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
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
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.
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.
-  INCLUSION CRITERIA: (MBL, CLL/SLL, MCL group)

 4.1.1.<TAB>Diagnosed with MBL, CLL/SLL, or MCL

 4.1.2.<TAB>Greater than or equal to 18 years of age

 4.1.3.<TAB>Neutrophil count (ANC) greater than or equal to 1000/mcL

 4.1.4.<TAB>Platelet count greater than or equal to 50K/mcL

 EXCLUSION CRITERIA: (MBL, CLL/SLL, MCL group)

 4.2.1.<TAB>Concomitant use of agents that have been described to affect the biology and/or
 proliferation rate of CLL cells but are not approved or accepted therapies for CLL, SLL,
 MCL, or MBL

 -  PDE-inhibitors (e.g. sildenafil, theophylline)

 -  Immunosuppressive agents (e.g., prednisone, cyclosporin-A, rapamycin)

 -  Green Tea extract (more than 2 cups per day)

 -  Cox-2 inhibitors

 4.2.2.<TAB>Chronic or current clinically significant infection, including HIV or
 uncontrolled infection

 4.2.3.<TAB>Receiving concurrent anticancer therapies

 4.2.4.<TAB>Women who are pregnant or nursing, as well as women of childbearing potential
 who are unwilling to use a an agreed upon form of contraception for the duration of
 participation in this study

 4.2.5<TAB>Sexually active males who are unwilling to follow the strict contraception
 requirements described in this protocol.

 4.2.6<TAB>Inability to understand the investigational nature of the study, inability to
 provide informed consent

 INCLUSION CRITERIA: (Healthy volunteer group)

 4.3.1<TAB>Health status will be confirmed by brief History and Physical Exam and blood work

 4.3.2<TAB>Greater than or equal to 18 years of age

 4.3.3<TAB>CBC and coagulation panel within the expected normal ranges for the subject

 EXCLUSION CRITERIA: (Healthy volunteer group)

 4.4.1.<TAB>Concomitant use of agents that have been described to affect the biology and/or
 proliferation rate of CLL cells

 -  PDE-inhibitors (e.g. , slidenafil, theophylline)

 -  Immunosuppressive agents (e.g., cyclosporin-A, rapamycin)

 -  Green Tea extract (more than 2 cups per day)

 -  Cox-2 inhibitors

 <TAB>

 4.4.2.<TAB>Women who are pregnant or nursing, as well as women of childbearing potential
 who are unwilling to use an agreed upon form of contraception for the duration of study
 participation.

 4.4.3<TAB> Sexually active males who are unwilling to follow the strict contraception
 requirements described in this protocol.

 4.4.4.<TAB>Inability to understand the investigational nature of the study, inability to
 provide informed consent