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.
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.
- 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
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
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
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.