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
  Purpose

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.


Condition Intervention Phase
Leukemia, Myeloid, Acute
Leukemia, Lymphoblastic, Acute
Leukemia, Myelocytic, Chronic
Other: Allogeneic Lymphocytes
Drug: Fludarabine
Drug: Cyclophosphamide
Drug: Methylprednisolone
Drug: Cyclosporine
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Mismatched Donor Lymphocyte Infusions for Relapsed Disease Following Allogeneic Stem Cell Transplantation

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Overall survival at 6-month post-relapse time point. [ Time Frame: Assessing efficacy. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 120
Study Start Date: February 2009
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Other: Allogeneic Lymphocytes
    N/A
    Drug: Fludarabine
    N/A
    Drug: Cyclophosphamide
    N/A
    Drug: Methylprednisolone
    N/A
    Drug: Cyclosporine
    N/A
Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   8 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00859586

Contacts
Contact: Deborah A Draper (301) 496-3841 draperde@mail.nih.gov
Contact: Minocher M Battiwalla, M.D. (301) 827-0939 battiwam@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Minocher M Battiwalla, M.D. National Heart, Lung, and Blood Institute (NHLBI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier: NCT00859586     History of Changes
Other Study ID Numbers: 090087, 09-H-0087
Study First Received: March 10, 2009
Last Updated: June 11, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Acute Myelogenous Leukemia (AML)
Acute Lymphoblastic Leukemia (ALL)
Chronic Lymphocytic Leukemia
Myelodyplastic Syndrome (MDS)
Acute Myelogenous Leukemia
AML
Acute Lymphoblastic Leukemia
ALL
Myelodysplastic Syndrome
MDS

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Cyclosporins
Cyclosporine
Fludarabine phosphate
Fludarabine
Methylprednisolone Hemisuccinate
Prednisolone
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 28, 2014