DESCRIPTION
Rituximab (RTX, trade name Rituxan®) is a chimeric mouse monoclonal antibody (moAb) directed against the human CD20 protein, a B cell specific surface marker, and leads to depletion of these cells.
It was the first moAb to be approved for use in the treatment of cancer. The introduction of the anti-CD20 moAb has led to substantial advances in treatment of diseases associated with B cells.
INDICATIONS
RTX is used for the treatment of hematological cancers such as:
- B cell chronic lymphocytic leukemia (CLL).
- B cell non-Hodgkin lymphomas (NHL), especially low-grade or follicular lymphoma, and diffuse large B cell lymphoma.
RTX was also approved to treat rheumatoid arthritis (RA), and it is being examined for treating other autoimmune diseases, such as systemic lupus erythematosus (SLE) and autoimmune anemias (The rationale for B lymphocyte depletion in Graves' disease. Monoclonal anti-CD20 antibody therapy as a novel treatment option, 2006).
This drug may have some utility in transplants involving incompatible blood groups.
In the US, rituximab is approved for use:
- in combination with fludarabine and cyclophosphamide in untreated or previously treated CD20-positive CLL;
- as monotherapy in relapsed or refractory, low-grade or follicular CD20-positive B-cell NHL;
- in combination with cyclophosphamide, vincristine and prednisone (CVP) in previously untreated, follicular CD20-positive B-cell NHL;
- in combination with cyclophosphamide plus doxorubicin, vincristine and prednisone (CHOP) or other anthracycline-based chemotherapy in previously untreated, diffuse large B-cell CD20-positive NHL.
In the EU, rituximab is approved for use:
- in combination with chemotherapy in previously untreated and relapsed or refractory CLL;
- as monotherapy in stage III–IV follicular lymphoma that is chemoresistant or in second or subsequent relapse after chemotherapy;
- as maintenance therapy in relapsed or refractory follicular lymphoma responding to induction therapy with chemotherapy with or without rituximab;
- in combination with chemotherapy in previously untreated stage III–IV follicular lymphoma;
- in combination with CHOP in diffuse large B-cell CD20-positive NHL.
PHARMACOKINETICS
RTX is somministrate by intravenous infusionmand should be started at a rate of 50 mg/h and, in the absence of infusion toxicity, increased by 50 mg/h at 30-minute intervals, to a maximum rate of 400mg/h.
Radiolabelled RTX is widely distributed to body organs, such as in the heart, liver, lungs, spleen and kidneys.
RTX is degraded in the liver and other organs by a process of nonspecific catabolism, and has an estimated median elimination half-life (t1⁄2) in patients with NHL of 22 days (Rituximab: a review of its use in chronic lymphocytic leukaemia, low-grade or follicular lymphoma and diffuse large B-cell lymphoma, 2010).
MOLECULAR MECHANISM
CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity. The protein has no known natural ligand and its function is to enable optimal B-cell immune response, specifically against T-independent antigens. CD20 is probably operating as a calcium channel, and may be involved in B cell proliferation, activation and differentiation, and signal transduction (The rationale for B lymphocyte depletion in Graves' disease. Monoclonal anti-CD20 antibody therapy as a novel treatment option, 2006).
The binding of RTX to CD20 expressed on normal and malignant B cells leads to B-cell depletion.
Although the precise mechanism by which binding of RTX to CD20 results in cytotoxicity is not known, RTX promoted antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of a human lymphoid cell line expressing CD20.
ADCC is triggered by the binding of the Fc domain of RTX to Fcγ receptors on immune effector cells, such as monocytes, natural killer cells and granulocytes. Rituximab-bound B cells are then destroyed by phagocytosis or by the release of cytotoxic granules from immune effector cells. The binding of the Fc domain of RTX to complement may also facilitate lymphoma cell death via CDC.
Thus, effective therapy with RTX, and most probably with several other anti-CD20 moAbs, is dependent on host effector functions.
SIDE EFFECTS AND TOXICITY
Rituximab monotherapy was generally well tolerated in patients with NHL. The most commonly occurring adverse reactions in patients with relapsed or refractory low-grade or follicular lymphoma receiving RTX monotherapy included:
In patients with previously untreated advanced follicular lymphoma, the addition of RTX to chemotherapy did not generally exacerbate toxicity.
Infusion reactions (including fever, chills, nausea, pruritus and angioedema) were one of the most commonly occurring adverse events among patients with CLL or NHL who received intravenous RTX. Infusion reactions generally occurred within 30–120 minutes of starting the first infusion and usually resolved if the infusion was slowed or interrupted, along with the use of supportive care, such as paracetamol (acetaminophen), diphenhydramine and intravenous saline.
In terms of haematological adverse events occurring in patients with relapsed or refractory low-grade or follicular lymphoma receiving RTX monotherapy, cytopenias occurred most commonly, with grade 3 or 4 lymphopenia, neutropenia, leukopenia, anaemia and thrombocytopenia, occurring in 40%, 6% 4%, 3% and 2% of RTX monotherapy recipients, respectively (Rituximab: a review of its use in chronic lymphocytic leukaemia, low-grade or follicular lymphoma and diffuse large B-cell lymphoma, 2010).
RESISTANCE
Anti-human anti-chimeric antibody (HACA) formation has been observed following RTX administration, although its clinical relevance is unclear.
Second generation antibodies, include ofatumumab, ocrelizumab and veltuzumab, can be tailored to be humanized or fully human with unmodified Fc domain, with the aim of reducing immunogenicity.
Likewise, third generation antibodies, include AME133v, Pro13192 (v114), GA101 and R603/EMAB-6, can be modified to include engineered Fc domains with the aim of improving the therapeutic activity in all patients, particularly in genetically defined subpopulations that express a low affinity version of the Fc receptor on their immune effector cells (Evolution of anti-CD20 monoclonal antibody therapeutics in oncology, 2010).
