Rituximab for Refractory Non-Hodgkin's LymphomaFrom
issue No. 243 (December, 1997) of Medical Sciences Bulletin
Issue 243 Contents
About 30,000 new cases of non-Hodgkin's
lymphoma (NHL) occur each year in the US and the incidence appears to be
increasing. These tumors represent the most common neoplasms among perons
aged 20-40 years. With the increasing incidence of AIDS, the number of
cases of NHL has increased. Some animal studies suggest that lymphomas may
have a viral etiology, although this association varies with the type of
lymphoma. Genetic predisposition has been found for certain lymphomas.
More than two-thirds of patients with NHL present with persistent,
painless, peripheral lymphadenopathy. A lymph node larger than 1 cm that
persists for 4 to 6 weeks should be considered suspicious and biopsied.
Patients with diffuse NHL may present with cutaneous lesions, testicular
masses, or solitary bone lesions. A number of grades of NHL are
recognized. Therapy is dependent on the grade of the diseases and includes
chemotherapy, bone marrow transplant, and radiation. Among the newest
approaches to treating the disease is the use of monoclonal antibodies
targeted to reduce the numbers of malignant B cells associated with the
tumors. The first of these to be approved in the US is rituximab.
How it Works
Rituximab in a genetically engineered monoclonal
antibody directed against the CD20 antigen found on the surface of normal
and malignant B lymphocytes. The antibody is composed of two heavy chains
and two light chains of amino acids. This antibody is produced by
mammalian cell culture and is purified by affinity ion exchange. The
purification process includes steps to ensure viral inactivation and
Rituximab binds to the CD20 antigen, which is found on pre-B and mature
B lymphocytes. This antigen is found on more than 90% of B-cells in NHL,
but is not found on stem cells, pro-B cells, normal plasma cells, or other
normal tissue. CD20 is important because it regulates early steps in the
activation process for cell cycle initiation and differentiation. Free
CD20 is not found in the circulation. Once rituximab binds to the CD20
antigen on B-lymphocytes, lysis of the B cell occurs. This lysis may be
complement-mediated. Although the drug has been found to bind to normal
lymphoid tissue in the thymus, the white pulp of the spleen, and a
majority of B-lymphocytes in peripheral blood and lymph nodes, little or
no binding has been observed in non-lymphoid tissues.
Rituximab is administered intravenously. It has
a long half-life (about 60 hours) after the first infusion, lengthening to
174 after the fourth infusion. Administration of rituximab results in
rapid and sustained depletion of circulating and tissue-based B cells.
Among the 166 patients in a pivotal study of the drug, circulating B cells
were depleted within the first three doses with sustained depletion for up
to 6 to 9 months after treatment in 83% of patients. In addition, patients
experience significant sustained reductions in IgM and IgG for up to 11
months after treatment. B-cell recovery generally begins about 6 months
following completion of treatment.
Because of the nature of the disease in question, only a small number
of patients (about 300) have been enrolled in studies in support of the
safety and effectiveness of the drug. Among these, 87% of patients
experienced an adverse event during therapy, the most common of which were
fever, chills, weakness, headache, nausea, leukopenia and angioedema.
Although immunoglobulins are decreased during rituximab therapy, the
incidence of infection does not appear to increase. The incidence of
adverse events does not appear to change following retreatment.
The recommended dose of rituximab is administered as an IV infusion
once weekly for four doses (days 1, 8, 15, and 22) and can be given in the
outpatient setting. IT SHOULD NEVER BE GIVEN AS AN IV PUSH OR BOLUS, but
must be diluted according to directions.
What The Patient Should Know
Hypersensitivity reactions may
occur, and the manufacturer recommends premedication with acetaminophen
and diphenhydramine before each infusion.
- Press OW, Applebaum F, Ledbetter JA, et al. Monoclonal antibody 1F5
(anti-CD20) serotherapy of human B-cell lymphomas. Blood.
- Reff ME, Carner C, Chambers KS, et al. Depletion of B cells in vivo
by a chimeric mouse human monoclonal antibody to CD20. Blood.
- Maloney DG, Liles TM, Czerwinski C, et al. Phase I clinical trial
using escalating single- dose infusion of chimeric anti-CD20 monoclonal
antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood.
- Maloney DG, Grillo-Lopez AJ, Bodkin D, et al. IDEC-C2B8: Results of
a phase I multiple-dose trial in patients with relapsed non-Hodgkins's
lymphoma. J Clin Oncol. 1997;15:3266-3274.
- Maloney DG, Grillo-Lopesz AJ, White CA, et al. IDEC-C2B8 (rituximab)
anti-CD20 monoclonal antibody therapy in patients with relapsed
low-grade non-Hodgkin's lymphoma. Blood. 1997;90:2188-2195.
© 1997 VirSci Corporation. All
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