Intentional Rejection of the Donor Graft Using Recipient Leukocyte Infusion(s) Following Nonmyeloablative Allogeneic Stem Cell Transplant

Study Overview
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Brief Summary
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The proposed study is based on our observation of paradoxical tumor regression after rejection of the donor graft in conjunction with the results of our murine experiments. We hypothesize that clinically meaningful responses can be achieved in patients with advanced malignancies with a transplant strategy using nonmyeloablative conditioning and related mismatched donor stem cell transplant where the intention will be to initially achieve mixed chimerism which will be followed by recipient lymphocyte infusion (RLI) in an attempt to deliberately reject the donor graft. This will lead to the development of novel transplant strategies for achieving antitumor effects without the risk of graft versus host disease (GVHD). This proposed protocol is a Pilot Study that will evaluate the safety of this outpatient transplant strategy, i.e., establishment of initial mixed chimerism followed by RLI for donor graft rejection, in patients with advanced lymphomas, and multiple myeloma. In addition, because RLI have been reported to reverse ongoing GVHD, this approach might potentially reverse GVHD while achieving antitumor responses if this complication unexpectedly occurs.

Official Title
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Intentional Rejection of the Donor Graft Using Recipient Leukocyte Infusion(s) Following Nonmyeloablative Allogeneic Stem Cell Transplant

Conditions
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Non Hodgkin's Lymphoma, Hodgkin Disease, Multiple Myeloma

Intervention / Treatment
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* Other: Fludarabine and total body irradiation
* Radiation: Total body irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with chemorefractory non-Hodgkin's or Hodgkin's lymphoma or multiple myeloma. Criteria for consideration of enrollment will include: primary refractory or refractory relapsed disease for which autologous HCT is unlikely to be beneficial; relapse after autologous HCT ineligibility for standard myeloablative or nonmyeloablative allo-HCT because of either lack of a donor or patient considerations Non Hodgkin's lymphoma, or Hodgkin's lymphoma: primary refractory or refractory relapse Multiple myeloma; primary refractory or refractory relapse Patients with the above malignancies who have had a previous autologous or allogeneic bone marrow or stem cell transplant. An estimated disease-free survival of less than one year. Age 18 to age < 75 years ECOG performance status of 0, 1, or 2. Exclusion Criteria: Patients whose life expectancy is limited by diseases other than their malignancy Patients who have a 5/6 or better matched related donor or a 4/6 or better umbilical cord blood donor and who are medically eligible for conventional myeloablative or non-myeloablative transplant will be excluded Cardiac disease: symptomatic congestive heart failure or RVG or echocardiogram determined LVEF ogf< 30%, active angina pectoris or uncontrolled hypertension Pulmonary disease: severe chronic obstructive lung disease, or symptomatic restrictive lung disease, or corrected DLCO < 40% of predicted Renal disease: serum creatinine > 3.0 mg/dl. Hepatic disease: serum bilirubin > 3.0 mg/dl or alkaline phosphatase, SGOT or SGPT > 3 x ULN Neurologic disease: symptomatic leukoencephalopathy, active CNS malignancy or other neuropsychiatric abnormalities believed to preclude transplantation (pervious CNS malignancy presently in CR is not an exclusion) Uncontrolled infection. Recipient leukocyte infusion (RLI) might involve the infusion of circulating tumor cells to the patients. To minimize this risk patients who have evidence of circulating tumor cells by light microscopy and flow cytometry will be excluded Patients with acute leukemia will be excluded because they will likely have much greater circulating tumor burden, which would increase the risk of infusion of clonal tumor cells

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Fludarabine<br>The patients in this cohort will receive fludarabine 30 mg/m2/day on days -4 to -2 and 200 cGy TBI on day 0. | Other: Fludarabine and total body irradiation<br>* The patients in the second cohort will receive fludarabine 30 mg/m2/day on days -4 to -2 and 200 cGy TBI on day 0.<br>|
| Active Comparator: TBI only<br>Patients will be given 200 centiGray (cGy) total body irradiation (TBI) in one fraction. TBI will be given on day 0, 4 to 6 hours prior to HCT. | Radiation: Total body irradiation<br>* Patients will receive 200 cGy TBI on day 0,4-6 hours prior to HCT.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the safety at ≤100 days of a non myeloablative mismatched related HCT when followed by recipient leukocyte infusion to induce deliberate rejection of the donor graft. |  | 100 days post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the incidence of acute and chronic GVHD |  | Up to 2 years post transplant | 
| To evaluate the incidence of loss of donor grafts |  | Up to 2 years post transplant | 
| To evaluate progression-free and overall survival |  | Up to 2 years post transplant | 
| To evaluate antitumor responses following this transplant strategy |  | Up to 2 years post transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Related stem cell transplant,, TBI,, Mismatched stem cell transplant, Fludarabine, Non-myeloablative, Lymphoma, Multiple myeloma