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

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Terminated
CT.gov ID
NCT00074490
Collaborator
(none)
442
2
6
163.5
221
1.4

Study Details

Study Description

Brief Summary

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

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

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).

Study Design

Study Type:
Interventional
Actual Enrollment :
442 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Jan 1, 2004
Actual Primary Completion Date :
Jul 20, 2017
Actual Study Completion Date :
Aug 16, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm IVD cohort 1 (Th2 DLI)

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)

Drug: Fludarabine
Fludarabine: 30 mg/m(2)/day intravenous (IV), days -6 to -3.
Other Names:
  • Fludara
  • Drug: Cyclophosphamide
    Cyclophosphamide, 300 mg/m(2)/day intravenous (IV), days -6 to -3.
    Other Names:
  • Cytoxan
  • Procedure: Peripheral blood stem cell (PBSC) transplantation
    PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell.

    Procedure: Allogeneic hematopoietic stem cell transplant (HSCT)
    Allogeneic Hematopoietic Stem Cell Transplant.

    Drug: Filgrastim
    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).
    Other Names:
  • Neupogen
  • Genetic: T-Rapa cell Donor Lymphocyte Infusion (DLI)
    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).

    Experimental: Arm IVD cohort 2 (conventional DLI)

    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)

    Drug: Fludarabine
    Fludarabine: 30 mg/m(2)/day intravenous (IV), days -6 to -3.
    Other Names:
  • Fludara
  • Drug: Cyclophosphamide
    Cyclophosphamide, 300 mg/m(2)/day intravenous (IV), days -6 to -3.
    Other Names:
  • Cytoxan
  • Procedure: Peripheral blood stem cell (PBSC) transplantation
    PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell.

    Genetic: T cell donor lymphocyte infusion (DLI) with unmanipulated donor T cells
    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).

    Procedure: Allogeneic hematopoietic stem cell transplant (HSCT)
    Allogeneic Hematopoietic Stem Cell Transplant.

    Drug: Filgrastim
    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).
    Other Names:
  • Neupogen
  • Experimental: Arm IVD cohort 3 (multiple 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)

    Drug: Rituximab
    Rituximab: 375 mg/m(2)/day intravenous (IV), day 1 (for cluster of differentiation 20 (CD20+) patients).
    Other Names:
  • Rituxan
  • Drug: Fludarabine
    Fludarabine: 30 mg/m(2)/day intravenous (IV), days -6 to -3.
    Other Names:
  • Fludara
  • Drug: Etoposide
    Etoposide: 50 mg/m(2)/day continuous intravenous (CIV), days 1-4.
    Other Names:
  • Toposar
  • Drug: Doxorubicin
    Doxorubicin:10 mg/m(2)/day continuous intravenous (CIV), days 1-4.
    Other Names:
  • Doxil
  • Drug: Vincristine
    Vincristine: 0.4 mg/m(2)/day continuous intravenous (CIV), days 1-4.
    Other Names:
  • Leurocristine
  • Drug: Cyclophosphamide
    Cyclophosphamide, 300 mg/m(2)/day intravenous (IV), days -6 to -3.
    Other Names:
  • Cytoxan
  • Procedure: Peripheral blood stem cell (PBSC) transplantation
    PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell.

    Drug: Prednisone
    Prednisone: 60 mg/m(2)/day by mouth (PO), days 1-5.
    Other Names:
  • Deltasone
  • Procedure: Allogeneic hematopoietic stem cell transplant (HSCT)
    Allogeneic Hematopoietic Stem Cell Transplant.

    Drug: Filgrastim
    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).
    Other Names:
  • Neupogen
  • Genetic: T-Rapa cell Donor Lymphocyte Infusion (DLI)
    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).

    Experimental: Arm IVA (12-day expanded Th2 DLI)

    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.

    Drug: Fludarabine
    Fludarabine: 30 mg/m(2)/day intravenous (IV), days -6 to -3.
    Other Names:
  • Fludara
  • Drug: Cyclophosphamide
    Cyclophosphamide, 300 mg/m(2)/day intravenous (IV), days -6 to -3.
    Other Names:
  • Cytoxan
  • Procedure: Peripheral blood stem cell (PBSC) transplantation
    PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell.

    Genetic: T cell donor lymphocyte infusion (DLI) with unmanipulated donor T cells
    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).

    Procedure: Allogeneic hematopoietic stem cell transplant (HSCT)
    Allogeneic Hematopoietic Stem Cell Transplant.

    Drug: Filgrastim
    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).
    Other Names:
  • Neupogen
  • Experimental: Arm IVB (6-day expanded Th2 DLI)

    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.

    Drug: Fludarabine
    Fludarabine: 30 mg/m(2)/day intravenous (IV), days -6 to -3.
    Other Names:
  • Fludara
  • Drug: Cyclophosphamide
    Cyclophosphamide, 300 mg/m(2)/day intravenous (IV), days -6 to -3.
    Other Names:
  • Cytoxan
  • Procedure: Peripheral blood stem cell (PBSC) transplantation
    PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell.

    Genetic: T cell donor lymphocyte infusion (DLI) with unmanipulated donor T cells
    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).

    Procedure: Allogeneic hematopoietic stem cell transplant (HSCT)
    Allogeneic Hematopoietic Stem Cell Transplant.

    Drug: Filgrastim
    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).
    Other Names:
  • Neupogen
  • Experimental: Arm IVC (6-day expanded Th2 DLI and High-Dose Sirolimus)

    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.

    Drug: Fludarabine
    Fludarabine: 30 mg/m(2)/day intravenous (IV), days -6 to -3.
    Other Names:
  • Fludara
  • Drug: Cyclophosphamide
    Cyclophosphamide, 300 mg/m(2)/day intravenous (IV), days -6 to -3.
    Other Names:
  • Cytoxan
  • Procedure: Peripheral blood stem cell (PBSC) transplantation
    PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell.

    Genetic: T cell donor lymphocyte infusion (DLI) with unmanipulated donor T cells
    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).

    Procedure: Allogeneic hematopoietic stem cell transplant (HSCT)
    Allogeneic Hematopoietic Stem Cell Transplant.

    Drug: Filgrastim
    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).
    Other Names:
  • Neupogen
  • Outcome Measures

    Primary Outcome Measures

    1. Percentage of Patients to Receive T Cell Infusion [first 100 days post-transplant]

      T cells administered by intravenous infusion after patient received transplant.

    2. Percentage of Patients With ≥ Grade 2 Acute Graft Versus Host Disease (GVHD) [first 100 days post-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.

    Secondary Outcome Measures

    1. Detection of of Post-transplantation Cluster of Differentiation 4 (CD4)+ and CD8+ T-cell Production of T Helper 1 -2 (Th1-Th2)-Type Cytokines [First 100 days post-transplant]

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

    2. Percentage of Patients With Opportunistic Infection [First 100 days post-transplant]

      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.

    3. Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0) [Date treatment consent signed to date off study, approximately 5 years]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    11 Years to 90 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    • INCLUSION CRITERIA: PATIENT RECIPIENT
    1. Patients with hematologic malignancies, myelodysplasia, or myeloproliferative disorders, as summarized in the following table. The diagnosis must be histologically confirmed by the Laboratory of Pathology of National Cancer Institute (NCI) or Hackensack (There will be no central pathology review).

    2. Chronic Lymphocytic Leukemia - Disease Status: a) Relapse post-fludarabine, b) Non-Complete Response (CR) after salvage regimen.

    Hodgkin's and Non-Hodgkin's Lymphoma (all types, including Mantle Cell Lymphoma)

    • Disease Status: a) Primary treatment failure, b) Relapse after autologous stem cell transplant (SCT), c) Non-CR after salvage regimen

    Special Cases of High-Risk Lymphoma, including but not limited to : (1) plasma dendritic cell type, 2) Hepato-splenic T cell type, 3) gamma delta pinniculitic T cell type, 4) Muco-cutaneous natural killer (NK) cell type and 5) stage III-IV nasal NK cell type- Disease Status: a) Primary treatment failure, b) Relapse after autologous, c) Non-CR after salvage regimen, d) In first CR or any later CR

    Chronic Epstein Barr Virus (EBV)-associated lymphoproliferative disease a) At any point after diagnosis, including up-front therapy

    Multiple Myeloma - Disease Status: a) Primary treatment failure, b) Relapse after autologous stem cell transplant (SCT), c) Non-CR after salvage regimen.

    Acute Myelogenous Leukemia - Disease Status: a) CR number 1 and high-risk [excludes t(8;21), t(15;17), or inv(16)], b) CR number 2 or greater).

    Acute Lymphocytic Leukemia - Disease Status: a) CR number 1 plus high-risk [t(9;22) or bcr-abl(+); t(4;11), 1(1;19), t(8;14)], b) In CR number2 or greater.

    Myelodysplastic Syndrome - Disease Status: a) Refractory Anemia with Excess Blasts (RAEB), b) Refractory Anemia with Excess Blasts in Transformation (RAEB-T) (requires marrow and blood blasts less than 10% after induction chemotherapy).

    Myeloproliferative disorders - Disease Status: a) Idiopathic myelofibrosis, b) Polycythemia vera, c) Essential thrombocytosis, d) Chronic myelomonocytic leukemia.

    Chronic Myelogenous Leukemia (CML) - Disease Status: a) Chronic phase CML, refractory to imatinib treatment b) Accelerated phase CML. b) Accelerated phase CML

    Patients with myeloproliferative disorders must be end-stage, which is primarily defined as disease severity refractory to splenectomy.

    1. Patient age of 16 to 75 years.

    2. Consenting first degree relative matched at 6/6 HLA antigens (A, B, and DR).

    3. Patient or legal guardian must be able to give informed consent.

    4. All previous intravenous therapy administered outside of the National Institutes of Health (NIH) Clinical Center must be completed at least 2 weeks prior to study entry, with recovery to less than or equal to non-hematologic grade 2 toxicity of previous therapy.

    5. Eastern Cooperative Oncology Group (ECOG) performance status equal to 0 or 1.

    6. Life expectancy of at least 3 months.

    7. Patients with acute leukemia must have chemotherapy sensitive disease, as defined by at least a 50% reduction in circulating absolute blast count due to the most proximal regimen.

    8. Left ventricular ejection fraction greater than or equal to 45%, preferably by 2-dimension (2-D) echo, or by multi-gated acquisition scan (MUGA). However, patients with left ventricular ejection fraction (LVEF) of between 35% and 44% may also be eligible provided that such patients are cleared by a Cardiology Consultation that must include a cardiac stress test.

    9. Corrected diffusing capacity or transfer of the lung for carbon monoxide (DLCO) greater than 50% of expected value.

    10. Creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than or equal to 50 ml/min.

    11. Serum total bilirubin less than 2.5 mg/dl; serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) equal 2.5 times upper limit of normal. Values above these levels may be accepted, at the discretion of the principal investigator (PI) or study chairman, if such elevations are thought to be due to liver involvement by malignancy or graft versus host disease (GVHD).

    12. Adequate central venous access potential.

    13. Potential patients referred for the study may not be eligible for the experimental protocol therapy due to reasons such as uncertainty about donor human leukocyte antigen (HLA) typing or need to control malignant disease, infection, or metabolic abnormality such as hypercalcemia on a emergent basis. Should a referred patient present to us in such a scenario, the patient will be referred back to their primary hematologist-oncologist for treatment. However, if referral back to the referring physician is not in the best interest of the patient according to the clinical judgement of the principal investigator (PI), then the patient may receive standard treatment for the malignant disease or complicating conditions (infection, metabolic problems under the current study. In other cases, a patient may have reasonable control of malignancy but does not meet the cluster of differentiation 4 (CD4) cell cut-off of 50 cells per microliter required for cohort 3 therapy; in such cases, standard care chemotherapy regimens may be administered for the specific goal of reducing the CD4 count (that is, immune depleting regimens such as the pentostatin plus cyclophosphamide combination, administered similar to the manner that we have developed on protocol 08-C- 0088). If it becomes apparent that the patient will not be able to proceed to experimental therapy, then he/she must come off study. Recipient-Subjects receiving a standard therapy, and availability of receiving the same treatment elsewhere, outside of a research protocol. Because such standard care therapy is not experimental, it is not necessary to complete the eligibility criteria prior to receiving such standard care; however, prior to initiation of the experimental therapy, the patient must meet each of the eligibility criteria detailed above. Attempts will be made to standardize such pretransplant chemotherapy (by administration of etoposide, prednisolone, oncovin, cyclophosphamide, hydroxydaunorubicin, fludarabine, rituximab (EPOCH-FR) chemotherapy, which is detailed later in this protocol); however, other regimens using approved agents will be allowed if such regimens are thought to be in the best interest of the patient.

    INCLUSION CRITERIA: DONOR

    1. First-degree relative with genotypic identity at 6/6 HLA loci (HLA- A, B, and DR).

    2. Age 11 to 90 years and able to give consent or assent. For donors < 18 years old, the legal guardian must be able to provide informed consent.

    3. Adequate venous access for peripheral apheresis, or consent to use a temporary central venous catheter for apheresis.

    4. Donors must be human immunodeficiency virus (HIV) negative.

    5. Donors with a history of hepatitis B or hepatitis C infection may be eligible. However, eligibility determination of such patients will require a hepatology consultation. The risk/benefit of the transplant and the possibility of transmitting hepatitis will be discussed with the patient and eligibility will then be determined by the principal investigator and lead associate investigator (LAI).

    6. Lactating donors must substitute formula feeding for her infant during period of filgrastim administration (to prevent any filgrastim effect on infant).

    EXCLUSION CRITERIA: PATIENT

    1. Active infection that is not responding to antimicrobial therapy.

    2. Active central nervous system (CNS) involvement by malignancy.

    3. HIV infection (treatment may result in progression of HIV and other viral infections).

    4. Chronic active hepatitis B. Patient may be hepatitis B core antibody positive. For patients with concomitant positive hepatitis B surface antigen, patient will require a hepatology consultation. The risk/benefit profile of transplant and hepatitis B will be discussed with the patient and eligibility determined by the principal investigator and Lead Associate Investigator.

    5. Hepatitis C infection. Patient may have hepatitis C infection. However, each patient will require a hepatology consultation. The risk/benefit profile of transplant and hepatitis C will be discussed with the patient and eligibility determined by the principal investigator and Lead Associate Investigator.

    6. Pregnant or lactating. Patients of childbearing potential must use an effective method of contraception. The effects of the chemotherapy, the subsequent transplant and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to the infant.

    7. History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.

    EXCLUSION CRITERIA: DONOR

    1. History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.

    2. History of hypertension that is not controlled by medication, stroke, autoimmune disease, or severe heart disease (donors with symptomatic angina will be excluded). Donors with a history of coronary artery bypass grafting or angioplasty who are symptom free will receive a cardiology evaluation and be considered on a case-by-case basis.

    3. History of prior malignancy. However, cancer survivors who have undergone potentially curative therapy may be considered for stem cell donation on a case-by-case basis. In addition, donors with localized cancer such as prostate cancer that are on a watch-and-wait management due to the low-risk of disease progression may also be considered for stem cell donation on a case-by-case basis. The risk/benefit of the transplant and the possibility of transmitting viable tumor cells at the time of transplantation will be discussed with the patient.

    4. Donors must not be pregnant (unknown effect of filgrastim on fetus). Donors of childbearing potential must use an effective method of contraception.

    5. Anemia (Hemoglobin (Hb) less than 11 gm/dl) or thrombocytopenia (platelets less than 100,000 per microliter). However, potential donors with Hb levels less than 11 gm/dl that is due to iron deficiency will be eligible as long as the donor is initiated on iron replacement therapy and the case is individually approved by National Institutes of Health (NIH) or Hackensack Blood Bank.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda Maryland United States 20892
    2 Hackensack University Medical Center Hackensack New Jersey United States 07601

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Steven Z Pavletic, M.D., National Cancer Institute (NCI)

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Steven Pavletic, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
    ClinicalTrials.gov Identifier:
    NCT00074490
    Other Study ID Numbers:
    • 040055
    • 04-C-0055
    • NCT00077480
    First Posted:
    Dec 15, 2003
    Last Update Posted:
    Dec 31, 2018
    Last Verified:
    Dec 1, 2018
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Steven Pavletic, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Enrollment was 442 (221 donors; 221 patients). 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.
    Arm/Group Title Arm IVD Cohort 1 (Th2 DLI) 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) Healthy Donors
    Arm/Group Description 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). 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. Donate donor immune cells for recipients. No data was collected from the donor population.
    Period Title: Overall Study
    STARTED 1 34 40 44 45 221
    COMPLETED 1 27 40 44 42 221
    NOT COMPLETED 0 7 0 0 3 0

    Baseline Characteristics

    Arm/Group Title Arm IVDcohort 1 (Th2 DLI) 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) Total
    Arm/Group Description 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 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. Total of all reporting groups
    Overall Participants 1 34 40 44 45 164
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    1
    100%
    33
    97.1%
    36
    90%
    41
    93.2%
    42
    93.3%
    153
    93.3%
    >=65 years
    0
    0%
    1
    2.9%
    4
    10%
    3
    6.8%
    3
    6.7%
    11
    6.7%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    56
    45.96
    (12.41)
    49.68
    (12.92)
    47.66
    (12.45)
    50.19
    (13.50)
    49.44
    (13.12)
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    8
    23.5%
    17
    42.5%
    21
    47.7%
    13
    28.9%
    59
    36%
    Male
    1
    100%
    26
    76.5%
    23
    57.5%
    23
    52.3%
    32
    71.1%
    105
    64%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    11
    32.4%
    8
    20%
    10
    22.7%
    4
    8.9%
    33
    20.1%
    Not Hispanic or Latino
    1
    100%
    23
    67.6%
    32
    80%
    34
    77.3%
    41
    91.1%
    131
    79.9%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    2
    5.9%
    0
    0%
    2
    4.5%
    1
    2.2%
    5
    3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    1
    2.9%
    4
    10%
    2
    4.5%
    4
    8.9%
    11
    6.7%
    White
    1
    100%
    20
    58.8%
    28
    70%
    30
    68.2%
    36
    80%
    115
    70.1%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    11
    32.4%
    8
    20%
    10
    22.7%
    4
    8.9%
    33
    20.1%
    Region of Enrollment (Count of Participants)
    United States
    1
    100%
    34
    100%
    40
    100%
    44
    100%
    45
    100%
    164
    100%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Patients to Receive T Cell Infusion
    Description T cells administered by intravenous infusion after patient received transplant.
    Time Frame first 100 days post-transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Arm IVD Cohort 1 (Th2 DLI) 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/Group Description 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 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.
    Measure Participants 1 27 40 44 42
    Number [percentage of patients]
    100
    100
    100
    100
    100
    2. Primary Outcome
    Title Percentage of Patients With ≥ Grade 2 Acute Graft Versus Host Disease (GVHD)
    Description 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.
    Time Frame first 100 days post-transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Arm IVD Cohort 1 (Th2 DLI) 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/Group Description 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 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.
    Measure Participants 1 27 40 44 42
    Number [percentage of patients]
    0
    11.11
    10
    40.91
    40.48
    3. Secondary Outcome
    Title Detection of of Post-transplantation Cluster of Differentiation 4 (CD4)+ and CD8+ T-cell Production of T Helper 1 -2 (Th1-Th2)-Type Cytokines
    Description Detection of cytokine secretion was done by enzyme-linked immunosorbent assay.
    Time Frame First 100 days post-transplant

    Outcome Measure Data

    Analysis Population Description
    This outcome measure was not done. Data was not collected for this outcome measure due to premature closure of study.
    Arm/Group Title Arm IVD Cohort 1 (Th2 DLI) 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/Group Description 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 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.
    Measure Participants 0 0 0 0 0
    4. Secondary Outcome
    Title Percentage of Patients With Opportunistic Infection
    Description 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.
    Time Frame First 100 days post-transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Arm IVD Cohort 1 (Th2 DLI) 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/Group Description 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 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. 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. 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.
    Measure Participants 1 27 40 44 42
    Number [percentage of participants]
    0
    0%
    11.11
    32.7%
    7.50
    18.8%
    9.09
    20.7%
    11.90
    26.4%
    5. Secondary Outcome
    Title Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0)
    Description 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.
    Time Frame Date treatment consent signed to date off study, approximately 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Arm IVD Cohort 1 (Th2 DLI) 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/Group Description 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 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.
    Measure Participants 1 27 40 44 42
    Count of Participants [Participants]
    1
    100%
    27
    79.4%
    40
    100%
    44
    100%
    42
    93.3%

    Adverse Events

    Time Frame Date treatment consent signed to date off study, approximately 5 years.
    Adverse Event Reporting Description 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.
    Arm/Group Title Arm IVD Cohort 1 (Th2 DLI) 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/Group Description 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 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.
    All Cause Mortality
    Arm IVD Cohort 1 (Th2 DLI) 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)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/1 (0%) 14/34 (41.2%) 22/40 (55%) 24/44 (54.5%) 22/45 (48.9%)
    Serious Adverse Events
    Arm IVD Cohort 1 (Th2 DLI) 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)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/1 (100%) 22/34 (64.7%) 37/40 (92.5%) 35/44 (79.5%) 31/45 (68.9%)
    Blood and lymphatic system disorders
    Blood/Bone Marrow - Other (engraftment syndrome) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Febrile neutropenia 0/1 (0%) 0 2/34 (5.9%) 3 10/40 (25%) 11 25/44 (56.8%) 25 5/45 (11.1%) 5
    Hemoglobin 0/1 (0%) 0 2/34 (5.9%) 2 8/40 (20%) 14 10/44 (22.7%) 16 3/45 (6.7%) 4
    Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Thrombotic microangiopathy 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Cardiac disorders
    Cardiac Arrhythmia - Other (atrial fibrillation) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Cardiac General - Other (congestive heart failure) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Cardiac ischemia/infarction 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Conduction abnormality/atrioventricular heart block::AV Block-First degree 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Conduction abnormality/atrioventricular heart block::AV Block-Second degree Mobitz Type II 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Left ventricular diastolic dysfunction 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Left ventricular systolic dysfunction 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 1/44 (2.3%) 1 2/45 (4.4%) 2
    Pericardial effusion (non-malignant) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Restrictive cardiomyopathy 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Supraventricular and nodal arrhythmia::Atrial fibrillation 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Supraventricular and nodal arrhythmia::Atrial flutter 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Supraventricular and nodal arrhythmia::Sinus tachycardia 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Supraventricular and nodal arrhythmia::Supraventricular tachycardia 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 2/44 (4.5%) 2 0/45 (0%) 0
    Endocrine disorders
    Pancreatic endocrine: glucose intolerance 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 5/44 (11.4%) 5 0/45 (0%) 0
    Thyroid function, high (hyperthyroidism, thyrotoxicosis) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Thyroid function, low (hypothyroidism) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 1/44 (2.3%) 1 0/45 (0%) 0
    Eye disorders
    Dry eye syndrome 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Ocular/Visual - Other (GVHD) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Ocular/Visual - Other (ocular GVHD, restasis started; EXTENSIVE CGVHD) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Ophthalmoplegia/diplopia (double vision) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Gastrointestinal disorders
    Colitis 0/1 (0%) 0 2/34 (5.9%) 2 1/40 (2.5%) 1 3/44 (6.8%) 3 0/45 (0%) 0
    Colitis, infectious (e.g., Clostridium difficile) 0/1 (0%) 0 1/34 (2.9%) 1 2/40 (5%) 2 7/44 (15.9%) 7 7/45 (15.6%) 7
    Diarrhea 1/1 (100%) 1 4/34 (11.8%) 4 10/40 (25%) 10 16/44 (36.4%) 16 11/45 (24.4%) 11
    Dry mouth/salivary gland (xerostomia) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Dysphagia (difficulty swallowing) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 2/44 (4.5%) 2 1/45 (2.2%) 1
    Esophagitis 0/1 (0%) 0 0/34 (0%) 0 3/40 (7.5%) 3 1/44 (2.3%) 1 0/45 (0%) 0
    Gastritis (including bile reflux gastritis) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Gastrointestinal - Other (Abdominal pain (GVHD of the gut) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Gastrointestinal - Other (abdominal pain, nausea and diarrhea c/w GVHD) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Hemorrhage, GI::Lower GI NOS 0/1 (0%) 0 2/34 (5.9%) 2 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Hemorrhage, GI::Rectum 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 2 1/44 (2.3%) 1 0/45 (0%) 0
    Hemorrhage, GI::Upper GI NOS 0/1 (0%) 0 1/34 (2.9%) 1 2/40 (5%) 2 0/44 (0%) 0 3/45 (6.7%) 3
    Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation) 0/1 (0%) 0 1/34 (2.9%) 1 3/40 (7.5%) 3 1/44 (2.3%) 1 0/45 (0%) 0
    Mucositis/stomatitis (clinical exam)::Oral cavity 0/1 (0%) 0 1/34 (2.9%) 1 3/40 (7.5%) 3 2/44 (4.5%) 2 0/45 (0%) 0
    Mucositis/stomatitis (functional/symptomatic)::Oral cavity 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Nausea 0/1 (0%) 0 2/34 (5.9%) 2 3/40 (7.5%) 4 5/44 (11.4%) 5 1/45 (2.2%) 1
    Obstruction, GI::Gallbladder 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Obstruction, GI::Small bowel NOS 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Pain::Abdomen NOS 0/1 (0%) 0 2/34 (5.9%) 2 2/40 (5%) 2 2/44 (4.5%) 2 3/45 (6.7%) 3
    Pain::Oral cavity 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 1/45 (2.2%) 1
    Perforation, GI::Small bowel NOS 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Typhlitis (cecal inflammation) 0/1 (0%) 0 1/34 (2.9%) 2 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Ulcer, GI::Stomach 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Vomiting 0/1 (0%) 0 1/34 (2.9%) 1 3/40 (7.5%) 3 1/44 (2.3%) 1 1/45 (2.2%) 1
    General disorders
    Death not associated with CTCAE term::Death NOS 0/1 (0%) 0 1/34 (2.9%) 1 3/40 (7.5%) 3 2/44 (4.5%) 2 5/45 (11.1%) 5
    Death not associated with CTCAE term::Disease progression NOS 0/1 (0%) 0 7/34 (20.6%) 8 9/40 (22.5%) 9 12/44 (27.3%) 12 11/45 (24.4%) 11
    Death not associated with CTCAE term::Multi-organ failure 0/1 (0%) 0 2/34 (5.9%) 2 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Death not associated with CTCAE term::Sudden death 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 2/44 (4.5%) 2 0/45 (0%) 0
    Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L) 0/1 (0%) 0 1/34 (2.9%) 1 14/40 (35%) 14 10/44 (22.7%) 10 0/45 (0%) 0
    Hemorrhage/Bleeding - Other (Conjunctival, low platelet ct) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Immune system disorders
    Allergic reaction/hypersensitivity (including drug fever) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infections and infestations
    Infection (documented clinically or microbiologically) 0/1 (0%) 0 2/34 (5.9%) 2 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Infection (documented clinically 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection 0/1 (0%) 0 8/34 (23.5%) 9 5/40 (12.5%) 6 13/44 (29.5%) 13 1/45 (2.2%) 1
    Infection 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils 0/1 (0%) 0 0/34 (0%) 0 7/40 (17.5%) 7 0/44 (0%) 0 0/45 (0%) 0
    Infection 0/1 (0%) 0 0/34 (0%) 0 3/40 (7.5%) 3 3/44 (6.8%) 3 0/45 (0%) 0
    Infection 0/1 (0%) 0 1/34 (2.9%) 2 1/40 (2.5%) 1 12/44 (27.3%) 12 2/45 (4.4%) 2
    Infection 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 0/44 (0%) 0 0/45 (0%) 0
    Infection 0/1 (0%) 0 0/34 (0%) 0 3/40 (7.5%) 4 1/44 (2.3%) 1 0/45 (0%) 0
    Infection 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 2/44 (4.5%) 2 0/45 (0%) 0
    Infection 0/1 (0%) 0 1/34 (2.9%) 1 1/40 (2.5%) 1 0/44 (0%) 0 1/45 (2.2%) 1
    Infection 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Infection 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 3/44 (6.8%) 3 0/45 (0%) 0
    Infection 0/1 (0%) 0 1/34 (2.9%) 1 1/40 (2.5%) 1 2/44 (4.5%) 2 1/45 (2.2%) 1
    Infection - Other (C.Diff: PCR +) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Infection - Other (HHV6 reactivation; admitted for anemia & leukocytosis) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection - Other (Influenza A +) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Infection - Other (R. wrist septic arthritis) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection - Other (pseudomonas bacteremia/sepsis.) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Infection - Other (worsening right great toe pain with drainage and now neutropenic) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Appendix 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Blood 1/1 (100%) 1 13/34 (38.2%) 14 10/40 (25%) 11 18/44 (40.9%) 22 13/45 (28.9%) 13
    Infection with normal ANC or Grade 1 or 2 neutrophils::Bone (osteomyelitis) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Brain (encephalitis, infectious) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 4/44 (9.1%) 5 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Brain + Spinal cord (encephalomyelitis) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils::Bronchus 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 1/45 (2.2%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils::Catheter-related 0/1 (0%) 0 0/34 (0%) 0 6/40 (15%) 6 4/44 (9.1%) 4 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Colon 1/1 (100%) 1 1/34 (2.9%) 1 7/40 (17.5%) 7 8/44 (18.2%) 8 6/45 (13.3%) 6
    Infection with normal ANC or Grade 1 or 2 neutrophils::External ear (otitis externa) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Lung (pneumonia) 0/1 (0%) 0 4/34 (11.8%) 4 12/40 (30%) 13 24/44 (54.5%) 24 11/45 (24.4%) 11
    Infection with normal ANC or Grade 1 or 2 neutrophils::Lymphatic 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 2/45 (4.4%) 2
    Infection with normal ANC or Grade 1 or 2 neutrophils::Oral cavity-gums (gingivitis) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils::Peritoneal cavity 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Pharynx 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Pleura (empyema) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Rectum 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 0/44 (0%) 0 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Sinus 0/1 (0%) 0 0/34 (0%) 0 4/40 (10%) 4 4/44 (9.1%) 4 2/45 (4.4%) 2
    Infection with normal ANC or Grade 1 or 2 neutrophils::Skin (cellulitis) 0/1 (0%) 0 0/34 (0%) 0 3/40 (7.5%) 4 3/44 (6.8%) 3 4/45 (8.9%) 4
    Infection with normal ANC or Grade 1 or 2 neutrophils::Stomach 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 1/44 (2.3%) 1 1/45 (2.2%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils::Upper airway NOS 0/1 (0%) 0 0/34 (0%) 0 6/40 (15%) 6 4/44 (9.1%) 4 6/45 (13.3%) 6
    Infection with normal ANC or Grade 1 or 2 neutrophils::Urinary tract NOS 0/1 (0%) 0 1/34 (2.9%) 1 4/40 (10%) 4 4/44 (9.1%) 4 1/45 (2.2%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils::Wound 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection with unknown ANC::Abdomen NOS 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Infection with unknown ANC::Blood 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 1/44 (2.3%) 1 2/45 (4.4%) 2
    Infection with unknown ANC::Lung (pneumonia) 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 3/44 (6.8%) 3 1/45 (2.2%) 1
    Infection with unknown ANC::Meninges (meningitis) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Infection with unknown ANC::Sinus 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 1/45 (2.2%) 1
    Infection with unknown ANC::Upper aerodigestive NOS 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection with unknown ANC::Upper airway NOS 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Infection with unknown ANC::Urinary tract NOS 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Viral hepatitis 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Injury, poisoning and procedural complications
    Fracture 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 3/44 (6.8%) 3 0/45 (0%) 0
    Investigations
    ALT, SGPT (serum glutamic pyruvic transaminase) 0/1 (0%) 0 5/34 (14.7%) 10 4/40 (10%) 6 16/44 (36.4%) 25 5/45 (11.1%) 18
    AST, SGOT(serum glutamic oxaloacetic transaminase) 0/1 (0%) 0 1/34 (2.9%) 1 4/40 (10%) 10 12/44 (27.3%) 16 1/45 (2.2%) 2
    Alkaline phosphatase 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 2 1/44 (2.3%) 1 0/45 (0%) 0
    Amylase 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Carbon monoxide diffusion capacity (DL(co)) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Cardiac troponin I (cTnI) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 1/44 (2.3%) 1 0/45 (0%) 0
    Creatinine 0/1 (0%) 0 0/34 (0%) 0 3/40 (7.5%) 8 4/44 (9.1%) 4 0/45 (0%) 0
    Leukocytes (total WBC) 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 0/44 (0%) 0 0/45 (0%) 0
    Lipase 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Neutrophils/granulocytes (ANC/AGC) 0/1 (0%) 0 3/34 (8.8%) 3 15/40 (37.5%) 21 13/44 (29.5%) 20 7/45 (15.6%) 10
    PTT (Partial Thromboplastin Time) 0/1 (0%) 0 1/34 (2.9%) 1 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Platelets 0/1 (0%) 0 2/34 (5.9%) 3 7/40 (17.5%) 8 7/44 (15.9%) 18 3/45 (6.7%) 9
    Prolonged QTc interval 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 1/44 (2.3%) 1 0/45 (0%) 0
    Weight loss 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Metabolism and nutrition disorders
    Acidosis (metabolic or respiratory) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 2/44 (4.5%) 2 0/45 (0%) 0
    Albumin, serum-low (hypoalbuminemia) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 1/44 (2.3%) 3 0/45 (0%) 0
    Alkalosis (metabolic or respiratory) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Anorexia 0/1 (0%) 0 1/34 (2.9%) 1 1/40 (2.5%) 1 2/44 (4.5%) 2 0/45 (0%) 0
    Calcium, serum-low (hypocalcemia) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Dehydration 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 0/44 (0%) 0 0/45 (0%) 0
    Glucose, serum-high (hyperglycemia) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 2/44 (4.5%) 2 0/45 (0%) 0
    Glucose, serum-low (hypoglycemia) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Metabolic/Laboratory - Other (ph>7.5 with life threating consequences ALKALOSIS) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Metabolic/Laboratory - Other (steroid induced hyperglycemia) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Phosphate, serum-low (hypophosphatemia) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 5/44 (11.4%) 7 1/45 (2.2%) 1
    Potassium, serum-high (hyperkalemia) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Potassium, serum-low (hypokalemia) 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 3 5/44 (11.4%) 6 0/45 (0%) 0
    Sodium, serum-low (hyponatremia) 0/1 (0%) 0 2/34 (5.9%) 2 2/40 (5%) 3 3/44 (6.8%) 3 0/45 (0%) 0
    Triglyceride, serum-high (hypertriglyceridemia) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Tumor lysis syndrome 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Uric acid, serum-high (hyperuricemia) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 1/45 (2.2%) 2
    Musculoskeletal and connective tissue disorders
    Arthritis (non-septic) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 2/44 (4.5%) 2 0/45 (0%) 0
    Muscle weakness, generalized or specific area (not due to neuropathy)::Whole body/generalized 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 3/44 (6.8%) 3 1/45 (2.2%) 1
    Osteonecrosis (avascular necrosis) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Pain::Back 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Pain::Bone 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Pain::Chest wall 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 2/44 (4.5%) 2 0/45 (0%) 0
    Pain::Neck 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Secondary Malignancy - 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Secondary Malignancy - possibly related to cancer treatment (squamous cell carcinoma) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Secondary Malignancy - possibly related to cancer treatment 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Nervous system disorders
    Bilirubin (hyperbilirubinemia) 0/1 (0%) 0 3/34 (8.8%) 4 6/40 (15%) 7 7/44 (15.9%) 8 0/45 (0%) 0
    CNS cerebrovascular ischemia 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 0/44 (0%) 0 0/45 (0%) 0
    Cognitive disturbance 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Dizziness 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Edema: head and neck 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Encephalopathy 0/1 (0%) 0 0/34 (0%) 0 3/40 (7.5%) 3 0/44 (0%) 0 0/45 (0%) 0
    Hemorrhage/Bleeding - Other (Massive Intracranial hemorrhage of left frontal lobe mass) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Leukoencephalopathy (radiographic findings) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Neuropathy: cranial::CN III Pupil, upper eyelid, extra ocular movements 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 0/44 (0%) 0 0/45 (0%) 0
    Neuropathy: cranial::CN VI Lateral deviation of eye 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Neuropathy: motor 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 3/44 (6.8%) 4 0/45 (0%) 0
    Neuropathy: sensory 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 2/44 (4.5%) 2 0/45 (0%) 0
    Pain::Head/headache 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 1/45 (2.2%) 1
    Seizure 0/1 (0%) 0 2/34 (5.9%) 2 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Somnolence/depressed level of consciousness 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 1/44 (2.3%) 1 0/45 (0%) 0
    Syncope (fainting) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Psychiatric disorders
    Confusion 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 1/44 (2.3%) 1 1/45 (2.2%) 1
    Mental status 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Psychosis (hallucinations/delusions) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 1/45 (2.2%) 1
    Renal and urinary disorders
    Cystitis 0/1 (0%) 0 1/34 (2.9%) 1 1/40 (2.5%) 1 1/44 (2.3%) 1 0/45 (0%) 0
    Hemorrhage, GU::Urinary NOS 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Renal failure 0/1 (0%) 0 1/34 (2.9%) 1 4/40 (10%) 4 5/44 (11.4%) 5 2/45 (4.4%) 2
    Stricture/stenosis (including anastomotic), GU::Urethra 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Adult Respiratory Distress Syndrome (ARDS) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Apnea 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Cough 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Dyspnea (shortness of breath) 0/1 (0%) 0 1/34 (2.9%) 1 5/40 (12.5%) 5 3/44 (6.8%) 3 1/45 (2.2%) 1
    Edema, larynx 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Hemorrhage, pulmonary/upper respiratory::Bronchopulmonary NOS 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 1/45 (2.2%) 1
    Hemorrhage, pulmonary/upper respiratory::Lung 0/1 (0%) 0 1/34 (2.9%) 1 1/40 (2.5%) 1 0/44 (0%) 0 1/45 (2.2%) 1
    Hemorrhage, pulmonary/upper respiratory::Nose 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 1/45 (2.2%) 1
    Hemorrhage/Bleeding - Other (diffuse alveolar hemorrhage) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Hypoxia 0/1 (0%) 0 1/34 (2.9%) 1 12/40 (30%) 13 11/44 (25%) 11 3/45 (6.7%) 3
    Obstruction/stenosis of airway::Bronchus 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Obstruction/stenosis of airway::Trachea 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Pain::Throat/pharynx/larynx 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Pleural effusion (non-malignant) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 5/44 (11.4%) 5 1/45 (2.2%) 1
    Pneumonitis/pulmonary infiltrates 0/1 (0%) 0 1/34 (2.9%) 1 6/40 (15%) 6 5/44 (11.4%) 5 0/45 (0%) 0
    Skin and subcutaneous tissue disorders
    Dermatology/Skin - Other 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Pruritus/itching 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Rash/desquamation 0/1 (0%) 0 1/34 (2.9%) 1 11/40 (27.5%) 11 9/44 (20.5%) 9 4/45 (8.9%) 4
    Rash: acne/acneiform 0/1 (0%) 0 2/34 (5.9%) 2 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Vascular disorders
    Acute vascular leak syndrome 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Hypertension 0/1 (0%) 0 1/34 (2.9%) 1 6/40 (15%) 7 3/44 (6.8%) 3 0/45 (0%) 0
    Hypotension 0/1 (0%) 0 1/34 (2.9%) 1 6/40 (15%) 6 2/44 (4.5%) 2 1/45 (2.2%) 1
    Thrombosis/embolism (vascular access-related) 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 4/44 (9.1%) 4 1/45 (2.2%) 1
    Thrombosis/thrombus/embolism 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 3/44 (6.8%) 3 1/45 (2.2%) 1
    Vasculitis 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Other (Not Including Serious) Adverse Events
    Arm IVD Cohort 1 (Th2 DLI) 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)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/1 (100%) 28/34 (82.4%) 40/40 (100%) 38/44 (86.4%) 36/45 (80%)
    Blood and lymphatic system disorders
    Edema: limb 0/1 (0%) 0 0/34 (0%) 0 3/40 (7.5%) 3 1/44 (2.3%) 1 3/45 (6.7%) 3
    Febrile neutropenia 0/1 (0%) 0 5/34 (14.7%) 9 1/40 (2.5%) 1 3/44 (6.8%) 3 4/45 (8.9%) 4
    Fibrinogen 0/1 (0%) 0 2/34 (5.9%) 2 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Hemoglobin 0/1 (0%) 0 14/34 (41.2%) 24 34/40 (85%) 112 27/44 (61.4%) 53 18/45 (40%) 36
    Lymphedema-related fibrosis 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Lymphopenia 0/1 (0%) 0 0/34 (0%) 0 6/40 (15%) 25 0/44 (0%) 0 0/45 (0%) 0
    Cardiac disorders
    Left ventricular systolic dysfunction 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 2/45 (4.4%) 2
    Ear and labyrinth disorders
    Thyroid function, low (hypothyroidism) 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 1/44 (2.3%) 1 0/45 (0%) 0
    Endocrine disorders
    Hot flashes/flushes 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 0/44 (0%) 0 0/45 (0%) 0
    Pancreatic endocrine: glucose intolerance 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 2/44 (4.5%) 2 1/45 (2.2%) 1
    Eye disorders
    Dry eye syndrome 0/1 (0%) 0 4/34 (11.8%) 4 7/40 (17.5%) 7 4/44 (9.1%) 4 5/45 (11.1%) 5
    Eyelid dysfunction 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Hemorrhage, GI::Colon 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Keratitis (corneal inflammation/corneal ulceration) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Ocular surface disease 0/1 (0%) 0 0/34 (0%) 0 3/40 (7.5%) 3 0/44 (0%) 0 0/45 (0%) 0
    Ocular/Visual - Other (GVHD Gd 1) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Ocular/Visual - Other (Occular GVHD) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Ocular/Visual - Other (Specify, __) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Ocular/Visual - Other (red and itchy eyes) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Taste alteration (dysgeusia) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Gastrointestinal disorders
    Ascites (non-malignant) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Colitis 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Colitis, infectious (e.g., Clostridium difficile) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 1/44 (2.3%) 1 1/45 (2.2%) 1
    Diarrhea 0/1 (0%) 0 5/34 (14.7%) 8 9/40 (22.5%) 9 6/44 (13.6%) 6 13/45 (28.9%) 13
    Distension/bloating, abdominal 0/1 (0%) 0 2/34 (5.9%) 2 1/40 (2.5%) 1 0/44 (0%) 0 2/45 (4.4%) 2
    Dry mouth/salivary gland (xerostomia) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 7/45 (15.6%) 7
    Dysphagia (difficulty swallowing) 0/1 (0%) 0 0/34 (0%) 0 4/40 (10%) 4 3/44 (6.8%) 3 4/45 (8.9%) 4
    Hemorrhage, GI::Lower GI NOS 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Mucositis/stomatitis (clinical exam)::Large bowel 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Mucositis/stomatitis (clinical exam)::Oral cavity 0/1 (0%) 0 1/34 (2.9%) 1 12/40 (30%) 12 4/44 (9.1%) 4 3/45 (6.7%) 3
    Mucositis/stomatitis (functional/symptomatic)::Large bowel 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Mucositis/stomatitis (functional/symptomatic)::Oral cavity 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 1/44 (2.3%) 1 1/45 (2.2%) 1
    Nausea 0/1 (0%) 0 2/34 (5.9%) 2 4/40 (10%) 4 0/44 (0%) 0 2/45 (4.4%) 2
    Pain::Dental/teeth/peridontal 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Pain::Esophagus 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 3/44 (6.8%) 3 0/45 (0%) 0
    Pain::Oral cavity 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Pain::Oral-gums 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Rigors/chills 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Vomiting 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 2/44 (4.5%) 2 3/45 (6.7%) 3
    General disorders
    Fatigue (asthenia, lethargy, malaise) 0/1 (0%) 0 1/34 (2.9%) 1 1/40 (2.5%) 1 0/44 (0%) 0 1/45 (2.2%) 1
    Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L) 0/1 (0%) 0 2/34 (5.9%) 2 9/40 (22.5%) 12 10/44 (22.7%) 10 1/45 (2.2%) 1
    Insomnia 0/1 (0%) 0 1/34 (2.9%) 2 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Pain - Other (jaw/scalp) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Pain::Abdomen NOS 0/1 (0%) 0 1/34 (2.9%) 2 1/40 (2.5%) 1 0/44 (0%) 0 2/45 (4.4%) 2
    Hepatobiliary disorders
    Cholecystitis 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Immune system disorders
    Allergic reaction/hypersensitivity (including drug fever) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infections and infestations
    Infection 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Infection (documented clinically or microbiologically) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection 0/1 (0%) 0 2/34 (5.9%) 2 1/40 (2.5%) 1 2/44 (4.5%) 2 2/45 (4.4%) 2
    Infection 0/1 (0%) 0 0/34 (0%) 0 3/40 (7.5%) 3 0/44 (0%) 3 0/45 (0%) 0
    Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils 0/1 (0%) 0 1/34 (2.9%) 1 3/40 (7.5%) 3 3/44 (6.8%) 3 1/45 (2.2%) 1
    Infection (documented clinically or microbiologically) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Infection (documented clinically or microbiologically) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Infection 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection 0/1 (0%) 0 2/34 (5.9%) 2 1/40 (2.5%) 1 2/44 (4.5%) 2 3/45 (6.7%) 3
    Infection 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 1/44 (2.3%) 1 0/45 (0%) 0
    Infection 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Infection 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Infection 0/1 (0%) 0 1/34 (2.9%) 2 1/40 (2.5%) 1 1/44 (2.3%) 1 4/45 (8.9%) 4
    Infection 0/1 (0%) 0 2/34 (5.9%) 3 1/40 (2.5%) 1 0/44 (0%) 0 2/45 (4.4%) 2
    Infection - Other (Specify, __) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection - Other (CMV reactivation) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection - Other (Possible bronchiolitis obliterans) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection - Other (Right arm pain and swelling-catheter celulitis) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection - Other (Sinusitis) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 2 0/44 (0%) 0 0/45 (0%) 0
    Infection - Other (Stool cultures 5/31: Yersinia, Novovirus as well as H. nana. 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils::Bladder (urinary) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Blood 0/1 (0%) 0 15/34 (44.1%) 19 7/40 (17.5%) 7 10/44 (22.7%) 11 14/45 (31.1%) 14
    Infection with normal ANC or Grade 1 or 2 neutrophils::Brain (encephalitis, infectious) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Bronchus 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Catheter-related 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 2/44 (4.5%) 2 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Colon 0/1 (0%) 0 1/34 (2.9%) 1 3/40 (7.5%) 3 1/44 (2.3%) 1 4/45 (8.9%) 4
    Infection with normal ANC or Grade 1 or 2 neutrophils::Conjunctiva 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 1/44 (2.3%) 1 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Dental-tooth 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 0/44 (0%) 0 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Eye NOS 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils::Lung (pneumonia) 0/1 (0%) 0 5/34 (14.7%) 6 4/40 (10%) 4 7/44 (15.9%) 7 10/45 (22.2%) 10
    Infection with normal ANC or Grade 1 or 2 neutrophils::Middle ear (otitis media) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Mucosa 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 3/44 (6.8%) 3 4/45 (8.9%) 4
    Infection with normal ANC or Grade 1 or 2 neutrophils::Nerve-peripheral 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Nose 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 3/45 (6.7%) 3
    Infection with normal ANC or Grade 1 or 2 neutrophils::Oral cavity-gums (gingivitis) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils::Paranasal 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 1/44 (2.3%) 1 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Pelvis NOS 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Penis 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils::Peritoneal cavity 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Pharynx 0/1 (0%) 0 2/34 (5.9%) 2 5/40 (12.5%) 5 0/44 (0%) 0 1/45 (2.2%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils::Rectum 0/1 (0%) 0 1/34 (2.9%) 1 1/40 (2.5%) 1 0/44 (0%) 0 1/45 (2.2%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils::Salivary gland 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Sinus 1/1 (100%) 1 2/34 (5.9%) 2 3/40 (7.5%) 3 5/44 (11.4%) 6 4/45 (8.9%) 4
    Infection with normal ANC or Grade 1 or 2 neutrophils::Skin (cellulitis) 0/1 (0%) 0 2/34 (5.9%) 2 2/40 (5%) 2 2/44 (4.5%) 2 3/45 (6.7%) 3
    Infection with normal ANC or Grade 1 or 2 neutrophils::Stomach 0/1 (0%) 0 1/34 (2.9%) 1 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Upper airway NOS 0/1 (0%) 0 12/34 (35.3%) 14 9/40 (22.5%) 11 17/44 (38.6%) 17 26/45 (57.8%) 26
    Infection with normal ANC or Grade 1 or 2 neutrophils::Urinary tract NOS 0/1 (0%) 0 9/34 (26.5%) 9 11/40 (27.5%) 11 5/44 (11.4%) 5 10/45 (22.2%) 10
    Infection with normal ANC or Grade 1 or 2 neutrophils::Vagina 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils::Wound 0/1 (0%) 0 2/34 (5.9%) 2 3/40 (7.5%) 3 0/44 (0%) 0 0/45 (0%) 0
    Infection with unknown ANC::Bladder (urinary) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Infection with unknown ANC::Lung (pneumonia) 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 1/44 (2.3%) 1 1/45 (2.2%) 1
    Infection with unknown ANC::Mucosa 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Infection with unknown ANC::Sinus 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 2/44 (4.5%) 2 0/45 (0%) 0
    Infection with unknown ANC::Skin (cellulitis) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Infection with unknown ANC::Upper airway NOS 0/1 (0%) 0 2/34 (5.9%) 2 0/40 (0%) 0 3/44 (6.8%) 3 1/45 (2.2%) 1
    Infection with unknown ANC::Urinary tract NOS 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Infection with unknown ANC::Vagina 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Injury, poisoning and procedural complications
    Fracture 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 1/44 (2.3%) 1 0/45 (0%) 0
    Investigations
    ALT, SGPT (serum glutamic pyruvic transaminase) 1/1 (100%) 1 17/34 (50%) 38 34/40 (85%) 53 29/44 (65.9%) 81 36/45 (80%) 78
    AST, SGOT(serum glutamic oxaloacetic transaminase) 0/1 (0%) 0 12/34 (35.3%) 17 24/40 (60%) 43 20/44 (45.5%) 27 24/45 (53.3%) 57
    Alkaline phosphatase 0/1 (0%) 0 4/34 (11.8%) 5 2/40 (5%) 2 3/44 (6.8%) 3 1/45 (2.2%) 1
    Amylase 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Carbon monoxide diffusion capacity (DL(co)) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 1/44 (2.3%) 1 1/45 (2.2%) 1
    Cardiac troponin I (cTnI) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Creatinine 0/1 (0%) 0 1/34 (2.9%) 2 3/40 (7.5%) 3 0/44 (0%) 0 1/45 (2.2%) 1
    Leukocytes (total WBC) 0/1 (0%) 0 0/34 (0%) 0 6/40 (15%) 12 0/44 (0%) 0 0/45 (0%) 0
    Lipase 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Neutrophils/granulocytes (ANC/AGC) 0/1 (0%) 0 7/34 (20.6%) 8 40/40 (100%) 136 37/44 (84.1%) 64 26/45 (57.8%) 44
    PTT (Partial Thromboplastin Time) 0/1 (0%) 0 5/34 (14.7%) 8 10/40 (25%) 12 9/44 (20.5%) 10 9/45 (20%) 10
    Platelets 0/1 (0%) 0 7/34 (20.6%) 10 28/40 (70%) 77 18/44 (40.9%) 33 23/45 (51.1%) 41
    Prolonged QTc interval 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Sodium, serum-high (hypernatremia) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Triglyceride, serum-high (hypertriglyceridemia) 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 2/44 (4.5%) 2 0/45 (0%) 0
    Weight loss 0/1 (0%) 0 1/34 (2.9%) 1 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Metabolism and nutrition disorders
    Albumin, serum-low (hypoalbuminemia) 0/1 (0%) 0 6/34 (17.6%) 10 10/40 (25%) 26 5/44 (11.4%) 7 9/45 (20%) 13
    Alkalosis (metabolic or respiratory) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 2/45 (4.4%) 2
    Anorexia 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    CPK (creatine phosphokinase) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Calcium, serum-high (hypercalcemia) 0/1 (0%) 0 1/34 (2.9%) 1 1/40 (2.5%) 2 1/44 (2.3%) 1 1/45 (2.2%) 1
    Calcium, serum-low (hypocalcemia) 0/1 (0%) 0 1/34 (2.9%) 1 3/40 (7.5%) 3 1/44 (2.3%) 1 1/45 (2.2%) 1
    GGT (gamma-Glutamyl transpeptidase) 0/1 (0%) 0 1/34 (2.9%) 1 1/40 (2.5%) 1 2/44 (4.5%) 3 1/45 (2.2%) 1
    Glucose, serum-high (hyperglycemia) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Magnesium, serum-high (hypermagnesemia) 0/1 (0%) 0 2/34 (5.9%) 2 9/40 (22.5%) 15 16/44 (36.4%) 23 6/45 (13.3%) 7
    Magnesium, serum-low (hypomagnesemia) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 3/44 (6.8%) 6 1/45 (2.2%) 1
    Phosphate, serum-low (hypophosphatemia) 0/1 (0%) 0 5/34 (14.7%) 6 17/40 (42.5%) 39 16/44 (36.4%) 30 19/45 (42.2%) 34
    Potassium, serum-high (hyperkalemia) 0/1 (0%) 0 5/34 (14.7%) 8 5/40 (12.5%) 7 3/44 (6.8%) 3 5/45 (11.1%) 7
    Potassium, serum-low (hypokalemia) 0/1 (0%) 0 7/34 (20.6%) 7 16/40 (40%) 32 10/44 (22.7%) 19 14/45 (31.1%) 21
    Sodium, serum-low (hyponatremia) 0/1 (0%) 0 3/34 (8.8%) 3 11/40 (27.5%) 17 4/44 (9.1%) 5 2/45 (4.4%) 2
    Tumor lysis syndrome 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Uric acid, serum-high (hyperuricemia) 0/1 (0%) 0 4/34 (11.8%) 5 4/40 (10%) 8 0/44 (0%) 0 2/45 (4.4%) 2
    Musculoskeletal and connective tissue disorders
    Arthritis (non-septic) 0/1 (0%) 0 0/34 (0%) 0 4/40 (10%) 4 0/44 (0%) 0 0/45 (0%) 0
    Muscle weakness, generalized or specific area (not due to neuropathy)::Extremity-upper 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Myositis (inflammation/damage of muscle) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Pain::Back 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 1/44 (2.3%) 1 0/45 (0%) 0
    Pain::Bone 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Pain::Chest/thorax NOS 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Pain::Joint 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 0/44 (0%) 0 0/45 (0%) 0
    Pain::Muscle 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 0/44 (0%) 0 0/45 (0%) 0
    Pain::Neck 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 3 0/44 (0%) 0 0/45 (0%) 0
    Nervous system disorders
    Bilirubin (hyperbilirubinemia) 0/1 (0%) 0 8/34 (23.5%) 15 7/40 (17.5%) 13 15/44 (34.1%) 24 14/45 (31.1%) 35
    Leukoencephalopathy (radiographic findings) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Mental status 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Mood alteration::Agitation 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Mood alteration::Anxiety 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Neuropathy: sensory 0/1 (0%) 0 0/34 (0%) 0 3/40 (7.5%) 3 1/44 (2.3%) 1 0/45 (0%) 0
    Pain::Head/headache 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 1/44 (2.3%) 1 0/45 (0%) 0
    Seizure 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Syncope (fainting) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Psychiatric disorders
    Confusion 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Renal and urinary disorders
    Cystitis 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 3/45 (6.7%) 3
    Hemorrhage, GU::Bladder 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Hemorrhage, GU::Urinary NOS 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Renal/Genitourinary - Other (Specify, __) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Urinary frequency/urgency 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Reproductive system and breast disorders
    Gynecomastia 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Sexual/Reproductive Function - Other (Specify, __) 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Sexual/Reproductive Function - Other (Specify, __) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Vaginal discharge (non-infectious) 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 0/44 (0%) 0 0/45 (0%) 0
    Vaginal dryness 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 1/45 (2.2%) 1
    Vaginal mucositis 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 2/44 (4.5%) 2 0/45 (0%) 0
    Vaginitis (not due to infection) 0/1 (0%) 0 0/34 (0%) 0 2/40 (5%) 2 0/44 (0%) 0 0/45 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Cough 0/1 (0%) 0 1/34 (2.9%) 1 3/40 (7.5%) 3 0/44 (0%) 0 2/45 (4.4%) 2
    Dyspnea (shortness of breath) 0/1 (0%) 0 3/34 (8.8%) 3 2/40 (5%) 2 1/44 (2.3%) 1 1/45 (2.2%) 1
    FEV(1) 0/1 (0%) 0 2/34 (5.9%) 2 0/40 (0%) 0 1/44 (2.3%) 1 1/45 (2.2%) 1
    Hemorrhage, pulmonary/upper respiratory::Nose 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Hyperpigmentation 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 2/44 (4.5%) 2 0/45 (0%) 0
    Hypoxia 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 1/44 (2.3%) 1 1/45 (2.2%) 1
    Induration/fibrosis (skin and subcutaneous tissue) 0/1 (0%) 0 2/34 (5.9%) 2 0/40 (0%) 0 1/44 (2.3%) 1 2/45 (4.4%) 2
    Pleural effusion (non-malignant) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 2/45 (4.4%) 2
    Pneumonitis/pulmonary infiltrates 0/1 (0%) 0 1/34 (2.9%) 1 0/40 (0%) 0 0/44 (0%) 0 2/45 (4.4%) 2
    Pulmonary/Upper Respiratory - Other (Specify, __) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Voice changes/dysarthria (e.g., hoarseness, loss or alteration in voice, laryngitis) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Skin and subcutaneous tissue disorders
    Cytokine release syndrome/acute infusion reaction 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Dermatology/Skin - Other (Specify, __) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Dermatology/Skin - Other (Specify, __) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Dermatology/Skin - Other (Specify, __) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Dermatology/Skin - Other (Specify, __) 0/1 (0%) 0 1/34 (2.9%) 2 0/40 (0%) 0 0/44 (0%) 0 0/45 (0%) 0
    Dermatology/Skin - Other (Specify, __) 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 1/44 (2.3%) 1 0/45 (0%) 0
    Dry skin 0/1 (0%) 0 0/34 (0%) 0 0/40 (0%) 0 0/44 (0%) 0 1/45 (2.2%) 1
    Hypopigmentation 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Pruritus/itching 0/1 (0%) 0 0/34 (0%) 0 5/40 (12.5%) 5 2/44 (4.5%) 2 2/45 (4.4%) 2
    Rash/desquamation 0/1 (0%) 0 5/34 (14.7%) 5 30/40 (75%) 30 17/44 (38.6%) 17 18/45 (40%) 18
    Rash: acne/acneiform 0/1 (0%) 0 3/34 (8.8%) 4 0/40 (0%) 0 2/44 (4.5%) 2 2/45 (4.4%) 2
    Vascular disorders
    Hypertension 0/1 (0%) 0 0/34 (0%) 0 5/40 (12.5%) 5 1/44 (2.3%) 1 1/45 (2.2%) 1
    Hypotension 0/1 (0%) 0 1/34 (2.9%) 1 1/40 (2.5%) 1 0/44 (0%) 0 1/45 (2.2%) 1
    Phlebitis (including superficial thrombosis) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 1/45 (2.2%) 1
    Thrombosis/embolism (vascular access-related) 0/1 (0%) 0 0/34 (0%) 0 1/40 (2.5%) 1 0/44 (0%) 0 0/45 (0%) 0
    Thrombosis/thrombus/embolism 0/1 (0%) 0 1/34 (2.9%) 1 1/40 (2.5%) 1 1/44 (2.3%) 1 0/45 (0%) 0

    Limitations/Caveats

    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.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Steven Pavletic
    Organization National Cancer Institute
    Phone 301-402-4899
    Email steven_pavletic@nih.gov
    Responsible Party:
    Steven Pavletic, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
    ClinicalTrials.gov Identifier:
    NCT00074490
    Other Study ID Numbers:
    • 040055
    • 04-C-0055
    • NCT00077480
    First Posted:
    Dec 15, 2003
    Last Update Posted:
    Dec 31, 2018
    Last Verified:
    Dec 1, 2018