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

Not Applicable

Completed

Conditions: Leukemia, Myelocytic, Chronic
Leukemia, Lymphoblastic, Acute
Leukemia, Myeloid, Acute

Interventions: Device: Miltenyi Magnetic cell sorter for CD3

Registration Number: NCT00859586

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 8

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Miltenyi Magnetic cell sorter for CD3	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.

Primary Outcome Measures

Name	Time	Method
Overall Recipient Survival at 6-month Post-relapse of Disease	6 months 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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Who Developed Limited Chronic GVHD	6 months post disease relapse	Number of participants who developed Limited Chronic Graft vs Host Disease (GVHD). Limited chronic GVHD is defined as GVHD occurring after day 100 that involved localized skin and/or mouth and/or liver.
Number of Participants Who Developed of Acute GVHD	6 months post disease relapse	Overall number incidences of participants who developed Acute Graft versus Host Disease (GVHD).
Number of Participants Who Developed Grade I, Acute GVHD	6 months post disease relapse	Number of participants who developed Grade I, Acute Graft vs Host Disease (GVHD) as defined by CIMBTR criteria for Organ Stages of Acute GVHD. Grade 1 is defined as: Skin = Maculopapular rash\< 25% of body surface area (BSA); Liver = Total Bilirubin 2-3 mg/dL; Lower GI = stool output/day is 500-999 mL/day. Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.
Number of Participants Who Developed Grade II, Acute GVHD	6 months post disease relapse	Number of participants who developed Grade II, Acute Graft vs Host Disease (GVHD) as defined by CIMBTR criteria for Organ Stages of Acute GVHD. Stage II Acute GVHD: Skin - rash on 25-50 percent body surface area; Liver - Total Bilirubin 3.1-6.0 mg/dL; Lower GI - Diarrhea 1001-1500 mL/day. Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.
Number of Participants Who Developed Grade III, Acute GVHD	6 months post disease relapse	Number of participants who developed Grade III, Acute Graft vs Host Disease (GVHD) as defined by CIMBTR criteria for Organ Stages of Acute GVHD. Stage III Acute GVHD: Skin - Rash on \>50% of body surface; Liver - Total Bilirubin 6.1 - 15.0 mg/dL; Lower GI - Diarrhea \> 1500 mL/day Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.
Number of Participants Who Developed of Grade IV, Acute GVHD	6 months post disease relapse	Number of participants who developed Grade IV, Acute Graft vs Host Disease (GVHD) as defined by CIMBTR criteria for Organ Stages of Acute GVHD. Grade IV, Acute GVHD is defined as: Skin = Generalized erythroderma plus bullous formation; Liver = Total Bilirubin \>15 mg/dL; Lower GI = Severe abdominal pain with or without ileus. Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.
Number of Participants Who Developed Chronic GVHD	6 months post disease relapse	Number of incidences of participants who developed Chronic Graft vs Host Disease (GVHD). Moderate GVHD is 3 or more organs with score 1, any organ with score 2, or lung with score 1, and usually requires systemic immune-suppressive treatment. Mild disease is associated with a good prognosis whereas severe disease is associated with higher treatment-related mortality and lower survival. Organs are scored on a 0 to 3 scale from no involvement/no symptoms to severe functional compromise.
Number of Participants With Extensive, Chronic GVHD	6 months post disease relapse	Number of participants with extensive, Chronic Graft vs Host Disease (GVHD). Extensive chronic GVHD is defined as GVHD occurring after day 100 that did not meet the definition of limited chronic GVHD.
Number of Participants With CD3+ Engraftment Who Achieved Peak Chimerism Post DLI	21 Days	Number of Participants with CD3+ Engraftment who Achieved Peak Chimerism post Donor Lymphocyte Infusion (DLI)
Number of Subjects Leukemia Response After Donor Lymphocyte Infusion (DLI)	21 days	Subjects experience leukemia response after partially human leukocyte antigen (HLA) matched DLI according to International Working Group criteria