Valproic Acid (Depakote[Registered Trademark]) to Treat Autoimmune Lymphoproliferative Syndrome (ALPS)
Condition: ALPS; Hypersplenism; Lymphadenopathy
MeSH terms: Lymphadenopathy; Hypersplenism; Autoimmune Lymphoproliferative Syndrome
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This study will test whether valproic acid (Depakote[Registered Trademark]) can shrink
      enlarged lymph glands and spleen in patients with autoimmune lymphoproliferative syndrome
      (ALPS). Depakote has been used for more than 30 years for treating various medical disorders
      in adults and children, including migraine headaches, seizures and psychiatric disorders. In
      animal studies, it was effective in shrinking both lymph nodes and spleen in animals with
      conditions similar to ALPS.

      People with ALPS who are between 2 and 70 years of age and who have had an enlarged spleen or
      lymph glands for at least 1 year may be eligible for this study.

      Participants take Depakote as a tablet or liquid or sprinkled on food twice a day for 16
      weeks. The drug dose is increased slowly over the first 3 to 4 weeks until the maximum
      tolerated dose is reached. Blood tests are done at 2, 4, 6, 8 and 10 weeks after starting the
      drug and 1 week after the drug is stopped to check for treatment side effects. Valproic acid
      blood levels will be checked during drug escalation, half way through therapy, and just
      before the end of treatment. A physical examination and CT scan (or ultrasound of the abdomen
      for patients who cannot undergo CT) are done before starting treatment and at the end of the
      16-week treatment period to evaluate the response to treatment.

      Patients who tolerate the treatment well and show shrinkage of the lymph glands or spleen may
      be offered extended treatment for up to 1 year in consultation with their primary physician.
      During the extended treatment period, blood tests are done at home every 6 to 8 weeks to
      monitor for drug side effects. Follow up evaluation visits are scheduled at the NIH Clinical
      Center every 3 months during the extended treatment period and 3, 6, and 12 months after
      treatment has ended.
    

Detailed description: 
      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 immunosuppressive treatments for many of its complications, there currently is no
      safe and effective therapy for this syndrome itself.

      Valproic acid has been recently used as a histone deacetylase (HDAC) inhibitor for inducing
      apoptosis in malignancies and is being incorporated as part of hematology/oncology clinical
      trials. A pilot study will be conducted on the safety and efficacy of the drug valproic acid
      (Depakote [R]) for the treatment of ALPS. Twelve subjects with ALPS, will be treated
      initially for 4 months with twice-daily administration of valproic acid at escalating doses
      adjusted by weight, with close monitoring of toxicity and side effects including laboratory
      parameters related to the drug. The effects of valproic acid treatment on lymph node and/or
      spleen size will be assessed by computerized tomography scan, ultrasound and physical
      examination. If valproic acid is effective in reducing the size of lymph nodes and/or spleen
      size as defined in the study design, subjects may be offered the option to continue further
      therapy with valproic acid for up to 1 year. The effect of treatment on other laboratory
      features specific to ALPS will also be assessed. Evaluating the effects of valproic acid on
      these clinical and laboratory parameters will help to determine if this drug demonstrates
      sufficient activity to warrant study in a larger randomized controlled trial.
    

Intervention name(s): Valproic Acid; CT Scan; Blood Sample
Intervention type(s): Drug; Procedure; Procedure
Intervention description(s): Oral administration of valproic acid; CT scans were done before and after treating the patient with valproic acid; Blood samples were collected before and after the intervention to monitor blood counts and biomarkers of ALPS
Other intervention name(s): Depakote; Computerized Tomography
Intervention MeSH terms: Valproic Acid
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: ALPS; Valproic Acid; Lymphadenopathy; Splenomegaly; Histone Deacytelase (HDAC) Inhibitor; Autoimmune Lymphoproliferative Syndrome