Study of Autoimmune Lymphoproliferative Syndrome (ALPS)

• ClinicalTrials.gov Identifier: NCT00001350
• Recruitment Status: Recruiting
• First Posted: November 4, 1999
• Last Update Posted: April 19, 2021
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Study Description

Brief Summary:

The purpose of the protocol is to allow for patients, and relatives of patients, who may have the newly described autoimmune lymphoproliferative syndrome, to be evaluated at the NIH Clinical Center. This evaluation will include blood and relevant tissue studies along with long-term clinical evaluations to define the biology, inheritance,clinical spectrum, and natural history of this syndrome. The aim of the research is to understand mechanisms involved in the development of expanded numbers of what is typically a rare population of immune cells (CD4-8-/TCRalpha/beta+ T cells, otherwise referred to as double negative T cells), and how these relate to the development of expanded numbers of immune cells and autoimmune (self against self) responses in patients with ALPS.

In some cases, we may proivide treatment related to ALPS. These treatments are consistent with standard medical practice.

Participants with ALPS will be invited to visit the NIH once a year or more frequently when clinically indicated for the next few years for clinicians and scientists to follow the course of their disease and to manage its complications. Knowledge gained from these studies provides important insights into the mechanisms of autoimmunity, the thymus gland, and the role that the immune system and genetics plays in ALPS.

Autoimmune lymphoproliferative syndrome is a rare disease that affects both children and adults. Each of these three words helps describe the main features of this condition. The word autoimmune (self-immune) identifies ALPS as a disease of the immune system. The tools used to fight germs turn against our own cells and cause problems. The word lymphoproliferative describes the unusually large numbers of white blood cells (called lymphocytes (stored in the lymph nodes and spleens of people with ALPS. The word syndrome refers to the many common symptoms shared by ALPS patients.

One of the causes of ALPS is defective apoptosis, or said another way, an individual has an abnormality in how well lymphocytes (immune cells) die when they are instructed to do so. It is normal for lymphocytes to disintegrate (e.g., die) when they have done their job. In people with ALPS and in some of their affected relatives, the genetic message for the cells to die is altered: the message is not received and the cells do not die when they should. As a result, people with ALPS develop an enlarged spleen, liver and lymph glands, along with a range of other problems involving white blood cell counts and overactive immune responses (autoimmune disease). Some patients have an increased risk of developing lymphatic cancers (lymphoma).

Provided is a description of eligible study candidates:

1. Any patient with ALPS, male or female and of any age. As a patient with ALPS, candidates must have:

   • a medical history of an enlarged spleen and/or enlarged lymph nodes over an extended period of time (past and/or current).
   • defective lymphocyte apoptosis, in vitro.
   • greater than or equal to 1 percent TCR alpha/beta+CD4-8- peripheral blood T cells.
2. Relatives (any age) of patients and normal controls (18-65).
3. Healthy normal volunteers will also be enrolled to provide data on normal cell behavior for comparison with patients.

Additional information regarding ALPS and the research being conducted at the National Institutes of Health is available at the following World Wide Web (e.g., Internet) locations:

http://www.niaid.nih.gov/publications/alps/

http://www.nhgri.nih.gov/DIR/GMBB/ALPS/.

Condition or disease
Benign Lymphoproliferative Disorder

Detailed Description:

The purpose of this family based natural history protocol is to allow for patients, and relatives of patients to be screened for Autoimmune Lymphoproliferative Syndrome (ALPS) and related disorders of apoptosis, RAS associated leukoproliferative disorder (RALD). Patients and relatives will be evaluated at the NIH Clinical Center if they meet the eligibility criteria. This evaluation will include blood and relevant tissue studies along with long-term clinical evaluation to define the biology, inheritance, clinical spectrum, and natural history of this syndrome. The aim of the research studies is to elucidate mechanisms underlying the immune dysregulation due to defective apoptosis in these patients. Knowledge gained from these studies provides important insights into the mechanisms of autoimmunity, normal thymic and extra thymic T cell differentiation, TCR repertoire selection, and lymphomagenesis. Medically indicated management of ALPS-related autoimmune disease and cytopenias will also be considered and provided, using standard of care treatments.

Study Design

• Study Type: Observational
• Estimated Enrollment: 1000 participants
• Observational Model: Case-Only
• Time Perspective: Prospective
• Official Title: Study of the Immunopathogenesis, Natural History, and Genetics of Autoimmune Lymphoproliferative Syndrome (ALPS) Associated With an Expansion of CD4-8-/TCR Alpha/Beta+ T Cells
• Actual Study Start Date: May 13, 1993

Groups and Cohorts

Group/Cohort
1; ALPS patients and relatives of all ages

Outcome Measures

Primary Outcome Measures :

1. Elucidate the mechanism of immune-dysregulation leading to ALPS and develop targeted treatments [ Time Frame: Median follow up of 25 years ]
   Improvement of underlying immune-dysregulation

Eligibility Criteria

• Ages Eligible for Study: up to 99 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

ALPS patients and relatives to include males and females of all ages

Criteria

• INCLUSION CRITERIA:

A. ALPS Natural History sample size and demographics:

Study size: up to 1000 patients, patients, relatives and normal controls.

Sex Distribution: Male and female

Age range: All ages acceptable

B. Eligibility Criteria for Natural History Study:

1. To be considered as having ALPS, patients must elevated TCR alpha/beta+ CD4-8- peripheral blood DNT cells (equal to or greater than 1.5 percent of total lymphocytes or 2.5 percent of CD3+ lymphocytes) in the setting of normal or evalted lymphocyte counts.
2. A history of chronic (greater than 6 months) non-malignant, non-infectious lymphadenopathy and/or splenomegaly.
3. Willingness to allow blood, tissue and other samples to be stored.
4. Patients with RALD (RAS associated leukoproliferative disorders) who present with autoimmunity, lymphadenopathy and/or splenomegaly, with elevated or normal DNT s and somatic mutations in NRAS and KRAS

C. Eligibility Criteria for Screening potential patients:

1. A history of chronic (greater than 6 months) lymphadenopathy and/or splenomegaly.
2. Willingness to allow blood, tissue and other samples to be stored.

D. Screening criteria for ALPS Relatives:

1. Extended family members of an ALPS patient are eligible for genetic screening to determine if they carry the mutation found in their family.
2. Willingness to allow blood, tissue and other samples to be stored.

E. Eligibility of special populations:

1. Women who are pregnant or breast feeding are eligible to enroll as probands or relatives. However, certain obstetric issues may pose a safety risk for travel and evaluation here. Eligibility for this group will be determined on a case by case basis by the PI. This protocol is not actively seeking women who are pregnant

F. 1. Apheresis will be done only on healthy volunteers or patients with ALPS who have adequate peripheral venous access. Women of childbearing age must have a negative pregnancy test within 24 hours of the procedure and must not be breast-feeding.

EXCLUSION CRITERIA:

1. Any condition that the Principal Investigator deems to be non-conducive to the research goals of the study.

Contacts and Locations

Contacts

Contact: Sharon F Webster; (202) 450-0696; sharon.webster@nih.gov

Contact: V. Koneti Rao, M.D.; (301) 496-6502; kr191c@nih.gov

Locations

United States, Maryland

National Institutes of Health Clinical Center, 9000 Rockville Pike; Recruiting

Bethesda, Maryland, United States, 20892

Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 prpl@cc.nih.gov

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: V. Koneti Rao, M.D.; National Institute of Allergy and Infectious Diseases (NIAID)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

http://www.niaid.nih.gov/publications/alps 

Publications:

Price S, Shaw PA, Seitz A, Joshi G, Davis J, Niemela JE, Perkins K, Hornung RL, Folio L, Rosenberg PS, Puck JM, Hsu AP, Lo B, Pittaluga S, Jaffe ES, Fleisher TA, Rao VK, Lenardo MJ. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood. 2014 Mar 27;123(13):1989-99. doi: 10.1182/blood-2013-10-535393. Epub 2014 Jan 7.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Xie Y, Pittaluga S, Price S, Raffeld M, Hahn J, Jaffe ES, Rao VK, Maric I. Bone marrow findings in autoimmune lymphoproliferative syndrome with germline FAS mutation. Haematologica. 2017 Feb;102(2):364-372. doi: 10.3324/haematol.2015.138081. Epub 2016 Oct 20.

Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, Lyons JJ, Engelhardt KR, Zhang Y, Topcagic N, Roberson ED, Matthews H, Verbsky JW, Dasu T, Vargas-Hernandez A, Varghese N, McClain KL, Karam LB, Nahmod K, Makedonas G, Mace EM, Sorte HS, Perminow G, Rao VK, O'Connell MP, Price S, Su HC, Butrick M, McElwee J, Hughes JD, Willet J, Swan D, Xu Y, Santibanez-Koref M, Slowik V, Dinwiddie DL, Ciaccio CE, Saunders CJ, Septer S, Kingsmore SF, White AJ, Cant AJ, Hambleton S, Cooper MA. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015 Jan 22;125(4):591-9. doi: 10.1182/blood-2014-09-602763. Epub 2014 Oct 30.

Rao VK, Oliveira JB. How I treat autoimmune lymphoproliferative syndrome. Blood. 2011 Nov 24;118(22):5741-51. doi: 10.1182/blood-2011-07-325217. Epub 2011 Sep 1. Review.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00001350
• Other Study ID Numbers: 930063; 93-I-0063
• First Posted: November 4, 1999
• Last Update Posted: April 19, 2021
• Last Verified: April 13, 2021

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):

Immunoregulation; T Cell Receptor Alpha/Beta; Lymphoproliferation; Fas; Autoimmune Disease; Autoimmune Lymphoproliferative Syndrome; ALPS

Additional relevant MeSH terms:

Lymphoproliferative Disorders; Autoimmune Lymphoproliferative Syndrome; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Genetic Diseases, Inborn; Autoimmune Diseases