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

NCT ID: NCT00859586

Last Updated: 2020-10-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-02-28
• Study Completion Date: 2014-09-30

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.

Conditions

Leukemia, Myeloid, Acute; Leukemia, Lymphoblastic, Acute; Leukemia, Myelocytic, Chronic

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Miltenyi Magnetic cell sorter for CD3

Miltenyi Magnetic cell sorter device will be used for CD3 selection of granulocyte colony stimulating factor mobilized allogeneic PBSCT. In stage 1, subjects will receive 1 x 10 to the eight power CD3 cells/kg. In stage II, the dose of CD3+ cells will be increased to 2 x 10 to the eight power cells/kg.

This phase II clinical trial is designed to evaluate a novel non-myeloablative but highly immunosuppressive disease specific conditioning regimen and infusion of unmanipulated lymphocytes from a haplo-identical familial donor in subjects with relapsed disease following matched sibling stem cell transplantation who are not candidates for alternative treatment options. The clinical trial will evaluate recipient survival at six months post-relapse of disease.

Group Type: EXPERIMENTAL

Miltenyi Magnetic cell sorter for CD3

Intervention Type: DEVICE

Receipts will receive 1 x 10 to eighth power CD3 cells/kg of familial haploidentical positively selected cluster of differentiation 34 (CD34)+ stem cells from the same DLI donor.

Interventions

Miltenyi Magnetic cell sorter for CD3

Receipts will receive 1 x 10 to eighth power CD3 cells/kg of familial haploidentical positively selected cluster of differentiation 34 (CD34)+ stem cells from the same DLI donor.

Intervention Type: DEVICE

Other Intervention Names

CliniMACS Miltenyi

Eligibility Criteria

Inclusion Criteria

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

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.

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

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.

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.

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

• Minimum Eligible Age: 8 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Minoo Battiwalla

Role: PRINCIPAL_INVESTIGATOR

National Heart, Lung, and Blood Institute (NHLBI)

Locations

National Institutes of Health

Bethesda, Maryland, United States

Countries

United States

References

Armitage JO. Bone marrow transplantation. N Engl J Med. 1994 Mar 24;330(12):827-38. doi: 10.1056/NEJM199403243301206. No abstract available.

Reference Type: BACKGROUND

PMID: 8114836 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17162214 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11786567 (View on PubMed)

Related Links

http://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2009-H-0087.html

NIH Clinical Center Detailed Web Page

Other Identifiers

09-H-0087

Identifier Type: OTHER

Identifier Source: secondary_id

090087

Identifier Type: -

Identifier Source: org_study_id