Compound Name:OfatumumabMolecular Target:CD20Molecular Structure:Human IgG1? monoclonal antibody, recombinantLicensed Indication:Chronic lymphocytic leukemia resistant to fludarabine and alemtuzumabManufacturer and/or Distributor:Glaxo Smith KlineInitial FDA Approval:2009Summary:Ofatumumab (Arzerra) is a human IgG1k monoclonal antibody directed to the B-cell surface antigen CD20. Ofatumumab binds to both the small and large extracellular loops of the CD20 molecule, which is an epitope specificity different from that of rituximab and most other CD20 directed antibodies. It appears to promote more effective complement deposition and ADCC. The recommended dose and schedule for ofatumumab is 300 mg by iv infusion on day 1 followed by 1000 mg on day 8 and then 7 weeks thereafter for up to a maximum of 2 years. Ofatumumab received accelerated approval from the FDA in 2009 for treating chronic lymphocytic leukemia (CLL) that is refractory to fludarabine and alemtuzumab and received regular approval in April 2014 for its use in combination with chlorambucil, for previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate. In 2015, FDA granted a priority review designation to ofatumumab as a maintenance therapy for relapsed CLL. In January 2016, FDA approved ofatumumab for extended treatment of patients who are in complete or partial response after at least two lines of therapy for the treatment of previously untreated patients with CLL. Its use in other conditions treated by rituximab is not yet established, but clinical trials are completed or underway for its use in follicular lymphoma, relapsed/refractory DLBCL, Non-Hodgkin’s Lymphoma, Acute lymphocytic leukemia, chronic graft-versus-host disease, Waldenstrom’s Macroglobulinemia, Pemphigus Vulgaris, and Multiple Sclerosis. The major safety concerns are infusion reactions, cytopenias, hepatitis B, and progressive multifocal leukoencephalopathy (PML), neutropenia, asthenia, headache, leukopenia, herpes simplex viral infection, lower respiratory tract infection, joint pain, and upper abdominal pain.References

Package Insert: http://us.gsk.com/products/assets/us_arzerra.pdf

1. Beum PV, Lindorfer MA, Beurskens F, Stukenberg PT, Lokhorst HM, Pawluczkowycz AW, et al. Complement activation on B lymphocytes opsonized with rituximab or ofatumumab produces substantial changes in membrane structure preceding cell lysis. J Immunol. 2008 Jul 1;181(1):822-832.


2. Gravanis I, Ersboll J, Skovlund E, Abadie E, Marty M, Pignatti F. The European Medicines Agency review of ofatumumab (Arzerra(R)) for the treatment of chronic lymphocytic leukemia in patients refractory to fludarabine and alemtuzumab: summary of the scientific assessment of the European medicines agency committee for medicinal products for human use. Oncologist. 2010;15(12):1335-1343.


3. Keating MJ, Dritselis A, Yasothan U, Kirkpatrick P. Ofatumumab. Nat Rev Drug Discov. 2010 Feb;9(2):101-102.


4. Lemery SJ, Zhang J, Rothmann MD, Yang J, Earp J, Zhao H, et al. U.S. Food and Drug Administration approval: ofatumumab for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab. Clin Cancer Res. 2010 Sep 1;16(17):4331-4338.


5. Wierda WG, Padmanabhan S, Chan GW, Gupta IV, Lisby S, Osterborg A. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood. 2011 Nov 10;118(19):5126-5129.


6. Veliz M, Pinilla-Ibarz J. Role of ofatumumab in treatment of chronic lymphocytic leukemia. J Blood Med. 2011; 2:71-77.


7. Rioufol C, Salles G. Obinutuzumab for chronic lymphocytic leukemia. Expert Rev Hematol. 2014 Oct;7(5):533-43.

8. Hutchinson L.  Haematological cancer: PROLONGing PFS with ofatumumab in patients with CLL. Nat Rev Clin Oncol. 2015 Nov;12(11):622.

9. Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015 May 9;385(9980):1873-83.