Medical Pharmacology Chapter 33-34: Anticancer Drugs
Alkylating Agents (Continued):
Overview: Chlorambucil (Leukeran)
Chlorambucil (Leukeran) is a nitrogen mustard-type alkylating agent.1,2
Chlorambucil exhibits similarities to melphalan with respect to good oral bioavailability (reduced in the presence of food) and its leukemogenic risk (nonlymphocytic leukemia).
Chlorambucil itself is an active agent but undergoes β-oxidation yielding an active metabolite, phenylacetic acid mustard.
Some of the agent's antineoplastic effects are likely due to this metabolite.
Chlorambucil has several clinical uses including treatment of chronic lymphocytic leukemia (CLL), Hodgkin's disease and malignant lymphoma, although it is presently used primarily for treating CLL.
Absorption, Distribution, Metabolism, Excretion:
Chlorambucil exerts its cytotoxic activity in a way similar to other nitrogen mustard alkylating agents thus affecting bone marrow, epithelial tissues and lymphoid organs.1,3
Given orally, this agent appears well tolerated when administered in small daily doses.
At single oral doses >20 mg, nausea and vomiting may be induced.
Oral absorption is considered both reliable and appropriate for drug efficacy.
This agent is substantially plasma protein-bound (99 %).
The plasma half-life has been estimated to be about 1.5 hours.
In addition to being oxidized to an active metabolite, chlorambucil is hydrolyzed to inactive products.1,3
The major clinical use of chlorambucil is in the treatment of chronic lymphocytic leukemia (CLL).1,4
The agent may be given daily for period of 3-6 weeks.
With clinical improvement or peripheral total leukocyte count decline, dosages are adjusted, allowing maintenance of platelets and neutrophils at acceptable levels.
Maintenance treatment is usually required for extended clinical response.
In some circumstances, chlorambucil treatment may continue for years with enhanced clinical response noted over time with limited additional toxicity.
With higher doses, bone hypoplasia may occur.
Myelosuppressive effects tend to be described as moderate, reversible and gradual in development. 1,4
However, at present chlorambucil as monotherapy is not considered standard first-line treatment for CLL patients.
Alkylating agents, such as cyclophosphamide or chlorambucil, either as monotherapy or in combination with corticosteroids was central to CLL treatment for a number of decades.
However, in the late 1980s initial results with fludarabine (Fludara) indicated that administration of this agent resulted in better response rates compared to chlorambucil in previously untreated CLL patients.1,4
Currently, first-line treatment is based on chemoimmunotherapy.4
This combination approach utilizes often a chimeric antibody, rituximab (Rituxan and others) in addition to another agent or agents such as fludarabine and cyclophosphamide (FCR regimen).
Rituximab targets the CD20 antigen which is a B cell-specific surface antigen, expressed on nearly all B cells (95%).
Rituximab binding to CD20 results in B cell lysis by mechanisms that involve:
complement-dependent cytotoxicity (CDC)
antibody-dependent cellular cytotoxicity (ADCC) and by
induction of programmed-cell-death or apoptosis.
Another antibody, ofatumumab (Azerra), has also been evaluated.4
Ofatumumab is a human IgG1 monoclonal antibody binding to a different region of CD20 compared to rituximab.
This agent induces a higher compliment-dependent cytotoxic response (CDC), compared to that obtained with rituximab.
A protocol using the combination ofatumumab and chlorambucil has been approved as first-line treatment for CLL patients for whom fludarabine-based treatment was not considered appropriate.
Obinutuzumab (Gazyva (US); Gazyvaro (EU) is a humanized type II CD 20 monoclonal antibody with an engineered Fc domain that enhances antibody-dependent cellular cytotoxicity (ADCC).4
Evaluation of obinutuzumab-based treatment has resulted in approval of obinutuzumab combined with chlorambucil for patients with previously untreated CLL.
Alemtuzumab (Lemtrada, Mabcampath, Campath) is a humanized monoclonal antibody that targets a different surface antigen, CD52.
This surface antigen is expressed on CLL cells as well as on normal B and T lymphocytes.
Alemtuzumab is considered a second-line CLL treatment, FDA-approved for those CLL patients who have been treated with alkylating drugs and who have not responded to fludarabine treatment.4
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