Fludarabine phosphate
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Fludarabine is a purine analogue and antineoplastic agent. It is generally used as its 5-O-phosphorylated form known as fludarabine phosphate, sold under the brand name Fludara among others. It is a chemotherapy medication used in the treatment of leukemia and lymphoma. These include
chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, nigh ...
, non-Hodgkin's lymphoma, acute myeloid leukemia, and acute lymphocytic leukemia. It is given by injection into a vein or by mouth. Common side effects include nausea, diarrhea, fever, rash, shortness of breath, numbness, vision changes, and feeling tired. Severe side effects include brain dysfunction, low blood cell counts, and lung inflammation. Use in pregnancy will likely result in harm to the fetus. Fludarabine is in the
purine analog Purine analogues are antimetabolites that mimic the structure of metabolic purines. Examples * Nucleobase analogues ** Thiopurines such as thioguanine are used to treat acute leukemias and remissions in acute granulocytic leukemias. ***Azathioprin ...
family of medications and works by interfering with the duplication of DNA. Fludarabine was approved for medical use in the United States in 1991. It is on the World Health Organization's List of Essential Medicines.


Medical uses

Fludarabine is highly effective in the treatment of
chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, nigh ...
, producing higher response rates than alkylating agents such as
chlorambucil Chlorambucil, sold under the brand name Leukeran among others, is a chemotherapy medication used to treat chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, and non-Hodgkin lymphoma. For CLL it is a preferred treatment. It is given by mouth. ...
alone. Fludarabine is used in various combinations with
cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...
,
mitoxantrone Mitoxantrone (INN, BAN, USAN; also known as Mitozantrone in Australia; trade name Novantrone) is an anthracenedione antineoplastic agent. Uses Mitoxantrone is used to treat certain types of cancer, mostly acute myeloid leukemia. It improves the ...
, dexamethasone and rituximab in the treatment of
indolent Indolent may refer to: *Laziness *A music label owned by Bertelsmann Music Group *indolent condition, a slowly progressive medical condition associated with little or no pain *The lowest of three grades of non-Hodgkin's lymphoma (NHL) *Indolent ul ...
non-Hodgkin's lymphomas Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of hematological malignancy, blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include lymphadenopathy, enlarged lymph nodes, fever ...
. As part of the ''FLAG'' or ''FLAMSA'' regimen, fludarabine is used together with
cytarabine Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given by in ...
and granulocyte colony-stimulating factor in the treatment of
acute myeloid leukaemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may include ...
. Because of its immunosuppressive effects, fludarabine is also used in some conditioning regimens prior to
allogeneic stem cell transplant Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...
.


Side effects

Fludarabine is associated with profound lymphopenia, and as a consequence, increases the risk of
opportunistic infection An opportunistic infection is an infection caused by pathogens (bacteria, fungi, parasites or viruses) that take advantage of an opportunity not normally available. These opportunities can stem from a variety of sources, such as a weakened immune ...
s. People who have been treated with fludarabine will usually be asked to take
co-trimoxazole Trimethoprim/sulfamethoxazole, sold under the brand name Bactrim among others, is a fixed-dose combination antibiotic medication used to treat a variety of bacterial infections. It consists of one part trimethoprim to five parts sulfamethoxazo ...
or to use monthly nebulised
pentamidine Pentamidine is an antimicrobial medication used to treat African trypanosomiasis, leishmaniasis, ''Balamuthia'' infections, babesiosis, and to prevent and treat pneumocystis pneumonia (PCP) in people with poor immune function. In African trypano ...
to prevent ''Pneumocystis jiroveci'' pneumonia. The profound lymphopenia caused by fludarabine renders patients susceptible to transfusion-associated graft versus host disease, an oftentimes 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 Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
, 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.


Pharmacology

Fludarabine is a
purine analog Purine analogues are antimetabolites that mimic the structure of metabolic purines. Examples * Nucleobase analogues ** Thiopurines such as thioguanine are used to treat acute leukemias and remissions in acute granulocytic leukemias. ***Azathioprin ...
, and can be given both orally and intravenously. Fludarabine inhibits DNA synthesis by interfering with
ribonucleotide reductase Ribonucleotide reductase (RNR), also known as ribonucleoside diphosphate reductase (rNDP), is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. It catalyzes this formation by removing the 2'-hydroxyl group of th ...
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.


History

Fludarabine was produced by John Montgomery and Kathleen Hewson of the Southern Research Institute in 1968.


Names

Fludarabine is generally administered as its 5-O-phosphorylated form known as fludarabine phosphate, which is rapidly dephosphorylated to fludarabine in the plasma.


References


External links

* {{portal bar, Medicine Organofluorides Purines Organophosphates Purine antagonists Arabinosides World Health Organization essential medicines Wikipedia medicine articles ready to translate