Nursing Pharmacology Chapter 33-34:  Anticancer Drugs

• Alkylating Agents (Continued)

  • Classification⁸

    • Nitrogen Mustards

      • 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 

      • Clinical uses:

        • 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

          • 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

             

          • "Obinutuzumab/chlorambucil gives OS benefit over rituximab in frontline CLL"⁴

            Attribution: Goede V (German CLL Study Group Colonge, Germany) VJHHemOnc-Video Journal of Hematological Oncology Obinutuzumab/chlorambucil gives OS benefit over rituximab in frontline CLL. https://www.youtube.com/watch?v=IZnO4D8i4Ng 4 (6/2018) VJHHemOnc Youtube Channel:  https://www.youtube.com/channel/UCsQXL4_zTA-FoG9RA1tEGiw

          •  

            "Management of Adverse Events with Newer Agents for CLL"⁶

            Attribution:  Call TG Management of adverse events with newer agents for CLL 2017 Great Debates & Updates in Hematologic Malignancies ImedexCME, (4/23/2017) https://www.youtube.com/watch?v=JDYDosf7EqI ImedexCME Youtube Channel:  https://www.youtube.com/channel/UChzdRqqisBHL_DgHGq0COFg