Antineoplastic and Pre-Transplant Conditioning Drugs

Antineoplastic drugs inhibit and combat the development of cancer and are used as induction therapies in most stem cell transplant scenarios. From the H&I laboratory point of view, a key action is to HLA type the patient before they commence their treatment. This would almost certainly always be the case in allogeneic transplantation but must not be missed for autologous transplantation, as the patient may need HLA matched platelet products if they become immunologically refractory to random platelets. Where a patient is not HLA typed before the induction therapy starts, a HLA type can be obtained by extracting DNA from a buccal cavity swap.

Antineoplastic drugs can be divided into five main categories based mainly on their mechanisms of action. These are 1) Alkylating agents, 2) Antimetabolites, 3) Plant Alkaloids, 4) Cytotoxic Antibiotics and related substances and 5) a set of ‘Other’ Antineoplastic agents which do not fall into the other four categories.


1.    Alkylating Agents


Alkylating agents are compounds which are capable of adding an alkyl group (CH4) to the guanine nucleotide bases of DNA molecules, causing damage by cross linking the guanine bases. As cancer cells have less error correction of their DNA during replication, they are disproportionately affected when compared to normal cells. In this way, alkylating agents inhibits cancer cell growth. Alkylating agents are used both for cancer treatment in the absence of transplantation as well as for induction prior to transplantation. Alkylating agents include but are not limited to Busulphan, Carmustine (BCNU), Cyclophosphamide, Isofamide, Lomustine (CCNU) and Melphalan.

 

Busulfan

Busulfan is a cell cycle non specific alkylating antineoplastic agent which causes profound myelosuppression in patients. It is often used together with Cyclophosphamide (Bu/Cy) as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukaemia (CML). 

 

Carmustine (BCNU)

Carmustine (also known as BCNU) is a mustard gas related compound with an alkylating mechanism of action. It is used in the treatment of several types of brain cancer, for treatment of Multiple Myeloma and for treatment of Hodgkins and non-Hodgkins Lymphoma. It is often used as a conditioning regime prior to allogeneic hematopoietic progenitor cell transplantation for lymphoma as part of the BEAM cocktail which includes BCNU (Carmustine), Etoposide, Arabinoside-C (also known as Cytarabine) and Melphalan.

 

Cyclophosphamide

Cyclophosphamide, an alkylating agent, is one of the most efficacious immunosuppressive drugs available. Cyclophosphamide is used for treatment of autoimmune disorders such as SLE and multiple sclerosis and as a broad spectrum anti cancer drug often given together with other drugs for treatment of non-Hodgkin’s lymphoma, leukaemia’s, multiple myeloma, breast and ovarian cancer.

 

Ifosfamide

Ifosfamide is an alkylating agent often used in the treatment of solid tumours, including testicular, breast and lung cancers and some lymphomas. When used for lymphoma treatment, Ifosfamide is often administered together with Cisplatin and Etoposide as part of the ICE cocktail or with Rituximab and ICE as part of the R-ICE cocktail.

 

Lomustine (CCNU)

Lomustine (also known as CCNU) is a lipid soluble alkylating agent capable of crossing the blood brain barrier and is used most often to treat brain tumours. It is also used to treat Hodgkins and non-Hodgkins Lymphomas.

 

Melphalan

Melphalan is a nitrogen mustard alkylating agent. It is mainly used in the treatment of multiple myeloma and for ovarian cancer. It is also used as a conditioning regime prior to allogeneic hematopoietic progenitor cell transplantation for lymphoma as part of the BEAM cocktail which includes BCNU (Carmustine), Etoposide, Arabinoside-C (also known as Cytarabine) and Melphalan.

 


2.    Antimetabolites


Antimetabolites are substances that bear a close structural similarity to another substance, a metabolite, that is required for normal physiological function and often exert their effect by interfering with the utilization of the essential metabolite. Antimetabolites most often used in cancer treatment are those that interfere with DNA production and therefore cell division and the growth of cancer cells. Antimetabolites are often used as induction therapy prior to stem cell transplantation. Antimetabolites include Cytarabine, Fludarabine and Methotrexate.

 

Cytarabine (ARA-C)

Cytarabine (also known as Arabinoside-C) is an anti-metabolite that inhibits DNA synthesis and is used most often to treat acute leukaemia’s and non-Hodgkins lymphomas. When used as a conditioning regime prior to allogeneic hematopoietic progenitor cell transplantation for lymphoma, it is often part of the BEAM cocktail which includes BCNU (Carmustine), Etoposide, Arabinoside-C (also known as Cytarabine) and Melphalan.

 

Fludarabine

Fludarabine is a purine analog that inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase. Fludarabine is highly effective in the treatment of chronic lymphocytic leukaemia (CLL), producing higher response rates than alkylating agents. Fludarabine is often used in Reduced Intensity Regimes (RIC) prior to stem cell transplantation either alongside reduced intensity TBI or together with Busulfan with or without ATG.

 

Methotrexate

Methotrexate (MXT) is a folic acid antagonist that inhibits dihydrofolate reductase, a key enzyme in the synthesis of the amino acids serine and methionine. Methotrexate is used in the treatment of some autoimmune diseases, including Psoriasis and Rheumatoid Arthritis as well as treatment of many types of cancer including ALL.

 


3.    Alkaloids


Alkaloids are a group of basic organic substances found in plants but also in many other organisms including bacteria and fungi, many of which are pharmacologically active. Alkaloids exert their effect by disrupting the cell cycle. Alkaloids are used both for cancer treatment in the absence of transplantation as well as for induction prior to transplantation. An example of an Alkaloid is Etoposide.

 

Etoposide

Etoposide is an alkaloid anticancer used in the treatment of solid tumours, including testicular, breast and small cell lung cancers and some lymphomas. Etoposide acts by inhibiting the enzyme topoisomerase II, which normally unwinds DNA, causing the DNA double strand to break. Cancer cells are less able to repair this damage compared to normal cells and are therefore disproportionately affected. When used as a conditioning regime prior to allogeneic hematopoietic progenitor cell transplantation for lymphoma, it is often part of the BEAM cocktail which includes BCNU (Carmustine), Etoposide, Arabinoside-C (also known as Cytarabine) and Melphalan.

 


4.    Cytotoxic Antibiotics


Cytotoxic antibodies are used in the treatment of many malignancies. Their mechanism of action is direct toxic action on cellular DNA, interfering with DNA replication and protein synthesis. They mimic the action of radiation and should not be used together with radiotherapy. Common examples of cytotoxic antibiotics include mitomycin and mitoxantrone.

 


5.    Other Antineoplastic Drugs


Other antineoplastic drugs include platinum compounds, monoclonal antibodies, protein kinase inhibitors and others.

 

Platinum compounds

Examples of Platinum compounds include Cisplatin and Carboplatin.


 

Monoclonal antibodies

Examples of Monoclonal Antibodies include Alemtuzumab (Campath 1H) and Rituximab.

 

Alemtuzumab (Campath 1H)

Alemtuzumab (also known as Campath 1H) is an anti-CD52 recombinant humanized monoclonal antibody used for the treatment of CLL and T cell Lymphoma. It binds to CD52, which is present on all mature lymphocytes but not on stem cells. Alemtuzumab is indicated for the treatment of B-cell chronic lymphocytic leukaemia (B-CLL) in patients who are refractory to first line treatment with Fludarabine.

 

Rituximab

Rituximab is an anti-CD20 recombinant chimeric murine-human monoclonal antibody. It is often used to treat non-Hodgkins lymphoma and CLL. It binds to CD-20 which is expressed on all B cells (but not on plasma cells). Binding triggers a series of cytotoxic immune response resulting in the elimination of B cells. The mechanism of action includes complement-mediated lysis, antibody-dependent cellular cytotoxicity and induction of apoptosis in the malignant lymphoma cells.


 

Protein kinase inhibitors

Protein Kinase Inhibitors include Tyrosine Kinase Inhibitors (TKI) and Serine Kinase Inhibitor (SKI). Protein Kinase Inhibitors act by inhibiting Tyrosine or Serine phosporylation, which is a key step in the signalling pathways which lead to various cellular processes including growth and differentiation. Inhibition of Protein Kinase activity disrupts the cell signalling pathway and reduces proliferation. Examples of Protein Kinase Inhibitors include Everolimus and Imatinib:

 

Everolimus

Everolimus is used as an immunosuppressant to prevent rejection in heart and kidney transplants and for treatment of advanced kidney cancer. Everolimus is a derivative of Sirolimus and is an mTOR (mammalian Target of Rapamycin) inhibitor. mTOR is a serine-threonine protein kinase that regulates cell growth, proliferation, motility, survival, protein synthesis and transcription. Inhibition of mTOR blocks cell responses to IL-2.

 

Imatinib

Imatinib is a Tyrosine Kinase Inhibitor used to treat CML. It selectively inhibits BRC-ABL, a constitutively active tyrosine kinase typical of CML. Use of Imatinib has significantly reduced the need for stem cell transplantation in CML patients.


 

Others

Bortezomib

Bortezomib is proteasome inhibitor used for the treatment of relapsed multiple myeloma and mantle cell lymphoma. Proteasomes are thought to support the immortal phenotype of multiple myeloma by rapidly degrading pro-apoptotic factors. Bortezomib binds to the catalytic site of proteasome with high affinity and specificity, inhibiting its action and permitting the activation of programmed cell death. Bortezomib induces apoptosis in plasma cells and shows some promise in desensitisation protocols in kidney transplantation.

 


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