Leukemia, Myeloid, Chronic, Lymphomas, Multiple Myeloma, Myelodysplastic Syndrome, Leukemia, Lymphocytic, Acute, Leukemia, Lymphocytic, Chronic, AML
Conditions
Keywords
donor lymphocyte infusions, BMT, bone marrow transplant
Brief summary
The purpose of this study is to test the hypothesis that a pre-infusion preparative regimen of cyclophosphamide and fludarabine will improve the effectiveness of DLI in patients with blood cancers.
Detailed description
When cancer relapses after donor bone marrow transplantation, regular dose chemotherapy offers little hope of prolonged survival. However, there is evidence that lymphocytes can attack cancer cells. There is considerable evidence that this immune attack on cancer cells is associated with graft-versus-host disease. Although graft-versus-host disease can cause problems, this immune reaction may, in part, be the way that bone marrow transplantation cures cancer. In this study we hope that infusion of immune cells from the subject's bone marrow donor plus a chemotherapy regimen of cyclophosphamide and fludarabine will activate the subject's immune system to attack their cancer.
Interventions
PROCEDUREDonor Lymphocyte Infusion
donor cells infused over 2 hrs at cell dose of 0.5 dx 10\^8 CD3+T-cells/kg
DRUGInduction Chemotherapy
Fludarabine 25 mg/m2 IV Cyclosphosphamide 60 mg/kg IV
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients (age \> or = 1 years) with a diagnosis of relapse after related or unrelated allogeneic stem cell transplantation for a hematological malignancy. * For CML, relapse will be defined as any cytogenetic evidence of a Philadelphia chromosome or persistence of BCR/ABL rearrangements by molecular testing on at least two measurements over a 6 month interval. If cytogenetics are normal and there is PCR evidence of a BCR/ABL fusion, patients will be eligible if they have evidence of a quantitative increase in CML measured either by quantitative PCR or by fluorescent in situ hybridization (FISH). * For non-CML, relapse will be defined based on disease specific morphologic criteria from a bone marrow biopsy and aspirate or recurrence of disease specific cytogenetics. For disease specific definition of relapse, see appendix 3. Relapse can be determined morphologically with less than 5 percent blasts if definitive relapse can be determined. Equivocal results for relapse should result in a repeated test after an appropriate time interval (suggested 1 month) to determine eligibility. Post-transplant lymphoproliferative diseases (often referred to as EBV-associated lymphomas) are NOT eligible for this protocol. * For Chronic Phase CML patients only * \- must have failed (no response in 3 months or incomplete response at 6 months) or refused treatment with Gleevec * \- if no prior DLI, CML patients will first have DLI- if relapse occurs after DLI, DLI with chemotherapy per this protocol will be offered * Patients must be within one year of identification of relapse or if beyond that time period, must have at least 10% donor DNA by RFLP or cytogenetics. * Same allogeneic donor (sibling or URD) used for transplantation is available for lymphocyte donation. * No severe organ damage (by laboratory or clinical assessment) as measured by: * \- blood creatinine ≤ 2.0 mg/dL * \- liver function tests \< 5 x normal * \- left ventricular ejection fraction \> 40% (testing required only if symptomatic or prior known impairment). * \- pulmonary functions \> 50% (testing required only if symptomatic or prior known impairment). Oxygen saturation (\>92%) can be used in child where PFT's cannot be obtained. * \- chest x-ray without evidence of active infection * Off prednisone and other immunosuppressive agents (given for any reason) for at least 3 days prior to DLI infusions. * Performance status ≥ 60% * Women must not be pregnant or lactating. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy * Women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception * Patient must given written informed consent indicating understanding of the nature of the treatment and its potential risks
Exclusion criteria
* Concurrent signs of acute or chronic graft-versus-host disease requiring ongoing treatment at the time of relapse will be ineligible. * Patients being treated for GVHD with prednisone, cyclosporine, Imuran or other immunosuppressive medications are not eligible until these medications are discontinued for at least 2 weeks without a flare of GVHD. * Active CNS leukemia * Active fungal infection or pulmonary infiltrates (stable prior treated disease is allowable) * HIV positive
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Alive | 1 Year | The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer. Also called survival rate. Overall survival will be defined as time from date of enrollment to date of death or censored at the date of last documented contact for patients still alive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Alive Without Disease | 1 Year | The number of patients alive one year after treatment without any signs or symptoms of the cancer being treated or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works. |
| Number of Participants With Complete Remission | one year | In complete remission, all signs and symptoms of cancer that can be detected with modern technology have disappeared, although cancer still may be in the body. |
| Number of Patients With Acute Graft-Versus-Host Disease | Day 100 | Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host. |
| Number of Patients With Bone Marrow Aplasia | Day 100 | Aplastic anemia is a disorder in which the bone marrow greatly decreases or stops production of blood cells. In aplastic anemia, the basic structure of the marrow becomes abnormal, and those cells responsible for generating blood cells (hematopoietic cells) are greatly decreased in number or absent. These hematopoietic cells are replaced by large quantities of fat. |
Countries
United States
Participant flow
Pre-assignment details
During the recruitment period of the study, the donor lymphocyte infusion (DLI) was reduced from 1.0 x 10\^8 CD3+ T-cells/kg to 0.5 x 10\^8 CD3+ T-cells/kg due to an excess rate and intensity of graft vs. host disease.
Participants by arm
| Arm | Count |
|---|---|
| DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 IV over 30 minutes DLI Cell Dose 1.0 x 10\^8 CD3+ T-cells/kg | 15 |
| DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg Cyclophosphamide 60mg/kg IV over 2 hours Fludarabine 25 mg/m2 DLI Cell Dose 0.5 x 10\^8 CD3+ T-cells/kg | 42 |
| Total | 57 |
Baseline characteristics
| Characteristic | DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg | DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Categorical >=65 years | 0 Participants | 4 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 36 Participants | 50 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 38 Participants | 53 Participants |
| Sex: Female, Male Female | 7 Participants | 18 Participants | 25 Participants |
| Sex: Female, Male Male | 8 Participants | 24 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 15 | 22 / 42 |
| other Total, other adverse events | 12 / 15 | 11 / 42 |
| serious Total, serious adverse events | 8 / 15 | 3 / 42 |
Outcome results
Primary
Number of Patients Alive
The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer. Also called survival rate. Overall survival will be defined as time from date of enrollment to date of death or censored at the date of last documented contact for patients still alive.
Time frame: 1 Year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg | Number of Patients Alive | 3 Participants |
| DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg | Number of Patients Alive | 20 Participants |
Secondary
Number of Participants With Complete Remission
In complete remission, all signs and symptoms of cancer that can be detected with modern technology have disappeared, although cancer still may be in the body.
Time frame: one year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg | Number of Participants With Complete Remission | 7 Participants |
| DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg | Number of Participants With Complete Remission | 22 Participants |
Secondary
Number of Patients Alive Without Disease
The number of patients alive one year after treatment without any signs or symptoms of the cancer being treated or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works.
Time frame: 1 Year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg | Number of Patients Alive Without Disease | 2 Participants |
| DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg | Number of Patients Alive Without Disease | 10 Participants |
Secondary
Number of Patients With Acute Graft-Versus-Host Disease
Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.
Time frame: Day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg | Number of Patients With Acute Graft-Versus-Host Disease | 10 Participants |
| DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg | Number of Patients With Acute Graft-Versus-Host Disease | 10 Participants |
Secondary
Number of Patients With Bone Marrow Aplasia
Aplastic anemia is a disorder in which the bone marrow greatly decreases or stops production of blood cells. In aplastic anemia, the basic structure of the marrow becomes abnormal, and those cells responsible for generating blood cells (hematopoietic cells) are greatly decreased in number or absent. These hematopoietic cells are replaced by large quantities of fat.
Time frame: Day 100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DLI Cell Dose of 1.0 x 10^8 CD3+ T-cells/kg | Number of Patients With Bone Marrow Aplasia | 0 Participants |
| DLI Cell Dose of 0.5 x 10^8 CD3+ T-cells/kg | Number of Patients With Bone Marrow Aplasia | 1 Participants |