Antibody-Based Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Alemtuzumab is approved by the FDA as a single agent for the first-line treatment of B-cell chronic lymphocytic leukemia (B-CLL). In other countries it is approved for B-CLL in patients who have been previously treated with alkylating agents and for whom fludarabine combination therapy is not appropriate. Alemtuzumab is also used in the treatment of Cutaneous T-Cell Lymphoma (CTCL) and T-Cell Lymphoma, and as second-line therapy for CLL. In some countries the use of alemtuzumab is restricted to those patients with previously untreated B-CLL and who have the cytogenetic 17p-deletion abnormality. It is also used in some conditioning regimens for bone marrow and kidney transplants, and is presently in clinical trials for the treatment of autoimmune diseases including multiple sclerosis and graft-versus-host disease. It is marketed by Genzyme (acquired by Sanofi in 2011), which obtained worldwide rights from Bayer AG in 2009. In 2012 CampathTM was withdrawn from both the US and European markets to prevent off-label use of the drug for multiple sclerosis in preparation for a re-launch using a different dosage under the trade name LemtradaTM (approved in 2014) aimed specifically at the multiple sclerosis market.
Specific Therapy for Lymphomas
Tariq I Mughal, John M Goldman, Sabena T Mughal in Understanding Leukemias, Lymphomas, and Myelomas, 2017
Immunotherapeutic agents demonstrating activity in PTCL include alemtuzumab and Ontak. Alemtuzumab has demonstrated excellent efficacy in a small phase II study with 32% complete responses. Larger studies are now in progress. Denileukin difitox (Ontak) is an immunotoxin which received FDA approval for cutaneous T-cell lymphoma in 1999 and was assessed in a phase II study for patients with relapsed/refractory PTCL, with results reported in 2007. Remarkably a 48% response rate with 20% complete remissions was observed in this cohort, including responses in patients with CD25 negative disease. Further studies are currently on-going. The toxicity profile of Ontak is quite favorable with little myelosuppression. A current trail is also testing Ontak plus CHOP in newly diagnosed PTCL. Interim responses of 86% have been reported and further accrual continues.
Pulmonary infection induced by drugs
Philippe Camus, Edward C Rosenow in Drug-induced and Iatrogenic Respiratory Disease, 2010
Alemtuzumab is used for fludarabine-refractory CLL; it is also effective at preventing GVHD among allogeneic transplant recipients receiving non-myeloablative conditioning regimens.34 Although concurrent treatment with other forms of immunosuppression complicates any assessment of the prevalence of infectious complications, available data suggest the risk of infection is high. In a study of 93 patients treated with alemtuzumab at 21 centres, infection developed in 55 per cent of patients, and was severe in 27 per cent. Opportunistic pulmonary infections included Pneumocystis pneumonia, aspergillosis, mucormycosis and cryptococcosis.35 Other infections of concern are invasive non-candidal fungi, such as Histoplasma capsulatum, as well as such parasitic pathogens as Toxoplasma gondii. CMV is thought to be a particularly significant problem. Among 101 patients receiving a non-myeloablative regimen containing alemtuzumab, GVHD – usually a predictor of CMV infection – occurred in only 4 per cent of recipients. But CMV infection, as determined by PCR positivity on two consecutive assays, occurred among 85 per cent of patients at risk.36 All patients who developed clinically apparent CMV disease died; infection was common 100 or more days after transplant. Taken in sum, this is much higher than the 40–50 per cent infection rate of CMV expected among recipients of unmanipulated stem-cell grafts. In another study with use of alemtuzumab for lymphoproliferative disease, the incidence of CMV reactivation among recipients taking alemtuzumab was 66.7 per cent, versus 37 per cent in the non-alemtuzumab group.2
Sequencing of disease-modifying therapies for relapsing–remitting multiple sclerosis: a theoretical approach to optimizing treatment
Published in Current Medical Research and Opinion, 2018
Francois Grand’Maison, Michael Yeung, Sarah A. Morrow, Liesly Lee, Francois Emond, Brian J. Ward, Pierre Laneuville, Robyn Schecter
Alemtuzumab is a humanized anti-CD52 monoclonal antibody that leads to depletion and subsequent repopulation of circulating T lymphocytes and B lymphocytes. This action is associated with alterations in the proportion and function of different lymphocyte subsets99. The two CARE-MS trials, both phase 3, randomized, active-controlled, and head-to-head studies of alemtuzumab versus IFN β-1a, showed that alemtuzumab could reduce relapse rates by ∼50% over a 2 year period. In CARE-MS I, all subjects were treatment-naïve; while in CARE-MS II, subjects had received prior treatment with either IFN or GA. There was no advantage of alemtuzumab over IFN β-1a in reducing the risk of 6-month sustained disability progression in CARE MS I but this outcome was reduced by 42% in CARE MS II99,100. In a cohort study using propensity-matched subjects with RRMS, alemtuzumab and natalizumab had similar effects on ARR, and alemtuzumab was better in mitigating relapse activity versus IFN and fingolimod. Natalizumab-treated subjects had significantly higher probability of disability improvement than those who received alemtuzumab52. The risk of disability progression did not differ between the alemtuzumab, IFN, and fingolimod groups; however, the follow-up period was short.
Neuro-ophthalmic literature review
Published in Neuro-Ophthalmology, 2018
Noel Chan, John Chen, Hui-Chen Cheng, Peter MacIntosh, John H Pula, Michael Vaphiades, Konrad P Weber
Alemtuzumab is a cytolytic monoclonal antibody used for B cell chronic lymphocytic leukaemia and relapsing-remitting multiple sclerosis (RRMS). Acute acalculous cholecystitis (AAC) is a necroinflammatory disease of the gallbladder which happens without cholelithiasis or choledocholithiasis. AAC is a potentially life-threatening disease, and urgent cholecystectomy is generally recommended. The authors of this study searched the Food and Drug Administration Adverse Event Reporting System and the medical literature to evaluate if AAC is a potential safety risk for patients treated with alemtuzumab. They identified 8 AAC cases in close temporal association with alemtuzumab, and all of them were patients with RRMS. The identified cases were different from typical AAC in female preponderance, lack of concurrent critical illness, inconsistent presence of other risk factors and resolution with conservative treatment. Acute cytokine release syndrome was proposed as possible mechanism because that most of the patients presented with AAC during or shortly after alemtuzumab treatment. The authors remind us the awareness of this new safety risk of alemtuzumab and the importance of postmarketing surveillance.
Emerging therapeutic targets for narcolepsy
Published in Expert Opinion on Therapeutic Targets, 2021
Marieke Vringer, Birgitte Rahbek Kornum
Finally, monoclonal antibody treatment has been attempted in NT1. Natalizumab inhibits the migration of immune cells into the brain and if NT1 is driven by an ongoing entry of autoreactive T cells to CNS, natalizumab would in theory dampen the autoimmune destruction of Hcrt neurons. However, natalizumab showed no effect on clinical symptoms and CSF Hcrt-1 levels in a NT1 patient [145]. The monoclonal antibody rituximab has an immunosuppressive effect via depletion of B-cells [14,146]. A dramatic improvement of NT1 symptoms was reported in a case report of a 12-year-old patient following rituximab treatment, but the improvement lasted only 2 months [146]. Another NT1 patient experienced less EDS but no improvement of cataplexy or CSF Hcrt-1 levels after rituximab treatment [147]. Alemtuzumab can inhibit an autoimmune response by depleting both circulating T- and B-cells. Complete disappearance of cataplexy was reported in a 68-years-old NT1 patient following alemtuzumab treatment, but all his other clinical symptoms remained unchanged [148].
Related Knowledge Centers
- Chronic Lymphocytic Leukemia
- Monoclonal Antibody
- Regulatory T Cell
- Lymphocyte
- Autoimmune Disease
- Stem Cell
- Medication
- Multiple Sclerosis
- Intravenous Therapy
- Antibody-Dependent Cellular Cytotoxicity