Fludarabine
Encyclopedia
Fludarabine or fludarabine phosphate (Fludara) is a chemotherapy
drug used in the treatment of hematological malignancies
. It has been unofficially and casually referred to as "AIDS in a bottle" amongst healthcare professionals due to its significant immunosuppresive activity.
s such as chlorambucil
alone.
Fludarabine is used in various combinations with cyclophosphamide
, mitoxantrone
, dexamethasone
and rituximab
in the treatment of indolent non-Hodgkins lymphomas
. As part of the FLAG regimen, fludarabine is used together with cytarabine
and granulocyte colony-stimulating factor
in the treatment of acute myeloid leukaemia. Because of its immunosuppressive effects, fludarabine is also used in some conditioning regimens prior to non myeloablative allogeneic stem cell transplant
.
analog
, and can be given both orally and intravenously. Fludarabine inhibits DNA synthesis
by interfering with ribonucleotide reductase
and DNA polymerase
. It is active against both dividing and resting cells. Being phosphorylated, fludarabine is ionized at physiologic pH and is effectually trapped in blood. This provides some level of specificity for blood cells, both cancerous and healthy.
s significantly. Patients who have been treated with fludarabine will usually be asked to take co-trimoxazole
or to use monthly nebulised pentamidine
to prevent Pneumocystis jiroveci pneumonia. The profound lymphopenia caused by fludarabine renders patients susceptible to transfusion-associated graft versus host disease
, a fatal complication of blood transfusion
. For this reason, all patients who have ever received fludarabine should only be given irradiated
blood components.
Fludarabine causes anemia, thrombocytopenia and neutropenia
, requiring regular blood count monitoring. Some patients require blood and platelet
transfusion, or G-CSF
injections to boost neutrophil counts.
Fludarabine is associated with the development of severe autoimmune hemolytic anemia
in a proportion of patients.
Difficulties are often encountered when harvesting peripheral blood stem cells from patients previously treated with fludarabine.
in 1968. Their previous work involved 2-fluoroadenosine, which was unsafe for use in humans; the change to this arabinose
analogue was inspired by the success of vidarabine
.
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
drug used in the treatment of hematological malignancies
Hematological malignancy
Hematological malignancies are the types of cancer that affect blood, bone marrow, and lymph nodes. As the three are intimately connected through the immune system, a disease affecting one of the three will often affect the others as well: although lymphoma is technically a disease of the lymph...
. It has been unofficially and casually referred to as "AIDS in a bottle" amongst healthcare professionals due to its significant immunosuppresive activity.
Indications
Fludarabine is highly effective in the treatment of chronic lymphocytic leukemia, producing higher response rates than alkylating agentAlkylating antineoplastic agent
An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group to DNA.The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring....
s such as chlorambucil
Chlorambucil
Chlorambucil is a chemotherapy drug that has been mainly used in the treatment of chronic lymphocytic leukemia...
alone.
Fludarabine is used in various combinations with cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
, mitoxantrone
Mitoxantrone
Mitoxantrone is an anthracenedione antineoplastic agent.-Uses:It is used in the treatment of certain types of cancer, mostly metastatic breast cancer, acute myeloid leukemia, and non-Hodgkin's lymphoma...
, dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
and rituximab
Rituximab
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
in the treatment of indolent non-Hodgkins lymphomas
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
. As part of the FLAG regimen, fludarabine is used together with cytarabine
Cytarabine
Cytarabine, or cytosine arabinoside, is a chemotherapy agent used mainly in the treatment of cancers of white blood cells such as acute myeloid leukemia and non-Hodgkin lymphoma. It is also known as Ara-C...
and granulocyte colony-stimulating factor
Granulocyte colony-stimulating factor
Granulocyte colony-stimulating factor is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 ....
in the treatment of acute myeloid leukaemia. Because of its immunosuppressive effects, fludarabine is also used in some conditioning regimens prior to non myeloablative allogeneic stem cell transplant
Bone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...
.
Pharmacology
Fludarabine is a purinePurine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
analog
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
, and can be given both orally and intravenously. Fludarabine inhibits DNA synthesis
DNA synthesis
DNA synthesis commonly refers to:*DNA replication - DNA biosynthesis *Polymerase chain reaction - enzymatic DNA synthesis *Oligonucleotide synthesis - chemical synthesis of nucleic acids...
by interfering with ribonucleotide reductase
Ribonucleotide reductase
Ribonucleotide reductase is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. Deoxyribonucleotides in turn are used in the synthesis of DNA. The reaction catalyzed by RNR is strictly conserved in all living organisms...
and DNA polymerase
DNA polymerase
A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand....
. It is active against both dividing and resting cells. Being phosphorylated, fludarabine is ionized at physiologic pH and is effectually trapped in blood. This provides some level of specificity for blood cells, both cancerous and healthy.
Side effects
Fludarabine is associated with profound lymphopenia, and as a consequence, increases the risk of opportunistic infectionOpportunistic infection
An opportunistic infection is an infection caused by pathogens, particularly opportunistic pathogens—those that take advantage of certain situations—such as bacterial, viral, fungal or protozoan infections that usually do not cause disease in a healthy host, one with a healthy immune system...
s significantly. Patients who have been treated with fludarabine will usually be asked to take co-trimoxazole
Co-trimoxazole
Trimethoprim/sulfamethoxazole or co-trimoxazole is a sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections.The name co-trimoxazole is the British Approved Name, and has been marketed worldwide...
or to use monthly nebulised pentamidine
Pentamidine
Pentamidine is an antimicrobial medication given for prevention and treatment of Pneumocystis pneumonia caused by Pneumocystis jirovecii , a severe interstitial type of pneumonia often seen in patients with HIV infection...
to prevent Pneumocystis jiroveci pneumonia. The profound lymphopenia caused by fludarabine renders patients susceptible to transfusion-associated graft versus host disease
Transfusion-associated graft versus host disease
Transfusion-associated graft versus host disease is a rare complication of blood transfusion, in which the donor T lymphocytes mount an immune response against the recipient's lymphoid tissue. Donor lymphocytes are usually identified as foreign and destroyed by the recipient's immune system...
, a fatal complication of blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
. For this reason, all patients who have ever received fludarabine should only be given irradiated
Irradiation
Irradiation is the process by which an object is exposed to radiation. The exposure can originate from various sources, including natural sources. Most frequently the term refers to ionizing radiation, and to a level of radiation that will serve a specific purpose, rather than radiation exposure to...
blood components.
Fludarabine causes anemia, thrombocytopenia and neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
, requiring regular blood count monitoring. Some patients require blood and platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
transfusion, or G-CSF
Granulocyte colony-stimulating factor
Granulocyte colony-stimulating factor is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 ....
injections to boost neutrophil counts.
Fludarabine is associated with the development of severe autoimmune hemolytic anemia
Autoimmune hemolytic anemia
Autoimmune hemolytic anemia occurs when antibodies directed against the person's own red blood cells cause the RBCs to burst , leading to insufficient plasma concentration. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases...
in a proportion of patients.
Difficulties are often encountered when harvesting peripheral blood stem cells from patients previously treated with fludarabine.
History
Fludarabine was produced by John Montgomery and Kathleen Hewson of the Southern Research InstituteSouthern Research Institute
Southern Research Institute is a not-for-profit institute that conducts basic and applied research sponsored by both commercial and non-commercial organizations in areas such as Drug Discovery, Drug Development and Engineering and Environmental Sciences....
in 1968. Their previous work involved 2-fluoroadenosine, which was unsafe for use in humans; the change to this arabinose
Arabinose
Arabinose is an aldopentose – a monosaccharide containing five carbon atoms, and including an aldehyde functional group.For biosynthetic reasons, most saccharides are almost always more abundant in nature as the "D"-form, or structurally analogous to D-glyceraldehyde.For sugars, the D/L...
analogue was inspired by the success of vidarabine
Vidarabine
Vidarabine or adenine arabinoside is an antiviral drug which is active against herpes simplex and varicella zoster viruses.- How the drug was discovered :...
.