Allogeneic Transplantation Using Total Lymphoid Irradiation (TLI) and Anti-Thymocyte Globulin (ATG) for Older Patients With Hematologic Malignancies

Sponsor
Stanford University (Other)
Overall Status
Completed
CT.gov ID
NCT00185640
Collaborator
(none)
303
1
1
154.1
2

Study Details

Study Description

Brief Summary

To measure how frequently and to what degree a complication of transplant cell acute graft versus host disease (GvHD) occurs.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

This study evaluated whether TLI-ATG conditioning followed by allogeneic hematpoietic cell transplant (HCT), which has provided excellent overall survival for patients with relapsed lymphoma after failed autologous HCT, provides a similar benefit in the setting of elderly patients with hematologic malignancies.

Study Design

Study Type:
Interventional
Actual Enrollment :
303 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Allogeneic Hematopoietic Cell Transplantation Using a Non-Myeloablative Preparative Regimen of Total Lymphoid Irradiation and Anti-Thymocyte Globulin for Older Patients With Hematologic Malignancies
Study Start Date :
Mar 1, 2003
Actual Primary Completion Date :
Apr 1, 2014
Actual Study Completion Date :
Jan 1, 2016

Arms and Interventions

Arm Intervention/Treatment
Experimental: Non-myeloablative transplantation

Pre-transplant total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) infusion with Day 0 allogeneic hematopoietic cell transplant (HCT), followed by post-transplant immunosuppression by cyclosporine and mycophenolate mofetil.

Drug: Cyclosporine
Starting day -3 at a dose of 5 mg/kg orally twice daily with a target trough level of 350 to 450 ng/mL
Other Names:
  • Cyclosporin
  • Cyclosporin A
  • Drug: Anti-thymocyte globulin (ATG)
    1.5 mg/kg for total dose of 7.5mg/kg, IV starting on day -11 to day -7 before HCT
    Other Names:
  • Thymoglobulin
  • Drug: Mycophenolate mofetil (MMF)
    Begins on day 0 after HCT at a dose of 15 mg/kg. Transplant recipients who received related donor grafts received MMF twice daily and those who received unrelated donor grafts received MMF 3 times daily.
    Other Names:
  • CellCept
  • Drug: Filgrastim
    Donors mobilized with 16 µg/kg/day filgrastim. As needed, myelosuppression in transplant recipients will be managed with subcutaneous filgrastim 5 µg/kg/day
    Other Names:
  • Neupogen
  • Granulocyte-colony stimulating factor (G-CSF; GCSF)
  • colony-stimulating factor 3 (CSF-3)
  • Radiation: Total Lymphoid Irradiation (TLI)
    0.8 Gy/day from day -11 to day -7 (inclusive) from day -4 to day -2 (inclusive) with 2 additional fractions of 0.8 Gy delivered on day -1 for total dose of 8 Gy.

    Outcome Measures

    Primary Outcome Measures

    1. Acute Graft vs Host Disease (GvHD) [100 days post-transplant]

      The incidence of acute GvHD after transplantation was assessed per Glucksberg GvHD grade, a compound scale based on the following combinations of disease stages. Skin Stages 0: No rash 1: Maculopapular (MP) rash <25% of body surface area 2: MP rash on 25-50% of body surface area 3: Generalized erythroderma (ED) 4: Generalized ED with bullous formation and desquamation Liver Stages (Bilirubin in mg/dL) 0: <2 1: 2-3 2: 3.01-6 3: 6.01-15.0 4: >15 Gastrointestinal (GI) Stages (diarrhea) 0: None or < 500 mL/day 1: 500-999 mL/day 2: 1000-1499 mL/day 3: >1500 mL/day 4: Severe abdominal pain, with or without ileus Glucksberg Overall grade Grade 1: Skin 1/2; GI 0; Liver 0; Karnofsky performance scale (KPS) 90-100% Grade 2: Skin 1-3; GI 1; Liver 1; KPS 70-80 Grade 2: Skin 2/3; GI 2/3; Liver 2-4; KPS 50-60 Grade 4: Skin 2-4; GI 2-4; Liver 2-4; KPS 30-40

    Secondary Outcome Measures

    1. Acute Graft vs Host Disease (GvHD), All Evaluable [100 days post-transplant]

      The incidence of acute GvHD after transplantation was assessed per Glucksberg GvHD grade, a compound scale based on the following combinations of disease stages. Skin Stages 0: No rash 1: Maculopapular (MP) rash <25% of body surface area 2: MP rash on 25-50% of body surface area 3: Generalized erythroderma (ED) 4: Generalized ED with bullous formation and desquamation Liver Stages (Bilirubin in mg/dL) 0: <2 1: 2-3 2: 3.01-6 3: 6.01-15.0 4: >15 Gastrointestinal (GI) Stages (diarrhea) 0: None or < 500 mL/day 1: 500-999 mL/day 2: 1000-1499 mL/day 3: >1500 mL/day 4: Severe abdominal pain, with or without ileus Glucksberg Overall grade Grade 1: Skin 1/2; GI 0; Liver 0; Karnofsky performance scale (KPS) 90-100% Grade 2: Skin 1-3; GI 1; Liver 1; KPS 70-80 Grade 2: Skin 2/3; GI 2/3; Liver 2-4; KPS 50-60 Grade 4: Skin 2-4; GI 2-4; Liver 2-4; KPS 30-40

    2. Incidence of Relapse [3 years]

      Reports the overall rate of disease relapse, occurring any time within 3 years after transplant

    3. Overall Survival (OS) [3 and 5 years]

    4. Event-free Survival (EFS) [3 and 5 years]

      Reports the number and proportion of participants who neither died due to any cause nor experienced relapse.

    5. Transplant-related Mortality [1 year]

      Reports the proportion of participants who expired within 1 year due to any complication or failure of the transplant.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    50 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    INCLUSION CRITERIA:
    • Any patient with one of the following hematolymphoid malignancies or syndromes in whom allogeneic hematopoietic stem cell transplant (HST) is warranted. Specific disease categories include:

    • Indolent advanced stage non-Hodgkin lymphomas

    • Mantle cell lymphoma

    • Chronic lymphocytic leukemia

    • Hodgkin disease (Hodgkin's lymphoma)

    • Acute leukemias in complete remission

    • Aplastic anemia

    • Paroxysmal nocturnal hemoglobinuria

    • Myelodysplastic or myeloproliferative syndromes.

    • Other selected malignancies/disorders may also be considered but must be approved by the transplant team and the Principal Investigator.

    • Age > 50 years, or if < 50 years of age, considered to be at high risk for regimen-related toxicity associated with conventional myeloablative transplants due to pre-existing medical conditions or prior therapy.

    • A fully human leukocyte antigen (HLA)-identical sibling or matched unrelated donor is available. Potential participants with one antigen mismatched donors can be considered but only after discussion with the transplant team and the Principal Investigator.

    • Participant must be competent to give consent.

    EXCLUSION CRITERIA:
    • Progressive hematolymphoid malignancies despite conventional therapies, or acute leukemias not in complete remission.

    • Uncontrolled central nervous system (CNS) involvement with disease

    • Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment

    • Pregnant

    • Cardiac ejection fraction < 30%

    • Uncontrolled cardiac failure

    • Pulmonary diffusing capacity (DLCO) < 40% predicted

    • Elevation of bilirubin to > 3 mg/dL

    • Transaminases > 4 x the upper limit of normal

    • Creatinine clearance < 50 cc/min (24-hour urine collection)

    • Karnofsky performance score < 60%

    • Poorly controlled hypertension on multiple antihypertensives

    • Documented fungal disease that is progressive despite treatment

    • HIV-positive. Other viral infections, ie, Hepatitis B- and C- positive, evaluated on a case-by-case basis

    • Psychiatric disorders or psychosocial problems which in the opinion of the primary physician or Principal Investigator would place the patient at unacceptable risk from this regimen.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Stanford University School of Medicine Stanford California United States 94305

    Sponsors and Collaborators

    • Stanford University

    Investigators

    • Principal Investigator: Robert Lowsky, Stanford University

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Robert Lowsky, Professor of Medicine, Stanford University
    ClinicalTrials.gov Identifier:
    NCT00185640
    Other Study ID Numbers:
    • IRB-11960
    • 78998
    • BMT153
    • NCT00186615
    First Posted:
    Sep 16, 2005
    Last Update Posted:
    Jun 29, 2021
    Last Verified:
    Jun 1, 2021
    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
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Non-myeloablative Transplantation
    Arm/Group Description Pre-transplant total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) infusion with Day 0 allogeneic hematopoietic cell transplant (HCT), followed by post-transplant immunosuppression by cyclosporine and mycophenolate mofetil
    Period Title: Overall Study
    STARTED 303
    Transplanted 296
    90 Days Post-transplant 161
    COMPLETED 158
    NOT COMPLETED 145

    Baseline Characteristics

    Arm/Group Title Non-myeloablative Transplantation
    Arm/Group Description Pre-transplant total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) infusion with Day 0 allogeneic hematopoietic cell transplant (HCT), followed by post-transplant immunosuppression by cyclosporine and mycophenolate mofetil
    Overall Participants 303
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    260
    85.8%
    >=65 years
    43
    14.2%
    Sex: Female, Male (Count of Participants)
    Female
    128
    42.2%
    Male
    175
    57.8%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    20
    6.6%
    Not Hispanic or Latino
    276
    91.1%
    Unknown or Not Reported
    7
    2.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    37
    12.2%
    Native Hawaiian or Other Pacific Islander
    7
    2.3%
    Black or African American
    6
    2%
    White
    233
    76.9%
    More than one race
    0
    0%
    Unknown or Not Reported
    20
    6.6%
    Histology (participants) [Number]
    Acute Biphenotypic Leukemia
    1
    0.3%
    Acute Leukemia, Nos
    1
    0.3%
    Acute Monocytic Leukemia
    2
    0.7%
    Acute Myeloid Leukemia
    84
    27.7%
    Acute Promyelocytic Leukemia
    4
    1.3%
    Angioimmunoblastic T-Cell Lymphoma
    1
    0.3%
    B lymphoblastic leukemia/lymphoma, NOS
    1
    0.3%
    B-Cell Chr. Lymph. Leuk./Small Lymph. Lymphoma
    45
    14.9%
    Chronic Myelogenous Leukemia, Bcr/Abl Positive
    1
    0.3%
    Chronic Myeloid Leukemia, Nos
    8
    2.6%
    Chronic Myeloproliferative Disease, Nos
    2
    0.7%
    Cutaneous T-Cell Lymphoma, Nos
    1
    0.3%
    Follicular Lymphoma, Grade 1-3
    4
    1.3%
    Hodgkin Lymphoma, Nodular Sclerosis, Nos
    4
    1.3%
    Hodgkin Lymphoma, Nos
    20
    6.6%
    Malignant Lymphoma, Non-Hodgkin
    86
    28.4%
    Mantle Cell Lymphoma
    10
    3.3%
    Marginal Zone B-Cell Lymphoma, Nos
    2
    0.7%
    Mature T-Cell Lymphoma, Nos
    1
    0.3%
    Ml, Large B-Cell, Diffuse
    2
    0.7%
    Ml, Small B Lymphocytic, Nos
    1
    0.3%
    Myelodysplastic Syndrome, Nos
    3
    1%
    Precursor Cell Lymphoblastic Leukemia, Nos
    15
    5%
    Prolymphocytic Leukemia, Nos
    1
    0.3%
    Prolymphocytic Leukemia, T-Cell Type
    1
    0.3%
    Subcutaneous Panniculitis-Like T-Cell Lymphoma
    1
    0.3%
    Unknown
    1
    0.3%

    Outcome Measures

    1. Primary Outcome
    Title Acute Graft vs Host Disease (GvHD)
    Description The incidence of acute GvHD after transplantation was assessed per Glucksberg GvHD grade, a compound scale based on the following combinations of disease stages. Skin Stages 0: No rash 1: Maculopapular (MP) rash <25% of body surface area 2: MP rash on 25-50% of body surface area 3: Generalized erythroderma (ED) 4: Generalized ED with bullous formation and desquamation Liver Stages (Bilirubin in mg/dL) 0: <2 1: 2-3 2: 3.01-6 3: 6.01-15.0 4: >15 Gastrointestinal (GI) Stages (diarrhea) 0: None or < 500 mL/day 1: 500-999 mL/day 2: 1000-1499 mL/day 3: >1500 mL/day 4: Severe abdominal pain, with or without ileus Glucksberg Overall grade Grade 1: Skin 1/2; GI 0; Liver 0; Karnofsky performance scale (KPS) 90-100% Grade 2: Skin 1-3; GI 1; Liver 1; KPS 70-80 Grade 2: Skin 2/3; GI 2/3; Liver 2-4; KPS 50-60 Grade 4: Skin 2-4; GI 2-4; Liver 2-4; KPS 30-40
    Time Frame 100 days post-transplant

    Outcome Measure Data

    Analysis Population Description
    Reports the incidence of Grades 2 to 4 acute GvHD, as observed for the initial 37 participants treated on this study, who constitute the Primary Analysis for the study. See linked citation Lowsky, et al. NEJM. 29Sep2005;353(13)1321-1331.
    Arm/Group Title Non-myeloablative Transplantation
    Arm/Group Description Pre-transplant total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) infusion with Day 0 allogeneic hematopoietic cell transplant (HCT), followed by post-transplant immunosuppression by cyclosporine and mycophenolate mofetil.
    Measure Participants 37
    Number [percentage of participants]
    2.7
    0.9%
    2. Secondary Outcome
    Title Acute Graft vs Host Disease (GvHD), All Evaluable
    Description The incidence of acute GvHD after transplantation was assessed per Glucksberg GvHD grade, a compound scale based on the following combinations of disease stages. Skin Stages 0: No rash 1: Maculopapular (MP) rash <25% of body surface area 2: MP rash on 25-50% of body surface area 3: Generalized erythroderma (ED) 4: Generalized ED with bullous formation and desquamation Liver Stages (Bilirubin in mg/dL) 0: <2 1: 2-3 2: 3.01-6 3: 6.01-15.0 4: >15 Gastrointestinal (GI) Stages (diarrhea) 0: None or < 500 mL/day 1: 500-999 mL/day 2: 1000-1499 mL/day 3: >1500 mL/day 4: Severe abdominal pain, with or without ileus Glucksberg Overall grade Grade 1: Skin 1/2; GI 0; Liver 0; Karnofsky performance scale (KPS) 90-100% Grade 2: Skin 1-3; GI 1; Liver 1; KPS 70-80 Grade 2: Skin 2/3; GI 2/3; Liver 2-4; KPS 50-60 Grade 4: Skin 2-4; GI 2-4; Liver 2-4; KPS 30-40
    Time Frame 100 days post-transplant

    Outcome Measure Data

    Analysis Population Description
    Reports data for all evaluable participants
    Arm/Group Title Non-myeloablative Transplantation
    Arm/Group Description Pre-transplant total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) infusion with Day 0 allogeneic hematopoietic cell transplant (HCT), followed by post-transplant immunosuppression by cyclosporine and mycophenolate mofetil.
    Measure Participants 303
    Number [percentage of participants]
    11
    3.6%
    3. Secondary Outcome
    Title Incidence of Relapse
    Description Reports the overall rate of disease relapse, occurring any time within 3 years after transplant
    Time Frame 3 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Non-myeloablative Transplantation
    Arm/Group Description Pre-transplant total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) infusion with Day 0 allogeneic hematopoietic cell transplant (HCT), followed by post-transplant immunosuppression by cyclosporine and mycophenolate mofetil.
    Measure Participants 303
    Number [percentage of participants]
    53
    17.5%
    4. Secondary Outcome
    Title Overall Survival (OS)
    Description
    Time Frame 3 and 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Non-myeloablative Transplantation
    Arm/Group Description Pre-transplant total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) infusion with Day 0 allogeneic hematopoietic cell transplant (HCT), followed by post-transplant immunosuppression by cyclosporine and mycophenolate mofetil.
    Measure Participants 303
    3 years
    70
    23.1%
    5 years
    64
    21.1%
    5. Secondary Outcome
    Title Event-free Survival (EFS)
    Description Reports the number and proportion of participants who neither died due to any cause nor experienced relapse.
    Time Frame 3 and 5 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Non-myeloablative Transplantation
    Arm/Group Description Pre-transplant total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) infusion with Day 0 allogeneic hematopoietic cell transplant (HCT), followed by post-transplant immunosuppression by cyclosporine and mycophenolate mofetil.
    Measure Participants 303
    3 years
    44
    14.5%
    5 years
    38
    12.5%
    6. Secondary Outcome
    Title Transplant-related Mortality
    Description Reports the proportion of participants who expired within 1 year due to any complication or failure of the transplant.
    Time Frame 1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Non-myeloablative Transplantation
    Arm/Group Description Pre-transplant total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) infusion with Day 0 allogeneic hematopoietic cell transplant (HCT), followed by post-transplant immunosuppression by cyclosporine and mycophenolate mofetil.
    Measure Participants 303
    Number [percentage of participants]
    6
    2%

    Adverse Events

    Time Frame 5 years
    Adverse Event Reporting Description Adverse events other than death, secondary malignancy, or relapse were not collected.
    Arm/Group Title Non-myeloablative Transplantation
    Arm/Group Description
    All Cause Mortality
    Non-myeloablative Transplantation
    Affected / at Risk (%) # Events
    Total 138/303 (45.5%)
    Serious Adverse Events
    Non-myeloablative Transplantation
    Affected / at Risk (%) # Events
    Total 138/303 (45.5%)
    Gastrointestinal disorders
    Deaths 138/303 (45.5%)
    Other (Not Including Serious) Adverse Events
    Non-myeloablative Transplantation
    Affected / at Risk (%) # Events
    Total 55/303 (18.2%)
    Blood and lymphatic system disorders
    Secondary malignancy 22/303 (7.3%) 22
    Gastrointestinal disorders
    Secondary malignancy 4/303 (1.3%) 4
    Reproductive system and breast disorders
    Secondary malignancy 2/303 (0.7%) 2
    Respiratory, thoracic and mediastinal disorders
    Secondary malignancy 1/303 (0.3%) 1
    Skin and subcutaneous tissue disorders
    Secondary malignancy 26/303 (8.6%) 26

    Limitations/Caveats

    [Not Specified]

    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 Robert Lowsky
    Organization Stanford University
    Phone 650-723-0822
    Email rlowsky@stanford.edu
    Responsible Party:
    Robert Lowsky, Professor of Medicine, Stanford University
    ClinicalTrials.gov Identifier:
    NCT00185640
    Other Study ID Numbers:
    • IRB-11960
    • 78998
    • BMT153
    • NCT00186615
    First Posted:
    Sep 16, 2005
    Last Update Posted:
    Jun 29, 2021
    Last Verified:
    Jun 1, 2021