Fludarabine Based Conditioning for Allogeneic Transplantation for Advanced Hematologic Malignancies

Sponsor
University of Illinois at Chicago (Other)
Overall Status
Completed
CT.gov ID
NCT01499147
Collaborator
(none)
100
1
2
158.9
0.6

Study Details

Study Description

Brief Summary

New conditioning regimens are still needed to maximize efficacy and limit treatment-related deaths of allogeneic transplantation for advanced hematologic malignancies. Over the past several years, the investigators have evaluated several new conditioning regimens that incorporate fludarabine, a novel immunosuppressant that has limited toxicity and that has synergistic activity with alkylating agents. Recent data have suggested that fludarabine may be used in combination with standard doses of oral or IV busulfan, thus reducing the toxicity previously observed with cyclophosphamide/ busulfan regimens.

Detailed Description

Treatment-related mortality and recurrence of disease account for the majority of treatment failures in allogeneic transplantation for advanced hematologic malignancies. The most commonly utilized conditioning regimens consist of cyclophosphamide and total-body irradiation or busulfan and cyclophosphamide. Other agents such as etoposide or thiotepa are sometimes added to maximize the antileukemic effect. New conditioning regimens are however still needed to maximize efficacy and limit treatment-related deaths. Over the past several years, the investigators have evaluated several new conditioning regimens that incorporate fludarabine, a novel immunosuppressant that has limited toxicity and that has synergistic activity with alkylating agents. Recent data have suggested that fludarabine may be used in combination with standard doses of oral or IV busulfan, thus reducing the toxicity previously observed with cyclophosphamide/ busulfan regimens.

Study Design

Study Type:
Interventional
Actual Enrollment :
100 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Fludarabine Based Conditioning for Allogeneic Transplantation for Advanced Hematologic Malignancies
Study Start Date :
Feb 1, 2000
Actual Primary Completion Date :
May 1, 2013
Actual Study Completion Date :
May 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Arm 1

All patients below age 55 should receive fludarabine/busulfan and ATG in case of unrelated or mismatched donor.

Drug: fludarabine/busulfan
All patients below age 55, should receive fludarabine/busulfan, and ATG in case of unrelated or mismatched donor, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl) and/or specific medical conditions such as preventing a standard myeloablative treatment, as per discussion with the PI.
Other Names:
  • Fludarabine:
  • Fludarabine Phosphate
  • Fludara
  • Busulfan:
  • Busulfex
  • Myleran
  • Drug: ATG
    Patients receiving a transplant from a matched unrelated or mismatched related/unrelated donor would receive ATG in the conditioning regimen.
    Other Names:
  • Thymoglobulin
  • Active Comparator: Arm 2

    All patients above age 55 or below age 65 should receive fludarabine/ melphalan and ATG.

    Drug: fludarabine/ melphalan
    All patients above age 55 or below age 65, should receive fludarabine/melphalan, and ATG, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl).
    Other Names:
  • Fludarabine:
  • Fludarabine phosphate
  • Fludara
  • Melphalan:
  • Alkeran
  • Drug: ATG
    Patients receiving a transplant from a matched unrelated or mismatched related/unrelated donor would receive ATG in the conditioning regimen.
    Other Names:
  • Thymoglobulin
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Engraftment. [Up to 30 days post-transplant]

      Median time to ANC engraftment and platelet engraftment in both groups as well as the transfusion requirements measured within 30 days after transplant.

    Secondary Outcome Measures

    1. Participants With 100 Day Transplant-related Mortality. [Up to 100 days post-transplant.]

      Day 100 transplant-related mortality was measured in both groups.

    2. Time to ANC and Platelet Engraftment [Up to 30 days post-transplant]

      Days to ANC or platelet engraftment

    3. Number of Participants With Moderate to Severe (Grade 2-4) Acute Graft Versus Host Disease (GVHD). [Up to 100 days post-transplant (acute GVHD).]

      Acute GVHD grade 2-4 was assessed in patients in the FluBU and FluMel groups up to 100 days after transplant.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    10 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients with the following diseases:

    • Acute myeloid or lymphocytic leukemia in first remission at standard or high-risk for recurrence.

    • Acute leukemia in greater than or equal to second remission, or with early relapse, or partial remission.

    • Chronic myelogenous leukemia in accelerated phase or blast-crisis.

    • Chronic myelogenous leukemia in chronic phase

    • Recurrent or refractory malignant lymphoma or Hodgkin's disease

    • Multiple myeloma.

    • Chronic lymphocytic leukemia, relapsed or with poor prognostic features.

    • Myeloproliferative disorder (polycythemia vera, myelofibrosis) with poor prognostic features.

    • Severe aplastic anemia after failure of immunosuppressive therapy.

    • Age 10-65 years.

    • Zubrod performance status less than or equal to 2.

    • Adequate cardiac and pulmonary function. Patients with decreased LVEF < 40% or DLCO < 50% of predicted will be evaluated by cardiology or pulmonary prior to enrollment on this protocol.

    • Patient or guardian able to sign informed consent.

    Exclusion Criteria:
    • Life expectancy is severely limited by concomitant illness.

    • Serum creatinine greater than 1.5 mg/dL or Creatinine Clearance less than 50 ml/min .

    • Serum bilirubin greater than or equal to 2.0 mg/dl, SGPT greater than 3 x upper limit of normal

    • Evidence of chronic active hepatitis or cirrhosis

    • HIV-positive

    • Patient is pregnant

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Illinois at Chicago Medical Center Chicago Illinois United States 60612

    Sponsors and Collaborators

    • University of Illinois at Chicago

    Investigators

    • Principal Investigator: Damiano Rondelli, MD, University of Illinois at Chicago

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Damiano Rondelli, MD, Professor, University of Illinois at Chicago
    ClinicalTrials.gov Identifier:
    NCT01499147
    Other Study ID Numbers:
    • 2000-0117
    First Posted:
    Dec 26, 2011
    Last Update Posted:
    Nov 8, 2018
    Last Verified:
    Oct 1, 2018

    Study Results

    Participant Flow

    Recruitment Details We analyzed the clinical outcome of patients with hematological malignancies at standard or high-risk, who were transplanted (allogeneic peripheral blood or BMT HSCT) after receiving FluBU as a conditioning regimen. A total of 30 patients were recruited for this study which was conducted at the UIC Medical Center Inpatient BMT unit.
    Pre-assignment Detail Criteria for FluBu conditioning: <60 years old; no diagnosis of myeloma or myelofibrosis (MF) in chronic phase; and not having received an autologous stem cell transplant with the last 2 years. Patients not fulfilling these criteria but still eligible for allogeneic transplantation were prepared with FluMel.
    Arm/Group Title Fludarabine/Busulfan + ATG Fludarabine/Melphalan + ATG
    Arm/Group Description All patients below age 55 should receive fludarabine/busulfan and ATG in case of unrelated or mismatched donor. fludarabine/busulfan: All patients below age 55, should receive fludarabine/busulfan, and ATG in case of unrelated or mismatched donor, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl) and/or specific medical conditions such as preventing a standard myeloablative treatment, as per discussion with the PI. All patients above age 55 or below age 65 should receive fludarabine/ melphalan and ATG. fludarabine/ melphalan: All patients above age 55 or below age 65, should receive fludarabine/melphalan, and ATG, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl).
    Period Title: Overall Study
    STARTED 33 17
    COMPLETED 18 12
    NOT COMPLETED 15 5

    Baseline Characteristics

    Arm/Group Title Arm 1 Arm 2 Total
    Arm/Group Description All patients below age 55 should receive fludarabine/busulfan and ATG in case of unrelated or mismatched donor. fludarabine/busulfan: All patients below age 55, should receive fludarabine/busulfan, and ATG in case of unrelated or mismatched donor, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl) and/or specific medical conditions such as preventing a standard myeloablative treatment, as per discussion with the PI. All patients above age 55 or below age 65 should receive fludarabine/ melphalan and ATG. fludarabine/ melphalan: All patients above age 55 or below age 65, should receive fludarabine/melphalan, and ATG, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl). Total of all reporting groups
    Overall Participants 18 12 30
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    34
    49
    42.5
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    18
    100%
    12
    100%
    30
    100%
    >=65 years
    0
    0%
    0
    0%
    0
    0%
    Sex: Female, Male (Count of Participants)
    Female
    8
    44.4%
    8
    66.7%
    16
    53.3%
    Male
    10
    55.6%
    4
    33.3%
    14
    46.7%
    Region of Enrollment (participants) [Number]
    United States
    18
    100%
    12
    100%
    30
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Engraftment.
    Description Median time to ANC engraftment and platelet engraftment in both groups as well as the transfusion requirements measured within 30 days after transplant.
    Time Frame Up to 30 days post-transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Fludarabine/Busulfan + ATG Fludarabine/Melphalan + ATG
    Arm/Group Description All patients below age 55 should receive fludarabine/busulfan and ATG in case of unrelated or mismatched donor. fludarabine/busulfan: All patients below age 55, should receive fludarabine/busulfan, and ATG in case of unrelated or mismatched donor, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl) and/or specific medical conditions such as preventing a standard myeloablative treatment, as per discussion with the PI. All patients above age 55 or below age 65 should receive fludarabine/ melphalan and ATG. fludarabine/ melphalan: All patients above age 55 or below age 65, should receive fludarabine/melphalan, and ATG, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl).
    Measure Participants 18 12
    Number [participants]
    18
    100%
    12
    100%
    2. Secondary Outcome
    Title Participants With 100 Day Transplant-related Mortality.
    Description Day 100 transplant-related mortality was measured in both groups.
    Time Frame Up to 100 days post-transplant.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Fludarabine/Busulfan + ATG Fludarabine/Melphalan + ATG
    Arm/Group Description All patients below age 55 should receive fludarabine/busulfan and ATG in case of unrelated or mismatched donor. fludarabine/busulfan: All patients below age 55, should receive fludarabine/busulfan, and ATG in case of unrelated or mismatched donor, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl) and/or specific medical conditions such as preventing a standard myeloablative treatment, as per discussion with the PI. All patients above age 55 or below age 65 should receive fludarabine/ melphalan and ATG. fludarabine/ melphalan: All patients above age 55 or below age 65, should receive fludarabine/melphalan, and ATG, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl).
    Measure Participants 18 12
    Number [participants]
    1
    5.6%
    1
    8.3%
    3. Secondary Outcome
    Title Time to ANC and Platelet Engraftment
    Description Days to ANC or platelet engraftment
    Time Frame Up to 30 days post-transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Fludarabine/Busulfan + ATG Fludarabine/Melphalan + ATG
    Arm/Group Description All patients below age 55 should receive fludarabine/busulfan and ATG in case of unrelated or mismatched donor. fludarabine/busulfan: All patients below age 55, should receive fludarabine/busulfan, and ATG in case of unrelated or mismatched donor, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl) and/or specific medical conditions such as preventing a standard myeloablative treatment, as per discussion with the PI. ATG: Patients receiving a transplant from a matched unrelated or mismatched related/unrelated donor would receive ATG in the conditioning regimen. All patients above age 55 or below age 65 should receive fludarabine/ melphalan and ATG. fludarabine/ melphalan: All patients above age 55 or below age 65, should receive fludarabine/melphalan, and ATG, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl). ATG: Patients receiving a transplant from a matched unrelated or mismatched related/unrelated donor would receive ATG in the conditioning regimen.
    Measure Participants 18 12
    Median (Full Range) [days to ANC and platelet engraftment]
    15
    12
    4. Secondary Outcome
    Title Number of Participants With Moderate to Severe (Grade 2-4) Acute Graft Versus Host Disease (GVHD).
    Description Acute GVHD grade 2-4 was assessed in patients in the FluBU and FluMel groups up to 100 days after transplant.
    Time Frame Up to 100 days post-transplant (acute GVHD).

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Fludarabine/Busulfan + ATG Fludarabine/Melphalan +ATG
    Arm/Group Description All patients below age 55 should receive fludarabine/busulfan and ATG in case of unrelated or mismatched donor. fludarabine/busulfan: All patients below age 55, should receive fludarabine/busulfan, and ATG in case of unrelated or mismatched donor, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl) and/or specific medical conditions such as preventing a standard myeloablative treatment, as per discussion with the PI. All patients above age 55 or below age 65 should receive fludarabine/ melphalan and ATG. fludarabine/ melphalan: All patients above age 55 or below age 65, should receive fludarabine/melphalan, and ATG, unless there is significant pulmonary, hepatic or cardiac damage: (E.g FEV1 <40%, DLCO<50%, LVEF<40, Serum bilirubin >1.5 mg% or serum transaminases > 2x nl).
    Measure Participants 18 12
    Number [participants]
    2
    11.1%
    1
    8.3%

    Adverse Events

    Time Frame 365 days post-transplant
    Adverse Event Reporting Description REGIMEN-RELATED TOXICITY ACCORDING TO ORGAN SYSTEM (ref: Bearman et al: J Clin Oncol vol 6, 1988, 1562-1568)
    Arm/Group Title Participants With Extra-hematological Toxicities FluBu Participants With Extra-hematological Toxicities FluMel Participants With Extra-hematological Toxicities
    Arm/Group Description We analyzed if different rates of severe extra-hematological toxicities could be detected in patients conditioned with FluBu and FluMel and receiving PBSC. We analyzed if different rates of severe extra-hematological toxicities could be detected in patients conditioned with FluBu and receiving PBSC. We analyzed if different rates of severe extra-hematological toxicities could be detected in patients conditioned with FluMel and receiving PBSC.
    All Cause Mortality
    Participants With Extra-hematological Toxicities FluBu Participants With Extra-hematological Toxicities FluMel Participants With Extra-hematological Toxicities
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Participants With Extra-hematological Toxicities FluBu Participants With Extra-hematological Toxicities FluMel Participants With Extra-hematological Toxicities
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 8/30 (26.7%) 5/18 (27.8%) 3/12 (25%)
    Gastrointestinal disorders
    stomatitis 3/30 (10%) 3 2/18 (11.1%) 2 1/12 (8.3%) 1
    Immune system disorders
    CMV reactivation 5/30 (16.7%) 5 3/18 (16.7%) 3 2/12 (16.7%) 2
    Other (Not Including Serious) Adverse Events
    Participants With Extra-hematological Toxicities FluBu Participants With Extra-hematological Toxicities FluMel Participants With Extra-hematological Toxicities
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/30 (0%) 0/18 (0%) 0/12 (0%)
    Hepatobiliary disorders
    Veno-occlusive disease 0/30 (0%) 0 0/18 (0%) 0 0/12 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE 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 Damiano Rondelli, MD
    Organization University of Illinois Cancer Center
    Phone 312-996-6179
    Email drond@uic.edu
    Responsible Party:
    Damiano Rondelli, MD, Professor, University of Illinois at Chicago
    ClinicalTrials.gov Identifier:
    NCT01499147
    Other Study ID Numbers:
    • 2000-0117
    First Posted:
    Dec 26, 2011
    Last Update Posted:
    Nov 8, 2018
    Last Verified:
    Oct 1, 2018