A Study of the Kinetics of Lymphoid Cells in Patients With Monoclonal B-cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL), Mantle Cell Lymphoma (MCL) and Healthy Volunteers
Condition: Lymphoma, Mantle-cell; CLL (Chronic Lymphocytic Leukemia); Monoclonal B-Cell Lymphocytosis; Healthy Volunteers; Small Lymphocytic Lymphoma
MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Lymphocytosis
Study type: Observational

Summary: 
      Background:

        -  Chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell
           lymphoma (MCL) are types of cancers in which there are too many abnormal lymphocytes (a
           type of white blood cell). Monoclonal B-cell lymphocytosis (MBL) is a condition in which
           the individual has a larger than normal number of lymphocytes. Individuals with CLL,
           SLL, MBL, and MCL may survive for many years without the need for treatment, but there
           is an apparent correlation between cell birth rates and disease activity. By studying
           the birth and death rates of lymphocytes, researchers hope to identify individuals who
           are at risk for worsening disease.

        -  Heavy water is similar in structure to regular water, but it has two deuterium atoms
           instead of two hydrogen atoms. Deuterium has one more neutron than hydrogen, which is
           what makes heavy water heavy. Heavy water is not radioactive, looks and tastes like
           regular water, and has no known harmful effects at research-level doses. When a small
           amount of heavy water is consumed daily, newly produced blood cells are labeled
           (tagged), which allows researchers to track cell growth and to measure the birth and
           death rates of CLL, SLL, MBL, MCL or normal lymphocytes.

      Objectives:

      - To study the birth and death rates of lymphocytes from individuals with MBL, CLL/SLL, and
      MCL, compared with lymphocytes from healthy volunteers.

      Eligibility:

        -  Individuals at least 18 years of age who have been diagnosed with MBL, CLL, SLL, or MCL,
           but who have not been taking certain agents (Viagra, Levitra, Cialis, or other
           PDE-inhibitors, prednisone, cyclosporin-A, rapamycin, or other immunosuppressive agents,
           more than 2 cups of green tea daily, or Celebrex) for 4 weeks prior to enrollment in the
           study.

        -  Healthy volunteers at least 18 years of age, but who have not been taking certain agents
           (Viagra, Levitra, Cialis, or other PDE-inhibitors, prednisone, cyclosporin-A, rapamycin,
           or other immunosuppressive agents, more than 2 cups of green tea daily, or Celebrex)for
           4 weeks prior to enrollment in the study.

      Design:

        -  Participants will be screened with a medical history, physical examination, and initial
           blood tests. Other tests may be administered to the individuals with cancer, as required
           by the study researchers.

        -  All participants will drink regular doses of heavy water daily for a total of 4 weeks
           (labeling period). There is an optional 6-month follow-up or wash-out period during
           which no additional heavy water will be consumed.

        -  Blood samples will be collected weekly during the labeling period, and a bone marrow
           biopsy will be obtained where possible. Individuals with cancer may also have a lymph
           node biopsy during this part of the study.

        -  Additional blood samples may be collected during the optional wash-out phase of the
           study to determine the rate at which cancer cells disappear.

        -  Treatment is not provided as part of this protocol.
    

Detailed description: 
      Chronic lymphocytic leukemia (CLL) and its lymphoma variant, small lymphocytic lymphoma (SLL)
      were for decades considered diseases caused by the progressive accumulation of abnormal
      lymphocytes. The prevailing view being that CLL and SLL disease processes were driven by an
      underlying defect in apoptosis. While resistance to apoptosis appears to be important in the
      CLL and SLL disease process, recent studies suggest that cellular proliferation is more
      important than previously realized.

      Cells from individuals with CLL who drank deuterated water (heavy water) for 6 weeks showed a
      turnover rate of 0.1 % to 1.1 % per day. In a second study involving CLL subjects who drank
      heavy water, average CLL turnover rates were in a similar range but approximately 2-fold
      lower than average B-cell turnover rates from healthy individuals. These studies have shown
      the safety and scientific value of using heavy water to study the kinetics of cell
      proliferation in patients and normal volunteers.

      We now propose this study to expand on findings by other investigators. This study will
      address the site of proliferation for CLL/SLL cells and will include individuals with
      monoclonal B-cell lymphocytosis (MBL), a possible precursor of CLL. Furthermore, we will
      include patients with mantle cell lymphoma (MCL), a disease in which tumor proliferation
      plays an important role.

      Study participants will drink heavy water daily for a total of 4 weeks (labeling period) with
      an optional 6 months follow up ( wash out period). Blood samples will be obtained weekly
      during the labeling period. A bone marrow and/or lymph node biopsy will be obtained where
      possible during the labeling period. Additional blood draws may be obtained during the
      optional wash-out phase of the study to determine the rate at which tumor cells disappear.

      The primary objective of this exploratory study is to obtain an estimate of the proliferation
      rate of tumor cells in individuals with MBL, CLL/SLL, and MCL. Secondary objectives include
      the comparison of proliferation rates between different anatomic compartments, specifically
      peripheral blood, lymph node, and bone marrow and the estimation of the attrition or
      disappearance rate of cells during an optional phase of the protocol. Healthy volunteers may
      be included for comparison.

      The primary objective of this exploratory study is to obtain an estimate of the proliferation
      rate of tumor cells in individuals with MBL, CLL/SLL, and MCL.

      Secondary endpoints include: Proliferation rate in tissue compared to blood, disappearance
      rate of labeled cells from the blood and tissue, and the safety profile of heavy water in the
      study population.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        All patients with eligible conditions or healthy volunteers aged 18 and over if
        participating as a normal volunteer who otherwise fulfill the eligibility criteria will be
        considered for the protocol.
      
Keywords: CLL (Chronic Lymphocytic Leukemia); Monoclonal B Cell Lymphocytosis; Small Lymphocytic Lymphoma; Mantle Cell Lymphoma; Cellular Proliferation; Chronic Lymphocytic Leukemia; CLL; Monoclonal B-Cell Lymphocytosis; MBL; SLL; MCL; Healthy Volunteer; HV