLUSION
We confirmed a high incidence of thyroid disease in alemtuzumab- and, to a smaller extent, AHSCT-treated patients and found a higher incidence of infection for AHSCT compared to both alemtuzumab and noninduction therapies. The incidence of nonthyroid autoimmune disease was low for both therapies.
CLASSIFICATION OF EVIDENCE
This study provides Class III evidence of an increased risk of thyroid disease with alemtuzumab and an increased risk of infection with AHSCT treatment.
Topics: Adult; Alemtuzumab; Cohort Studies; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Infections; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Registries; Sweden; Thyroid Diseases; Transplantation, Autologous
PubMed: 33514645
DOI: 10.1212/WNL.0000000000011545 -
European Journal of Neurology Dec 2021Alemtuzumab, a monoclonal CD52 antibody, is a high-efficacy disease-modifying-therapy in relapsing-remitting multiple sclerosis (RRMS). Recently, intracerebral...
BACKGROUND AND PURPOSE
Alemtuzumab, a monoclonal CD52 antibody, is a high-efficacy disease-modifying-therapy in relapsing-remitting multiple sclerosis (RRMS). Recently, intracerebral hemorrhage (ICH) was reported as a possible treatment-related adverse event. Arterial hypertension during infusion was suggested as a potential cause, although platelet or endothelial dysfunction may also contribute. This study aimed to screen for occult hemorrhagic cerebral lesions after alemtuzumab treatment and to further elucidate risk factors.
METHODS
We included 30 RRMS patients who received alemtuzumab treatment at Ghent University Hospital or Sint-Jan Bruges Hospital. Retrospective data concerning vital signs, adverse effects and thrombocyte levels during treatment were collected. The occurrence of occult intracranial hemorrhagic lesions was assessed by magnetic resonance imaging with susceptibility-weighted imaging (SWI).
RESULTS
The mean (standard deviation [SD]) systolic blood pressure (SBP) during the morning, afternoon and evening was 120 (3.38) mmHg during first administration and 114 (4.40) mmHg during second administration (N = 13). There was no significant increase in SBP when comparing morning, afternoon and evening per day, nor was there a significant difference in daily mean SBP between consecutive administration days. Thrombocyte count during treatment cycles ranged between 107 × 10 /L and 398 × 10 /L, with a mean (SD) absolute reduction of 59.3 × 10 /L (50.65) or a mean (SD) relative reduction of 25.0 (12.84)% (N = 20). No patient had ICH, nor did SWI show any cerebral microbleeds or other hemorrhagic lesions post-treatment (N = 23).
CONCLUSIONS
In our patient population, alemtuzumab treatment was not associated with arterial hypertension, ICH or occult microbleeds. Possible differences in administration regimen (ambulatory vs. in-hospital setting) and patient population (cardiovascular risk) might explain an increased risk in different populations.
Topics: Alemtuzumab; Humans; Magnetic Resonance Imaging; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Retrospective Studies; Risk Factors
PubMed: 34374173
DOI: 10.1111/ene.15054 -
JAMA Jan 2019Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed... (Comparative Study)
Comparative Study Observational Study
IMPORTANCE
Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.
OBJECTIVE
To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.
DESIGN, SETTING, AND PARTICIPANTS
Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up.
EXPOSURES
The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).
MAIN OUTCOME AND MEASURE
Conversion to objectively defined secondary progressive MS.
RESULTS
Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1).
CONCLUSIONS AND RELEVANCE
Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.
Topics: Adult; Alemtuzumab; Cohort Studies; Disease Progression; Female; Fingolimod Hydrochloride; Glatiramer Acetate; Humans; Immunologic Factors; Immunosuppressive Agents; Interferon-beta; Male; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Time-to-Treatment
PubMed: 30644981
DOI: 10.1001/jama.2018.20588 -
Journal of the American Pharmacists... 2023Currently, 19 disease-modifying therapies (DMTs) have been approved for the treatment of patients with relapsing forms of multiple sclerosis (RMS). (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Currently, 19 disease-modifying therapies (DMTs) have been approved for the treatment of patients with relapsing forms of multiple sclerosis (RMS).
OBJECTIVE
The objective of this study was to conduct a systematic review and network meta-analysis to evaluate the efficacy and safety of DMTs in adults with RMS.
METHODS
We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, the Food and Drug Administration, and European Medicines Agency websites for randomized controlled trials (RCTs) (from inception to July 2021). Eligible RCTs evaluated approved treatments for RMS as monotherapy and reported at least one of the primary outcome measures of interest. The primary outcome was efficacy (annualized relapse rate and 12-week confirmed disability progression) and safety (serious adverse events [AEs] and discontinuation due to AEs). We assessed the risk of bias (RoB) of included studies using the Cochrane RoB tool version 2.0 (https://www.bmj.com/content/343/bmj.d5928) for RCTs. Surface under the cumulative ranking (SUCRA) was used to rank therapies and to assess quality of general evidence, respectively. The Grading of Recommendations Assessment, Development and Evaluation framework was used to rank therapies and to assess quality of general evidence.
RESULTS
A total of 43 records represent 45 RCTs selected for network meta-analysis. In total, 30,720 participants (median of 732; interquartile range: 248-931) were included, of which 67% were female. By SUCRA analysis, alemtuzumab (94.3%) presented the highest probability of being the best alternative for annualized relapse rate, whereas ofatumumab (93.5%) presented the highest probability of being the best alternative for 12-week confirmed disability progression. Interferon beta-1b subcutaneous (87.0%) presented the highest probability of the best safety among all DMTs for serious AEs, whereas alemtuzumab (92.4%) presented the highest probability of the best safety among all DMTs for discontinuation due to AEs.
CONCLUSION
Network meta-analysis shows that alemtuzumab and ofatumumab present the highest efficacy among DMTs. Because there is little difference between these probabilities for many treatments, health professionals should use clinical shared decision making when formulating treatment plans with patients.
Topics: United States; Adult; Female; Humans; Male; Alemtuzumab; Network Meta-Analysis; Multiple Sclerosis; Chronic Disease; Recurrence
PubMed: 36055929
DOI: 10.1016/j.japh.2022.07.009 -
European Journal of Neurology Apr 2021Blood pressure (BP) changes during alemtuzumab infusions are poorly understood. The aim of this study was to examine BP changes during alemtuzumab infusions in persons...
BACKGROUND AND PURPOSE
Blood pressure (BP) changes during alemtuzumab infusions are poorly understood. The aim of this study was to examine BP changes during alemtuzumab infusions in persons with multiple sclerosis (PwMS).
METHODS
This was a retrospective cohort review of systolic (S) and diastolic (D) BP in PwMS receiving alemtuzumab.
RESULTS
Thirty-one patients were identified; 22 (64.5%) were women. Mean age and disease duration were 35.2 ± 7.1 and 9.2 ± 5.4 years, respectively. There was no history of hypertension or vascular events. Mean baseline SBP was 119.8 ± 15.1 mmHg, 118.8 ± 14.3 mmHg and 106.5 ± 6.1 mmHg whilst mean DBP was 75.3 ± 9.2 mmHg, 74.1 ± 12.4 mmHg and 69.2 ± 4.3 mmHg at doses 1, 6 and 9, respectively. During the first cycle, SBP increased by 19.2 ± 9.4 mmHg, with comparable percentage increases over the five infusions (16%, 22%, 17%, 11%, 13%, respectively). DBP increased by 6.2 ± 3.8 mmHg with similar percentage increases over the five infusions (8.4%, 11.5%, 5.5%, 7%, 3%). For the second cycle, SBP increased by 16.9 ± 3.2 mmHg, with similar increases over the 3 days (12%, 15%, 17%). DBP increased by 5.4 ± 4.2 mmHg (11%, 9%, 12.8%). The third cycle demonstrated increased mean and percentage of SBP and DBP by 8.9 ± 2.3 mmHg (10%, 70%, 11.8%) and 4.2 ± 1.9 mmHg (3%, 2%, 6.5%), respectively. Collectively, for 31 patients, in the first cycle, mean SBP increased from 119.8 ± 15.1 mmHg to 138.8 ± 13 mmHg (p ˂ 0.001), whilst mean DBP increased from 74.5 ± 9.2 mmHg to 79.2 ± 9.1 mmHg (p = 0.007). Overall, 17 (54.8%) patients had increasing BP by ≥20% and nine (29%) had increasing BP by ≥20 mmHg from baseline.
CONCLUSIONS
This demonstrates significant increases in BP during alemtuzumab infusions in PwMS.
Topics: Alemtuzumab; Blood Pressure; Female; Humans; Hypertension; Multiple Sclerosis; Retrospective Studies
PubMed: 33175474
DOI: 10.1111/ene.14633 -
Journal of Investigational Allergology... Dec 2022
Topics: Humans; Alemtuzumab; Flow Cytometry; Antineoplastic Agents, Immunological; Antibodies, Monoclonal, Humanized; Blood Cells; Multiple Sclerosis
PubMed: 35225791
DOI: 10.18176/jiaci.0795 -
Multiple Sclerosis and Related Disorders Jan 2019Alemtuzumab administration is known to cause secondary autoimmune disease but has not been associated with the development of neurologic autoimmune conditions....
BACKGROUND
Alemtuzumab administration is known to cause secondary autoimmune disease but has not been associated with the development of neurologic autoimmune conditions. Lambert-Eaton myasthenic syndrome (LEMS) is caused by autoantibodies directed against calcium channels on the neuromuscular junction.
CASE REPORT
We report a case of a patient with relapsing-remitting multiple sclerosis (RRMS) treated with alemtuzumab who develop generalized weakness initially attributed to progression of MS but eventually determined to be due to LEMS.
CONCLUSION
Alemtuzumab treatment can result in the development of neurologic autoimmune conditions that could mimic MS progression.
Topics: Alemtuzumab; Humans; Immunologic Factors; Lambert-Eaton Myasthenic Syndrome; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting
PubMed: 30384197
DOI: 10.1016/j.msard.2018.10.015 -
Transplant International : Official... Dec 2021Alemtuzumab is a monoclonal antibody targeting CD52, increasingly used as induction therapy after transplantation. The aim of this study was to analyze the outcomes of...
Alemtuzumab is a monoclonal antibody targeting CD52, increasingly used as induction therapy after transplantation. The aim of this study was to analyze the outcomes of alemtuzumab induction therapy followed by a low-dose maintenance immunosuppression in a large single-center cohort of lung transplant recipients. All patients, who received alemtuzumab induction followed by a low-dose maintenance immunosuppression were included in the analysis. Short- and long-term outcomes were analyzed. 721 lung transplant recipients, transplanted between January 2008 and June 2019, were included in this retrospective study. Freedom from higher-grade ACR at 1, 5, and 10 years was 98%, 96%, and 96%, respectively. Thirty-nine patients (5%) developed clinical AMR. Twenty-one percent of patients developed high-grade CKD. A total of 1488 infections were recorded. Sixteen percent were diagnosed within the first 3 months. Sixty-two patients (9%) developed a malignancy during follow-up. Freedom from CLAD at 1, 5, and 10 years was 94%, 72%, and 53%, respectively. Overall survival rates at 1, 5, and 10 years were 85%, 71%, and 61%, respectively. Alemtuzumab induction combined with a low-dose tacrolimus protocol is safe and associated with low rates of acute and chronic rejection, as well as an excellent long-term survival.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Induction Chemotherapy; Lung Transplantation; Retrospective Studies
PubMed: 34738249
DOI: 10.1111/tri.14153