Mismatched Donor Lymphocyte Infusions for Relapsed Disease Following Allogeneic Stem Cell Transplantation

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier:
NCT00859586
First received: March 10, 2009
Last updated: June 11, 2014
Last verified: September 2013

March 10, 2009
June 11, 2014
February 2009
December 2015   (final data collection date for primary outcome measure)
Overall survival at 6-month post-relapse time point. [ Time Frame: Assessing efficacy. ] [ Designated as safety issue: No ]
Overall survival at 6 month post relapse time point.
Complete list of historical versions of study NCT00859586 on ClinicalTrials.gov Archive Site
Incidence and severity induced GvHD, proportion of DLI engraftment, peak chimerism, leukemia response at days post DLI, residual leukemia measured by patient chimerism, leukemia free survival from date relapse, safety of mismatched DLI procedure... [ Time Frame: Severity of GvHD. ] [ Designated as safety issue: No ]
Incidence and severity induced GvHD, proportion of DLI engrafement, peak chimerism, leukemia response at days post DLI, residual leukemia measured by patient chimerism, leukemia free survival from date relapse, safety of mismatched DLI procedure.
Not Provided
Not Provided
 
Mismatched Donor Lymphocyte Infusions for Relapsed Disease Following Allogeneic Stem Cell Transplantation
Mismatched Donor Lymphocyte Infusions for Relapsed Disease Following Allogeneic Stem Cell Transplantation

Patients receiving allogeneic stem cell transplantation for hematological malignancies who suffer a relapse of their disease post-transplant have limited treatment options and a poor prognosis. With the exception of patients with chronic leukemias who may achieve prolonged remissions after donor lymphocyte infusions (DLIs), treatments using either chemotherapy or a DLI achieve less than a 10% median survival beyond 6 months. Most of these patients die of progressive leukemia, underlying the need for new therapeutic approaches.

HLA-mismatched DLIs appear to possess a more potent graft-versus-leukemia (GvL) effect. However, when given after an HLA-mismatched transplant DLIs have a high risk of causing graft-versus-host disease (GvHD), which can be severe. To reduce the risk of GvHD, infusions of mismatched lymphocytes from an alternative donor may be used to avoid permanent engraftment and associated risk of GvHD.

In this study, we propose to use a novel strategy to treat leukemias relapsing after HLA matched allogeneic stem cell transplantation by using haplo-identical DLIs to promote the associated antileukemic effect while minimizing the possibility of permanent engraftment and associated GvHD. To achieve only temporary engraftment and to promote disease control we will give fludarabine immunosuppression prior to the DLI. We anticipate the infusion of HLA-mismatched donor lymphocytes in this setting will produce no detectible engraftment or only temporary engraftment, but may result in a strong GvL effect regardless of engraftment outcome. We will select patients for this protocol who fall into the worst category for post-transplant relapse. Specifically, we will enroll patients with acute leukemia or MDS relapsing within 6 months of transplant, of which less than 5% survive beyond a year from relapse.

The primary objective of this phase II clinical trial will be to evaluate the safety and efficacy of using a non-engraftment model and a lymphocytes infusion from a haplo-identical donor to treat relapsed disease following matched sibling stem cell transplantation in subjects who are not candidates for alternative treatment options.

We therefore propose this is a phase II clinical trial the primary objective of which is to evaluate the safety and efficacy of a non-myeloablative but highly immunosuppressive disease specific conditioning regimen and infusion of unmanipulated lymphocytes from a haplo-identical donor in subjects with relapsed disease following matched sibling stem cell transplantation who are not candidates for alternative treatment options.

The primary endpoint of this phase 2 study is survival at 6 month post-relapse of disease. Successful outcome of the study will be a survival 100% greater than the NHLBI historical 25% at 6-months.

Secondary endpoints will include: incidence and severity induced GvHD, proportion of DLI engraftment, peak chimerism, leukemia response at 21 days post DLI, residual leukemia measured by patient chimerism, leukemia free survival from date relapse, safety of the mismatched DLI procedure.

Patients receiving allogeneic stem cell transplantation for hematological malignancies who suffer a relapse of their disease post-transplant have limited treatment options and a poor prognosis. With the exception of patients with chronic leukemias who may achieve prolonged remissions after donor lymphocyte infusions (DLIs), treatments using either chemotherapy or a DLI achieve less than a 10% median survival beyond 6 months. Most of these patients die of progressive leukemia, underlying the need for new therapeutic approaches.

HLA-mismatched DLIs appear to possess a more potent graft-versus-leukemia (GvL) effect. However, when given after an HLA-mismatched transplant DLIs have a high risk of causing graft-versus-host disease (GvHD), which can be severe. To reduce the risk of GvHD, infusions of mismatched lymphocytes from an alternative donor may be used to avoid permanent engraftment and associated risk of GvHD.

In this study, we propose to use a novel strategy to treat leukemias relapsing after HLA matched allogeneic stem cell transplantation by using haplo-identical DLIs to promote the associated antileukemic effect while minimizing the possibility of permanent engraftment and associated GvHD. To achieve only temporary engraftment and to promote disease control we will give fludarabine immunosuppression prior to the DLI. We anticipate the infusion of HLA-mismatched donor lymphocytes in this setting will produce no detectible engraftment or only temporary engraftment, but may result in a strong GvL effect regardless of engraftment outcome. We will select patients for this protocol who fall into the worst category for post-transplant relapse. Specifically, we will enroll patients with acute leukemia or MDS relapsing within 6 months of transplant, of which less than 5% survive beyond a year from relapse.

The primary objective of this phase II clinical trial will be to evaluate the safety and efficacy of using a non-engraftment model and a lymphocytes infusion from a haplo-identical donor to treat relapsed disease following matched sibling stem cell transplantation in subjects who are not candidates for alternative treatment options.

We therefore propose this is a phase II clinical trial is to evaluate the safety and efficacy of an infusion of unmanipulated lymphocytes from a haplo-identical donor in subjects with relapsed disease following matched sibling stem cell transplantation who are not candidates for alternative treatment options.

The primary endpoint of this phase 2 study is survival at 6 month post-relapse of disease. Successful outcome of the study will be a survival of 100% greater than the NHLBI historical 25% at 6-months.

Secondary endpoints will include: incidence and severity of induced GvHD, proportion of DLI engraftment, peak chimerism, leukemia response at 21 days post DLI, residual leukemia measured by patient chimerism, leukemia free survival from date relapse, and safety of the mismatched DLI procedure.

Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Leukemia, Myeloid, Acute
  • Leukemia, Lymphoblastic, Acute
  • Leukemia, Myelocytic, Chronic
  • Other: Allogeneic Lymphocytes
    N/A
  • Drug: Fludarabine
    N/A
  • Drug: Cyclophosphamide
    N/A
  • Drug: Methylprednisolone
    N/A
  • Drug: Cyclosporine
    N/A
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
120
December 2015
December 2015   (final data collection date for primary outcome measure)
  • ELIGIBILITY CRITERIA:

Inclusion Criteria- Recipient:

  1. Diagnosed with one of the following hematological conditions:

    • Acute lymphoblastic leukemia (ALL) of any subtype or
    • Acute myelogenous leukemia (AML) of any subtype or
    • Myelodysplastic syndrome (MDS) of any subtype or
    • Blastic phase CML
  2. Relapsed disease within 6 months of matched sibling allogeneic stem cell transplant procedure
  3. Evaluation for protocol within 8 weeks of relapse and enrollment within 12 weeks or relapse
  4. 8-75 years of age
  5. Availability of previous HLA identical (6/6) related donor (ages 8 to 17 must have previously donated bone marrow [not peripheral blood]
  6. At least one haploidentical (1-3 antigen mismatched) related donor available for apheresis

Exclusion Criteria Recipient (any of the following):

  1. Active grade II-IV GvHD
  2. Extensive chronic GvHD
  3. Post-transplant DLI from original donor within 1 month of protocol enrollment.
  4. Progressive disease despite post-relapse chemo or monoclonal therapy.
  5. Co-morbidity of such severity that it would preclude the patient s ability to tolerate protocol therapy.
  6. AST/SGOT greater than 10 x ULN (grade 3, CTCAE).
  7. Bilirubin greater than 5 x ULN (grade 3, CTCAE).
  8. Creatinine greater than 3.5 mg/dl (grade 3, CTCAE).
  9. HIV positive (Recipients who are positive for hepatitis B (HBV), hepatitis C (HCV) or human T-cell lymphotropic virus (HTLV-I/II) are not excluded from participation).
  10. Positive pregnancy test for women of childbearing age.
  11. Severe psychiatric illness or mental deficiency sufficiently severe as to make compliance with the transplant treatment unlikely and informed consent impossible.

Inclusion Criteria- Stem Cell Donors:

  1. HLA-matched sibling stem cell donor from the original transplant to participate in a stem cell rescue only in the setting of severe, refractory GvHD caused by the haploidentical cells.
  2. Related HLA haplo-identical (1-3 A, B or DR antigens mismatched with recipient). To maximize the GvL that is associated with HLA disparity, the haploidentical donor will be chosen based on the greatest HLA mismatch (preference: 3/6 greater than 4/6 greater than 5/6). Parents and siblings will be considered equally.
  3. Weight greater than or equal to 18 kg
  4. Age greater than or equal to 8 or less than or equal to 80 years old.

Exclusion Criteria Stem Cell Donor (any of the following):

  1. Pregnant or lactating
  2. Unfit to receive filgrastim (G-CSF) or previous filgrastim mobilization for donors under 18 years of age.
  3. Unfit to undergo apheresis (abnormal blood counts, history of stroke, uncontrolled hypertension).
  4. Sickling hemoglobinopathies such as HbSS or HbSC.
  5. HIV positive. Donors who are positive for hepatitis B (HBV), hepatitis C (HCV), human T-cell lymphotropic virus (HTLV-I/II), or T.cruzi (Chagas) will be used at the discretion of the investigator following counseling and approval from the recipient.
  6. Severe psychiatric illness or mental deficiency sufficiently severe as to make compliance with the donation of stem cells unlikely and/or informed consent impossible.

Inclusion criteria- Haplo Lymphocyte Donors:

  1. Related HLA haplo-identical (1-3 A, B or DR antigens mismatched with recipient). To maximize the GvL that is associated with HLA disparity, the haploidentical donor will be chosen based on the greatest HLA mismatch (preference: 3/6 greater than 4/6 greater than 5/6). Donors age less than 80 years required, and parents and siblings will be considered equally.
  2. Age greater than or equal to 18 or less than or equal to 80 years old.

Exclusion Criteria Haplo Lymphocyte Donor (any of the following):

  1. Pregnant or lactating
  2. Unfit to undergo apheresis (abnormal blood counts, history of stroke, uncontrolled hypertension).< TAB>
  3. Sickling hemoglobinopathies such as HbSS and HbSC .
  4. HIV positive. Donors who are positive for hepatitis B (HBV), hepatitis C (HCV) or human T-cell lymphotropic virus (HTLV-I/II), or T.cruzi (Chagas) will be used at the discretion of the investigator following counseling and approval from the recipient.
  5. Severe psychiatric illness or mental deficiency sufficiently severe as to make compliance with the donation of stem cells unlikely and/or informed consent impossible
Both
8 Years to 75 Years
No
Contact: Deborah A Draper (301) 496-3841 draperde@mail.nih.gov
Contact: Minocher M Battiwalla, M.D. (301) 827-0939 battiwam@mail.nih.gov
United States
 
NCT00859586
090087, 09-H-0087
Not Provided
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
National Heart, Lung, and Blood Institute (NHLBI)
Not Provided
Principal Investigator: Minocher M Battiwalla, M.D. National Heart, Lung, and Blood Institute (NHLBI)
National Institutes of Health Clinical Center (CC)
September 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP