Protocol Number: 08-I-0053

Title:

Pilot (Phase I-II) Study of Valproic Acid (Depakote) for the Treatment of the Autoimmune Lymphoproliferative Syndrome (ALPS)

Number:

08-I-0053

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.

Sponsoring Institute:

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: Yes

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

1. All subjects must fulfill the published criteria for the diagnosis of ALPS (documented nonmalignant lymphadenopathy and/or splenomegaly of at least 1-year duration; greater than1% TCR alpha/beta+ CD4-CD8- T cells in the peripheral blood). This must include clinically documented lymphadenopathy involving more than 2 nodes in more than 1 regional group of nodes measuring greater than 2cm in size and/or a palpable spleen.

2. Age greater than or equal to 2 years through less than or equal to 70 years.

3. Must have a personal primary care physician who is willing to follow the protocol required evaluations during the study period.

4. Must be willing to sign a consent form.

5. Patients on immunosuppression (e.g., corticosteroid, mycophenolate mofetil, azathioprine, cyclophosphamide) are eligible if the dose of the immunosuppressive drug has been stable for at least 3 months prior to enrollment and their hematologic parameters do not meet the exclusion criteria (1) as outlined below.

EXCLUSION CRITERIA:

1. A hemoglobin concentration of less than 8 gm/dL, a platelet count of less than 75 K/mm(3), or an absolute neutrophil count of less than 500/mm(3), at study entry.

2. Liver disease determined by an alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin 2.5 times greater than the upper limit of normal.

3. History of pancreatitis by clinical features and/or laboratory abnormalities in the last 12 months.

4. Renal dysfunction determined by a calculated urine creatinine clearance of less than 70 mL/min/1.73 m(2) in children and less than 60 mL/min in adults, or using the Schwartz formula or Levy formula based on serum creatinine.

5. Patients clinically suspected of suffering from urea cycle disorders will be excluded.

6. Patients with history of seizure disorders and/or those already receiving valproic acid will be excluded.

7. Sensitive to or have ever had an allergic reaction to Depakote.

8. Not able to abstain from alcohol during the length of the study.

9. Pregnancy. Female adults and adolescents who have attained menarche must have a negative pregnancy test at study entry and commit to using an acceptable method of barrier or hormonal contraception (e.g., condoms, diaphragms, oral contraceptives, or long acting progestin agents) if sexually active during the study and for 3 months after the last dose of valproic acid.

10. Lactating mothers who are breast feeding their babies will not be eligible.

11. ALPS patients who have been treated with bone marrow toxic chemotherapy regimens for Non-Hodgkin's lymphoma or other malignancies are not eligible for this pilot study.

12. Unwilling or unable to comply with the need to have periodic blood tests to monitor possible side effects of treatment, or other major requirements of this study will be an exclusion criteria.

Special Instructions:

Currently Not Provided

Keywords:

ALPS

Valproic Acid

Lymphadenopathy

Splenomegaly

Histone Deacytelase (HDAC) Inhibitor

Recruitment Keyword(s):

Autoimmune Lymphoproliferative Syndrome

ALPS

Condition(s):

ALPS

Hypersplenism

Lymphadenopathy

Investigational Drug(s):

None

Investigational Device(s):

None

Intervention(s):

Drug: Valproic Acid

Procedure/Surgery: CT Scan

Procedure/Surgery: Blood Sample

Supporting Site:

National Institute of Allergy and Infectious Diseases

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Sneller MC, Straus SE, Jaffe ES, Jaffe JS, Fleisher TA, Stetler-Stevenson M, Strober W. A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J Clin Invest. 1992 Aug;90(2):334-41.

Rao VK, Straus SE. Causes and consequences of the autoimmune lymphoproliferative syndrome. Hematology. 2006 Feb;11(1):15-23.

Rao VK, Carrasquillo JA, Dale JK, Bacharach SL, Whatley M, Dugan F, Tretler J, Fleisher T, Puck JM, Wilson W, Jaffe ES, Avila N, Chen CC, Straus SE. Fluorodeoxyglucose positron emission tomography (FDG-PET) for monitoring lymphadenopathy in the autoimmune lymphoproliferative syndrome (ALPS) Am J Hematol. 2006 Feb;81(2):81-5.

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