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

NCT00859586 | Completed Results DMC

• 2 other identifiers: 09008709-H-0087
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (1)

• Overall Recipient Survival at 6-month Post-relapse of Disease

  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.

  6 months post-relapse of disease

Secondary Outcomes (10)

• Number of Participants Who Developed of Acute GVHD

  6 months post disease relapse

• Number of Participants Who Developed Grade I, Acute GVHD

  6 months post disease relapse

• Number of Participants Who Developed Grade II, Acute GVHD

  6 months post disease relapse

• Number of Participants Who Developed Grade III, Acute GVHD

  6 months post disease relapse

• Number of Participants Who Developed of Grade IV, Acute GVHD

  6 months post disease relapse

Study Arms (1)

Miltenyi Magnetic cell sorter for CD3

EXPERIMENTAL

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.

Device: Miltenyi Magnetic cell sorter for CD3

Interventions

Miltenyi Magnetic cell sorter for CD3 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.

Also known as: CliniMACS Miltenyi

Miltenyi Magnetic cell sorter for CD3

Eligibility Criteria

• Age: 8 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• Relapsed disease within 6 months of matched sibling allogeneic stem cell transplant procedure
• Evaluation for protocol within 8 weeks of relapse and enrollment within 12 weeks or relapse
• years of age
• Availability of previous HLA identical (6/6) related donor (ages 8 to 17 must have previously donated bone marrow \[not peripheral blood\]
• At least one haploidentical (1-3 antigen mismatched) related donor available for apheresis

You may not qualify if:

• Active grade II-IV Graft vs. Host Disease (GvHD)
• Extensive chronic Graft vs. Host Disease (GvHD)
• Post-transplant donor lymphocyte infusion (DLI) from original donor within 1 month of protocol enrollment.
• Progressive disease despite post-relapse chemo or monoclonal therapy.
• Co-morbidity of such severity that it would preclude the patients ability to tolerate protocol therapy.
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) greater than 10 x ULN (grade 3, CTCAE).
• Bilirubin greater than 5 x Upper Limit of Normal (ULN) (grade 3, CTCAE).
• Creatinine greater than 3.5 mg/dl (grade 3, CTCAE).
• 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).
• Positive pregnancy test for women of childbearing age.
• Severe psychiatric illness or mental deficiency sufficiently severe as to make compliance with the transplant treatment unlikely and informed consent impossible.
• 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.
• 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.
• Weight greater than or equal to 18 kg
• Age greater than or equal to 8 or less than or equal to 80 years old.

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health

Bethesda, Maryland, 20852, United States

Location

Related Publications (3)

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

  PMID: 8114836 BACKGROUND

• 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.

  PMID: 17162214 BACKGROUND

• 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.

  PMID: 11786567 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Lymphocytic, Chronic, B-Cell; Myelodysplastic Syndromes

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Myeloproliferative Disorders; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, B-Cell

Results Point of Contact

• Title: Dr. Minoo Battiwalla
• Organization: NIH NHLBI

battiwam@nhlbi.nih.gov

301-827-0939

Study Officials

• Minoo Battiwalla

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 10, 2009
• First Posted: March 11, 2009
• Study Start: February 1, 2009
• Primary Completion: September 1, 2014
• Study Completion: September 1, 2014
• Last Updated: October 27, 2020
• Results First Posted: November 6, 2015

Record last verified: 2014-08

Locations

US (1)