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Patients' tumor tissue including bone marrow, blood, buccal swab or mouthwash, lymph node, urine or other specimens will be collected from patients who consent to the protocol

Irene Ghobrial, MD

Joseph Grider

Olga Kozyreva, MD

Saida Hussain

Pedro Sanz-Altamira, MD

Laura Melancon

Michael Constantine, MD

Rebeka Lovato

Kathleen Allen

Mohammad Omaira, MD

Shannon Peabody

Jeanna Walsh, MD

Blood cancers occur when the molecules that control normal cell growth are damaged. Many of these changes can be detected by directly examining parts of the cancer or cells in blood. Several alterations that occur repeatedly in certain types of blood cancers have already been identified, and these discoveries have led to the development of new drugs that target those alterations. More remain to be discovered.

Some of these abnormalities include alterations in genes. Genes are the part of cells that contain the instructions which tell the investigators bodies how to grow and work, and determine physical characteristics such as hair and eye color. Genes are composed of DNA letters that spell out these instructions. Studies of the DNA molecules that make up the genes are called "molecular" analyses. Molecular analyses are ways of reading the DNA letters to identify errors in genes that may contribute to an increased risk of cancer or to the behavior of the cancer cells. Some changes in genes occur only in cancer cells. Others occur in the genes that are passed from parent to child. This research study will examine both kinds of genes. The best way to find these genes is to study large numbers of people. The investigators expect that as many 1000 individuals will enroll in this study.

This research study is trying to help doctors and scientists understand why cancer occurs and to develop ways to better treat and prevent it. To participate in this study the participant must have cancer now, had it in the past, or are at risk of developing cancer. The participant will not undergo tests or procedures that are not required as part of their routine clinical care. The investigators will ask the participant to provide an additional sample from tissue that is obtained for their clinical care including blood, bone marrow, or tissue sample. The investigators will also ask for a gentle scrape of the inside of their cheek, mouthwash or a skin sample to obtain their germline DNA

The purpose of this research study is to perform these molecular analyses on tissues (obtained from biopsies), blood, or other body fluids such as saliva. Importantly, this study will use tissue specimens that have already been collected as part of a participant's clinical care. The participant's tissue sample may be used to create a living tissue sample (called a "cell line") that can be grown in the laboratory. This allows researchers to have an unlimited supply of cells in the future without asking for more samples.

In this study, analyses will be performed on material only after all necessary clinical tests have been performed. In general, no additional procedures will be required. However, the investigators are asking the participant's permission to obtain one additional sample of blood (a few teaspoons), a gentle swab from the inside of their mouth or a sample of skin to obtain some cells. These are sources of normal, non-cancer cells which are needed for some types of analyses.

To fully understand the effects that molecular alterations have on blood cancers, they must be analyzed in the context of clinical behavior. Therefore, this study also asks the participant's permission to link the molecular alterations in their cancer or leukemia with clinical information that has been generated during the course of their clinical care. No additional clinical tests will be required. The investigator will ask to see the participant for follow up at regular interval to follow their risk of progression.

Some of participant's specimens as well as some of the material generated during the analysis of their tissues or blood may be useful for future study. The Investigator's are asking for the participant's permission to store these specimens and materials in a secure storage facility for possible later use.

Finally, rapid progress in understanding and treating cancer will occur when some of the molecular information derived from tissue and blood can be shared with other researchers. In particular, the National Institutes of Health (NIH) and other organizations have developed special data (information) repositories that analyze data and collect the results of certain types of genetic studies. These central banks will store genetic information and samples and give them to other researchers to do more studies. Therefore, the Investigators are also asking your permission to share your results with these special banks. The participant's information will be sent with only a code number attached. The participant's name or other directly identifiable information will not be given to central banks. There are many safeguards in place to protect the participant's information and samples while stored in repositories and used for research. The investigators do not think that there will be further risks to the participant's privacy and confidentiality by sharing this information with these banks. However, the investigator's cannot predict how genetic information will be used in the future.

Blood, buccal swabs or mouthwashes, and urine

Study of MGUS, Smoldering Myeloma, Early MDS and CLL to Assess Molecular Events of Progression and Clinical Outcome

Study of Precursor Hematological Malignancies to Assess the Relationship Between Molecular Events of Progression and Clinical Outcome

The Leukemia and Lymphoma Society

Dana-Farber Cancer Institute

Principal Investigator

Nervous System Diseases

Infections

Behaviors and Mental Disorders

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Parkinson Disease

Dementia

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Leukocytosis

Leukocyte Disorders

Familial Alzheimer Disease

Individuals over the age of 40 attending to the Clalit HMO clinics in the North of Israel for regular blood tests.

Geffen Kleinstern

The aim of this proposal is to identify immune biomarkers, genetic risk, and the clinical consequences of low count monoclonal B-cell lymphocytosis (LC MBL), a common premalignant condition affecting up to 17% of European adults age\&amp;gt;40. LC MBL is a precursor to chronic lymphocytic leukemia (CLL), characterized by a circulating population of clonal B-cells. It is relatively understudied, despite emerging evidence of clinical consequences such as increased risk for life-threatening infections and lymphoid malignancies. Studies reported that male sex, age, family history of CLL, and CLL-susceptibility genetic loci were associated with LC MBL risk. These findings were reported in European ancestry individuals and have not been generalized to other thnicities. This study will provide this missing knowledge using a unique multi-ethnic Israeli population of Jews and Arabs that have one of the highest and lowest age-standardized incidence rates of CLL in the world, respectively, and characterized with different genetic backgrounds.

Risk and Clinical Consequences of Low Count Monoclonal B-cell Lymphocytosis (LC MBL)

Immune Biomarkers, Genetic Risk, and the Clinical Consequences of Low Count Monoclonal B-cell Lymphocytosis (LC MBL)

Blood samples will be screened for MBL using flow cytometry, while data on the various outcomes will be collected from electronic medical records from Clalit Health Services.

DNA will be extracted from the blood sample and sequenced.

Blood samples will be screened for MBL using flow cytometry, ethnicity and sex will be determined using a demographic questionnaire

Blood sample will be screened for MBL using flow cytometry, and immune biomarkers will be screened from plasma samples.

Other clinical conditions will be determined from electronic medical records from Clalit Health Services

Clalit Health Services, Haifa and West Galilee

Bnai Zion Medical Center

University of Haifa

Senior Lecturer

Lymphoma

Lymphoma, B-Cell, Marginal Zone

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

Lymphosarcoma

Marginal Zone Lymphoma

B-cell Lymphoma

Patients with monoclonal B cell lymphocytosis (MBL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), lymphoplasmacytic lymphoma (LPL)/Waldenstr(SqrRoot)(Delta)m macroglobulinemia (WM), and splenic marginal zone lymphoma (SMZL).

Rachel Adams

Clare C Sun, M.D.

Background:

The development of new technologies now allow scientists to investigate the molecular basis and clinical manifestations of monoclonal B cell lymphocytosis (MBL), chronic lymphocytic leukemia(CLL)/small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM), and splenic marginal zone lymphoma (SMZL). Applying these methods in a natural history study can clarify processes involved in disease progression and possibly lead to the discovery or validation of treatment targets.

* Objectives:

  * Study the history of MBL/CLL/SLL/LPL/WM/SMZL in patients prior to and after treatment.
  * Characterize clinical, biologic and molecular events of disease stability and progression of patients enrolled on this protocol.
* Eligibility:

  * Diagnosis of MBL/CLL/SLL/LPL/WM/SMZL
  * Age greater than or equal to 18 years.
  * Patients with CLL/SLL in remission after chemotherapy are excluded.
  * ECOG performance status of 0-2.
* Design:

  * Patients are typically followed every 6 to 24 months in the clinic and have blood drawn. When required patients may undergo additional testing that may include bone marrow biopsy and aspiration, blood drawing, lymph node biopsy, x-ray studies, positron emission tomography and CT and MRI scans. Some of these tests may be required to monitor CLL/SLL, LPL/WM, and SMZL patients. Other tests, such as bone marrow biopsy and aspiration, lymph node biopsy, may not be clinically indicated, but patients may be asked to undergo these procedures for research purposes.
  * No treatment will be administered on this study. If a patients requires treatment for their cancer, available NIH clinical trials and alternative treatment options will be discussed with the patient.

The purpose of this protocol is to collect blood, tissue (bone marrow and lymph node biopsies) and/or imaging studies (PET and CT scans) from patients with monoclonal B cell lymphocytosis (MBL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM), and splenic marginal zone lymphoma (SMZL).

Assessments will be used for clinical and translational research investigating the molecular basis of MBL, CLL/SLL, LPL/WM, SMZL and their clinical manifestations. New technologies now permit the simultaneous characterization of pathogenic events ranging from the control of gene expression to the characterization of the molecular events of cell-cell interactions. Applying these methods to MBL/CLL/SLL/LPL/WM/SMZL in the context of a natural history protocol can help unravel cellular pathways involved in pathogenesis and disease progression and lead to the discovery or the validation of therapeutic targets. MBL/CLL/SLL/LPL/WM/SMZL is an incurable disease for which there are no reliable cell lines and only a few mouse models. There is an urgent need to obtain a flow of primary samples to advance research into pathogenesis and novel treatment approaches.

Eligibility:

Diagnosis of MBL/CLL/SLL/LPL/WM/SMZL

Age greater than or equal to 18 years.

ECOG performance status of 0-2.

-Design:

Patients will be typically followed every 6-12 months for the first 2 years and every 12-24 months thereafter. Interim visits may occur at the discretion of the research team. Patients may donate cellular products or tissues as appropriate for research purposes. Clinical information will be obtained and stored in a central databank.

* Objectives:

  * Describe the history of MBL/CLL/SLL/WM/SMZL in patients prior to and after treatment.
  * Apply the expertise and available technologies of the investigators to advance our understanding of disease pathogenesis by studying MBL/CLL/SLL and closely related B-cell malignancies, LPL/WM and SMZL
  * Develop novel treatment approaches for CLL/SLL/LPL/WM/SMZL.
  * Provide evaluation, diagnostic studies and monitoring for patients on study.
  * Provide blood and tissue linked to clinical and biologic information for translational studies.
* Endpoints:

  * Treatment-free survival, measured as the time from diagnosis or last therapy to the development of active disease that requires treatment at which time patients will be evaluated for a treatment protocol or seek treatment outside of NIH.

Natural History Study of Monoclonal B Cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Lymphoplasmacytic Lymphoma (LPL)/Waldenstrom Macroglobulinemia (WM), and Splenic Marginal Zone Lymphoma (SMZL)

Treatment free survival, measured as the time from diagnosis or last therapy to the development of active disease that requires treatment at which time patients will be able to change to a treatment protocol or seek treatment outside of NIH.

Describe the underlying biologic heterogeneity of tumor cells in relation to treatment free survival

National Heart, Lung, and Blood Institute (NHLBI)

Lymphoma, Mantle-Cell

Hyperplasia

Mantle Cell Lymphoma

Chronic lymphocytic leukemia/small lymphocytic lymphoma

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.

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.

Northwell Health

Study title	NCT ID	Conditions	Eligibility	Organization
Study of MGUS, Smoldering Myeloma, Early MDS and CLL to Assess Molecular Events of Progression and Clinical Outcome	NCT02269592	Monoclonal Gamm... Chronic Lymphoc... Myelodysplastic... Hematological M... B-cell Malignan... Myelodysplastic... IgG Monoclonal ... Smoldering Mult... Waldenstrom Mac...	18 Years -	Dana-Farber Cancer Institute
Risk and Clinical Consequences of Low Count Monoclonal B-cell Lymphocytosis (LC MBL)	NCT06416267	Monoclonal B-Ce... Chronic Lymphoc... Infections Cancers Cardiovascular ... Alzheimer Disea... Dementia Autoimmune Dise... Parkinson Disea...	40 Years -	University of Haifa
Natural History Study of Monoclonal B Cell Lymphocytosis (MBL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Lymphoplasmacytic Lymphoma (LPL)/Waldenstrom Macroglobulinemia (WM), and Splenic Marginal Zone Lymphoma (SMZL)	NCT00923507	Waldenstrom Mac... Lymphoplasmacyt... Monoclonal B-Ce... Small Lymphocyt... CLL (Chronic Ly...	18 Years - 110 Years	National Institutes of Health Clinical Center (CC)
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	NCT01117142	Lymphoma, Mantl... CLL (Chronic Ly... Monoclonal B-Ce... Healthy Volunte... Small Lymphocyt...	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
Risk and Clinical Consequences of Low Count Monoclonal B-cell Lymphocytosis (LC MBL)	NCT06416267	Monoclonal B-Ce... Chronic Lymphoc... Infections Cancers Cardiovascular ... Alzheimer Disea... Dementia Autoimmune Dise... Parkinson Disea...	40 Years -	University of Haifa

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