Compound Name:AlemtuzumabMolecular Target:CD52 (cell surface glycoprotein)Molecular Structure:humanized IgG1?, recombinantLicensed Indication:Chronic B-lymphocyte Leukemia (B-CLL)Manufacturer and/or Distributor:Genzyme; Bayer Healthcare PharmaceuticalsInitial FDA Approval2001SummaryAlemtuzumab (Campath-1H) is a humanized monoclonal IgG1k antibody directed against the cell surface antigen CD52; it contains the human variable framework and IgG1 constant regions, and complementarity-determining regions from a murine (rat) monoclonal antibody. Its target, CD52, is a 21-28 kDa cell surface glycoprotein of unknown function found principally on lymphocytes (T & B), as well as monocytes/macrophages, NK cells and granulocytes; it is also expressed in the genital tract. Plasma cells and bone marrow stem cells have little or no CD52. The proposed mechanism of action of alemtuzumab is antibody dependent cellular cytotoxicity (ADCC), although complement dependent lysis and direct apoptosis may also play a role. Alemtuzumab currently exists under 2 brand names with distinct indications and dosing regimens: Alemtuzumab (Campath) is indicated for intravenous use as a single agent to treat B-cell chronic lymphocytic leukemia (B-CLL). Dosages are escalated to target 90 mg cumulative weekly, for ta total duration of 12 weeks. Alemtuzumab (Campath) was withdrawn from the markets in 2012 by the manufacturer to prepare for a higher-priced relaunch of Lemtrada for the treatment of multiple sclerosis, which was approved by the FDA in November 2014. Alemtuzumab (Lemtrada) is indicated for adult patients with relapsing-remitting multiple sclerosis with active disease (defined by clinical or imaging features). The recommended dosage is an initial treatment course of intravenous infusion of alemtuzumab 12 mg/day on 5 consecutive days, followed by a second treatment course at the same dosage on 3 consecutive days, 12 months after the initial treatment course, and a recommended safety follow-up of 48 months after the final infusion. Notable adverse events (based on product monograph and cited references): (1) Lymphopenia: Within minutes of infusion, a single dose of alemtuzumab depletes peripheral lymphocyte to undetectable levels. The rate and degree of recovery vary with cell type: B cells recover rapidly after treatment (typically within 3 months after treatment), whereas T cell lymphopenia is prolonged with CD4 and CD8 cells taking 35 and 20 months respectively to reach the lower limit of normal. The lymphopenia is associated with a change in subset composition, with mature naïve B cells (CD19+ CD23+ CD27-) and effector memory T cells dominating upon reconstitution. (2) Neutropenia: In previously untreated patients: incidence of grade 3/4 neutropenia was 42%; median time to onset: 31 days; median duration of 37 days. In previously treated patients: incidence of grade 3/4 neutropenia was 64%; median duration of 28 days. 10-17% of neutropenic patients required G-CSF. (3) Anemia: In previously untreated patients: incidence of grade 3/4 anemia was 12%; median time to onset: 31 days; median duration of 8 days. In previously treated patients: incidence of grade 3/4 neutropenia was 38%. 17-66% of anemic patients required erythropoiesis-stimulating agents, transfusions, or both. (4) Thrombocytopenia: In previously untreated patients: incidence of grade 3/4 thrombocytopenia was 14%; median time to onset: 9 days; median duration of 14 days. In previously treated patients: incidence of grade 3/4 neutropenia was 52%; median duration of 21 days. (5) Infections: Patients receiving Alemtuzumab (Campath) are at risk for CMV infection/disease. CMV monitoring via PCR-based method is recommended during therapy and for at least the first 2 months following therapy. Other infections include bacterial (16%), fungal (7%), other viral (4%), or unidentified etiology (76%). (6) Infusion reactions, e.g. pyrexia, chills, hypotension, urticarial, dyspnea. (7) Autoimmunity (based on published literature): Secondary autoimmune disorders may develop following lymphocyte reconstitution after the use of alemtuzumab. Most commonly, 30% of patients after alemtuzumab develop autoimmune thyroid disease, both Graves’ disease and hypothyroidism. Immune thrombocytopenic purpura (ITP) occurs in 1–3% of patients receiving alemtuzumab.References

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1. Waldmann H, Hale G. CAMPATH: from concept to clinic. Philos Trans R Soc Lond B Biol Sci. 2005 Sep 29;360(1461):1707-1711.

2. Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002 May 15;99(10):3554-3561.

3. Yamaguchi R, Yamagata K, Hasuwa H, Inano E, Ikawa M, Okabe M. Cd52, known as a major maturation-associated sperm membrane antigen secreted from the epididymis, is not required for fertilization in the mouse. Genes Cells. 2008 Aug;13(8):851-861.

4. Coles AJ, et al. Alemtuzumab vs interferon beta-1a in early multiple sclerosis. New England Journal of Medicine 2008;359:1786-1801.

5. Warner J, Arnason J. Alemtuzumab use in relapsed and refractory chronic lymphocytic leukemia: a history and discussion of future rational use. Therapeutic advances in hematology. 2012;3(6):375-389.

6. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012;380:1819-28.

7. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012;380:1829-39.

8. Hartung HP, Aktas O, Boyko AN. Alemtuzumab: A new therapy for active relapsing-remitting multiple sclerosis. Mult Scler. 2014 Oct 24. pii: 1352458514549398.

9. Jones JL, Coles AJ. Mode of action and clinical studies with alemtuzumab. Exp Neurol. 2014 Dec;262 Pt A:37-43.

10. Kousin-Ezewu O, Coles A. Alemtuzumab in multiple sclerosis: latest evidence and clinical prospects. Ther Adv Chronic Dis. 2013 May;4(3):97-103.