NMA Allogeneic Hematopoietic Cell Transplant in Hematologic Cancer/Disorders

Sponsor
Roswell Park Cancer Institute (Other)
Overall Status
Completed
CT.gov ID
NCT00053989
Collaborator
(none)
41
1
1
197.6
0.2

Study Details

Study Description

Brief Summary

RATIONALE: Giving low doses of chemotherapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving immunosuppressive therapy before or after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well chemotherapy followed by donor peripheral stem cell transplant works in treating patients with hematologic cancer or aplastic anemia.

Condition or Disease Intervention/Treatment Phase
  • Biological: anti-thymocyte globulin
  • Biological: graft-versus-tumor induction therapy
  • Biological: sargramostim
  • Biological: therapeutic allogeneic lymphocytes
  • Drug: cyclophosphamide
  • Drug: fludarabine phosphate
  • Drug: methylprednisolone
  • Drug: mycophenolate mofetil
  • Drug: tacrolimus
  • Procedure: allogeneic bone marrow transplantation
  • Procedure: peripheral blood stem cell transplantation
  • Procedure: umbilical cord blood transplantation
Phase 2

Detailed Description

OBJECTIVES:
  • Determine the safety and toxic effects of nonmyeloablative allogeneic peripheral blood stem cell transplantation in patients with a hematologic malignancy or aplastic anemia.

  • Determine clinical response and overall outcome of patients treated with this regimen.

  • Determine the incidence of graft-vs-tumor effect, graft-vs-host disease, and chimerism in patients treated with this regimen.

OUTLINE:
  • Preparative regimen:

  • Matched related and unrelated donor transplantation:

  • Patients receive cyclophosphamide IV over 2 hours on days -5 and -4 and fludarabine IV over 30 minutes on days -5 to -1.

  • Cord blood transplantation:

  • Patients receive the same regimen as above plus anti-thymocyte globulin IV over 4 hours on days -3 to -1.

  • Graft-vs-host disease (GVHD) prophylaxis:

  • Matched related and unrelated donor transplantation:

  • Patients receive oral tacrolimus (or IV) once daily and oral mycophenolate mofetil (MMF) (or IV) twice daily on days -1 to 60 followed by tapering* of this regimen. Patients then receive methotrexate IV on days 1, 3, and 6.

  • Cord blood transplantation:

  • Patients receive tacrolimus and MMF in the same regimen as above plus methylprednisolone twice daily on days 1-19 or until blood counts recover.

  • Allogeneic stem cell reinfusion: Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim (GM-CSF) subcutaneously daily beginning on day 7 and continuing until blood counts recover.

  • Donor lymphocyte infusion (DLI): Patients not converting to 100% donor T-cell chimerism by day 120 and showing signs of progresson of disease after tacrolimus and MMF withdrawal may receive DLI every 8 weeks for up to 3 infusions. Cord blood recipients do not receive DLI.

Patients are followed at day 100-120, every 3 months for 2 years, and then every 6 months for 5 years.

PROJECTED ACCRUAL: A total of 30-60 patients will be accrued for this study within 6-7 years.

Study Design

Study Type:
Interventional
Actual Enrollment :
41 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Non-Myeloablative Allogeneic Hematopoietic Peripheral Blood Stem Cell Transplantation for Hematologic Malignancies and Disorders
Actual Study Start Date :
Jan 29, 2002
Actual Primary Completion Date :
Jul 19, 2018
Actual Study Completion Date :
Jul 19, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: All patients

All patients enrolled on study

Biological: anti-thymocyte globulin
iv

Biological: graft-versus-tumor induction therapy
iv

Biological: sargramostim
iv

Biological: therapeutic allogeneic lymphocytes
iv

Drug: cyclophosphamide
injection

Drug: fludarabine phosphate
iv
Other Names:
  • FLUDARA
  • Drug: methylprednisolone
    oral

    Drug: mycophenolate mofetil
    oral

    Drug: tacrolimus
    oral

    Procedure: allogeneic bone marrow transplantation
    iv

    Procedure: peripheral blood stem cell transplantation
    iv

    Procedure: umbilical cord blood transplantation
    iv

    Outcome Measures

    Primary Outcome Measures

    1. Day 100 TRM [from start or conditioning (day -6 or -5) through day +100 after HSC infusion]

      treatment related mortality within 100 days from hematopoietic stem cell (HSC) infusion on day 0

    2. Day 100 Best Response [from start of conditioning on day -6 or -5 through day +100 after HSC infusion]

      Best disease response measured within 100 days from hematopoietic stem cell (HSC) infusion on day 0 using disease specific response criteria defined in the protocol

    Secondary Outcome Measures

    1. PFS [1 year]

      Progression free survival defined as time from HSC infusion (day 0) until progression of disease or death due to any cause. Patients are censored if alive without disease progression through 1 year after HSC infusion

    2. OS [1 year]

      Overall survival with events defined as death due to any cause and censored patients are alive as of 1 year post HSC infusion

    3. Acute GvHD [Day +100]

      overall grade II-IV acute GvHD

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    4 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    DISEASE CHARACTERISTICS:
    • Diagnosis of aplastic anemia

    • Severe disease

    • Failed at least 1 course of standard immunosuppressive regimen with cyclosporine and anti-thymocyte globulin OR

    • Histologically confirmed hematologic malignancy including the following:

    • Acute leukemia

    • Any of the following types:

    • Acute myeloid leukemia (AML) with antecedent myelodysplastic syndromes

    • Secondary AML

    • AML with high-risk cytogenetic abnormalities

    • Acute lymphoblastic leukemia with high-risk cytogenetic abnormalities

    • Resistant or recurrent disease after combination chemotherapy with at least 1 standard regimen OR

    • In first remission at high risk of relapse

    • Chronic myelogenous leukemia

    • Chronic phase meeting at least 1 of the following criteria:

    • Failed imatinib mesylate

    • Failed interferon after at least 6 months of treatment with minimum of 21 million units of interferon per week

    • Unable to tolerate interferon

    • Accelerated phase (blasts less than 20%)

    • Myeloproliferative and myelodysplastic syndromes

    • Myelofibrosis (after splenectomy)

    • Refractory anemia

    • Refractory anemia with excess blasts

    • Chronic myelomonocytic leukemia

    • Lymphoproliferative disease

    • Chronic lymphocytic leukemia

    • Symptomatic disease after first-line chemotherapy

    • Low-grade non-Hodgkin's lymphoma (recurrent or persistent)

    • Symptomatic disease after first-line chemotherapy

    • Multiple myeloma

    • Progressive disease after autologous stem cell transplantation

    • Waldenstrom's macroglobulinemia

    • Failed 1 standard regimen

    • Non-Hodgkin's lymphoma meeting the following criteria:

    • Intermediate or high grade

    • Controlled and chemosensitive disease

    • First remission lymphoblastic or small non-cleaved cell lymphoma at high risk of relapse

    • Hodgkin's lymphoma

    • Relapsed and chemosensitive disease

    • Not eligible for standard myeloablative allogeneic stem cell transplantation

    • Availability of any of the following donor types:

    • Related donor matched at 5 or 6 HLA antigens (A, B, DR)

    • Unrelated donor fully matched by molecular analysis at A, B, DRB1, and DQB1 loci

    • Single antigen mismatch at C allowed

    • Cord blood that is 4, 5, or 6 match with recipient HLA antigens (A, B, DR) NOTE: No syngeneic donors permitted

    • No uncontrolled CNS disease (for hematologic malignancies) NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

    PATIENT CHARACTERISTICS:

    Age

    • 4 to 75 (if related or unrelated donor peripheral blood or marrow transplantation)

    • 4 to 60 (if unrelated cord blood transplantation)

    Performance status

    • Karnofsky > 50%

    Life expectancy

    • Not specified

    Hematopoietic

    • Not specified

    Hepatic

    • Bilirubin less than 3 times normal

    • Alkaline phosphatase less than 3 times normal

    • AST/ALT less than 3 times normal

    • No Child's class B or C liver failure

    Renal

    • Creatinine clearance greater than 40 mL/min

    Cardiovascular

    • Cardiac ventricular ejection fraction at least 35% by MUGA

    • No cardiovascular disease

    Pulmonary

    • DLCO at least 40% of predicted, corrected for hemoglobin and/or alveolar ventilation

    Other

    • Not pregnant or nursing

    • Negative pregnancy test

    • Fertile patients must use effective contraception

    • HIV antibody negative

    • No uncontrolled diabetes mellitus

    • No active serious infection

    • No other disease that would preclude study therapy

    • No other concurrent malignancy except non-melanoma skin cancer

    • No concurrent serious psychiatric illness

    PRIOR CONCURRENT THERAPY:

    Biologic therapy

    • See Disease Characteristics

    • patients may have received a prior autologous blood or marrow transplantation (BMT)

    • At least 6 months since prior allogeneic BMT

    Chemotherapy

    • See Disease Characteristics

    • At least 2 weeks since prior chemotherapy, radiation or surgery

    Endocrine therapy

    • Not specified

    Radiotherapy

    • At least 2 weeks since prior radiotherapy

    Surgery

    • At least 2 weeks since prior surgery

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Roswell Park Cancer Institute Buffalo New York United States 14263-0001

    Sponsors and Collaborators

    • Roswell Park Cancer Institute

    Investigators

    • Principal Investigator: Philip L. McCarthy, MD, Roswell Park Cancer Institute

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Roswell Park Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT00053989
    Other Study ID Numbers:
    • CDR0000269673
    • RP01-05
    First Posted:
    Feb 6, 2003
    Last Update Posted:
    Feb 10, 2020
    Last Verified:
    Dec 1, 2019
    Keywords provided by Roswell Park Cancer Institute
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title All Patients
    Arm/Group Description All patients enrolled on study Patients received cyclophosphamide 50 mg/kg on days -5 and -4, and fludarabine 25 mg/m2 on days -5, -4, -3, -2, -1. Hematopoietic cells from peripheral blood or marrow were infused on day 0. Patients who received hematopoietic cells from cord blood additionally received ATG 30 mg/kg on days -3, -2, -1. Fanconi anemia patients received cyclophosphamide 7.5 mg/kg on days -6, -5, -4, -3, fludarabine 25 mg/m2 on days -6, -5, -4, -3, -2 and ATG 30 mg/kg on days -3, -2, -1 and hematopoietic cells infused on day 0.
    Period Title: Overall Study
    STARTED 41
    COMPLETED 41
    NOT COMPLETED 0

    Baseline Characteristics

    Arm/Group Title All Patients
    Arm/Group Description All patients enrolled on study Patients received cyclophosphamide 50 mg/kg on days -5 and -4, and fludarabine 25 mg/m2 on days -5, -4, -3, -2, -1. Hematopoietic cells from peripheral blood or marrow were infused on day 0. Patients who received hematopoietic cells from cord blood additionally received ATG 30 mg/kg on days -3, -2, -1. Fanconi anemia patients received cyclophosphamide 7.5 mg/kg on days -6, -5, -4, -3, fludarabine 25 mg/m2 on days -6, -5, -4, -3, -2 and ATG 30 mg/kg on days -3, -2, -1 and hematopoietic cells infused on day 0.
    Overall Participants 41
    Age (Count of Participants)
    <=18 years
    1
    2.4%
    Between 18 and 65 years
    37
    90.2%
    >=65 years
    3
    7.3%
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    52
    Sex: Female, Male (Count of Participants)
    Female
    17
    41.5%
    Male
    24
    58.5%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    1
    2.4%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    0
    0%
    White
    40
    97.6%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    41
    100%
    Diagnosis (Count of Participants)
    Acute lymphoblastic or myeloid leukemia
    12
    29.3%
    Hodgkin/non-Hodgkin lymphoma/prolymphocytic leukem
    21
    51.2%
    Multiple Myeloma
    2
    4.9%
    Myelodysplastic syndrome
    5
    12.2%
    Fanconi anemia
    1
    2.4%

    Outcome Measures

    1. Primary Outcome
    Title Day 100 TRM
    Description treatment related mortality within 100 days from hematopoietic stem cell (HSC) infusion on day 0
    Time Frame from start or conditioning (day -6 or -5) through day +100 after HSC infusion

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title All Patients
    Arm/Group Description All patients enrolled on study
    Measure Participants 41
    Count of Participants [Participants]
    4
    9.8%
    2. Primary Outcome
    Title Day 100 Best Response
    Description Best disease response measured within 100 days from hematopoietic stem cell (HSC) infusion on day 0 using disease specific response criteria defined in the protocol
    Time Frame from start of conditioning on day -6 or -5 through day +100 after HSC infusion

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title All Patients
    Arm/Group Description All patients enrolled on study
    Measure Participants 41
    Complete Response
    22
    53.7%
    Partial Response
    5
    12.2%
    Early Death/NE
    4
    9.8%
    No Response/Stable Disease
    2
    4.9%
    Progressed
    8
    19.5%
    3. Secondary Outcome
    Title PFS
    Description Progression free survival defined as time from HSC infusion (day 0) until progression of disease or death due to any cause. Patients are censored if alive without disease progression through 1 year after HSC infusion
    Time Frame 1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title All Patients
    Arm/Group Description All patients enrolled on study
    Measure Participants 41
    Number (95% Confidence Interval) [percentage of participants]
    27
    65.9%
    4. Secondary Outcome
    Title OS
    Description Overall survival with events defined as death due to any cause and censored patients are alive as of 1 year post HSC infusion
    Time Frame 1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title All Patients
    Arm/Group Description All patients enrolled on study
    Measure Participants 41
    Number (95% Confidence Interval) [percentage of participants]
    44
    107.3%
    5. Secondary Outcome
    Title Acute GvHD
    Description overall grade II-IV acute GvHD
    Time Frame Day +100

    Outcome Measure Data

    Analysis Population Description
    2 participants died before they were eligible for this outcome
    Arm/Group Title All Patients
    Arm/Group Description All patients enrolled on study
    Measure Participants 39
    Count of Participants [Participants]
    16
    39%

    Adverse Events

    Time Frame 100 days
    Adverse Event Reporting Description SAE=died before absolute neutrophil count recovery (DBE) or survived to day +28 without absolute neutrophil count recovery (FTE) AE=overall grade III-IV acute GVHD
    Arm/Group Title All Patients
    Arm/Group Description All patients enrolled on study
    All Cause Mortality
    All Patients
    Affected / at Risk (%) # Events
    Total 8/41 (19.5%)
    Serious Adverse Events
    All Patients
    Affected / at Risk (%) # Events
    Total 3/41 (7.3%)
    Blood and lymphatic system disorders
    DBE/FTE 3/41 (7.3%) 3
    Other (Not Including Serious) Adverse Events
    All Patients
    Affected / at Risk (%) # Events
    Total 6/41 (14.6%)
    Immune system disorders
    acute GVHD grade III-IV 6/41 (14.6%) 6

    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 Theresa Hahn, PhD
    Organization Roswell Park Comprehensive Cancer Center
    Phone 716084505819
    Email theresa.hahn@roswellpark.org
    Responsible Party:
    Roswell Park Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT00053989
    Other Study ID Numbers:
    • CDR0000269673
    • RP01-05
    First Posted:
    Feb 6, 2003
    Last Update Posted:
    Feb 10, 2020
    Last Verified:
    Dec 1, 2019