Allogeneic HCT With HLA-matched Donors : a Phase II Randomized Study Comparing 2 Nonmyeloablative Conditionings

Sponsor
University of Liege (Other)
Overall Status
Completed
CT.gov ID
NCT00603954
Collaborator
Maastricht University Medical Center (Other), KU Leuven (Other)
107
Enrollment
11
Locations
2
Arms
102
Actual Duration (Months)
9.7
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The present project aims at comparing two nonmyeloablative regimens currently used in 2 major HCT centers in the US for patients with HLA-matched related or unrelated donor: the one from the Seattle group consisting of 2 Gy TBI with fludarabine (90 mg/m²) versus the one from the Stanford group combining 8 Gy TLI with ATG.

Condition or DiseaseIntervention/TreatmentPhase
  • Drug: Conditioning regimen: TBI + Fludarabine
  • Drug: Conditioning regimen:TLI (8 Gy) + ATG
Phase 2

Detailed Description

  1. OBJECTIVES

The present project aims at comparing two nonmyeloablative regimens currently used in 2 major HCT centers in the US for patients with HLA-matched related or unrelated donor: the one from the Seattle group consisting of 2 Gy TBI with fludarabine (90 mg/m²) versus the one from the Stanford group combining 8 Gy TLI with ATG.

  1. DESIGN OF THE STUDY

The study is a multicenter, randomized phase II study, comparing two conditioning regimens. Sixty patients with HLA-matched donors will be randomized between the TBI or the DLI regimen. There will be a stratification between centers. There will be a stopping rule for graft rejection > 15% at day 180 (in each group separately), and for nonrelapse mortality > 35% at day 180 (in each group separately). If the stopping rules are not triggered after 60 patients and no statistically significant differences are seen between the 2 arms in terms of acute GVHD, graft rejection and survival, a second cohort of 40 patients will be included.

  1. TREATMENT PLAN

III.1. Pre-transplant procedures Peripheral blood mononucleated cells from the patient as well as from the donor will be collected before conditioning, as per standard practice for all routine allogeneic HSC transplants. Part will be cryopreserved in 10 % DMSO and stored at -180°C in liquid nitrogen. The other part will be devoted to identification of specific donor and patient markers to be used in later measurements of chimerism.

III.2. Conditioning regimens The conditioning regimens used will be either the one developed in Seattle (TBI arm) or the one developed by the Stanford group (TLI arm). These 2 regimens have been extensively reported in major medical journals. In the TBI arm, conditioning will consist of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells. In the TLI arm, conditioning will consist of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7.

III.3. PBSC collection and transplantation PBSC mobilization and collection in the donor will be performed as per standard practice for all routine allogeneic HSC transplants. This is briefly described below.

The donor will be given SC injections of G-CSF at a dose of 10-15 µg/kg for 6 days (days -5 through 0). Additional doses of G-CSF may be given on days +1 and +2 if the first 2 leukaphereses do not yield sufficient numbers of CD34+ cells. G-CSF will generally be administered :

  • In the evening on days -5, -4, -3, -2;

  • Before 7:00 on days -1 and 0 (and on days 1 and 2 if necessary). Collection of PBSC will be carried out on day -1 and in the morning on day 0. Leukaphereses will be performed using a continuous flow blood cell separator and following a mononuclear cell collection protocol. The volume of blood processed will be 15-20 liters if donor is an adult or 10 liters/m2 if donor is a child. Anticoagulation will be performed with the ACD-A solution. The PBSC from the first day of harvest will be stored overnight at 4°C in the patient's own plasma. After the second harvest, PBSC from the first and second day of harvest will be infused into the patient.

Based on previous reports suggesting that higher dose of CD34 cells are associated with better outcomes after nonmyeloablative HCT, high doses of CD34+ cells (>6.5 x 106/kg) should be ideally administered. Nevertheless, to limit donor procedures, only two leukaphereses are required. However, in case the required minimal number of cells (3 x 106 CD34+ cells/kg recipient) cannot be obtained with the first two collections, additional leukaphereses should be carried out unless contra-indicated for the donor.

Cells will be infused through a central catheter according to standard procedures.

III.4. Other treatments of the recipient

III.4.1. Immunosuppressive therapy The immunosuppressive regimens used will be the one used in standard practice for routine NM-HCT at our centers, i.e. an association of tacrolimus and mycophenolate mofetil (MMF).

MMF will be administered orally from the evening of day 0 through day 28 (sibling recipients) or day 42 (alternative donor recipients) at the dose of 15 mg/kg t.i.d.

Tacrolimus will be given orally at the dose of 0.06 mg/kg bid starting on day -3. The dose will then be adapted according to through whole blood values following standard procedures (between 15 and 20 ng/ml the first 28 days and between 10-15 ng/ml thereafter). Full doses will be given until day 100 (sibling recipients) or 180 (alternative donor recipients). Doses will then be progressively tapered to be definitely discontinued by day 180 (sibling donors) or 365 (alternative donor recipients) in the absence of GVHD. Tacrolimus may be stopped earlier in case of disease progression or graft rejection or continued longer in case of low donor T-cell chimerism or GVHD.

GVHD will be assessed according to standard criteria. Therapy for acute or chronic GVHD will use standard procedures/current protocols.

III.4.2. Growth factors Growth factors will be used as per standard practice for all routine NM-HCT. No myeloid growth factor will be administered unless the granulocyte count falls below 1000/µl. Patients may then be treated with 5 µg/kg/day of G-CSF to maintain the granulocyte count > 1,000/µl. Erythropoietin may be administered as required.

III.4.3. Infection prophylaxis Infection prophylaxis against bacterial, fungal, viral and parasitic agents will be carried out as per standard practice for all routine NM-HCT.

III.4.4. Donor lymphocyte infusion Donor lymphocyte infusion (DLI) will be given as per standard practice for all routine NM-HCT. DLI may be given in case of poor T-cell chimerism or disease progression according to standard procedures/current protocols.

  1. PATIENTS' FOLLOW-UP

IV.1. Quality controls of cell products

IV.1.1. Peripheral blood of donor on days of PBSC collection As per standard practice for all routine allogeneic PBSC transplants.

IV.1.2. Leukapheresis product As per standard practice for all routine allogeneic PBSC transplants including determination of the number of TNC, CD34, CD3 , CD4 and CD8 cells transplanted.

IV.2. Toxicities of cell infusions Potential toxicities associated with PBSC infusions will be carefully monitored per the standard procedures.

IV.3. Chimerism The chimeric status of hematopoietic cells will be carefully monitored post-transplant, as per standard practice for all routine allogeneic transplants. Donor chimerism will be measured in whole blood as well as bone marrow. In addition, peripheral blood cells will be separated by RosetteSep procedure (Stem Cell Technologies, Vancouver, Canada) to determine the proportion of donor and recipient cells in pure population of T (CD3+) cells. Fluorescent in-situ hybridization (FISH) for X and Y chromosome will be used preferentially for sex-mismatched HCT, while PCR techniques based on short tandem repeat (STR) markers will be used for sex-matched HCT. Pre-transplant donor and recipient peripheral WBC will serve to identify specific markers.

We define complete chimerism as the presence of >95% of T cells of donor origin and mixed chimerism as the presence of 6-94% of T cells of donor origin. Graft rejection is defined as the occurrence of T cell chimerism < 5% and engraftment as the occurrence of more than 5% T cells of donor origin in the first month following the transplant.

The proportion of donor chimerism will be determined at the following time points:
  1. peripheral blood :
  • Days 28, 42, 60, 100, 180 and 365 post-transplant : whole blood and CD3+ cells;

  • Analyses on day 60 are only necessary when chimerism is < 80% on days 28 and/or 42;

  • Analyses on whole blood on days 42, 100, 180 and 365 are only necessary when bone marrow analyses are not feasible/successful.

  1. bone marrow : • Days 42, 100, 180 and 365 post-transplant : whole bone marrow.

IV.4. Clinical data Patient will be carefully observed and the following clinical parameters will be recorded (see appendices B and C). Appendices B and C should be send not more than 3 months after the patient achieved the target day after HSCT (day 100, day 180, 1-yr, 2-yr, 3-yr, 4-yr and 5-yr) to Frederic Baron at the fax # 32-4-366 8855.

  • Incidence, timing and severity of acute GVHD, its treatment and outcome;

  • Incidence, timing and severity of chronic GVHD, its treatment and outcome;

  • Incidence, timing and severity of cytopenia, its treatment and outcome; number of platelet and RBC transfusions; G-CSF usage;

  • Time to achieve 500 neutrophils, 1000 neutrophils, 20 000 platelets and 50 000 platelets;

  • Duration of hospitalization, if any;

  • Incidence of bacterial infections;

  • Incidence of fungal infections;

  • Incidence of CMV infections (by quantitative PCR) and CMV disease;

  • Incidence of other viral infections;

  • Incidence of other infections;

  • Evolution of the primary malignant disease : response, relapse, its treatment and outcome;

  • Any other serious complication associated with the transplant procedure;

  • Death and survival.

IV.5. Immunologic data. In patients transplanted at the university of Liège, immune reconstitution in the patient will be monitored as per standard practice at ULg for all routine allogeneic transplants. For patients transplanted outside of the University of Liège and willing to participate to the immune recovery study, 50 mL of fresh heparinized blood collected on days 42, 100, 180, 365 and 730 can be send at room temperature to Olivier Dengis, Department of Clinical Hematology, CHU Sart-Tilman, B4000 Liège.

Study Design

Study Type:
Interventional
Actual Enrollment :
107 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Allogeneic Hematopoietic Cell Transplantation With HLA-matched Donors : a Phase II Randomized Study Comparing 2 Nonmyeloablative Conditionings
Actual Study Start Date :
Jan 1, 2008
Actual Primary Completion Date :
Jul 1, 2016
Actual Study Completion Date :
Jul 1, 2016

Arms and Interventions

ArmIntervention/Treatment
Active Comparator: TBI + fludarabine

Conditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells.

Drug: Conditioning regimen: TBI + Fludarabine
2 Gy TBI, Fludarabine 90 mg/m²
Other Names:
  • total body irradiation (TBI) + fludarabine
  • Active Comparator: TLI + ATG

    Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7.

    Drug: Conditioning regimen:TLI (8 Gy) + ATG
    TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kg
    Other Names:
  • Total Lymphoid Irradiation (TLI) and Anti-Thymocyte Globulin (ATG)
  • Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants With Grade II-IV Acute GVHD Between the 2 Groups [180 days after HCT]

      Percentage of participants with aGVHD according grades: Grade I: rash skin < 25 % area; bilirubin: 20-30 mg/ml; diarrhea: 500-1000 ml/day Grade II: rash skin 25-50 % area; bilirubin: 30-60 mg/ml; diarrhea: 10000-1500 ml/day Grade III:rash skin > 50 % area; bilirubin: 60-150 mg/ml; diarrhea: >1500 ml/day Grade IV: erythroderma; bilirubin: > 150 mg/ml; diarrhea: >2000 ml/day Grade IV is the worst grade Patients given a second allogeneic HCT were censured for GVHD analyses.

    Secondary Outcome Measures

    1. Number of Participants With Graft Rejection as Defined by Whole Blood and T Cell Chimerism [1 year after HCT]

      graft rejection are reported in outcome measure data table (defined as ≤ 5% donor chimerism in T cells, total white blood cells and/or total bone marrow cells).

    2. Percentage of Participants With Chronic GVHD in the 2 Groups [2 years after HCT]

      Comparaison of the number of Participants with chronic GVHD in the 2 groups

    3. Incidences of Bacterial, Fungal and Viral Infections in the 2 Groups. [D100 after HCT]

    4. Percentage of Relapse Rate in the 2 Groups [1 year after HCT]

    5. Quality and Timing of Immunologic Reconstitution: Concentration of ATG Levels [Day 0, Day 3 and Day 10]

      Analyses of ATG levels in order to assess the immune system recuperation

    6. Percentage of Non Relapse Mortality in the 2 Groups [1 year after HCT]

    7. Percentage of 4-year Progression Free Survival in the 2 Groups [4 year after HCT]

    8. Percentage of 5-year Progression Free Survival in the 2 Groups [5 year after HCT]

    9. Percentage of 4-year Overall Survival in the 2 Groups [4 year after HCT]

    10. Percentage of 5-year Overall Survival in the 2 Groups [5 year after HCT]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    N/A to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:

    PATIENT

    1. Diseases
    Hematological malignancies confirmed histologically and not rapidly progressing:
    • AML in CR (defined as ≤ 5% marrow blasts and absence of blasts in the peripheral blood);

    • MDS with ≤ 5% marrow blasts and absence of blasts in the peripheral blood;

    • CML in CP;

    • MPS not in blast crisis and not with extensive marrow fibrosis,

    • ALL in CR;

    • Multiple myeloma not rapidly progressing;

    • CLL;

    • Non-Hodgkin's lymphoma (aggressive NHL should have chemosensitive disease);

    • Hodgkin's disease with chemosensitive disease.

    1. Clinical situations
    • Theoretical indication for a standard allo-transplant, but not feasible because:

    • Age > 50 yrs;

    • Unacceptable end organ performance;

    • Patient's refusal.

    • Indication for a standard auto-transplant: perform mini-allotransplantation 2-6 months after standard autotransplant.

    1. Other inclusion criteria
    • Male or female; fertile patients must use a reliable contraception method;

    • Age < 75 yrs;

    • Informed consent given by patient or his/her guardian if of minor age.

    DONOR

    • Related to the recipient (sibling, parent or child) or unrelated;

    • Male or female;

    • Any age;

    • 10 of 10 (HLA-A, -B, -C, -DRB1, and -DQB1) HLA allele matched;

    • Weight > 15 Kg (because of leukapheresis);

    • Fulfills criteria for allogeneic PBSC donation according to standard procedures;

    • Informed consent given by donor or his/her guardian if of minor age, as per donor center standard procedures.

    Exclusion Criteria:

    PATIENT

    • Any condition not fulfilling inclusion criteria;

    • HIV positive;

    • Non-hematological malignancy(ies) (except non-melanoma skin cancer) < 3 years before nonmyeloablative HCT.

    • Life expectancy severely limited by disease other than malignancy;

    • Administration of cytotoxic agent(s) for "cytoreduction" within three weeks prior to initiating the nonmyeloablative transplant conditioning (Exceptions are hydroxyurea and imatinib mesylate);

    • CNS involvement with disease refractory to intrathecal chemotherapy.

    • Terminal organ failure, except for renal failure (dialysis acceptable)

    • Uncontrolled infection;

    • Karnofsky Performance Score <70%;

    • Patient is a fertile man or woman who is unwilling to use contraceptive techniques during and for 12 months following treatment;

    • Patient is a female who is pregnant or breastfeeding;

    • Previous radiation therapy precluding the use of 2 Gy TBI or 8 Gy TLI;

    DONOR

    • Any condition not fulfilling inclusion criteria;

    • Unable to undergo leukapheresis because of poor vein access or other reasons.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1AZ Gasthuisberg LeuvenLeuvenFlamish BrabantBelgium3000
    2UZ GentGentFlanders OostBelgium
    3University Hospital Mont-GodinneGodinneNamurBelgium
    4AZ St-JanBruggeWest FlandersBelgium
    5UZA StuyvenbergAntwerpenBelgium
    6UZAAntwerpenBelgium
    7Bordet InstituteBrusselsBelgium
    8St Luc UCLBrusselsBelgium
    9UZ BrusselsBrusselsBelgium
    10CHU Sart TilmanLiegeBelgium4000
    11University Hospital MaastrichtMaastrichtLimburgNetherlands6200

    Sponsors and Collaborators

    • University of Liege
    • Maastricht University Medical Center
    • KU Leuven

    Investigators

    • Study Chair: Frederic Baron, MD, PhD, CHU-ULg
    • Study Chair: Yves Beguin, MD, PhD, CHU-ULg
    • Principal Investigator: Johan Maertens, MD, KUL
    • Principal Investigator: Koen Theunissen, MD, KUL
    • Principal Investigator: Harry Schouten, MD, Maastricht University Medical Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Yves Beguin, Prof, University of Liege
    ClinicalTrials.gov Identifier:
    NCT00603954
    Other Study ID Numbers:
    • TJB0702P1
    First Posted:
    Jan 29, 2008
    Last Update Posted:
    Jan 26, 2022
    Last Verified:
    Nov 1, 2021

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleFlu-TBITLI-ATG
    Arm/Group DescriptionConditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells. Conditioning regimen TBI + Fludarabine: 2 Gy TBI, Fludarabine 90 mg/m²Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7. Conditioning regimen II (TLI 8 Gy + ATG [Thymoglobulin]): TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kg
    Period Title: Overall Study
    STARTED5047
    COMPLETED4945
    NOT COMPLETED12

    Baseline Characteristics

    Arm/Group TitleFlu-TBITLI-ATGTotal
    Arm/Group DescriptionConditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells. Conditioning regimen TBI + Fludarabine: 2 Gy TBI, Fludarabine 90 mg/m²Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7. Conditioning regimen II (TLI 8 Gy + ATG [Thymoglobulin]): TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kgTotal of all reporting groups
    Overall Participants494594
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    36
    73.5%
    35
    77.8%
    71
    75.5%
    >=65 years
    13
    26.5%
    10
    22.2%
    23
    24.5%
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    60
    59
    60
    Sex: Female, Male (Count of Participants)
    Female
    14
    28.6%
    16
    35.6%
    30
    31.9%
    Male
    35
    71.4%
    29
    64.4%
    64
    68.1%
    Region of Enrollment (Count of Participants)
    Netherlands
    4
    8.2%
    2
    4.4%
    6
    6.4%
    Belgium
    45
    91.8%
    43
    95.6%
    88
    93.6%
    Donor: HLA-identical sibling/ 10/10 HLA-allele matched URD (participants) [Number]
    HLA-identical sibling
    29
    59.2%
    25
    55.6%
    54
    57.4%
    10/10 HLA-allele matched URD
    20
    40.8%
    20
    44.4%
    40
    42.6%

    Outcome Measures

    1. Primary Outcome
    TitlePercentage of Participants With Grade II-IV Acute GVHD Between the 2 Groups
    DescriptionPercentage of participants with aGVHD according grades: Grade I: rash skin < 25 % area; bilirubin: 20-30 mg/ml; diarrhea: 500-1000 ml/day Grade II: rash skin 25-50 % area; bilirubin: 30-60 mg/ml; diarrhea: 10000-1500 ml/day Grade III:rash skin > 50 % area; bilirubin: 60-150 mg/ml; diarrhea: >1500 ml/day Grade IV: erythroderma; bilirubin: > 150 mg/ml; diarrhea: >2000 ml/day Grade IV is the worst grade Patients given a second allogeneic HCT were censured for GVHD analyses.
    Time Frame180 days after HCT

    Outcome Measure Data

    Analysis Population Description
    Patients given a second allogeneic HCT were censured for GVHD analyses.
    Arm/Group TitleFlu-TBITLI-ATG
    Arm/Group DescriptionConditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells. Conditioning regimen TBI + Fludarabine: 2 Gy TBI, Fludarabine 90 mg/m²Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7. Conditioning regimen II (TLI 8 Gy + ATG [Thymoglobulin]): TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kg
    Measure Participants4840
    Number [percentage of participants with aGVHD]
    12.2
    24.9%
    8.9
    19.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.508
    Comments
    MethodMultivariate Cox models
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments At day 180
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.02
    Comments
    MethodWilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments At Day 365
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.002
    Comments
    MethodWilcoxon (Mann-Whitney)
    Comments
    2. Secondary Outcome
    TitleNumber of Participants With Graft Rejection as Defined by Whole Blood and T Cell Chimerism
    Descriptiongraft rejection are reported in outcome measure data table (defined as ≤ 5% donor chimerism in T cells, total white blood cells and/or total bone marrow cells).
    Time Frame1 year after HCT

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleFlu-TBITLI-ATG
    Arm/Group DescriptionConditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells. Conditioning regimen TBI + Fludarabine: 2 Gy TBI, Fludarabine 90 mg/m²Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7. Conditioning regimen II (TLI 8 Gy + ATG [Thymoglobulin]): TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kg
    Measure Participants4945
    Number [participants]
    3
    6.1%
    4
    8.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments At day 100
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.09
    Comments
    MethodWilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments At Day 40
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.03
    Comments
    MethodWilcoxon (Mann-Whitney)
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments At Day 180
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.01
    Comments
    MethodWilcoxon (Mann-Whitney)
    Comments
    3. Secondary Outcome
    TitlePercentage of Participants With Chronic GVHD in the 2 Groups
    DescriptionComparaison of the number of Participants with chronic GVHD in the 2 groups
    Time Frame2 years after HCT

    Outcome Measure Data

    Analysis Population Description
    Patients given a second allogeneic HCT were censured for GVHD analyses.
    Arm/Group TitleFlu-TBITLI-ATG
    Arm/Group DescriptionConditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells. Conditioning regimen TBI + Fludarabine: 2 Gy TBI, Fludarabine 90 mg/m²Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7. Conditioning regimen II (TLI 8 Gy + ATG [Thymoglobulin]): TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kg
    Measure Participants4840
    Number [percentage of participants]
    40.8
    83.3%
    18.8
    41.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.0165
    Comments
    MethodMultivariate Cox models
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.010
    Comments
    MethodMutivariate
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.3
    Confidence Interval (2-Sided) 95%
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.0495
    Comments
    MethodMultivariate
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.5
    Confidence Interval (2-Sided) 95%
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.001
    Comments
    MethodMultivariate
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value3.8
    Confidence Interval (2-Sided) 95%
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    TitleIncidences of Bacterial, Fungal and Viral Infections in the 2 Groups.
    Description
    Time FrameD100 after HCT

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleFlu-TBITLI-ATG
    Arm/Group DescriptionConditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells. Conditioning regimen TBI + Fludarabine: 2 Gy TBI, Fludarabine 90 mg/m²Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7. Conditioning regimen II (TLI 8 Gy + ATG [Thymoglobulin]): TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kg
    Measure Participants4945
    Bacterial infection
    19
    38.8%
    25
    55.6%
    Fungal infection
    3
    6.1%
    7
    15.6%
    CMV reactivation
    15
    30.6%
    21
    46.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments 19 of 49 Flu-TBI patients (39%) versus 25 of 45 TLI ATG patients (56%) had a least one episode of bacterial infection the first 100 days after transplantation (P = 0.15).
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.15
    Comments
    MethodFisher Exact
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments For fungal infections, the figures were 3 of 45 (6%) and 7 of 45 (16%), respectively (P = 0.19)
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.19
    Comments
    MethodFisher Exact
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments Among CMV-seropositive patients and/or donors, the 100-day cumulative incidence of CMV reactivation was 31% in Flu-TBI patients versus 47% in TLI-ATG patient
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.12
    Comments
    MethodFisher Exact
    Comments
    5. Secondary Outcome
    TitlePercentage of Relapse Rate in the 2 Groups
    Description
    Time Frame1 year after HCT

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleFlu-TBITLI-ATG
    Arm/Group DescriptionConditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells. Conditioning regimen TBI + Fludarabine: 2 Gy TBI, Fludarabine 90 mg/m²Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7. Conditioning regimen II (TLI 8 Gy + ATG [Thymoglobulin]): TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kg
    Measure Participants4945
    Number [percentage of Relapse]
    22
    50
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments Four-year cumulative incidences of relapse/progression were 22% and 50% in Flu-TBI and TLI-ATG patients, respectively
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.017
    Comments
    MethodCumulative incidence curves
    Comments
    Method of EstimationEstimation ParameterMultivariate Cox models
    Estimated Value2.3
    Confidence Interval (2-Sided) 95%
    1.1 to 4.7
    Parameter Dispersion Type: Standard Deviation
    Value: 0.02
    Estimation Comments
    6. Secondary Outcome
    TitleQuality and Timing of Immunologic Reconstitution: Concentration of ATG Levels
    DescriptionAnalyses of ATG levels in order to assess the immune system recuperation
    Time FrameDay 0, Day 3 and Day 10

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTLI-ATG
    Arm/Group DescriptionConditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7. Conditioning regimen II (TLI 8 Gy + ATG [Thymoglobulin]): TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kg
    Measure Participants15
    Median ATG serum levels at day 0
    4
    Median ATG serum levels at day 3
    2.2
    Median ATG serum levels at day 10
    0.95
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Flu-TBI
    Comments This statistical analysis applies to median ATG serum levels at day 0
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterMedian Difference (Final Values)
    Estimated Value4
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Flu-TBI
    Comments This statistical analysis applies to median ATG serum levels at day 3
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterMean Difference (Final Values)
    Estimated Value2.2
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Flu-TBI
    Comments This statistical analysis applies to median ATG serum levels at day 10
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterMean Difference (Final Values)
    Estimated Value0.95
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    7. Secondary Outcome
    TitlePercentage of Non Relapse Mortality in the 2 Groups
    Description
    Time Frame1 year after HCT

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleFlu-TBITLI-ATG
    Arm/Group DescriptionConditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells. Conditioning regimen TBI + Fludarabine: 2 Gy TBI, Fludarabine 90 mg/m²Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7. Conditioning regimen II (TLI 8 Gy + ATG [Thymoglobulin]): TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kg
    Measure Participants4945
    Number [percentage of participants]
    24
    49%
    13
    28.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.5
    Comments
    MethodCumulative incidence curve
    Comments
    8. Secondary Outcome
    TitlePercentage of 4-year Progression Free Survival in the 2 Groups
    Description
    Time Frame4 year after HCT

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleFlu-TBITLI-ATG
    Arm/Group DescriptionConditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells. Conditioning regimen TBI + Fludarabine: 2 Gy TBI, Fludarabine 90 mg/m²Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7. Conditioning regimen II (TLI 8 Gy + ATG [Thymoglobulin]): TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kg
    Measure Participants4945
    Number [percentage of participants]
    54
    110.2%
    37
    82.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.14
    Comments
    MethodKaplan-Meier method
    Comments
    Method of EstimationEstimation Parametermultivariate analyses
    Estimated Value2
    Confidence Interval (2-Sided) 95%
    1 to 4.1
    Parameter Dispersion Type: Standard Deviation
    Value: 0.07
    Estimation Comments
    9. Secondary Outcome
    TitlePercentage of 5-year Progression Free Survival in the 2 Groups
    Description
    Time Frame5 year after HCT

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleFlu-TBITLI-ATG
    Arm/Group DescriptionConditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells. Conditioning regimen TBI + Fludarabine: 2 Gy TBI, Fludarabine 90 mg/m²Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7. Conditioning regimen II (TLI 8 Gy + ATG [Thymoglobulin]): TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kg
    Measure Participants4945
    Number [percentage of participants]
    50
    102%
    37
    82.2%
    10. Secondary Outcome
    TitlePercentage of 4-year Overall Survival in the 2 Groups
    Description
    Time Frame4 year after HCT

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleFlu-TBITLI-ATG
    Arm/Group DescriptionConditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells. Conditioning regimen TBI + Fludarabine: 2 Gy TBI, Fludarabine 90 mg/m²Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7. Conditioning regimen II (TLI 8 Gy + ATG [Thymoglobulin]): TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kg
    Measure Participants4945
    Number [percentage of participants]
    53
    108.2%
    54
    120%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.9
    Comments
    MethodKaplan-Meier method
    Comments
    Method of EstimationEstimation Parametermultivariate analyses
    Estimated Value1.2
    Confidence Interval (2-Sided) 95%
    1 to 1.4
    Parameter Dispersion Type: Standard Deviation
    Value: 0.02
    Estimation Comments
    11. Secondary Outcome
    TitlePercentage of 5-year Overall Survival in the 2 Groups
    Description
    Time Frame5 year after HCT

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleFlu-TBITLI-ATG
    Arm/Group DescriptionConditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells. Conditioning regimen TBI + Fludarabine: 2 Gy TBI, Fludarabine 90 mg/m²Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7. Conditioning regimen II (TLI 8 Gy + ATG [Thymoglobulin]): TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kg
    Measure Participants4945
    Number [percentage of participants]
    53
    108.2%
    55
    122.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Flu-TBI, TLI-ATG
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.96
    Comments
    MethodKaplan-Meier method
    Comments
    Method of EstimationEstimation Parametermultivariate analyses
    Estimated Value1.2
    Confidence Interval (2-Sided) 95%
    1 to 1.4
    Parameter Dispersion Type: Standard Deviation
    Value: 0.02
    Estimation Comments

    Adverse Events

    Time Frame5 years
    Adverse Event Reporting Description
    Arm/Group TitleFlu-TBITLI-ATG
    Arm/Group DescriptionConditioning regimen consisting of fludarabine 30 mg/m2 on days -4, -3 and -2 (total dose 90 mg/m2), followed by a singe dose of 2 Gy TBI administered on day 0, at a low dose-rate (≈ 7 cGy/min), before infusion of cells. Conditioning regimen TBI + Fludarabine: 2 Gy TBI, Fludarabine 90 mg/m²Conditioning consisting of 8 Gy TLI and ATG. TLI will be administered by linear accelerator at a dose of 80 cGy daily, starting 11 days before transplantation, until a total of 10 doses (800 cGy) has been delivered. The irradiation will consist of a supradiaphragmatic mantle field, a subdiaphragmatic field including an inverted Y and splenic ports, encompassing all major lymphoid organs, including the thymus, spleen, and lymph nodes, as used in the treatment of Hodgkin's disease (Kaplan HS, Cancer Research 26:1268-1276, 1966). The Waldeyer ring is not included. ATG (Thymoglobulin®, Genzyme), at a dose of 1.5 mg/kg/d, will be given intravenously on days -11 through -7. Conditioning regimen II (TLI 8 Gy + ATG [Thymoglobulin]): TLI 8 Gy + ATG (Thymoglobulin) 7.5 mg/kg
    All Cause Mortality
    Flu-TBITLI-ATG
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total22/49 (44.9%) 19/45 (42.2%)
    Serious Adverse Events
    Flu-TBITLI-ATG
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total41/49 (83.7%) 41/45 (91.1%)
    Blood and lymphatic system disorders
    Graft failure3/49 (6.1%) 4/45 (8.9%)
    Relapse/progression12/49 (24.5%) 22/45 (48.9%)
    Hemolytic anemia0/49 (0%) 1/45 (2.2%)
    Alveolar Hemorrhage1/49 (2%) 1/45 (2.2%)
    Hematuria0/49 (0%) 1/45 (2.2%)
    Gastrointestinal disorders
    GI complains4/49 (8.2%) 3/45 (6.7%)
    General disorders
    Fever unknown origin3/49 (6.1%) 5/45 (11.1%)
    Multiple organ failure0/49 (0%) 1/45 (2.2%)
    Immune system disorders
    acute Graft versus Host Disease5/49 (10.2%) 5/45 (11.1%)
    chronic Graft versus Host Disease20/49 (40.8%) 13/45 (28.9%)
    Infections and infestations
    Lung7/49 (14.3%) 2/45 (4.4%)
    Septic shock5/49 (10.2%) 5/45 (11.1%)
    Viral infection6/49 (12.2%) 4/45 (8.9%)
    Catheter2/49 (4.1%) 0/45 (0%)
    Urinary tract2/49 (4.1%) 0/45 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Second maligancy1/49 (2%) 1/45 (2.2%)
    Nervous system disorders
    Neurologic troubles4/49 (8.2%) 1/45 (2.2%)
    Epilepsy1/49 (2%) 0/45 (0%)
    Renal and urinary disorders
    Acute renal failure0/49 (0%) 2/45 (4.4%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrom1/49 (2%) 0/45 (0%)
    Dyspnea2/49 (4.1%) 0/45 (0%)
    Surgical and medical procedures
    surgical procedure2/49 (4.1%) 3/45 (6.7%)
    Other (Not Including Serious) Adverse Events
    Flu-TBITLI-ATG
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total15/49 (30.6%) 21/45 (46.7%)
    Infections and infestations
    CMV reactivation15/49 (30.6%) 21/45 (46.7%)

    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/TitleDr. Frédéric Baron
    OrganizationCHU de Liège
    Phone003243667201
    Emailf.baron@ulg.ac.be
    Responsible Party:
    Yves Beguin, Prof, University of Liege
    ClinicalTrials.gov Identifier:
    NCT00603954
    Other Study ID Numbers:
    • TJB0702P1
    First Posted:
    Jan 29, 2008
    Last Update Posted:
    Jan 26, 2022
    Last Verified:
    Nov 1, 2021