На главную

Cladribine, экспериментальный пероральный (принимаемый через рот) лекарственный препарат для противорецидивного лечения рассеянного склероза, показал свою эффективность в уменьшении числа рецидивов согласно новому исследованию, сообщенному сегодня.

Испытание под названием CLARITY, проводилось в течение двух лет, включило 1.326 людей с прогридиентным/ремиттрирующим течением рассеянного склероза, получавших одну из 2 доз cladribine или плацебо.

Во время исследования, люди, получающие низкую дозу cladribine показали уменьшение на 58% рецидивов по сравнению с группой, получавшей плацебо (средняя величина 0.14 рецидивов по сравнению с 0.33). Побочные эффекты включили лимфопению, уменьшение количества лейкоцитов, головные боли и назофарингиты (простуду).

Детальные результаты исследования будут представлены на конференции в 2009 и изготовители, Merck Serono, надеются представить препарат для лицензирования в течение года. Национальный институт здоровья и Clinical Excellence (NICE) уже предполагают, что они смогут включить cladribine в их следующий круг исследования.

Pam Macfarlane, глава общества по рассеянному склерозу сказал: ŤМы приветствуем позитивные результаты изучения. Мы ожидаем более полных результатов, которые мы надеемся, дадут более ясное представление об эффективности этого препарата для людей с рассеянным склерозомť.

29 января 2009

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.

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, [ [http://www.mantlecelllymphoma.org/default.asp?pgid=121 Mantle Cell Lymphoma initiative] ] and for multiple sclerosis.

According to the Histiocytosis Association of America, cladribine is used to treat histiocytosis. [ [http://www.histio.org Histiocytosis Association of America] ]

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.cite journal |author=von Rohr A, Schmitz SF, Tichelli A, "et al" |title=Treatment of hairy cell leukemia with cladribine (2-chlorodeoxyadenosine) by subcutaneous bolus injection: a phase II study |journal=Ann. Oncol. |volume=13 |issue=10 |pages=16419 |year=2002 |pmid=12377655 |doi= |url=http://annonc.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=12377655]

An oral pill form is being tested for multiple sclerosis.

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.cite journal |author=Aurer I, Mitrović Z, Kovacević-Metelko J, "et al" |title= [Treatment of hairy cell leukemia with cladribine] |language=Croatian |journal=Lijec Vjesn |volume=129 |issue=3-4 |pages=803 |year=2007 |pmid=17557550 |doi=] 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.cite journal |author=Robak T, Jamroziak K, Gora-Tybor J, "et al" |title=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 |journal=Blood |volume=109 |issue=9 |pages=36725 |year=2007 |pmid=17209059 |doi=10.1182/blood-2006-08-042929 |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=17209059]

Adverse effects

Among hairy cell leukemia (HCL) 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 in case the fever is caused by a sudden infection instead of by the dying blood cells. Persistent fevers late in treatment are much more likely to be caused by infection.

Existing studies estimate that from 18% to 42% of patients will experience a fever. This is usually a transient fever easily treated with acetaminophen (paracetamol).cite journal |author=Nelson MC, Hogan DK |title=The role of cladribine in the treatment of lymphoid malignancies |journal=Oncol Nurs Forum |volume=22 |issue=9 |pages=1395400 |year=1995 |pmid=8539180 |doi=] These fevers resolve in less than 48 hours,cite journal |author=Lauria F, Benfenati D, Raspadori D, "et al" |title=Retreatment with 2-CdA of progressed HCL patients |journal=Leuk. Lymphoma |volume=14 Suppl 1 |issue= |pages=1435 |year=1994 |pmid=7820047 |doi=] have no evidence of being related to infection.

However, some patients have fevers that last longer and may be caused by an infection.cite journal |author=Lauria F, Benfenati D, Raspadori D, Rondelli D, Zinzani PL, Tura S |title=High complete remission rate in hairy cell leukemia treated with 2-chlorodeoxyadenosine |journal=Leuk. Lymphoma |volume=11 |issue=5-6 |pages=399404 |year=1993 |pmid=7907247 |doi=] 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.cite journal
author=Juliusson G, Lenkei R, Tjřnnfjord G, Heldal D, Liliemark J
title=Neutropenic fever following cladribine therapy for symptomatic hairy-cell leukemia: predictive factors and effects of granulocyte-macrophage colony-stimulating factor
journal=Ann. Oncol.
volume=6
issue=4
pages=3715
year=1995
month=April
pmid=7619752
doi=
url=http://annonc.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7619752] 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.cite journal |author=Saven A, Burian C, Adusumalli J, Koziol JA |title=Filgrastim for cladribine-induced neutropenic fever in patients with hairy cell leukemia |journal=Blood |volume=93 |issue=8 |pages=24717 |year=1999 |pmid=10194424 |doi= |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=10194424] 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.cite journal |author=Van Den Neste E, Delannoy A, Vandercam B, "et al" |title=Infectious complications after 2-chlorodeoxyadenosine therapy |journal=Eur. J. Haematol. |volume=56 |issue=4 |pages=23540 |year=1996 |pmid=8641392 |doi=]

Some HCL patients will require blood transfusions 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.

Response

According to the drug's FDA-approved prescribing information,cite web |url=http://www.orthobiotech.com/common/prescribing_information/LEUSTATIN/PDF/Leustatin_PI.pdf |title=Leustatin prescribing information |date=August 2007 revision |format=PDF |publisher=Ortho Biotech Products, L.P. (a subsidiary of Johnson & Johnson |pages= ] 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.