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Patients receive low intensity fludarabine phosphate intravenous (IV) and cyclophosphamide IV on days -6 to -3. Patients undergo donor lymphocyte infusion (DLI) with sirolimus generated donor T-helper 2 (Th2) cells on day 14 (single T-Rapa cell DLI in patients with cluster of differentiation 4 (CD4) count between 100 and 200 inclusive)

Patients receive low intensity fludarabine phosphate IV and cyclophosphamide IV on days -6 to -3. Patients undergo DLI with unmanipulated donor T-cells on day 14 (single T- cell DLI in patients with low CD4 count between 100 and 200 inclusive)

Patients with nonlymphoma diagnosis or rapidly progressive lymphoma undergo DLI with multiple infusions of sirolimus generated donor Th2 cells beginning on day 14 (multiple T-Rapa cell DLI in patients with CD4 count lower than 100 or ALC lower than 300)

Patients receive low-intensity preparative chemotherapy with fludarabine phosphate IV and cyclophosphamide IV on days -6 to -3, cyclosporine by mouth twice a day (PO BID) on days -4 to 100, and standard dose sirolimus PO on days -2 to 14. Patients undergo mobilized allogeneic peripheral blood stem cells (PBSC) on day 0. Patients undergo DLI with 12-day expanded sirolimus-generated donor Th2 cells on day 14.

Patients receive low-intensity preparative chemotherapy with fludarabine phosphate IV and cyclophosphamide IV on days -6 to -3, cyclosporine PO BID on days -4 to 100, and standard dose sirolimus PO on days -2 to 14. Patients undergo mobilized allogeneic PBSC or bone marrow transplant on day 0. Patients undergo DLI with 6-day expanded sirolimus-generated donor Th2 cells on day 14.

Patients receive low-intensity preparative chemotherapy with fludarabine phosphate IV and cyclophosphamide IV on days -6 to -3, cyclosporine PO BID on days -7 to 100 and high dose sirolimus PO on days -4 to 7, Patients undergo mobilized allogeneic PBSC on day 0. Patients undergo DLI with 6-day expanded sirolimus-generated donor Th2 cells on day 14.

Rituximab: 375 mg/m(2)/day intravenous (IV), day 1 (for cluster of differentiation 20 (CD20+) patients).

Fludarabine: 30 mg/m(2)/day intravenous (IV), days -6 to -3.

Etoposide: 50 mg/m(2)/day continuous intravenous (CIV), days 1-4.

Doxorubicin:10 mg/m(2)/day continuous intravenous (CIV), days 1-4.

Vincristine: 0.4 mg/m(2)/day continuous intravenous (CIV), days 1-4.

Cyclophosphamide, 300 mg/m(2)/day intravenous (IV), days -6 to -3.

PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell.

Peripheral blood stem cell (PBSC) transplantation

The dose of the T cells will attempt to be held constant for each study recipient (target dose 2.5 x 10(7) T cells/kg; minimum dose will be 1 x 10(7) T cells/kg).

T cell donor lymphocyte infusion (DLI) with unmanipulated donor T cells

Prednisone: 60 mg/m(2)/day by mouth (PO), days 1-5.

Allogeneic Hematopoietic Stem Cell Transplant.

Allogeneic hematopoietic stem cell transplant (HSCT)

Filgrastim: 5 mcg/kg/day subcutaneous (SC), day 6 (require absolute neutrophil count (ANC) \> 1000, two values; or ANC \> 5000 cells/ul on one occasion).

Filgrastim

The dose of T helper 2 (Th2) cells or unmanipulated donor T cells will attempt to be held constant for each study recipient (target dose 2.5 x 10(7) Th2/kg; minimum dose will be 1 x 10(7) Th2/kg).

T-Rapa cell Donor Lymphocyte Infusion (DLI)

Steven Z Pavletic, M.D.

Background:

Patients with cancers of the blood and immune system often benefit from transplants of stem cells from a genetically well-matched sibling. However, severe problems may follow these transplants because of the high-dose chemotherapy and radiation that accompany the procedure. Also, donated immune cells sometimes attack healthy tissues in a reaction called graft-versus-host disease (GVHD), damaging organs such as the liver, intestines and skin. To reduce toxicity of high-dose preparative chemotherapy, this study performs allogeneic transplant after low doses of chemotherapy. In an attempt to improve anti-tumor effects without increasing GVHD, this study uses donor immune cells (T helper 2 (Th2) cells) grown in the laboratory; some patients will receive standard donor immune cells (not grown in laboratory). All patients will receive immune modulating drugs sirolimus and cyclosporine to prevent GVHD.

Objective:

To determine the safety, treatment effects and rate of GVHD in patients receiving transplants that use low-intensity chemotherapy, sirolimus plus cyclosporine, and transplant booster with either Th2 cells or standard immune cells.

Eligibility:

Patients 16 to 75 years of age with acute or chronic leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or myelodysplastic syndrome.

Patients must have a suitable genetically matched sibling donor and adequate kidney, heart and lung function.

Design: The protocol has three treatment groups: cohort 1, Th2 booster at two weeks post-transplant; cohort 2, standard T cell booster at two weeks post-transplant; cohort 3, multiple infusion of Th2 cells.

Condition: Hematologic Neoplasms, Myeloproliferative Disorders

Intervention: Biological; therapeutic allogeneic lymphocytes

Drug: Sirolimus

Study Type: Interventional

Study Design: Primary Purpose: Treatment

Phase: Phase II

Background

In protocol 99-C-0143, we evaluated a new approach to allogeneic hematopoietic stem cell transplant (HSCT) that involved intensive host T cell ablation and graft augmentation with in vitro generated donor T helper 2 (Th2) cells. Rapid full donor engraftment occurred with this regimen; however, grade II to IV acute graft versus host disease (GVHD) was not significantly reduced in Th2 cell recipients. In an attempt to improve clinical results using Th2 cell graft engineering, this second-generation Th2 cell clinical trial was developed that incorporates the following interventions: (1) In an attempt to reduce transplant-related toxicity, this protocol now uses a very low-intensity host preparative chemotherapy; (2) In an attempt to reduce GVHD, this study will utilize Th2 cells expanded in the presence of the immune modulation agent, rapamycin (sirolimus), as murine Th2 cells grown in rapamycin reduce GVHD more effectively than control Th2 cells; (3) To further reduce GVHD, subjects will receive a short-course of sirolimus therapy in addition to standard cyclosporine GVHD prophylaxis; and (4) Using this novel low-intensity transplant platform, compare in a preliminary manner the post-transplant outcome of patients receiving pre-emptive donor lymphocyte infusion (DLI) using either Th2 cells or unmanipulated donor T cells.

Objectives

In the setting of human leukocyte antigen (HLA)-matched sibling allogeneic HSCT using GVHD prophylaxis of cyclosporine and short-course sirolimus, compare in a preliminary manner the safety, feasibility, alloengraftment, clinical anti-tumor effects, and GVHD rate of low-intensity Preparative Chemotherapy with pre-emptive DLI using either Th2 cells or unmanipulated T cells at day 14 post-HSCT.

Eligibility

Subjects that are 16 to 75 years of age that have a suitable 6/6 HLA-matched sibling donor are potentially eligible. Subjects with a diagnosis of acute or chronic leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or myelodysplastic syndrome are potentially eligible. Adequate kidney, cardiac, and pulmonary function are required.

Design

* Patients age 18 or older with lymphoma (all types) or chronic lymphocytic leukemia will be randomized just prior to the transplant regimen to receive DLI with either donor Th2 cells (cohort 1) or unmanipulated T cells (cohort 2); n=10 patients will be accrued to each arm provided that stopping rules pertaining to excessive GVHD or graft rejection are not met. For these randomized patients, the preparative regimen will consist of low-intensity fludarabine (120 mg/m(2)) plus cyclophosphamide (1200 mg/m(2)) and GVHD prophylaxis will consist of short-course, high-dose sirolimus followed by maintenance cyclosporine. Cohorts 1 and 2 will be compared in a preliminary manner with respect to their post-transplant outcome, in particular: (a) conversion of mixed chimerism to predominant donor chimerism; (b) rate and severity of classical acute and late acute GVHD at the day 100 and day 180 post-transplant time points; and (c) time to induction of leukemia/lymphoma remission (if entering transplant with disease) or time to relapse (if entering transplant in remission).
* Patients with non-lymphoma diagnoses, patients with lymphoma that are under the age of 18 and lymphoma patients that are projected to be unable to complete the protocol-defined therapy through day 180 post-transplant will not be randomized but will be treated on cohort 3 (n=40), which will evaluate transplantation without the Flu/Cy preparative regimen and with pre-emptive Th2 cell DLI. The primary objective of cohort 3 is to evaluate whether transplantation without a preparative regimen will reduce the rate of acute GVHD associated with Th2 cell DLI from 41% (the rate observed with the fludarabine/cyclophosphamide (Flu/Cy) preparative regimen) to a rate of 15% (6 cases out of 40).

Donor Stem Cell Transplant With No or Low-Intensity Chemotherapy Using Sirolimus and Treated Immune Cells to Treat Blood and Lymph Cancers

Allogeneic HSCT Without Preparative Chemotherapy or With Low-Intensity Preparative Chemotherapy Using Sirolimus and Sirolimus-Generated Donor Th2 Cells for Therapy of Refractory Leukemia, Lymphoma, Myeloma, or Myelodysplastic Syndrome

T cells administered by intravenous infusion after patient received transplant.

GVHD of the skin, liver and gut were graded on a scale of 1, 2, 3, and 4 (e.g. the grades are not added together) using the National Institutes of Health Consensus Criteria. Grade 1 is minimal GVHD, Grade 2 is moderate GVHD, Grade 3 is severe GVHD and Grade 4 is very severe GVHD. Grade 4 is a worse outcome than Grade 1.

Detection of cytokine secretion was done by enzyme-linked immunosorbent assay.

Participants are susceptible to opportunistic infections such as bacterial, fungal, viral, protozoan infections and more due to immune suppression from chemotherapy drugs used to treat their disease.

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

National Cancer Institute (NCI)

Principal Investigator

Enrollment was 442 (221 donors; 221 patients). No data was collected from the donor population. 57 recipients were treated on cohorts no longer in the protocol due to amendments. Thus, 164 of 221 recipient data is presented. No patients were eligible for therapy on arm IVD, cohort 2.

Patients receive low intensity fludarabine phosphate intravenous (IV) and cyclophosphamide IV on days -6 to -3. Patients undergo donor lymphocyte infusion (DLI) with sirolimus generated donor T-helper 2 (Th2) cells on day 14 (single T-Rapa cell DLI in patients with cluster of differentiation 4 (CD4) count between 100 and 200 inclusive).

Arm IVD Cohort 1 (Th2 DLI)

Patients with nonlymphoma diagnosis or rapidly progressive lymphoma undergo DLI with multiple infusions of sirolimus generated donor Th2 cells beginning on day 14 (multiple T-Rapa cell DLI in patients with CD4 count lower than 100 or ALC lower than 300).

Arm IVD Cohort 3 (Multiple Th2 DLI)

Arm IVA (12-day Expanded Th2 DLI)

Arm IVB (6-day Expanded Th2 DLI)

Arm IVC (6-day Expanded Th2 DLI and High Dose Sirolimus)

Arm IVDcohort 1 (Th2 DLI)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

118 subjects were enrolled on this study on cohorts no longer represented in the protocol due to amendments. Of the 118, 50% were participants and 50% were donors. These participants are not represented in the data being reported.

Dr. Steven Pavletic

Percentage of Patients to Receive T Cell Infusion

Percentage of Patients With ≥ Grade 2 Acute Graft Versus Host Disease (GVHD)

This outcome measure was not done. Data was not collected for this outcome measure due to premature closure of study.

Detection of of Post-transplantation Cluster of Differentiation 4 (CD4)+ and CD8+ T-cell Production of T Helper 1 -2 (Th1-Th2)-Type Cytokines

Arm IVB Patients receive low-intensity preparative chemotherapy with fludarabine phosphate IV and cyclophosphamide IV on days -6 to -3, cyclosporine PO BID on days -4 to 100, and standard dose sirolimus PO on days -2 to 14. Patients undergo mobilized allogeneic PBSC or bone marrow transplant on day 0. Patients undergo DLI with 6-day expanded sirolimus-generated donor Th2 cells on day 14.

Percentage of Patients With Opportunistic Infection

Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0)

Patients receive low intensity fludarabine phosphate intravenous (IV) and cyclophosphamide IV on days -6 to -3. Patients undergo donor lymphocyte infusion (DLI) with sirolimus generated donor T-helper 2 (Th2) cells on day 14 (single T-Rapa cell DLI in patients with cluster of differentiation 4 (CD4) count between 100 and 200 inclusive).

Etoposide: Etoposide: 50 mg/m(2)/day continuous intravenous (CIV), days 1-4

Doxorubicin: Doxorubicin:10 mg/m(2)/day CIV, days 1-4

Vincristine: Vincristine:0.4 mg/m(2)/day CIV, days 1-4

Cyclophosphamide: Cyclophosphamide, 750 mg/m(2)/day IV, day 5

T cell donor lymphocyte infusion (DLI) with sirolimus generated donor TH-2 cells: The cell of the Th2 cells will attempt to be held constant for each study receipient (target dose 2.5 x 107 Th2/kg; minimum dose will be 1 x 107 Th2/kg).

Donate donor immune cells for recipients.

No data was collected from the donor population.

Healthy Donors

Overall Study

Lymphoma, Non-Hodgkin

Lymphoma, Follicular

Hodgkin Disease

Follicular Lymphoma

Hodgkin Lymphoma

Asian cases with lymphoid or myeloid neoplasma

Controls with selected non-cancer diagnosis who were hospitalized in Hong Kong, Chengdu and Tianjin of Mainland China, and Taiwan

Qing Lan, M.D.

Background:

- Lymphoma rates in Asia have been lower than in the West, but rates have been rising in recent years. Most studies of lymphoma patients have been conducted in the West. Less information is available about the factors that might contribute to the rise of lymphoma in Asia. Researchers want to collect medical and personal histories and samples from people who have recently been diagnosed with lymphoma. This information will help them study possible reasons for this increase.

Objectives:

- To collect samples and histories as part of an introductory study of lymphoma in Asia.

Eligibility:

* People between 18 and 79 years of age who have entered study hospitals in Hong Kong, Taiwan, and mainland China for treatment for any type of lymphoma.
* Healthy volunteers between 18 and 79 who have never had lymphoma.

Design:

* Participants will be screened with a physical exam and medical history.
* They will provide blood samples and cheek cell samples for testing.
* Participants will complete a questionnaire about their personal health history. They will answer questions about exposures to chemicals like pesticides. They will also be asked about family medical history and work and residential history. Finally they will answer questions about lifestyle factors like diet and exercise.
* They will give permission for the researchers to see their medical records. Researchers will also have access to any tumor samples collected as part of treatment.

The contribution of environmental, occupational and genetic factors to lymphoma has generated a series of novel findings in studies of Caucasians. However, none of the chemical associations have been conclusively established and the identification of the key, functional alleles in gene regions associated with risk of NHL requires further elucidation. Further, the ability to follow-up, confirm, and extend these observations is limited by the low prevalence and limited range of several important chemical exposures and the high to complete linkage disequilibrium among key candidate genetic loci in Western populations. To optimize the ability to build on and clarify these findings, it is necessary to investigate populations that differ from Caucasians in both exposure patterns and underlying genetic structure. A multidisciplinary case-control study of lymphoma in Asia provides an opportunity to replicate and extend recent and novel observations made in studies among Caucasians in a population that is distinctly different with regard to patterns of key risk factors, including range of exposures, prevalence of exposures, correlations between exposures, and variation in gene regions of particular interest. Thus, a hospital-based case-control study of lymphoma in Eastern Asia (i.e., AsiaLymph) of 4,200 cases and 4,200 controls to be enrolled over a three-year period will be conducted. In addition, 2,000 cases of myeloid leukemias and an additional 2,400 cases with less common lymphoma subtypes will be enrolled as well. The major postulated risk factors for evaluation in this study are chemical exposures (i.e., organochlorines, trichloroethylene, and benzene) and genetic susceptibility. Other factors potentially related to NHL, such as viral infections, UV exposure, medical conditions, and other lifestyle factors will also be explored. A particularly noteworthy aspect of AsiaLymph is central pathology review with immunophenotyping by two of the world s leading lymphoma pathologists, which will enable accurate analysis of findings by molecular and histologic subtypes. AsiaLymph represents the optimal next step in the DCEG lymphoma portfolio. AsiaLymph should confirm and extend previous findings, and yield novel insights into the causes of lymphoma and leukemia in both Asia and the West.

Study of Lymphoma in Asia

A Multi-Center International Hospital-Based Case-Control Study of Lymphoma in Asia (AsiaLymph)

A large-scale evaluation of genes associated with lymphoma in Asian populations that parallels efforts being conducted in Caucasian populations (e.g., currently a genome-wide association study (GWAS)) would be particularly informative because of Asian population genetic differences in patterns of LD and local haplotype structure.

Other factors potentially related to NHL, such as viral infections, UV exposure, medical conditions, and other lifestyle factors will also beexplored.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Donor Stem Cell Transplant With No or Low-Intensity Chemotherapy Using Sirolimus and Treated Immune Cells to Treat Blood and Lymph Cancers	NCT00074490	Lymphoma Leukemia Myeloproliferat... Multiple Myleom... Myelodysplastic...	Rituximab Fludarabine Etoposide Doxorubicin Vincristine Cyclophosphamid... Peripheral bloo... T cell donor ly... Prednisone Allogeneic hema... Filgrastim T-Rapa cell Don...	11 Years - 90 Years	National Institutes of Health Clinical Center (CC)
Study of Lymphoma in Asia	NCT01584141	Lymphoma, Folli... Lymphoma, Non-H... Multiple Myleom... Lympocytic, Fol... Leukemia Hodgkin Lymphom...		18 Years - 79 Years	National Institutes of Health Clinical Center (CC)

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