ALPS, Hypersplenism, Lymphadenopathy
Conditions
Keywords
ALPS, Valproic Acid, Lymphadenopathy, Splenomegaly, Histone Deacytelase (HDAC) Inhibitor, Autoimmune Lymphoproliferative Syndrome
Brief 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.
Interventions
DRUGValproic Acid
Oral administration of valproic acid
PROCEDURECT Scan
CT scans were done before and after treating the patient with valproic acid
PROCEDUREBlood Sample
Blood samples were collected before and after the intervention to monitor blood counts and biomarkers of ALPS
Sponsors
Koneti Rao
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 70 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Response | 3 monthly (12 week) intervals | Reduction of lymph node and/or spleen size measured by CT imaging, or physical exam and abdominal ultrasound. A clinical response is defined as a greater than 40% reduction in lymph node size and/or greater than 40% reduction in spleen size. A CT scan with contrast measured lymph node size as well as spleen size. |
Secondary
| Measure | Time frame |
|---|---|
| To Determine Whether the Treatment Alters, in Favorable Directions, Laboratory Markers of ALPS (e.g., Number of DNT Cells, Immunoglobin Levels, Vitamin B12 Levels, IL-10 Levels, Autoantibody Titers, Fas Mediated Apoptosis) | 3 monthly (12 week) intervals |
Countries
United States
Participant flow
Recruitment details
All patients were started on valproic acid at the NIH Clinical Center then followed locally
Participants by arm
| Arm | Count |
|---|---|
| Valproic Acid valproic acid administered starting at 10 mg/kg/day in divided doses twice daily x 3 days, increase to 15mg/kg/day x 3 days, increase to 20 mg/kg/day on day 7, increase to 30 mg/kg/day on day 14, maximum dose of 40mg/kg/day on day 21, if tolerated, to achieve plasma level 50-100 mcg/mL. | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Valproic Acid |
|---|---|
| Age, Categorical <=18 years | 4 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 1 / 5 |
Outcome results
Primary
Number of Participants With Response
Reduction of lymph node and/or spleen size measured by CT imaging, or physical exam and abdominal ultrasound. A clinical response is defined as a greater than 40% reduction in lymph node size and/or greater than 40% reduction in spleen size. A CT scan with contrast measured lymph node size as well as spleen size.
Time frame: 3 monthly (12 week) intervals
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Valproic Acid | Number of Participants With Response | 0 participants |
Secondary
To Determine Whether the Treatment Alters, in Favorable Directions, Laboratory Markers of ALPS (e.g., Number of DNT Cells, Immunoglobin Levels, Vitamin B12 Levels, IL-10 Levels, Autoantibody Titers, Fas Mediated Apoptosis)
Time frame: 3 monthly (12 week) intervals
Population: outcome measure not assessed because 0 participants had a response