Clinical trial NCT00859586: Mismatched Donor Lymphocyte Infusions for Relapsed Disease Following Allogeneic Stem Cell Transplantation
Official title: Mismatched Donor Lymphocyte Infusions for Relapsed Disease Following Allogeneic Stem Cell Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Leukemia, Myeloid, Acute
Leukemia, Lymphoblastic, Acute
Leukemia, Myelocytic, Chronic
Keywords: Acute Myelogenous Leukemia (AML)
Acute Lymphoblastic Leukemia (ALL)
Chronic Lymphocytic Leukemia
Myelodysplastic Syndrome (MDS)
Acute Myelogenous Leukemia
AML
Acute Lymphoblastic Leukemia
ALL
Myelodysplastic Syndrome
MDS
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2009-03-11
Enrollment: 8
Sex: ALL
Minimum age (years): 8
Maximum age (years): 75
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: The CliniMACS CD34 Reagent System is a medical device used in vitro to select and enrich specific cell populations (CD34+ cells from heterogeneous hematological cell populations). In stage 1, subjects will receive 1 x 108 CD3 cells/kg on day 0. We will progress to stage 2 where the dose of CD3+ cells will be increased to 2 x 108 cells/kg.
Primary purpose: TREATMENT

Brief summary: 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.

Human leukocyte antigen (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.

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 National Heart Lung and Blood (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 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 Chronic Myeloid Leukemia (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 Graft vs. Host Disease (GvHD)
2. Extensive chronic Graft vs. Host Disease (GvHD)
3. Post-transplant donor lymphocyte infusion (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 patients ability to tolerate protocol therapy.
6. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) greater than 10 x ULN (grade 3, CTCAE).
7. Bilirubin greater than 5 x Upper Limit of Normal (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).
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

Primary outcomes:
measure: Overall Recipient Survival at 6-month Post-relapse of Disease
timeFrame: 6 months post-relapse of disease
Secondary outcomes:
measure: Number of Participants Who Developed of Acute GVHD
timeFrame: 6 months post disease relapse
measure: Number of Participants Who Developed Grade I, Acute GVHD
timeFrame: 6 months post disease relapse
measure: Number of Participants Who Developed Grade II, Acute GVHD
timeFrame: 6 months post disease relapse
measure: Number of Participants Who Developed Grade III, Acute GVHD
timeFrame: 6 months post disease relapse
measure: Number of Participants Who Developed of Grade IV, Acute GVHD
timeFrame: 6 months post disease relapse
measure: Number of Participants Who Developed Chronic GVHD
timeFrame: 6 months post disease relapse
measure: Number of Participants Who Developed Limited Chronic GVHD
timeFrame: 6 months post disease relapse
measure: Number of Participants With Extensive, Chronic GVHD
timeFrame: 6 months post disease relapse
measure: Number of Participants With CD3+ Engraftment Who Achieved Peak Chimerism Post DLI
timeFrame: 21 Days
measure: Number of Subjects Leukemia Response After Donor Lymphocyte Infusion (DLI)
timeFrame: 21 days
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health
state: Maryland
Study officials:
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
name: Minoo Battiwalla
role: PRINCIPAL_INVESTIGATOR
References:
citation: Armitage JO. Bone marrow transplantation. N Engl J Med. 1994 Mar 24;330(12):827-38. doi: 10.1056/NEJM199403243301206. No abstract available.
citation: Montero A, Savani BN, Shenoy A, Read EJ, Carter CS, Leitman SF, Mielke S, Rezvani K, Childs R, Barrett AJ. T-cell depleted peripheral blood stem cell allotransplantation with T-cell add-back for patients with hematological malignancies: effect of chronic GVHD on outcome. Biol Blood Marrow Transplant. 2006 Dec;12(12):1318-25. doi: 10.1016/j.bbmt.2006.08.034.
citation: Levine JE, Braun T, Penza SL, Beatty P, Cornetta K, Martino R, Drobyski WR, Barrett AJ, Porter DL, Giralt S, Leis J, Holmes HE, Johnson M, Horowitz M, Collins RH Jr. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol. 2002 Jan 15;20(2):405-12. doi: 10.1200/JCO.2002.20.2.405.