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

Study Overview
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Brief Summary
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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
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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.

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

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

Intervention / Treatment
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* Device: Miltenyi Magnetic cell sorter for CD3


Participation Criteria
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Eligibility Criteria
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ELIGIBILITY CRITERIA: Inclusion Criteria- Recipient: 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 8-75 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 Exclusion Criteria Recipient (any of the following): 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. Inclusion Criteria- Stem Cell Donors: 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. Exclusion Criteria Stem Cell Donor (any of the following): Pregnant or lactating Unfit to receive filgrastim (G-CSF) or previous filgrastim mobilization for donors under 18 years of age. Unfit to undergo apheresis (abnormal blood counts, history of stroke, uncontrolled hypertension). Sickling hemoglobinopathies such as HbSS or HbSC. 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. 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: 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. 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): Pregnant or lactating Unfit to undergo apheresis (abnormal blood counts, history of stroke, uncontrolled hypertension). Sickling hemoglobinopathies such as HbSS and HbSC . 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. Severe psychiatric illness or mental deficiency sufficiently severe as to make compliance with the donation of stem cells unlikely and/or informed consent impossible

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Miltenyi Magnetic cell sorter for CD3<br>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<br>* 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.<br>* Other names: CliniMACS Miltenyi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Developed of Acute GVHD | Overall number incidences of participants who developed Acute Graft versus Host Disease (GVHD). | 6 months post disease relapse | 
| Number of Participants Who Developed Grade I, Acute GVHD | 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. | 6 months post disease relapse | 
| Number of Participants Who Developed Grade II, Acute GVHD | 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. | 6 months post disease relapse | 
| Number of Participants Who Developed Grade III, Acute GVHD | 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. | 6 months post disease relapse | 
| Number of Participants Who Developed of Grade IV, Acute GVHD | 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. | 6 months post disease relapse | 
| Number of Participants Who Developed Chronic GVHD | 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. | 6 months post disease relapse | 
| Number of Participants Who Developed Limited Chronic GVHD | 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. | 6 months post disease relapse | 
| Number of Participants With Extensive, Chronic GVHD | 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. | 6 months post disease relapse | 
| Number of Participants With CD3+ Engraftment Who Achieved Peak Chimerism Post DLI | Number of Participants with CD3+ Engraftment who Achieved Peak Chimerism post Donor Lymphocyte Infusion (DLI) | 21 Days | 
| Number of Subjects Leukemia Response After Donor Lymphocyte Infusion (DLI) | Subjects experience leukemia response after partially human leukocyte antigen (HLA) matched DLI according to International Working Group criteria | 21 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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