Lymphoma
Conditions
Keywords
Stem cell transplant, matched donor, NK infusion
Brief summary
Evaluate the safety of natural killer (NK) cell infusion using CD56 monoclonal antibody selected with Miltenyi Biotec system following nonmyeloablative stem cell transplantation (SCT) from matched donors. This pilot study will evaluate toxicity including mortality, occurrence of acute graft versus host disease and other severe toxicity.
Detailed description
The use of non-selected donor lymphocyte infusions (DLIs) (to help early immune recovery and induce antitumor response) following nonmyeloablative allogeneic stem cell transplantation (ASCT) is also complicated by the risk of acute graft versus host disease (aGVHD) with 30-40% of patients experiencing grade III-IV aGVHD. Data suggests that the use of natural killer (NK) cells (instead of nonselected DLIs) in this setting may mediate a graft versus tumor (GVT) effect independently of aGVHD. This pilot study is designed to evaluate the efficacy and toxicity of donor natural killer (NK) cell selection and infusion following nonmyeloablative allogeneic stem cell transplantation (ASCT) from matched donors.
Interventions
DEVICENK Cell infusion using CD56 monoclonal antibody
The cells from leukapheresis will be natural killer (NK) cell selected using a CD56 antibody and a cell column system provided by Miltenyi Biotec. The target cell dose for each NK cell infusion will be up to 1 X 10(7) CD56+ cells/kg patient weight with less than 0.5 X 10(6) CD3+ cells/kg patient weight. The first NK cell infusion will be administered 6 weeks post transplant in patients who have ≤ grade II acute graft versus host disease (aGVHD) at the time of infusion. Patients will be evaluated for toxicity and response until 20 weeks after the last NK Infusion.
PROCEDUREDonor Apheresis
Apheresis repeated daily up to 3 days until target dose of cells reached (preferably without donor receiving growth factors). Cells were transfused immediately after collection and processing. If collections occurred during initial mobilization at the time of stem cell transplant, the donor was off growth factor for \>24 hours. These extra cell collections from the donor were sufficient for the natural killer cells used in the trial. The cells were NK selected using a CD56 antibody (CliniMACS CD56 Reagent), CliniMACSplus instrument and CliniMACS tubing set provided by Miltenyi Biotec using the company protocol (Miltenyi Biotec Inc, Auburn, California). Pre and post processing cell count, viability, Hematopoietic Progenitor Cell Assay (HPCA) and flow analysis were done.
Sponsors
David Rizzieri, MD
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with who have undergone a non-myeloablative allogeneic transplant, using a 6/6 human leukocyte antigen (HLA) matched sibling donor. Measureable disease is not needed at study entry. * Performance status must be Karnofsky 50-100%. * Donor cellular engraftment of at least 2.5% from the non-myeloablative procedure. * ≤ Grade 2 acute Graft versus Host Disease (aGvHD) at time of infusion of natural killer (NK) cell infusion. Patients with treated aGVHD must be on a stable dose of therapy (no increase in immunosuppressive therapy for the 2 weeks before planned natural killer cell infusion \[NKI\]). The dosage/level of immunosuppressive therapy at the time of NKI should be no greater than 1 mg/kg of prednisone daily or mycophenolate 1000 mg bid daily or cyclosporine with a target level of 200 or equivalent. * Estimated survival at least 8 weeks. * Age \> or equal to 18 years of age.
Exclusion criteria
* Pregnant or lactating women, * Patients with other major medical or psychiatric illnesses, which the treating physician feels, could seriously compromise tolerance to this protocol. * Patients who had biopsy proven overall Grade 4 GVHD lasting longer than 7 days, from the non-myeloablative therapy, are not eligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity | 5 months | Evaluate the toxicity post-infusion including mortality, occurrence of acute graft versus host disease (GVHD) and other severe toxicity until a minimum of 8 weeks following the last infusion, then at least monthly for 3 additional months. Unacceptable toxicity was defined as grade ≥ III aGVHD of the gut or liver or Grade 4 aGVHD of the skin lasting \> 7 days; other Grade 4 toxicity from the procedure in the major organs that lasted \> 5 days; or treatment-related mortality (TRM). Though these infusions are provided early following transplantation and severe toxicity could still have occurred due to the primary transplant procedure, for this study any aGVHD or other toxicities occurring after the first day of infusion of the natural killer (NK) cell enriched Donor Lymphocyte Infusions (DLIs) is considered here as study related. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy - Progression Free Survival | 3 years | Evaluate efficacy of natural killer (NK) cell infusions in terms of progression free survival (PFS) in number of months without disease progression. |
| Efficacy - Overall Survival | 8 years | Evaluate efficacy of natural killer (NK) cell infusions in terms of overall survival (OS). |
| Efficacy - Disease Progression | 3 years | Evaluate efficacy of natural killer (NK) cell infusions in terms of number of patients with disease progression. |
Countries
United States
Participant flow
Recruitment details
Twenty five participants were recruited through the Adult Bone Marrow Transplant Program at Duke University Medical Center. Recruitment began in May, 2005 and ended in April, 2010. Patients who met the eligibility criteria were approached about the study and informed consent was conducted for those who agreed.
Pre-assignment details
Prior to initiating therapy, donors and subjects will have complete history, physical exam, routine laboratory tests, and/or radiographic tests. Recipients may have Bone marrow aspirate/biopsy repeated to check for prior abnormalities. If disease progression present, patient didn't continue with treatment.
Participants by arm
| Arm | Count |
|---|---|
| NK Cell Infusion Natural Killer (NK) Cell infusion using CD56 monoclonal antibody: The cells from leukapheresis will be natural killer (NK) cell selected using a CD56 antibody and a cell column system provided by Miltenyi Biotec. The target cell dose for each NK cell infusion will be up to 1 X 10(7) CD56+ cells/kg patient weight with less than 0.5 X 10(6) CD3+ cells/kg patient weight. The first NK cell infusion will be administered 6 weeks post transplant in patients who have ≤ grade II acute graft versus host disease (aGVHD) at the time of infusion. | 25 |
| Donor Apheresis Apheresis repeated daily up to 3 days until target dose of cells reached (preferably without donor receiving growth factors). Cells were transfused immediately after collection and processing. If collections occurred during initial mobilization at the time of stem cell transplant, the donor was off growth factor for \>24 hours. These extra cell collections from the donor were sufficient for the natural killer cells used in the trial. The cells were NK selected using a CD56 antibody (CliniMACS CD56 Reagent), CliniMACSplus instrument and CliniMACS tubing set provided by Miltenyi Biotec using the company protocol (Miltenyi Biotec Inc, Auburn, California). Pre and post processing cell count, viability, Hematopoietic Progenitor Cell Assay (HPCA) and flow analysis were done. | 22 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 2 | 0 |
| Overall Study | Disease Progression | 10 | 0 |
| Overall Study | Lab can't accommodate | 1 | 0 |
| Overall Study | Lack of Efficacy | 2 | 0 |
Baseline characteristics
| Characteristic | NK Cell Infusion | Donor Apheresis | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 18 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 22 Participants | 47 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 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 | 24 Participants | 21 Participants | 45 Participants |
| Region of Enrollment United States | 25 participants | 22 participants | 47 participants |
| Sex: Female, Male Female | 9 Participants | 8 Participants | 17 Participants |
| Sex: Female, Male Male | 16 Participants | 14 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 21 |
| serious Total, serious adverse events | 4 / 21 |
Outcome results
Primary
Toxicity
Evaluate the toxicity post-infusion including mortality, occurrence of acute graft versus host disease (GVHD) and other severe toxicity until a minimum of 8 weeks following the last infusion, then at least monthly for 3 additional months. Unacceptable toxicity was defined as grade ≥ III aGVHD of the gut or liver or Grade 4 aGVHD of the skin lasting \> 7 days; other Grade 4 toxicity from the procedure in the major organs that lasted \> 5 days; or treatment-related mortality (TRM). Though these infusions are provided early following transplantation and severe toxicity could still have occurred due to the primary transplant procedure, for this study any aGVHD or other toxicities occurring after the first day of infusion of the natural killer (NK) cell enriched Donor Lymphocyte Infusions (DLIs) is considered here as study related.
Time frame: 5 months
Population: Participants who completed cell infusion.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NK Cell Infusion | Toxicity | Death | 1 participants |
| NK Cell Infusion | Toxicity | GvHD | 8 participants |
Secondary
Efficacy - Disease Progression
Evaluate efficacy of natural killer (NK) cell infusions in terms of number of patients with disease progression.
Time frame: 3 years
Population: Participants who completed cell infusion.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NK Cell Infusion | Efficacy - Disease Progression | 10 participants |
Secondary
Efficacy - Overall Survival
Evaluate efficacy of natural killer (NK) cell infusions in terms of overall survival (OS).
Time frame: 8 years
Population: Participants who completed infusion. 9 patients were still alive at the time of this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| NK Cell Infusion | Efficacy - Overall Survival | 31 months alive post-infusion |
Secondary
Efficacy - Progression Free Survival
Evaluate efficacy of natural killer (NK) cell infusions in terms of progression free survival (PFS) in number of months without disease progression.
Time frame: 3 years
Population: Participants who completed cell infusion.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| NK Cell Infusion | Efficacy - Progression Free Survival | 12 months |