Protocol Number: 09-H-0087

Title:

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

Number:

09-H-0087

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.

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 cyclophosphamide and 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 novel 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 days post DLI, residual leukemia measured by patient chimerism, leukemia free survival from date relapse, safety of the mismatched DLI procedure.

Sponsoring Institute:

National Heart, Lung and Blood Institute (NHLBI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

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 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

2. Weight greater than or equal to 18 kg

3. 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.

Special Instructions:

Currently Not Provided

Keywords:

Acute Myelogenous Leukemia (AML)

Acute Lymphoblastic Leukemia (ALL)

Chronic Lymphocytic Leukemia

Myelodyplastic Syndrome (MDS)

Recruitment Keyword(s):

Acute Myelogenous Leukemia

AML

Acute Lymphoblastic Leukemia

ALL

Chronic Lymphocytic Leukemia

Myelodysplastic Syndrome

MDS

Condition(s):

Leukemia, Myeloid, Acute

Leukemia, Lymphoblastic, Acute

Leukemia, Myelocytic, Chronic

Investigational Drug(s):

None

Investigational Device(s):

None

Intervention(s):

Other: Allogeneic Lymphocytes

Drug: Fludarabine

Drug: Cyclophosphamide

Drug: Methylprednisolone

Drug: Cyclosporine

Supporting Site:

National Heart, Lung, and Blood Institute

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Armitage JO. Bone marrow transplantation. N Engl J Med. 1994 Mar 24;330(12):827-38.

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.

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.

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