Clinical Trial: Pyrimethamine to Treat Autoimmune Lymphoproliferative Syndrome

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Pilot (Phase I-II) Study of Pyrimethamine (Daraprim) for the Treatment of the Autoimmune Lymphoproliferative Syndrome (ALPS)

Brief Summary:

This study will examine whether the drug pyrimethamine can shrink lymph nodes and spleen in patients with autoimmune lymphoproliferative syndrome (ALPS). In this disease, lymphocytes (white blood cells) do not die as they normally would. As a result, patients have enlarged lymph glands, spleen, or liver, and other problems that may involve blood cell counts and autoimmune disease (overactivity of the immune system). Pyrimethamine is an orally administered antibiotic that has been used to treat or prevent malaria and toxoplasma, and may be effective in shrinking lymph nodes and spleen.

Patients with ALPS who are between 2 and 70 years of age and have had lymph gland enlargement for at least 1 year may be eligible for this study. Candidates will be screened with a medical history and physical examination, blood tests, and possibly a bone marrow test. Females of reproductive age will be screened with a urine pregnancy test. Women who are capable of becoming pregnant must use an effective method of birth control during the entire study period, because, taken during early months of pregnancy, pyrimethamine can cause birth defects in the fetus. Women who are pregnant or nursing are excluded from the study.

Participants will undergo the following tests and procedures:

• CT scan: For this test, the patient lies still in the CT scanner while images are taken of the neck, chest, and stomach area. A contrast dye is injected into a vein to brighten the CT images. Very young children will be evaluated on a case by case basis to determine whether a CT scan will be performed.
• Bone marrow biopsy: Participants undergo this test to rule out underlying bone marrow disease if they have not had a bone marrow test done in the last
  

  Detailed Summary:

  The Autoimmune Lymphoproliferative Syndrome (ALPS) is an inherited disease associated with a defect of lymphocyte apoptosis that leads to lymphoproliferation and autoimmunity. Although, there are treatments for many of its complications, there currently is no safe and effective therapy for this syndrome itself. Recently investigators in Europe serendipitously observed that some children with ALPS showed reductions in spleen and lymph node size while in pyrimethamine/sulfadoxine (Fansidar) for Pneumocystis carinii prophylaxis. Our own subsequent pilot clinical trial of Fansidar (Protocol #01-I-0132) was terminated after failure to recruit well-defined ALPS patients who lacked histories suspicious for allergies to sulfa drugs. Our own in vitro studies, however revealed that pyrimethamine and not sulfadoxine induces lymphocyte apoptosis and this observation has suggested to us that pyrimethamine may be beneficial alone, thus avoiding the added risks of allergy and hypersensitivity associated with the sulfa drugs. However, potential bone marrow toxicity that may result from an escalating dose schedule of pyrimethamine should respond to the addition of folinic acid (Leucovorin) to the regimen.

  We propose to conduct a pilot study on the safety and efficacy of the drug, pyrimethamine for the treatment of ALPS. Six to 8 individuals, with ALPS will be treated for up to 3 months, initially, with twice-weekly pyrimethamine (Daraprim) at escalating doses adjusted by weight, with the addition of folinic acid when needed to aid management of marrow toxicity. The effects of pyrimethamine treatment on lymph node and/or spleen size will be assessed by CT scan. The effect of treatment on other laboratory features of ALPS will also be assessed. Evaluating the effects of pyrimethamine on these clinical and laboratory parameters will allow us to determine if this drug demonstrates sufficient
  Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
  

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  Original Primary Outcome:
  
  

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  Original Secondary Outcome:
  
  Information By: National Institutes of Health Clinical Center (CC)
  

  Dates:
  Date Received: July 21, 2003
  Date Started: July 2003
  Date Completion: June 2005
  Last Updated: March 3, 2008
  Last Verified: June 2005