Cladribine
Encyclopedia
Cladribine is a drug
used to treat hairy cell leukemia
(HCL, leukemic reticuloendotheliosis) and multiple sclerosis
. Its chemical name is 2-chlorodeoxyadenosine (2CDA).
As a purine analog, it is a synthetic anti-cancer agent that also suppresses the immune system. Chemically, it mimics the nucleoside
adenosine and thus inhibits the enzyme adenosine deaminase
, which interferes with the cell's ability to process DNA. It is easily destroyed by normal cells except for blood
cells, with the result that it produces relatively few side effects and results in very little non-target cell loss.
It is under investigation for other B cell leukemias and lymphomas, such as mantle cell lymphoma
, and for use in the treatment of multiple sclerosis
.
According to the Histiocytosis Association of America, cladribine is used to treat histiocytosis
.
Russia
was the first country to approve it for use treating multiple sclerosis on July 12, 2010. In the European Union
, the European Medicines Agency
's CHMP did not approve cladribine in the first application, as did the U.S. Food and Drug Administration
(FDA). As of March 2, 2011, the FDA has rejected oral cladribine for multiple sclerosis, "acknowledging sufficient data on the drug’s efficacy in multiple sclerosis but requiring more data on safety and risk-benefit "
June 2011 : Merck has decided to withdraw all marketing applications for cladribine tablets, and to stop selling it in Russia and Australia which had approved it.
, cladribine can be given by i.v. infusion or subcutaneous (s.c.) injection.
For outpatient i.v. infusions, the delivery time (not including time to place the i.v. line) may range from one to four hours; two hours is most common. Continuous i.v. infusion may be chosen; this approach drips in the cladribine slowly, 24 hours a day using a portable pump and a central venous catheter
or a PICC line. By contrast, s.c. injections take less than ten seconds per day.
The same total doses are given by both routes. Intravenous and s.c. routes have the same overall outcomes, and the s.c. route may be reduce the infections and other risks associated with venipuncture.
An oral tablet form of cladribine has been successfully tested in patients with relapsing multiple sclerosis
.
Actual doses are calculated according to the surface area of the patient's skin instead of by weight, and divided by the number of planned treatments.
All schedules produce the same benefits and disadvantages. Five-day and seven-day daily schedules give the same total amount of drug and have the same outcomes, including remissions and adverse effects. Daily and weekly schedules give the same total amount of drug and have the same outcomes, including similar proportions of complete responses and similar proportions of patients hospitalized for fevers
and opportunistic infection
s.
However, some patients have fevers that last longer and may be caused by an infection
. Very few infections have actually been documented, but they do happen, and these infections are largely responsible for the 3% mortality rate associated with cladribine therapy in HCL. Factors that increased the likelihood of a neutropenic fever (with or without concomitant infection) include: anemia
, hypocholesterolemia
, a high proportion of hairy cells in the bone marrow with a low proportion of myelopoietic cells, low albumin
, and high C-reactive protein
. These are all signs of an advanced case of HCL.
In patients with hairy cell leukemia, there is no benefit to using hormones
such as filgrastim
or Granulocyte macrophage colony-stimulating factor to raise white blood cell counts prophylactically. The use of these expensive drugs does not reduce the number of patients who experience fevers, the number of days that the fevers last, or the number of patients admitted to the hospital for antibiotic treatments. Therefore routine adjunctive use (that is, use when there are no signs of infection) is not recommended.
In addition to fevers, cladribine increases the risk of herpes virus infections, particularly shingles.
Some patients develop a rash
after treatment. Nearly all patients who develop a rash are taking other drugs, notably allopurinol
or a sulfa drug, which are known to cause rashes, and the rash is likely due to these drugs rather than to cladribine itself.
Some HCL patients will require blood transfusion
s of platelets or packed red blood cells.
Patients are expected to experience a decline in blood cell counts during treatment. Several weeks after successful treatment, cell counts will begin to rebound, with platelet
and neutrophil counts recovering before red blood cells and T cells. T4 cell counts may never reach pre-disease levels. Patients are usually advised to avoid sick people and large crowds of people as well as to wash their hands and keep their hands away from their eyes, nose, and mouth until their neutrophil counts have recovered.
Many patients experience fatigue, even in the absence of anemia
, but since fatigue is a common feature of the disease, this may be caused by the disease instead of by the drug.
This drug does not cause hair loss, vomiting, or other side effects that are commonly associated with "old style" alkylating chemotherapy
drugs. However, peripheral neuropathy has been reported occasionally after repeated doses of cladribine in the treatment of hairy cell leukemia
. Overdose may cause kidney damage.
s, eight weeks for hemoglobin
, and nine weeks for a patient to have all three parameters normalized. Weeks are counted from the first day of treatment, and all patients were on a seven-day daily treatment schedule for these studies.
.
In 2008, Ernest Beutler
won the Wallace H. Coulter Award for Lifetime Achievement in Hematology from the Coulter Foundation and the American Society of Hematology
in part because of the clinical trial
s he ran, which established cladribine as the most effective treatment for hairy cell leukemia (HCL).
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
used to treat hairy cell leukemia
Hairy cell leukemia
Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a sub-type of chronic lymphoid leukemia...
(HCL, leukemic reticuloendotheliosis) and multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
. Its chemical name is 2-chlorodeoxyadenosine (2CDA).
As a purine analog, it is a synthetic anti-cancer agent that also suppresses the immune system. Chemically, it mimics the nucleoside
Nucleoside
Nucleosides are glycosylamines consisting of a nucleobase bound to a ribose or deoxyribose sugar via a beta-glycosidic linkage...
adenosine and thus inhibits the enzyme adenosine deaminase
Adenosine deaminase
Adenosine deaminase is an enzyme involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues.-Reactions:...
, which interferes with the cell's ability to process DNA. It is easily destroyed by normal cells except for blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
cells, with the result that it produces relatively few side effects and results in very little non-target cell loss.
Indications
Cladribine (as injections) is indicated [approved] for the treatment of symptomatic hairy cell leukemia.It is under investigation for other B cell leukemias and lymphomas, such as mantle cell lymphoma
Mantle cell lymphoma
Mantle cell lymphoma is one of the rarest of the non-Hodgkin's lymphomas , comprising about 6% of NHL cases. There are only about 15,000 patients presently in the U.S. While it is difficult to treat and seldom considered cured, investigations into better treatments are actively pursued worldwide...
, and for use in the treatment of multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
.
According to the Histiocytosis Association of America, cladribine is used to treat histiocytosis
Histiocytosis
In medicine, histiocytosis refers to an excessive number of histiocytes, , and is typically used to refer to a group of rare diseases which share this as a characteristic...
.
Multiple sclerosis
In January 2010, a large clinical trial involving more than 1000 patients documented significant reduction in relapse rates in multiple sclerosis patients with use of oral cladribine and thus making its use as the first oral medication in multiple sclerosis patients, most likely in year [2011].Russia
Russia
Russia or , officially known as both Russia and the Russian Federation , is a country in northern Eurasia. It is a federal semi-presidential republic, comprising 83 federal subjects...
was the first country to approve it for use treating multiple sclerosis on July 12, 2010. In the European Union
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
, the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
's CHMP did not approve cladribine in the first application, as did the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA). As of March 2, 2011, the FDA has rejected oral cladribine for multiple sclerosis, "acknowledging sufficient data on the drug’s efficacy in multiple sclerosis but requiring more data on safety and risk-benefit "
June 2011 : Merck has decided to withdraw all marketing applications for cladribine tablets, and to stop selling it in Russia and Australia which had approved it.
Routes of administration
For hairy cell leukemiaHairy cell leukemia
Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a sub-type of chronic lymphoid leukemia...
, cladribine can be given by i.v. infusion or subcutaneous (s.c.) injection.
For outpatient i.v. infusions, the delivery time (not including time to place the i.v. line) may range from one to four hours; two hours is most common. Continuous i.v. infusion may be chosen; this approach drips in the cladribine slowly, 24 hours a day using a portable pump and a central venous catheter
Central venous catheter
In medicine, a central venous catheter is a catheter placed into a large vein in the neck , chest or groin...
or a PICC line. By contrast, s.c. injections take less than ten seconds per day.
The same total doses are given by both routes. Intravenous and s.c. routes have the same overall outcomes, and the s.c. route may be reduce the infections and other risks associated with venipuncture.
An oral tablet form of cladribine has been successfully tested in patients with relapsing multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
.
Treatment schedule
Using either i.v. or s.c. routes of administration, cladribine can be administered on a daily or a weekly schedule. Daily schedules involve one s.c. injection or one i.v. infusion per day for five to seven consecutive days. Weekly schedules involve one injection or infusion each week, for five or six weeks. One cycle is normally sufficient to produce a complete response, but in the event of a partial response, cycles may safely be repeated one to three months after the end of the first cycle.Actual doses are calculated according to the surface area of the patient's skin instead of by weight, and divided by the number of planned treatments.
All schedules produce the same benefits and disadvantages. Five-day and seven-day daily schedules give the same total amount of drug and have the same outcomes, including remissions and adverse effects. Daily and weekly schedules give the same total amount of drug and have the same outcomes, including similar proportions of complete responses and similar proportions of patients hospitalized for fevers
Febrile neutropenia
Febrile neutropenia is the development of fever, often with other signs of infection, in a patient with neutropenia, an abnormally low number of neutrophil granulocytes in the blood. The term neutropenic sepsis is also applied, although it tends to be reserved for patients who are less well...
and opportunistic infection
Opportunistic 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.
Adverse effects
Existing studies estimate that from 18% to 42% of patients will experience a fever after cladribine infusion. This is usually a transient fever which can be treated with acetaminophen (paracetamol). These fevers, which resolve in less than 48 hours, have no evidence of being related to infection.However, some patients have fevers that last longer and may be caused by an infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
. Very few infections have actually been documented, but they do happen, and these infections are largely responsible for the 3% mortality rate associated with cladribine therapy in HCL. Factors that increased the likelihood of a neutropenic fever (with or without concomitant infection) include: anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, hypocholesterolemia
Hypocholesterolemia
Hypocholesterolemia is the presence of abnormally low levels of cholesterol in the blood . Although the presence of high cholesterol has been linked strongly with cardiovascular disease, a defect in the body's production of cholesterol can lead to adverse consequences as well...
, a high proportion of hairy cells in the bone marrow with a low proportion of myelopoietic cells, low albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
, and high C-reactive protein
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...
. These are all signs of an advanced case of HCL.
In patients with hairy cell leukemia, there is no benefit to using hormones
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
such as filgrastim
Filgrastim
Filgrastim is a granulocyte colony-stimulating factor analog used to stimulate the proliferation and differentiation of granulocytes. It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli. ...
or Granulocyte macrophage colony-stimulating factor to raise white blood cell counts prophylactically. The use of these expensive drugs does not reduce the number of patients who experience fevers, the number of days that the fevers last, or the number of patients admitted to the hospital for antibiotic treatments. Therefore routine adjunctive use (that is, use when there are no signs of infection) is not recommended.
In addition to fevers, cladribine increases the risk of herpes virus infections, particularly shingles.
Some patients develop a rash
Rash
A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
after treatment. Nearly all patients who develop a rash are taking other drugs, notably allopurinol
Allopurinol
Allopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :...
or a sulfa drug, which are known to cause rashes, and the rash is likely due to these drugs rather than to cladribine itself.
Some HCL patients will require 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...
s of platelets or packed red blood cells.
Patients are expected to experience a decline in blood cell counts during treatment. Several weeks after successful treatment, cell counts will begin to rebound, with 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...
and neutrophil counts recovering before red blood cells and T cells. T4 cell counts may never reach pre-disease levels. Patients are usually advised to avoid sick people and large crowds of people as well as to wash their hands and keep their hands away from their eyes, nose, and mouth until their neutrophil counts have recovered.
Many patients experience fatigue, even in the absence of anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, but since fatigue is a common feature of the disease, this may be caused by the disease instead of by the drug.
This drug does not cause hair loss, vomiting, or other side effects that are commonly associated with "old style" alkylating chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
drugs. However, peripheral neuropathy has been reported occasionally after repeated doses of cladribine in the treatment of hairy cell leukemia
Hairy cell leukemia
Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a sub-type of chronic lymphoid leukemia...
. Overdose may cause kidney damage.
Response
According to the drug's FDA-approved prescribing information, the median time to normalization of blood counts in patients with hairy cell leukemia is: two weeks for platelets, five weeks for absolute neutrophil countAbsolute neutrophil count
Absolute neutrophil count is a measure of the number of neutrophil granulocytes present in the blood...
s, eight weeks for hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
, and nine weeks for a patient to have all three parameters normalized. Weeks are counted from the first day of treatment, and all patients were on a seven-day daily treatment schedule for these studies.
History
Cladribine was designed by Dennis A. Carson as an anti-lymphocyte compound. It was first synthesized at Brigham Young UniversityBrigham Young University
Brigham Young University is a private university located in Provo, Utah. It is owned and operated by The Church of Jesus Christ of Latter-day Saints , and is the United States' largest religious university and third-largest private university.Approximately 98% of the university's 34,000 students...
.
In 2008, Ernest Beutler
Ernest Beutler
Ernest Beutler was a German-born American hematologist and biomedical scientist. He made important discoveries about the causes of a number of diseases, including anemias, Gaucher disease, disorders of iron metabolism and Tay-Sachs disease...
won the Wallace H. Coulter Award for Lifetime Achievement in Hematology from the Coulter Foundation and the American Society of Hematology
American Society of Hematology
The American Society of Hematology is a professional organization representing hematologists. It was founded in 1958. Its annual meeting is held in December of every year and has attracted nearly 20,000 attendees. The society publishes the medical journal Blood, one of the most cited peer-review...
in part because of the clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s he ran, which established cladribine as the most effective treatment for hairy cell leukemia (HCL).