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Antineoplastic Agents

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All Drugs and Chemicals

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Subjects will receive a myeloablative conditioning regimen of cyclophosphamide, fludarabine and total body irradiation, followed by an infusion of a stem cell product prepared using the Miltenyi CliniMacs system for CD34 selection and a lymphocyte product that has been selectively depleted using the photodepletion approach. Older subjects will receive a lower dose of irradiation to reduce the regimen intensity. Determine appropriate level of post transplant immunosuppression

Subjects will receive a myeloablative conditioning regimen of cyclophosphamide, fludarabine and total body irradiation, followed by an infusion of a stem cell product prepared using the Miltenyi CliniMacs system for CD34 selection and a lymphocyte product that has been selectively depleted using the photodepletion approach.

Miltenyi system

Minocher M Battiwalla, M.D.

This study will try to improve the safety and effectiveness of stem cell transplant procedures in patients with cancers of the blood. It will use a special machine to separate immune cells (T cells) from the blood of both the donor and the patient and will use photodepletion, a laboratory procedure that selectively kills cancer cells exposed to light. These special procedures may reduce the risk of graft-versus-host-disease (GVHD), a serious complication of stem cell transplants in which the donor's immune cells destroy the patient's healthy tissues, and at the same time may permit a greater graft-versus-leukemia effect, in which the donated cells fight any residual tumor cells that might remain in the body.

Patients between 18 and 75 years of age with a life-threatening disease of the bone marrow (acute or chronic leukemia, myelodysplastic syndrome, or myeloproliferative syndrome) may be eligible for this study. Candidates must have a family member who is a suitable tissue match.

Peripheral blood stem cell transplant research carried out by the NHLBI BMT Unit focus on approaches in transplant techniques designed to decrease graft versus host disease (GVHD), increase the graft-versus-leukemia (GVL) effect, and/or reduce the risk for post-transplant graft rejection or disease relapse.

Ex vivo selective depletion of alloreacting T cells, hereafter referred as selective depletion (SD), represents a translational strategy aiming to reduce severe GVHD whilst preserving GVL. We found that selectively depleted transplants are safe to administer and associated with less severe acute GVHD. This protocol is designed to evaluate the safety and efficacy of photodepletion (PD) as an improved selective depletion procedure in the HLA-matched peripheral blood stem cell transplant setting and to determine whether post-transplant immunosuppression with cyclosporine is necessary to prevent severe GVHD after a photodepleted transplant.

The protocol will accrue subjects ages 18-75 who are diagnosed with a hematological malignancy where allogeneic stem cell transplantation from an HLA-matched sibling would be normally indicated. Diagnostic categories will include acute and chronic leukemias, myelodysplastic syndromes, B-cell lymphomas, multiple myeloma, and myeloproliferative syndromes.

Participants have a central intravenous (IV) line placed into a large vein. The tube is used for giving the donated stem cells and antibiotics and other medicines, for transfusions of red blood cells and platelets, and for collecting blood samples. Treatment starts with a conditioning regimen of chemotherapy (fludarabine and cyclophosphamide) and total body irradiation to suppress immunity and prevent rejection of the donated stem cells. The day after chemotherapy ends, the stem cells are given through the central line. This is followed by transfusion of the donor's immune cells, which have been treated to remove cells that could cause severe GVHD. Also to minimize the risk of GVHD, patients are given cyclosporine. Not all participants receive the same amount of this drug; in order to determine how much immunosuppression is needed to protect against severe GVHD, the length of treatment with cyclosporine varies among patients, depending on when they entered the study and how well preceding patients did.

The average hospital stay for stem cell transplantation is 3 to 4 weeks. Patients return for frequent follow-up visits for the first 2 to 4 months after transplantation. The patient's referring physician is asked to send results of any laboratory testing to the NIH researchers at least every 3 months for the first 3 years and annually thereafter. Patient follow-up visits are scheduled at NIH at 1, 2, and 3 years after transplantation. After 3 years, participants are offered the opportunity to enroll in NHLBI's long-term evaluation and follow-up care protocol.

Subjects will receive a myeloablative conditioning regimen of cyclophosphamide, fludarabine and total body irradiation, followed by an infusion of a stem cell product prepared using the Miltenyi CliniMacs system for CD34 selection and a lymphocyte product that has been selectively depleted using the photodepletion approach (Kiadis Pharma). Older subjects will receive a lower dose of irradiation to reduce the regimen intensity.

To determine appropriate level of post transplant immunosuppression, we will utilize a three sequential de-escalation stage design involving 17 subjects per cohort (minimum 17, maximum 51 total evaluable subjects in study). Stopping rules for non-relapse mortality in each cohort will determine whether to continue to the next stage; to continue accumulating subjects at the same level; or to stop the protocol.

Cohort 1: Low dose cyclosporine until day 90 then dose tapered to stop within 2 weeks.

Cohort 2: If no severe GVHD is encountered in Cohort 1, the cyclosporine withdrawal will begin on day 45.

Cohort 3: If no severe GVHD is encountered in Cohort 2, cyclosporine will not be used in the post-transplant period.

Primary endpoints will be the incidence of acute grade III/IV GVHD at day 90. Secondary endpoints will be standard transplant outcome variables: toxicity, non relapse mortality and survival.

Evaluation of selective depletion of alloreactive T cells to prevent graft vs host disease

Stem Cell Transplantation for Patients With Cancers of the Blood

Selective Depletion of Alloreacting T Cells Using a Photodepletion Technique to Prevent GVHD After HLA-Matched Peripheral Blood Stem Cell Transplantation for Subjects With Hematologic Malignancies

Patients will receive a selectively photodepleted lymphocyte product which will be delivered together with the T cell depleted stem cell product on the day of transplantation. Subjects will receive a conditioning regimen of cyclophosphamide, fludarabine and total body irradiation followed by an infusion of a stem cell product prepared using the Miltenyi CliniMacs system for CD34-selection and a lymphocyte product that has been selectively depleted using the photodepletion approach. Older subjects will receive a lower dose of irradiation to reduce the regimen intensity. To determine appropriate level of post transplant immunosuppression, a three sequential de-escalation stage design for timing of cyclosporine will be utilized. To determine if selective T cell depletion using the photodepletion procedure can substantially reduce the number of severe acute GVHD (grade III/IV) after transplantation followed by low-dose or no immunosuppression.

National Heart, Lung, and Blood Institute (NHLBI)

Subjects will receive a myeloablative conditioning regimen of cyclophosphamide, fludarabine and total body irradiation, followed by an infusion of a stem cell product prepared using the Miltenyi CliniMacs system for CD34 selection and a lymphocyte product that has been selectively depleted using the photodepletion approach. Older subjects will receive a lower dose of irradiation to reduce the regimen intensity. To determine appropriate level of post transplant immunosuppression, a three sequential de-escalation stage design for timing of cyclosporine will be utilized.

Selective T Cell Depletion Transplant Recipients

Sex: Female, Male

United States

Region of Enrollment

Age, Categorical

Minocher Battiwalla, MD

Subjects affected by Acute Grade III/ IV GVHD

Subjects unaffected by Acute Grade III/ IV GVHD

Subjects will receive a myeloablative conditioning regimen of cyclophosphamide, fludarabine and total body irradiation, followed by an infusion of a stem cell product prepared using the Miltenyi CliniMacs system for CD34 selection and a lymphocyte product that has been selectively depleted using the photodepletion approach (Kiadis Pharma). Older subjects will receive a lower dose of irradiation to reduce the regimen intensity.

To determine appropriate level of post transplant immunosuppression.

The study accrued 31 transplant recipents and 30 donors. Of the 31 transplant recipients, there were 24 evaluable recipients. Seven of the 24 recipients did not receive transplantation.

To Determine if Selective T Cell Depletion Using the Photodepletion Procedure Can Substantially Reduce the Rate of Severe Acute GVHD (Grade III/IV) After Matched Sibling Transplantation Followed by Low-dose or no Immunosuppression.

Overall Study

Antibodies

Antibodies, Monoclonal

Immunomodulating Agents

Immunoglobulins

Ofatumumab

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antimetabolites

For patients with non-high risk FISH changes

Fludarabine Phosphate

Inhye Ahn, M.D.

Background:

- Ofatumumab was approved by the U.S. Food and Drug Administration to treat patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have not responded to standard chemotherapy. Ofatumumab is a substance that recognizes specific types of white blood cells called B-lymphocytes, which become cancerous in CLL/SLL. Ofatumumab attaches to a molecule called CD20, which is found on the surface of B-cells, and destroys them. Previous studies have shown that ofatumumab can decrease the number of B-cells in patients with CLL/SLL who have been treated with chemotherapy, but more research is needed to determine it if can also be used to treat patients with previously untreated CLL/SLL.

Objectives:

- To determine a safe and effective dose of ofatumumab, along with chemotherapy, to treat chronic lymphocytic leukemia or small lymphocytic lymphoma.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with CLL or SLL that has not been treated with chemotherapy.

Design:

* Eligible participants will be screened with a physical exam, blood samples, lymph node and bone marrow biopsies, and imaging studies.
* Participants will be separated into 2 groups: all participants will receive ofatumumab and fludarabine, and some participants will be selected to also receive cyclophosphamide (based on results of certain blood tests).
* Participants will receive the study drugs (ofatumumab and fludarabine, and optional cyclophosphamide) by infusion for a maximum of 6 days, followed by 21 days off drug.
* Participants will have 6 cycles of treatment according to a schedule set by the study doctors, and may have their dose levels adjusted if side effects develop.
* Participants who have disease remaining after 6 cycles will receive additional ofatumumab every 2 months, starting 2 months after the end of the 6th cycle and continuing for a total of 4 doses, before entering the follow-up phase of the trial. Participants who do not have residual disease after 6 cycles will not receive additional therapy, and will immediately enter the follow-up phase of the trial.
* Participants will have a follow-up exam every 2 to 4 months for 2 years after the end of treatment, and then as required by the study doctors for as long as the study remains open. These visits will involve a full medical exam, blood samples, lymph node and bone marrow biopsies, and imaging studies.

OUTLINE:

Patients with adverse interphase cytogenetics (11q22 or 17p13 deletion) receive FCO induction therapy:

* Ofatumumab is given IV on day 1 (300 mg) and day 8 (1000 mg) of course 1 and on day 1 (1000 mg) of all subsequent courses.
* Fludarabine phosphate (25mg/m2/d) and cyclophosphamide (250mg/m2/d) are given IV on days 2 through 4 of course 1 and on days 1 through 3 of all subsequent courses. Patients age 70 or older will be given reduced doses of fludarabine (20mg/m2/d) and cyclophosphamide (150mg/m2/d).
* Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.

Patients without adverse interphase cytogenetics receive FO induction therapy:

* Ofatumumab is given IV on day 1 (300mg) and day 8 (1000mg) of course 1 and on day 1 (1000mg) of all subsequent courses.
* Fludarabine phosphate (25mg/m2/d) is given IV on days 2 through 6 of course 1 and on days 1 through 5 of all subsequent courses.
* Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.

All patients are evaluated for minimal residual disease (MRD) by four-color flow cytometric analysis of the peripheral blood after completion of FO or FCO induction therapy, and are subsequently stratified into two groups:

* Patients who are MRD-positive and without evidence of disease progression proceed to consolidation therapy beginning approximately 5 months after completion of induction therapy, consisting of ofatumumab (1000mg) given IV on day 1 of all courses. Treatment repeats every 2 months for up to 4 courses in the absence of disease progression. Patients are followed clinically 2 and 6 months after the last dose of ofatumumab is given, and then every 6 months thereafter.
* Patients who are MRD-negative and without evidence of disease progression are followed clinically every 4 months for 1 year and every 6 months thereafter.

Ofatumumab-based Induction Chemoimmunotherapy in Previously Untreated Patients With CLL/SLL

A Phase II Study of Ofatumumab-Based Induction Chemoimmunotheraphy Followed by Consolidation Ofatumumab Immunotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Death or disease progression defined by the 2008 IWCLL guideline as follows;

* Greater than or equal to 50% increase in the SPD of at least 2 lymph nodes (at least one node must be greater than or equal to 2 cm); appearance of any new lymph nodes on physical examination or imaging
* Greater than or equal to 50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin or CT scan or appearance of palpable hepatomegaly or splenomegaly, which was not previously present
* Greater than or equal to 50% increase in the absolute number of circulating lymphocytes to at least 5000/ul
* Transformation to a more aggressive histology
* Occurrence of any cytopenia attributable to CLL. After treatment: the progression of any cytopenia (unrelated to autoimmune cytopenia), as documented by a decrease of Hb levels by more than 20 g/L (2 g/dL) or to less than 100 g/L (10 g/dL), or by a decrease of platelet counts by more than 50% or to les

Number of Grade 3 and 4 treatment related adverse events as defined by CTCAE version 3.0 criteria.

CTCAE (Common Terminology Criteria for Adverse Events) provides a list of adverse event (AE) terms commonly reported. Each AE term is defined and accompanied by a grading scale that indicates the severity of the AE. The CTCAE v3.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 is a Mild AE; Grade 2 is a Moderate AE; Grade 3 is a Severe AE; Grade 4 is a Life-threatening or disabling AE; and Grade 5 is a Death related to AE

Participants with minimal residual disease (MRD) negativity following the completion of induction chemoimmunotherapy.

Participants with MRD negativity at the completion of consolidation immunotherapy who failed to achieve MRD negativity following completion of induction chemoimmunotherapy

Participants with complete response rates to induction chemoimmunotherapy.

Criteria for complete response (CR): CR requires all of the following:

* Peripheral blood lymphocytes \< 4000/uL
* Absence of significant lymphadenopathy by physical examination and appropriate radiographic techniques (CT or MRI). All lymph nodes must have regressed to \<=1.5cm in greatest diameter
* Absence of hepatomegaly or splenomegaly by physical examination, or appropriate radiographic techniques. Spleen, if enlarged before therapy must have regressed in size and must not be palpable by physical exam.
* Absence of constitutional symptoms
* Normal CBC, defined as: - Polymorphonuclear cells ≥ 1,500/uL - Platelets \> 100,000/uL (untransfused) - Hemoglobin \> 11 g/dL (untransfused)
* Bone marrow biopsy demonstrates normal cellularity for age, with less than 30% of nucleated cells being lymphocytes. Lymphoid nodules should be absent

Participants with complete response rates to induction chemoimmunotherapy.

Criteria for complete response (CR) requires all of the following: Peripheral blood lymphocytes \< 4000/uL. No significant lymphadenopathy. Lymph nodes regressed to \<=1.5cm. No hepatomegaly or splenomegaly. Spleen, if enlarged before therapy must have regressed in size and not be palpable. Absence of constitutional symptoms. Bone marrow biopsy demonstrates normal cellularity for age, with less than 30% of nucleated cells being lymphocytes. No lymphoid nodules.

Criteria for partial response (PR) requires at least one element of an abnormal CBC and at least one of the following: ≥ 50% decrease in peripheral blood lymphocyte count; ≥ 50% reduction in the sum of the products of lymph nodes up to 6 nodes or nodal masses. No new sites or increase in size of nodes; ≥ 50% reduction in pathologic enlargement of the liver and/or spleen by 50%.

Participants overall survival rate 2 years after initiation of induction chemoimmunotherapy

Median relationship of biomarker, CD20 expression with MRD negativity clinical response rate. Flow cytometry was use to quantified surface CD20 on peripheral blood.

University of Virginia

GlaxoSmithKline

Based on CTCAE version 4 for non-hematologic toxicities and 2008 IWCLL guidelines for hematologic toxicities

Fludarabine, cyclophosphamide, and ofatumumab for patients with high-risk FISH changes

FCO (Fludarabine, Cyclophosphamide, and Ofatumumab)

Fludarabine and ofatumumab for patients with non-high-risk FISH changes

FO (Fludarabine and Ofatumumab)

FO Arm (Fludarabine and Ofatumumab)

FCO Arm (Fludarabine, Cyclophosphamide, and Ofatumumab)

Total

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) requiring first-line therapy for CLL or SLL

Wiestner, Adrian MD, PhD

FO Arm

FCO Arm

The analyses included only those subjects who completed the induction period.

Progression Free Survival Rate 2 Years After Initiation of Induction Therapy

Neutropenia Grade 3

Thrombocytopenia Grade 3

Nausea Grade 3

Infusion reaction Grade 3

Neutropenia Grade 4

Lymphopenia Grade 4

Participants received Fludarabine and ofatumumab for patients with non-high-risk FISH changes or Fludarabine, cyclophosphamide, and ofatumumab for patients with high-risk FISH changes.

FO + FCO Arms

All patients included in safety analysis. It was pre-specified to recombine Arms/Groups for this assessment and report irrespective of randomized group.

Number of Grade 3 and 4 Treatment Related Adverse Events

FO ARM

FCO ARM

Participants With Minimal Residual Disease (MRD) Negativity

Participants who achieved MRD negativity at the completion of consolidation immunotherapy

Participants With MRD Negativity at the Completion of Consolidation Immunotherapy Who Failed to Achieve MRD Negativity

FCO Arms

Participants With Complete Response Rates Following Induction Chemoimmunotherapy.

Participants received Fludarabine, cyclophosphamide, and ofatumumab for patients with high-risk FISH changes.

Participants Overall Response Rates Following Induction Chemoimmunotherapy.

Participants Overall Survival Rate After Initiation of Induction Chemoimmunotherapy

Participants with Minimal Residual Disease (MRD) positivity following induction therapy received consolidation Ofatumumab for 4 cycles.

Minimal Residual Disease (MRD) Positivity

No additional therapy received for participants that had Minimal Residual Disease (MRD) negativity.

Minimal Residual Disease (MRD) Negativity

The analyses included only those subjects who completed the induction period. It was pre-specified to have arms/groups recombine for this assessment and report irrespective of randomized group.

Median Relationship of CD20 Expression With MRD Negativity Rate

Heart and Blood Diseases

Lymphoma, B-Cell, Marginal Zone

Lymphocytosis

Waldenstrom Macroglobulinemia

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

Neoplasms, Plasma Cell

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hemorrhagic Disorders

Leukocytosis

Leukocyte Disorders

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

Myeloablative conditioning (Flu/Cy/TBI) followed by CD3/19/34 selected stem cell graft.

Stem Cell Transplantation

Background:

- People who have some kinds of cancer can benefit from donated bone marrow stem cells. These stem cells help produce healthy bone marrow and slow or stop the spread of abnormal cells. However, stem cells transplants do not always work. Also, they may have serious side effects that can cause illness or death. The Bone Marrow Stem Cell Transplant Program is studying methods to make stem cell transplant procedures safer and more effective.

Objectives:

- To test a new procedure that may improve the success and decrease the side effects of stem cell transplants.

Eligibility:

* Individuals 10 to 75 years of age who have a life-threatening illness that may require a stem cell transplant.
* Healthy siblings who are able to provide stem cells for transplant.

Design:

* Participants will be screened with a medical history, physical exam, and blood and urine tests.
* Donor procedures:
* Stem cell donors will start by having apheresis to donate white blood cells.
* Donors will receive filgrastim shots for 5 days to help move stem cells into the blood for collection.
* Donors will have another round of apheresis to donate the stem cells for transplant.
* Recipient procedures:
* Before the transplant, recipients will have radiation twice a day for 3 days and chemotherapy for 7 days.
* After the radiation and chemotherapy, recipients will receive the stem cells provided by the donor.
* After the transplant, recipients will receive the white blood cells provided by the donor.
* Recipients will be monitored closely for 4 months to study the success of the transplant. They will have more followup visits at least yearly thereafter.
* Recipients will have a research apheresis prior to transplant and at 3 months.

Peripheral blood stem cell transplant research carried out by the NHLBI BMT Unit focus on transplant techniques designed to decrease graft versus host disease (GVHD), increase the graft-versus-leukemia (GVL) effect and reduce the risk of post-transplant graft rejection.

Through incremental transplant clinical trials we have shown that by controlling the stem cell (CD34+ cell) and T lymphocyte (CD3+ cell) dose, severe GVHD can be reduced whilst beneficial GVL effects can be preserved. We found that T cell depleted transplants using the Nexell/Baxter Isolex 300i system and subsequently, the Miltenyi CD34+ CliniMACs system to obtain high CD34+ doses depleted of lymphocytes were safe to administer and associated with less severe acute GVHD and promising response rates and overall survival. Our previous trials have helped us to create the transplant environment (significant lymphodepletion and minimal post transplant immunosuppression) that make for an ideal platform for adoptive cellular immunotherapy

This protocol is designed to evaluate the safety and efficacy of an improved ex vivo graft manipulation procedure using the Miltenyi CliniMACs CD 34, 3 and 19 selection system in HLA-matched sibling allogeneic peripheral blood stem cell transplant. The manipulation of the graft is the primary research intervention and all other aspects of clinical management on this protocol are the standard of care. The target CD34+ dose range will be 3 times 10(6)/kg to 10 times 10(6)/kg and the target CD3+ dose range will be 5 x 10(4)/kg to 1 times 10(6)/kg. The technique will preserve greater numbers of NK cells. Once we demonstrate adequacy of engraftment in the first ten recipients, we plan an amendment to permit further use of this protocol to serve as a platform for several planned adoptive cellular therapy initiatives.

The protocol will accrue up to 44 subjects aged 10-75 with a hematological malignancy and their HLA-matched sibling donors, in whom allogeneic stem cell transplantation from an HLA-matched sibling would be routinely indicated. Diagnostic categories will include acute and chronic leukemia, myelodysplastic syndromes, lymphomas, multiple myeloma and myeloproliferative syndromes.

Subjects will receive a myeloablative conditioning regimen of cyclophosphamide (120 mg/kg total), fludarabine (125 mg/m(2) total) and total body irradiation (1200 cGy with lung shielding to 600 cGy), followed by an infusion of a stem cell product prepared using the Miltenyi CliniMACS system for CD34, 3 \& 19 selection. Older subjects will receive a lower dose of irradiation (600 cGy) without lung shielding to reduce the regimen intensity.

The overall objective is to assess the feasibility of using this system as a platform for cellular immunotherapy initiatives. The primary study endpoint will be overall survival at day plus 200. Non-relapse mortality at day plus 200 will be monitored for safety. Secondary endpoints will be standard transplant outcome variables such as non-hematologic toxicity, incidence and severity of acute and chronic GVHD and relapse of disease.

Improving Blood Stem Cell Collection and Transplant Procedures

Peripheral Blood Stem Cell Allotransplantation for Hematological Malignancies Using Ex Vivo CD3, CD19 Depletion and CD34 Selection

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Stem Cell Transplantation for Patients With Cancers of the Blood	NCT00467961	CML (Chronic My... CLL (Chronic Ly... AML (Acute Myel... Acute Lymphocyt... MDS (Myelodyspl...	Miltenyi system	18 Years - 75 Years	National Institutes of Health Clinical Center (CC)
Ofatumumab-based Induction Chemoimmunotherapy in Previously Untreated Patients With CLL/SLL	NCT01145209	Small Lymphocyt... CLL (Chronic Ly...	Fludarabine Pho... Ofatumumab Cyclophosphamid...	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
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)
Improving Blood Stem Cell Collection and Transplant Procedures	NCT01517035	Myelodysplastic... Chronic Myeloge... Acute Lymphobla... CML (Chronic My... CLL (Chronic Ly...	Stem Cell Trans...	2 Years - 80 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)
Improving Blood Stem Cell Collection and Transplant Procedures	NCT01517035	Myelodysplastic... Chronic Myeloge... Acute Lymphobla... CML (Chronic My... CLL (Chronic Ly...	Stem Cell Trans...	2 Years - 80 Years	National Institutes of Health Clinical Center (CC)
Stem Cell Transplantation for Patients With Cancers of the Blood	NCT00467961	CML (Chronic My... CLL (Chronic Ly... AML (Acute Myel... Acute Lymphocyt... MDS (Myelodyspl...	Miltenyi system	18 Years - 75 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for cll (chronic lymphocytic leukemia)