Induction of Mixed Hematopoietic Chimerism in Older Patients With B-Cell Malignancies and in Selected Other Diseases, Using Low Dose TBI , PBSC Infusion and Post-Transplant Immunosuppression With Cyclosporine and Mycophenolate Mofetil to be Followed by Donor Lymphocyte Infusion: A Pilot Study.
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 63
- 试验地点
- 5
- 主要终点
- Incidence of GVHD, myelosuppression, and infections
研究概览
简要总结
This pilot clinical trial studies low-dose total body irradiation and donor peripheral blood stem cell transplant followed by donor lymphocyte infusion in treatment patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, or multiple myeloma. Giving total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them. Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) may boost this effect.
详细描述
PRIMARY OBJECTIVES:
I. To determine whether mixed hematopoietic chimerism can be safely established using a non-myeloablative conditioning regimen in patients with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma.
II. To determine whether mixed chimerism, established with non- myeloablative conditioning regimens, can be safely converted to full donor hematopoietic chimerism by infusions of donor lymphocytes (DLI).
OUTLINE:
CYTOREDUCTION: If necessary, patients with advanced malignancies undergo cytoreductive chemotherapy to reduce tumor size at discretion of primary physician and study investigators.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 50 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients aged > 49 years and < 66 years with NHL, CLL and multiple myeloma who are not eligible for autologous transplantation or have failed prior autologous transplantation; patients with NHL and CLL must have failed prior therapy with an alkylating agent and/or fludarabine; patients with multiple myeloma must have stage II or III disease and received prior chemotherapy
- •Patients < 50 years of age with NHL, CLL and multiple myeloma at high risk of regimen related toxicity through prior autologous transplant or through pre-existing chronic disease affecting kidneys, liver, lungs, and heart will be considered on a case by case basis and presented to professional clinical counselor (PCC)
- •Patients < 66 years of age with other diseases treatable by allogeneic bone marrow transplant (BMT) whom through pre-existing chronic disease affecting kidneys, liver, lungs, and heart are considered to be at high risk for regimen related toxicity using standard high dose regimens; autografting must also be contraindicated in these patients and they must be approved for this protocol by both PCC and by the principal investigator; the following diseases are the likely candidates but other less common diseases may be considered and approved by PCC:
- •Myelodysplastic syndromes
- •Myeloproliferative syndromes
- •Acute leukemia in remission
- •Chronic myelogenous leukemia (CML) in 2nd chronic phase
- •Hodgkin's disease
- •Selected patients with any of the above diagnosis who are (a) older than 65 years and < 75 years with a Karnofsky score >= 70 and who, apart from age, fulfill eligibility criteria, or (b) < 66 years but ineligible solely because of renal dysfunction; these patients must be approved for transplant by both PCC and the principal investigator
- •DONOR: Human leukocyte antigen (HLA) genotypically identical sibling
- •DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis
- •DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian)
- •DONOR: Age < 75
排除标准
- •Eligible for autologous transplantation
- •Patients with rapidly progressive high grade NHL
- •History of central nervous system (CNS) involvement with disease
- •Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
- •Females who are pregnant
- •Patients with a creatinine clearance < 50 ml/min
- •Cardiac ejection fraction < 40% or cardiac failure requiring therapy
- •Severe defects in pulmonary function testing (defects are currently categorized as mild, moderate and severe) as defined by the pulmonary consultant, or receiving supplementary continuous oxygen
- •Total bilirubin > 2 x the upper limit of normal
- •Serum glutamate pyruvate transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) 4 x the upper limit of normal
- •Karnofsky score < 50
- •Patients with poorly controlled hypertension
- •DONOR: Identical twin
- •DONOR: Age less than 12 years
- •DONOR: Pregnancy
- •DONOR: Infection with human immunodeficiency virus (HIV)
- •DONOR: Inability to achieve adequate venous access
- •DONOR: Known allergy to G-CSF
- •DONOR: Current serious systemic illness
- •DONOR: Failure to meet Fred Hutchinson Cancer Research Center (FHCRC) criteria for donation as described in the Standard Practice Guidelines
研究组 & 干预措施
Treatment (irradiation, transplant, immunosuppression, DLI)
CYTOREDUCTION: If necessary, patients with advanced malignancies undergo cytoreductive chemotherapy to reduce tumor size at discretion of primary physician and study investigators.
CONDITIONING REGIMEN: Patients undergo low-dose total-body irradiation followed by allogeneic PBSC transplant on day 0.
IMMUNOSUPPRESSION: Patients receive cyclosporine IV BID on days -1 to 0 and then PO BID on days 1-35 with taper to day 56. Patients also receive mycophenolate mofetil PO BID on days 0-27.
POST-TRANSPLANT DLI: Patients with mixed chimerism on day 56 and no evidence of GVHD undergo DLI over 30 minutes on day 65 and may receive up to 3 additional infusions in the absence of GVHD and disease progression or persistence. Patients who have not achieved mixed chimerism at day 56 undergo DLI if complete response is not obtained after a 2 month monitoring period.
干预措施: chemotherapy (Drug)
Treatment (irradiation, transplant, immunosuppression, DLI)
CYTOREDUCTION: If necessary, patients with advanced malignancies undergo cytoreductive chemotherapy to reduce tumor size at discretion of primary physician and study investigators.
CONDITIONING REGIMEN: Patients undergo low-dose total-body irradiation followed by allogeneic PBSC transplant on day 0.
IMMUNOSUPPRESSION: Patients receive cyclosporine IV BID on days -1 to 0 and then PO BID on days 1-35 with taper to day 56. Patients also receive mycophenolate mofetil PO BID on days 0-27.
POST-TRANSPLANT DLI: Patients with mixed chimerism on day 56 and no evidence of GVHD undergo DLI over 30 minutes on day 65 and may receive up to 3 additional infusions in the absence of GVHD and disease progression or persistence. Patients who have not achieved mixed chimerism at day 56 undergo DLI if complete response is not obtained after a 2 month monitoring period.
干预措施: total-body irradiation (Radiation)
Treatment (irradiation, transplant, immunosuppression, DLI)
CYTOREDUCTION: If necessary, patients with advanced malignancies undergo cytoreductive chemotherapy to reduce tumor size at discretion of primary physician and study investigators.
CONDITIONING REGIMEN: Patients undergo low-dose total-body irradiation followed by allogeneic PBSC transplant on day 0.
IMMUNOSUPPRESSION: Patients receive cyclosporine IV BID on days -1 to 0 and then PO BID on days 1-35 with taper to day 56. Patients also receive mycophenolate mofetil PO BID on days 0-27.
POST-TRANSPLANT DLI: Patients with mixed chimerism on day 56 and no evidence of GVHD undergo DLI over 30 minutes on day 65 and may receive up to 3 additional infusions in the absence of GVHD and disease progression or persistence. Patients who have not achieved mixed chimerism at day 56 undergo DLI if complete response is not obtained after a 2 month monitoring period.
干预措施: peripheral blood stem cell transplantation (Procedure)
Treatment (irradiation, transplant, immunosuppression, DLI)
CYTOREDUCTION: If necessary, patients with advanced malignancies undergo cytoreductive chemotherapy to reduce tumor size at discretion of primary physician and study investigators.
CONDITIONING REGIMEN: Patients undergo low-dose total-body irradiation followed by allogeneic PBSC transplant on day 0.
IMMUNOSUPPRESSION: Patients receive cyclosporine IV BID on days -1 to 0 and then PO BID on days 1-35 with taper to day 56. Patients also receive mycophenolate mofetil PO BID on days 0-27.
POST-TRANSPLANT DLI: Patients with mixed chimerism on day 56 and no evidence of GVHD undergo DLI over 30 minutes on day 65 and may receive up to 3 additional infusions in the absence of GVHD and disease progression or persistence. Patients who have not achieved mixed chimerism at day 56 undergo DLI if complete response is not obtained after a 2 month monitoring period.
干预措施: cyclosporine (Drug)
Treatment (irradiation, transplant, immunosuppression, DLI)
CYTOREDUCTION: If necessary, patients with advanced malignancies undergo cytoreductive chemotherapy to reduce tumor size at discretion of primary physician and study investigators.
CONDITIONING REGIMEN: Patients undergo low-dose total-body irradiation followed by allogeneic PBSC transplant on day 0.
IMMUNOSUPPRESSION: Patients receive cyclosporine IV BID on days -1 to 0 and then PO BID on days 1-35 with taper to day 56. Patients also receive mycophenolate mofetil PO BID on days 0-27.
POST-TRANSPLANT DLI: Patients with mixed chimerism on day 56 and no evidence of GVHD undergo DLI over 30 minutes on day 65 and may receive up to 3 additional infusions in the absence of GVHD and disease progression or persistence. Patients who have not achieved mixed chimerism at day 56 undergo DLI if complete response is not obtained after a 2 month monitoring period.
干预措施: mycophenolate mofetil (Drug)
Treatment (irradiation, transplant, immunosuppression, DLI)
CYTOREDUCTION: If necessary, patients with advanced malignancies undergo cytoreductive chemotherapy to reduce tumor size at discretion of primary physician and study investigators.
CONDITIONING REGIMEN: Patients undergo low-dose total-body irradiation followed by allogeneic PBSC transplant on day 0.
IMMUNOSUPPRESSION: Patients receive cyclosporine IV BID on days -1 to 0 and then PO BID on days 1-35 with taper to day 56. Patients also receive mycophenolate mofetil PO BID on days 0-27.
POST-TRANSPLANT DLI: Patients with mixed chimerism on day 56 and no evidence of GVHD undergo DLI over 30 minutes on day 65 and may receive up to 3 additional infusions in the absence of GVHD and disease progression or persistence. Patients who have not achieved mixed chimerism at day 56 undergo DLI if complete response is not obtained after a 2 month monitoring period.
干预措施: allogeneic hematopoietic stem cell transplantation (Procedure)
Treatment (irradiation, transplant, immunosuppression, DLI)
CYTOREDUCTION: If necessary, patients with advanced malignancies undergo cytoreductive chemotherapy to reduce tumor size at discretion of primary physician and study investigators.
CONDITIONING REGIMEN: Patients undergo low-dose total-body irradiation followed by allogeneic PBSC transplant on day 0.
IMMUNOSUPPRESSION: Patients receive cyclosporine IV BID on days -1 to 0 and then PO BID on days 1-35 with taper to day 56. Patients also receive mycophenolate mofetil PO BID on days 0-27.
POST-TRANSPLANT DLI: Patients with mixed chimerism on day 56 and no evidence of GVHD undergo DLI over 30 minutes on day 65 and may receive up to 3 additional infusions in the absence of GVHD and disease progression or persistence. Patients who have not achieved mixed chimerism at day 56 undergo DLI if complete response is not obtained after a 2 month monitoring period.
干预措施: therapeutic allogeneic lymphocytes (Biological)
结局指标
主要结局
Incidence of GVHD, myelosuppression, and infections
时间窗: Up to 5 years
At the conclusion of the study, all unexpected toxicities will be summarized and reported.
Greater than 10% incidence of treatment-related mortality (TRM) after PBSC infusion, defined as death without evidence of disease progression
时间窗: Within 65 days of transplant
Greater than 20% incidence of TRM after DLI, defined as death without evidence of disease progression
时间窗: Within 12 months of DLI
Proportion of patients with mixed chimerism who successfully achieve full donor chimerism
时间窗: Up to 5 years
The proportion of patients with mixed chimerism who are successfully converted to full donor chimerism in each group (patients with NHL, CLL or multiple myeloma vs patients with other malignancies) will be estimated and corresponding confidence intervals will be presented.
Proportion of patients who successfully achieve mixed chimerism
时间窗: Up to 5 years
The proportion of patients who successfully establish mixed chimerism in each group (patients with NHL, CLL or multiple myeloma vs patients with other malignancies) will be estimated and corresponding confidence intervals will be presented.
次要结局
- Incidence of non-relapse mortality(Up to 5 years)
- Incidence of grades 2-4 acute GVHD after PBSC infusion(Up to day 56)
- Response of malignancy to DLI(Up to 5 years)
- Incidence of myelosuppression after initial PBSC transplant(Up to day 56)
- Incidence of aplasia after DLI(Up to day 90)
- Incidence of grades 2-4 acute GVHD after DLI(Up to day 90 post-DLI)
- Incidence of chronic extensive GVHD after DLI(Up to 1 year post-DLI)
- Dose of cluster of differentiation (CD)3+ cells required to convert mixed to full lymphoid chimeras(Up to 5 years)