Hematopoietic Stem Cell Mobilization in Idiopathic CD4 Lymphocytopenia Patients and Healthy Controls for the Study of T Cell Maturation and Trafficking in Murine Models

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Brief Title

Hematopoietic Stem Cell Mobilization in Idiopathic CD4 Lymphocytopenia Patients and Healthy Controls for the Study of T Cell Maturation and Trafficking in Murine Models

Official Title

Hematopoietic Stem Cell Mobilization in Idiopathic CD4 Lymphocytopenia Patients and Healthy Controls for the Study of T Cell Maturation and Trafficking in Murine Models

Brief Summary

      Idiopathic CD4 lymphocytopenia (ICL) is a rare syndrome defined by consistently low CD4 T
      cell counts (<300/mm3) without evidence of HIV infection or other known immunodeficiency.
      Patients with ICL are at risk for opportunistic infections typically associated with HIV/AIDS
      such as disseminated cryptococcal infection and severe human papillomavirus-related
      dysplasia. More than 20 years since the description of ICL, its etiology, pathogenesis, and
      management remain unclear. In this study we propose to administer the combination of
      granulocyte colony stimulating factor (G-CSF) and plerixafor to ICL patients and healthy
      volunteers with the objective of harvesting mobilized CD34+ hematopoietic progenitor cells
      (HPCs) by apheresis for transfer into immunocompromised mice and for study with in vitro
      assays. The mice studies would serve to investigate thymic development, survival, and
      trafficking of the mobilized human cells within murine lymphoid and non-lymphoid organs.

      HPCs are used for various therapies and there is an increasing use of agents that stimulate
      the bone marrow to produce progenitor cells and move them into the bloodstream where they may
      be harvested by apheresis. Not all patients respond to GCSF with vigorous HPC mobilization.
      The binding of chemokine receptor CXCR4 to stromal cell derived factor (SDF-1 or CXCL12) is
      an important interaction between a hematopoietic progenitor cell and its marrow environment.
      Plerixafor is a CXCR4 inhibitor which blocks binding to SDF-1 resulting in the release of
      hematopoietic progenitor cells (CD34+) into peripheral circulation. In pharmacodynamic
      studies of plerixafor in conjunction with G-CSF compared to G-CSF and placebo, a two-fold
      increase in CD34+ cell count was observed.

      Due to the important role CXCR4 plays in immune cell trafficking and its potential role in
      the pathogenesis of ICL, we propose as a secondary objective to assess peripheral CD4 T cell
      and CD34+ hematopoietic progenitor cell numbers and functions in ICL patients compared to
      controls following G-CSF and plerixafor administration.

      Study participants will be screened within 12 weeks prior to the study period. Eligible
      participants will receive G-CSF for 5 days with hospitalization on Day 4 for plerixafor
      injection followed by apheresis on Day 5. Participants will return for examinations and blood
      draws on Days 8 and 12.

      ...
    

Detailed Description

      Idiopathic CD4 lymphocytopenia (ICL) is a rare syndrome defined by consistently low CD4 T
      cell counts (<300/3microL) without evidence of HIV infection or other known immunodeficiency.
      Patients with ICL are at risk for opportunistic infections typically associated with HIV/AIDS
      such as disseminated cryptococcal infection and severe human papillomavirus-related
      dysplasia. More than 20 years since the description of ICL, its etiology, pathogenesis, and
      management remain unclear. In this study we propose to administer the combination of
      granulocyte colony stimulating factor (G-CSF) and plerixafor to ICL patients and healthy
      volunteers with the objective of harvesting mobilized CD34+ hematopoietic progenitor cells
      (HPCs) by apheresis for transfer into immunocompromised mice and for study with in vitro
      assays. The mice studies would serve to investigate thymic development, survival, and
      trafficking of the mobilized human cells within murine lymphoid and non-lymphoid organs.

      HPCs are used for various therapies and there is an increasing use of agents that stimulate
      the bone marrow to produce progenitor cells and move them into the bloodstream where they may
      be harvested by apheresis. Not all patients respond to GCSF with vigorous HPC mobilization.
      The binding of chemokine receptor CXCR4 to stromal cell derived factor (SDF-1 or CXCL12) is
      an important interaction between a hematopoietic progenitor cell and its marrow environment.
      Plerixafor is a CXCR4 inhibitor which blocks binding to SDF-1 , resulting in the release of
      HPCs (CD34+) into peripheral circulation. In pharmacodynamic studies of plerixafor in
      conjunction with G-CSF compared to G-CSF and placebo, a two-fold increase in CD34+ cell count
      was observed.

      Due to the important role CXCR4 plays in immune cell trafficking and its potential role in
      the pathogenesis of ICL, we propose as a secondary objective to assess peripheral CD4 T cell
      and CD34+ hematopoietic progenitor cell numbers and functions in ICL patients compared to
      controls following G-CSF and plerixafor administration.

      Study participants will be screened within 12 weeks prior to the study period. Eligible
      participants will receive G-CSF for 5 days with hospitalization on Day 4 for plerixafor
      injection followed by apheresis or large volume blood draw (120 cc) on Day 5. Participants
      will return for examinations and blood draws on Days 8 and 12.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

To mobilize CD34+ HPCs in ICL patients and healthy volunteers for collection and transfer into immunocompromised mice to investigate thymic development, survival, and trafficking of these cells in murine lymphoid and non-lymphoid organs.

Secondary Outcome

 To assess peripheral CD4 T cell and CD34+ HPC numbers and functions in ICL subjects compared to controls following G-CSF and plerixafor administration.

Condition

Idiopathic CD4 Positive

Intervention

Filgrastim

Study Arms / Comparison Groups

 Filgrastim
Description:  ICL and healthy volunteers will be given 10 g/kg daily for 5 days administered according to a vialbased algorithm to reduce wastage and increase the G-CSF dose given to lighter- Filgrastim weight donors to improve CD34+ yields

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

40

Start Date

January 15, 2014

Completion Date

October 31, 2026

Primary Completion Date

October 31, 2026

Eligibility Criteria

        -  INCLUSION CRITERIA

        ICL patients:

          1. Documented history of idiopathic CD4 lymphocytopenia as defined by CD4 T cell count
             <300 cells/microL or <20% of total T lymphocytes on 2 occasions at least 6 weeks apart
             in the absence of any illness or medications accounting for CD4 lymphocytopenia.
             Although the protocol will primarily enroll ICL patients who are lymphopenic at the
             time of enrollment, up to three patients who had clear documentation of ICL in the
             past and are currently not lymphopenic may still be enrolled for comparative purposes.

          2. Hemoglobin greater than or equal to 9 g/dL

          3. Human T-lymphotropic virus Type 1 (HTLV-1) and HTLV-2 seronegative

          4. Persons with documented history of ICL in whom genetic analysis revealed inherited
             defects that are either known or suspected to be involved in development, maturation,
             or homeostasis of hematopoietic cells.

        Healthy volunteers: white blood cell count >2500/microL and hemoglobin greater than or
        equal to 12.5 g/dL

        ICL patients and healthy volunteers:

          1. Age 18-65 years

          2. Weight at least 50 kg but less than 167 kg and <175% ideal body weight (due to lack of
             data regarding appropriate dosing of plerixafor)

          3. Ability to give informed consent

          4. Capacity and willingness to adhere to study procedures, including scheduled follow-up
             visits

          5. Willingness to have blood samples stored for future research

          6. Willingness to undergo HLA testing

          7. Willingness to be hospitalized for approximately 24 hours

          8. Established primary care provider

          9. HIV-1 and HIV-2 seronegativity and plasma HIV-1 RNA polymerase chain reaction (PCR)
             below the limit of detection

         10. Adequate venous access to allow leukapheresis without use of a central line or a large
             volume blood draw

         11. Participant agrees to be heterosexually inactive or consistently use effective birth
             control (e.g., barrier methods, oral contraceptives, intrauterine devices, vasesctomy)
             for the duration of study participation and for approximately 8 weeks after the last
             dose of G-CSF. This is necessary for both male and female participants.

         12. For women of childbearing potential:

               1. Negative serum or urine pregnancy test

        EXCLUSION CRITERIA

          1. Active uncontrolled infection at the time of enrollment

          2. Current autoimmune conditions requiring systemic (oral, injection, or other
             parenteral) therapy

          3. History of vasculitis

          4. Current or history of hematologic or lymphoid malignancy (leukemia)

          5. History of splenomegaly or current splenomegaly on exam or ultrasound (for ICL
             patients)

          6. History of hypersensitivity to plerixafor and/or G-CSF

          7. Systemic immune-modulatory agent within the past 6 months

          8. Thrombocytopenia (platelets <100,000 cells/microL)

          9. Hepatitis B and C seropositivity (HBsAg positive and anti-HCV positive) Need for
             anticoagulant medication (e.g., warfarin, heparin), other than aspirin, clopidogrel,
             or other antiplatelet agent

         10. Creatinine clearance <50 mL/min including end-stage renal disease requiring
             hemodialysis

         11. Symptomatic coronary artery disease

         12. Uncontrolled hypertension (i.e., resting systolic blood pressure >160 mmHg or resting
             diastolic blood pressure >90 mmHg) despite pharmacologic antihypertensive treatment
             confirmed with a second blood pressure measurement done later on the same day

         13. Cardiac, pulmonary, thyroid, renal, hepatic, neurological (central or peripheral)
             disease or disorder of hemostasis requiring therapy and considered to be significant
             by the protocol team

         14. Active drug or alcohol use or dependence that, in the opinion of the investigator,
             would interfere with adherence to study requirements

         15. Currently receiving lithium due to contraindication of co-administration of G-CSF with
             lithium

         16. Past or current psychiatric illness that, in the opinion of the investigator, would
             interfere with protocol adherence or the ability to give written informed consent

         17. Any illness or condition that, in the opinion of the investigator, may substantially
             increase the risk associated with participation in the study or compromise the
             scientific objectives

         18. Participation in a clinical protocol which includes an intervention that, in the
             opinion of the investigator, may affect the results of the current study

         19. Previous history of anaphylactic reaction to aspirin or other nonsteroidal
             anti-inflammatory drugs (NSAIDs)

         20. Female of child-bearing potential who is breast-feeding.
      

Gender

All

Ages

18 Years - 65 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Irini Sereti, M.D., (301) 761-6644, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02015013

Organization ID

140020

Secondary IDs

14-I-0020

Responsible Party

Sponsor

Study Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)


Study Sponsor

Irini Sereti, M.D., Principal Investigator, National Institute of Allergy and Infectious Diseases (NIAID)


Verification Date

February 15, 2022