Fludarabine

Last updated
Fludarabine
Fludarabine.svg
Clinical data
Trade names Fludara, others
AHFS/Drugs.com Monograph
MedlinePlus a692003
Routes of
administration 		Intravenous, by mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 55%
Protein binding 19 to 29%
Elimination half-life 20 hours
Excretion Kidney
Identifiers
  • (2R,3S,4S,5R)-2-(6-amino-2-fluoropurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.123.703 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H12FN5O4
Molar mass 285.235 g·mol−1
3D model (JSmol)
  • Fc1nc(c2ncn(c2n1)[C@@H]3O[C@@H]([C@@H](O)[C@@H]3O)CO)N
  • InChI=1S/C10H12FN5O4/c11-10-14-7(12)4-8(15-10)16(2-13-4)9-6(19)5(18)3(1-17)20-9/h2-3,5-6,9,17-19H,1H2,(H2,12,14,15)/t3-,5-,6+,9-/m1/s1 Yes check.svgY
  • Key:HBUBKKRHXORPQB-FJFJXFQQSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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. [3] These include chronic lymphocytic leukemia, non-Hodgkin's lymphoma, acute myeloid leukemia, and acute lymphocytic leukemia. [3] It is given by injection into a vein or by mouth. [3]

Contents

Common side effects include nausea, diarrhea, fever, rash, shortness of breath, numbness, vision changes, and feeling tired. [3] Severe side effects include brain dysfunction, low blood cell counts, and lung inflammation. [3] Use in pregnancy will likely result in harm to the fetus. [3] Fludarabine is in the purine analog family of medications and works by interfering with the duplication of DNA. [3] [4]

Fludarabine was approved for medical use in the United States in 1991. [3] It is on the World Health Organization's List of Essential Medicines. [5]

Medical uses

Fludarabine is highly effective in the treatment of chronic lymphocytic leukemia, producing higher response rates than alkylating agents such as chlorambucil alone. [6] Fludarabine is used in various combinations with cyclophosphamide, mitoxantrone, dexamethasone and rituximab in the treatment of indolent non-Hodgkin's lymphomas. As part of the FLAG or FLAMSA 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 allogeneic stem cell transplant.

Side effects

Fludarabine is associated with profound lymphopenia, and as a consequence, increases the risk of opportunistic infections. People 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, 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, 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. [7]

Difficulties are often encountered when harvesting peripheral blood stem cells from patients previously treated with fludarabine. [8]

Pharmacology

Fludarabine is a purine 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.

History

Fludarabine was produced by John Montgomery and Kathleen Hewson of the Southern Research Institute in 1968. [9]

Names

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

Related Research Articles

<span class="mw-page-title-main">Leukemia</span> Blood cancers forming in the bone marrow

Leukemia is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising, bone pain, fatigue, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically made by blood tests or bone marrow biopsy.

<span class="mw-page-title-main">Myelodysplastic syndrome</span> Diverse collection of blood-related cancers

A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.

<span class="mw-page-title-main">Chronic lymphocytic leukemia</span> Bone marrow cancer in which lymphocytes are overproduced

Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow. In CLL, the bone marrow makes too many lymphocytes, which are a type of white blood cell. Many people do not have any symptoms when they are first diagnosed. Those with symptoms may experience fevers, fatigue, night sweats, and weight loss. These patients may also have painless lymph node swelling, enlargement of the spleen, and/or a low red blood cell count (anemia). These symptoms may worsen over time.

<span class="mw-page-title-main">Tumors of the hematopoietic and lymphoid tissues</span> Tumors that affect the blood, bone marrow, lymph, and lymphatic system

Tumors of the hematopoietic and lymphoid tissues or tumours of the haematopoietic and lymphoid tissues are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all intimately connected through both the circulatory system and the immune system, a disease affecting one will often affect the others as well, making aplasia, myeloproliferation and lymphoproliferation closely related and often overlapping problems. While uncommon in solid tumors, chromosomal translocations are a common cause of these diseases. This commonly leads to a different approach in diagnosis and treatment of hematological malignancies. Hematological malignancies are malignant neoplasms ("cancer"), and they are generally treated by specialists in hematology and/or oncology. In some centers "hematology/oncology" is a single subspecialty of internal medicine while in others they are considered separate divisions. Not all hematological disorders are malignant ("cancerous"); these other blood conditions may also be managed by a hematologist.

<span class="mw-page-title-main">Cytarabine</span> Chemical compound (chemotherapy medication)

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 injection into a vein, under the skin, or into the cerebrospinal fluid. There is a liposomal formulation for which there is tentative evidence of better outcomes in lymphoma involving the meninges.

<span class="mw-page-title-main">Rasburicase</span> Pharmaceutical drug

Rasburicase, sold under the brand name Elitek in the US and Fasturtec in the EU, is a medication that helps to clear uric acid from the blood. It is a recombinant version of urate oxidase, an enzyme that metabolizes uric acid to allantoin. Urate oxidase is known to be present in many mammals but does not naturally occur in humans. Rasburicase is produced by a genetically modified Saccharomyces cerevisiae strain. The complementary DNA (cDNA) coding for rasburicase was cloned from a strain of Aspergillus flavus.

<span class="mw-page-title-main">Rituximab</span> Biopharmaceutical drug

Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow intravenous infusion.

<span class="mw-page-title-main">Alemtuzumab</span> Medication

Alemtuzumab, sold under the brand names Campath and Lemtrada among others, is a medication used to treat chronic lymphocytic leukemia and multiple sclerosis. In chronic lymphocytic leukemia, it has been used as both a first line and second line treatment. It is given by injection into a vein.

<span class="mw-page-title-main">Chlorambucil</span> Chemical compound

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.

Autoimmune hemolytic anemia (AIHA) is an autoimmune disorder which occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to an insufficient number of oxygen-carrying red blood cells in circulation (anemia). The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases. The intracellular components of the RBCs are released into the circulating blood and into tissues, leading to some of the characteristic symptoms of this condition. The antibodies are usually directed against high-incidence antigens, therefore they also commonly act on allogenic RBCs. AIHA is a relatively rare condition, with an incidence of 5–10 cases per 1 million persons per year in the warm-antibody type and 0.45 to 1.9 cases per 1 million persons per year in the cold-antibody type. Autoimmune hemolysis might be a precursor of later onset systemic lupus erythematosus.

Paroxysmal cold hemoglobinuria (PCH) or Donath–Landsteiner hemolytic anemia (DLHA) is an autoimmune hemolytic anemia featured by complement-mediated intravascular hemolysis after cold exposure. It can present as an acute non-recurrent postinfectious event in children, or chronic relapsing episodes in adults with hematological malignancies or tertiary syphilis. Described by Julius Donath (1870–1950) and Karl Landsteiner (1868–1943) in 1904, PCH is one of the first clinical entities recognized as an autoimmune disorder.

<span class="mw-page-title-main">Bendamustine</span> Chemical compound

Bendamustine, sold under the brand name Treanda among others, is a chemotherapy medication used in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, and non-Hodgkin's lymphoma. It is given by injection into a vein.

Hematologic diseases are disorders which primarily affect the blood and blood-forming organs. Hematologic diseases include rare genetic disorders, anemia, HIV, sickle cell disease and complications from chemotherapy or transfusions.

Obinutuzumab, sold under the brand name Gazyva among others, is a humanized anti-CD20 monoclonal antibody used as a treatment for cancer. It was originated by GlycArt Biotechnology AG and developed by Roche.

Acquired hemolytic anemia can be divided into immune and non-immune mediated forms of hemolytic anemia.

<span class="mw-page-title-main">Ibrutinib</span> Medication used in cancer treatment

Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.

FCM, or FMC in the context of chemotherapy is an acronym for a chemotherapy regimen that is used in the treatment of indolent B cell non-Hodgkin's lymphomas. In combination with Rituximab, this regimen is called R-FCM or R-FMC, or FCM-R, FMC-R.

FLAG is a chemotherapy regimen used for relapsed and refractory acute myeloid leukemia (AML). The acronym incorporates the three primary ingredients of the regimen:

  1. Fludarabine: an antimetabolite that, while not active toward AML, increases formation of an active cytarabine metabolite, ara-CTP, in AML cells;
  2. Arabinofuranosyl cytidine : an antimetabolite that has been proven to be the most active toward AML among various cytotoxic drugs in single-drug trials; and
  3. Granulocyte colony-stimulating factor (G-CSF): a glycoprotein that shortens the duration and severity of neutropenia.
<span class="mw-page-title-main">Venetoclax</span> Medication

Venetoclax, sold under the brand names Venclexta and Venclyxto, is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML).

References

  1. ↑ "Product monograph brand safety updates". Health Canada . 7 July 2016. Retrieved 3 April 2024.
  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  3. 1 2 3 4 5 6 7 8 "Fludarabine Phosphate". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  4. ↑ Helms RA, Quan DJ (2006). Textbook of Therapeutics: Drug and Disease Management. Lippincott Williams & Wilkins. p. 2309. ISBN   9780781757348. Archived from the original on 2016-12-20.
  5. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  6. ↑ Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, et al. (December 2000). "Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia". The New England Journal of Medicine. 343 (24): 1750–1757. doi: 10.1056/NEJM200012143432402 . PMID   11114313.
  7. ↑ Gonzalez H, Leblond V, Azar N, Sutton L, Gabarre J, Binet JL, et al. (June 1998). "Severe autoimmune hemolytic anemia in eight patients treated with fludarabine". Hematology and Cell Therapy. 40 (3): 113–118. PMID   9698219.
  8. ↑ Tournilhac O, Cazin B, Leprètre S, Diviné M, Maloum K, Delmer A, et al. (January 2004). "Impact of frontline fludarabine and cyclophosphamide combined treatment on peripheral blood stem cell mobilization in B-cell chronic lymphocytic leukemia". Blood. 103 (1): 363–365. doi: 10.1182/blood-2003-05-1449 . PMID   12969985.
  9. ↑ Sneader W (2005). Drug discovery: a history. New York: Wiley. p. 258. ISBN   0-471-89979-8.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.