Cladribine
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Cladribine
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| Systematic (IUPAC) name | |
| 5-(6-amino-2-chloro-purin-9-yl)-2-(hydroxymethyl)oxolan-3-ol | |
| Identifiers | |
| CAS number | |
| ATC code | L01 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C10H12ClN5O3 |
| Mol. mass | 285.687 g/mol |
| Pharmacokinetic data | |
| Bioavailability | 100% (IV) |
| Protein binding | 20% |
| Metabolism | ? |
| Half life | 5.4 hours |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
D(US) |
| Legal status | |
| Routes | IV, oral |
Cladribine is a drug commonly used to treat hairy cell leukemia (leukemic reticuloendotheliosis). Its brand name is Leustatin, and it is commonly referred to as 2CDA.
A purine analog, it is a synthetic antineoplastic agent with immunosuppressive effects. 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 in the body except for blood cells, with the result that it produces relatively few side effects and results in very little non-target cell loss.
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[edit] Indications
Cladribine is indicated for the treatment of symptomatic hairy cell leukemia (HCL).
It is under investigation for other B cell leukemias and lymphomas, such as mantle cell lymphoma,[1] and for multiple sclerosis.
According to the Histiocytosis Association of America, cladribine is used to treat histiocytosis.[2]
[edit] Routes of administration
For hairy cell leukemia, cladribine can be given by IV infusion or subcutaneous ("sub-q" or SQ) injection.
For outpatient IV infusions, the delivery time (not including time to place the IV line) may range from one to four hours; two hours is most common. Continuous IV 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, SQ injections take less than ten seconds per day.
The same total doses are given by both routes. IV and SQ routes have the same overall outcomes, and the SQ route may be reduce the infections and other risks associated with venipuncture.[3]
An oral pill form is being tested for multiple sclerosis.
[edit] Treatment schedule
Using either IV or SQ routes of administration, cladribine can be administered on a daily or a weekly schedule. Daily schedules involve one SQ injection or one IV 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.[4] 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 infections.[5]
[edit] Adverse effects
Among hairy cell leukemia patients, about half have no significant side effects from this treatment.
Most other patients have a high fever that is caused by cancerous and non-cancerous white blood cells dying from the drug. As patients are at risk, from the disease as well as from the drug, for infections, most physicians give antibiotics to all patients with this fever just in case the fever is caused by a sudden infection instead of from the drug. Persistent fevers late in treatment are much more likely to be caused by infection.
Existing studies estimate that from 18% [6] to 42%[7] of patients will experience a fever. This is usually a transient fever easily treated with acetaminophen (paracetamol).[8] These fevers resolve in less than 48 hours,[9] have no evidence of being related to infection. However, some patients have fevers that last longer and may be caused by an infection.[10][9] Very few infections have actually been documented.[7]
In patients with hairy cell leukemia, there is no benefit to using hormones such as filgrastim to raise white blood cell counts prophylactically.[7] 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.[7] Therefore routine adjunctive use (that is, use when there are no signs of infection) is not recommended. [7]
In addition to fevers, cladribine increases the risk of herpes virus infections, particularly shingles.[6]
Some HCL patients will require blood transfusions of platelets or packed red blood cells.[4]
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.
[edit] Response
According to the drug's FDA-approved prescribing information,[11] the median time to normalization of blood counts in patients with hairy cell leukemia is: two weeks for platelets, five weeks for absolute neutrophil counts, 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.
[edit] References
- ^ Mantle Cell Lymphoma initiative
- ^ Histiocytosis Association of America
- ^ von Rohr A, Schmitz SF, Tichelli A, et al (2002). "Treatment of hairy cell leukemia with cladribine (2-chlorodeoxyadenosine) by subcutaneous bolus injection: a phase II study". Ann. Oncol. 13 (10): 1641-9. PMID 12377655.
- ^ a b Aurer I, Mitrović Z, Kovacević-Metelko J, et al (2007). "[Treatment of hairy cell leukemia with cladribine]" (in Croatian). Lijec Vjesn 129 (3-4): 80-3. PMID 17557550.
- ^ Robak T, Jamroziak K, Gora-Tybor J, et al (2007). "Cladribine in a weekly versus daily schedule for untreated active hairy cell leukemia: final report from the Polish Adult Leukemia Group (PALG) of a prospective, randomized, multicenter trial". Blood 109 (9): 3672-5. doi:. PMID 17209059.
- ^ a b Van Den Neste E, Delannoy A, Vandercam B, et al (1996). "Infectious complications after 2-chlorodeoxyadenosine therapy". Eur. J. Haematol. 56 (4): 235-40. PMID 8641392.
- ^ a b c d e Saven A, Burian C, Adusumalli J, Koziol JA (1999). "Filgrastim for cladribine-induced neutropenic fever in patients with hairy cell leukemia". Blood 93 (8): 2471-7. PMID 10194424.
- ^ Nelson MC, Hogan DK (1995). "The role of cladribine in the treatment of lymphoid malignancies". Oncol Nurs Forum 22 (9): 1395-400. PMID 8539180.
- ^ a b Lauria F, Benfenati D, Raspadori D, et al (1994). "Retreatment with 2-CdA of progressed HCL patients". Leuk. Lymphoma 14 Suppl 1: 143-5. PMID 7820047.
- ^ Lauria F, Benfenati D, Raspadori D, Rondelli D, Zinzani PL, Tura S (1993). "High complete remission rate in hairy cell leukemia treated with 2-chlorodeoxyadenosine". Leuk. Lymphoma 11 (5-6): 399-404. PMID 7907247.
- ^ Leustatin prescribing information (PDF). Ortho Biotech Products, L.P. (a subsidiary of Johnson & Johnson (August 2007 revision).
