Safety and Efficacy of Abatacept for Treating Chronic Cytopenia in Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) Haploinsufficiency

Rare heterozygous mutations in cytotoxic T-lymphocyte antigen-4 (CTLA4) lead to a monogenetic
defect that presents with a heterogeneous clinical phenotype of recurrent infections,
lymphoproliferation, autoimmunity, and lymphocytic infiltration of target organs. Management
is challenging and focuses on treating infections, autoimmune complications, and end organ
damage due to lymphocytic infiltrates. Experience with the natural history of the disease and
therapies for underlying complications are limited. There is no established standard of care
for these patients.

Abatacept is a biologically engineered CTLA4-mimetic that is approved as an intravenous (IV)
infusion to treat adult rheumatoid arthritis, adult psoriatic arthritis, and juvenile
idiopathic arthritis. Given that abatacept mimics CTLA4 function, we hypothesize that the
drug will prevent T-cell hyper-activation, restore regulatory T-cell function, and thereby
treat the autoimmune and immune dysregulatory manifestations of CTLA4 deficiency.

This study is a phase 1/2, double-blind, randomized, intra-patient dose-escalation,
placebo-controlled trial designed to evaluate the safety and efficacy of abatacept in
participants with CTLA4 deficiency and cytopenia. Participants will come to the NIH Clinical
Center

monthly for 210 days to receive infusions of study agent or placebo and to undergo safety and
research evaluations, including blood draw for cytopenia evaluation and scoring of disease
severity. Before and after the treatment period, participants will also have imaging,
pulmonary function testing, bone marrow biopsy, and endoscopy (symptomatic participants
only). Primary endpoints will be evaluated at Day 210. After completing the blinded treatment
trial, participants will be offered the option to enroll in a 6-month open-label extension
study for long-term safety evaluation of abatacept.

- INCLUSION CRITIERIA:

Individuals must meet all of the following criteria to be eligible for study participation:

1. Age 8-65 years.

2. Documented CTLA4 mutation (requires documentation of confirmed mutation via Sanger
sequencing at a laboratory approved by the Clinical Laboratory Improvement Amendments
[CLIA]).

3. At least one of the following established hematologic abnormalities during the past 6
months (including results from outside CLIA-certified laboratories) prior to
screening:

- ANC < 750 cells/microL.

- Platelet count < 75,000 cells/microL.

- Hemoglobin < 7.5 g/dL.

4. The above mentioned hematologic abnormalities should require active treatment with
steroids, immunomodulatory agents (e.g., mycophenolate mofetil, cyclosporine,
tacrolimus, mercaptopurine, methotrexate, sirolimus, high dose intravenous
immunoglobulin [IVIG]), and/or other agents (e.g., TPO agonists) for at least 60 days
prior to screening.

5. The dose of any concomitant medication(s) aimed at treating cytopenia should be stable
in the 60 days prior to screening. Stable is defined as:

- No new concomitant medications for cytopenia were initiated.

- No dose increase of the medication was required.

6. Did not receive blood product transfusions within 30 days prior to screening.

7. Did not receive abatacept within 60 days prior to screening.

8. Did not receive rituximab within 3060 days of screening.

9. Did not receive alemtuzumab at any time.

10. Has access to healthcare provider at home.

11. Able to provide informed consent.

12. Willing to allow storage of biological specimens for future use in medical research.

13. Females of childbearing potential must agree to use appropriate birth control methods
when engaging in sexual activities that can result in pregnancy, beginning Day -30
through 30 days after the last dose of study agent. Appropriate methods should include
2 forms of contraception, one from each of the following categories:

- Hormonal contraception or placement of an intrauterine device or intrauterine
system.

- Barrier method: Condom or occlusive cap (diaphragm or cervical/vault cap) with a
spermicide.

EXCLUSION CRITERIA:

Patients meeting any of the following criteria are not eligible for this study:

1. History of hypersensitivity to abatacept.

2. Any live vaccines (including attenuated live vaccines) within 6 weeks of screening.

3. History of acquired immunodeficiency diseases, including a positive HIV polymerase
chain reaction (PCR) test result.

4. Untreated chronic hepatitis B (positive PCR) or hepatitis C (positive PCR) infection.
Patients with chronic hepatitis must be on medical treatment for at least 3 months
before screening and have evidence of decreased viral loads after starting treatment.

5. EBV viral load > 4log on 2 or more laboratory checks greater than 1 month apart and
within 6 months of screening.

6. History of malignancy of any organ system (other than localized basal cell carcinoma
of the skin), treated or untreated, within the past 5 years, regardless of evidence of
local recurrence or metastases.

7. Current active infectious disease (bacterial or fungal) including evidence of
tuberculosis (TB) infection as defined by a positive QuantiFERON TB-Gold test. Test
results within the past 6 months will be accepted. If presence of latent TB is
established, then treatment must be completed before the patient can be considered for
enrollment. The patient may also be considered for enrollment after completing
treatment of any other active bacterial or fungal infection.

8. Contraindication to PFT or CT scan.

9. Pregnancy or breastfeeding.

10. Any condition that, in the opinion of the investigator, contraindicates participation
in this study.