Immunodeficiency
Conditions
Keywords
Donor Lymphocyte Infusion, Immune Recovery, T cell depleted transplant, Mismatched related donor transplants, Unrelated donor transplants
Brief summary
The purpose of this study is to determine the ability of a donor lymphocyte infusion (DLI) given with methotrexate to hasten immune recovery without causing severe graft-versus-host disease (GVHD) in recipients who have had a T-cell depleted transplant.
Detailed description
Studies have shown that giving donor T cells after a mismatched T cell-depleted stem cell transplant can speed up recovery of T cells in the patient. This approach can cause severe graft versus host disease (GVHD). The purpose of this study is to determine whether giving a donor lymphocyte infusion (DLI) with methotrexate can accelerate immune recovery in recipients of T cell-depleted stem cell transplants. Thirty days after a T-cell depleted transplant, patients will be given a DLI. They will be monitored for immune recovery as measured by CD4 count and for GVHD toxicity. Patients will be separated into six cohorts based on dose of DLI received: 3 x 10\^4, 4 x 10\^4, 5 x 10\^4, 6 X 10\^4, 8 x 10\^4, and 10 X10\^4 cells/ kg of body weight. A minimum of 3 patients will be tested at each dose starting with the lowest dose. Dose escalation will continue until the dose associated with CD4 count \>100 at Day +120 after transplant without significant GVHD is determined. All patients will receive thirteen doses of methotrexate after the DLI to prevent GVHD. Patients will be followed for 2 years for outcomes.
Interventions
BIOLOGICALInfusion of donor lymphocytes
A donor lymphocyte infusion will be given to provide T cells. There will be a dose escalation: 3 x 10\^4, 4 x 10\^4, 5 x 10\^4, 6 X 10\^4, 8 x 10\^4, and 10 X10\^4 cells/kg body weight. At least three patients will be assessed at each dose to determine safety before dose is increased.
Sponsors
Wake Forest University Health Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 30 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have been treated on the LCH BMT 09-01 protocol * Signed informed consent by patient or legal guardian
Exclusion criteria
* Active GVHD at the time when DLI are due * History of acute GVHD \> grade I prior to DLI * Disease due to viral infection (eg. CMV) when DLI are due (asymptomatic viral replication or viral shedding is not a contraindication) * Uncontrolled bacterial or fungal infection * O2 saturation by pulse oximetry \< 95% * Bilirubin \> 3mg/dL or ALT \> 5 x upper limit of normal * Creatinine \> 3x baseline (at transplant) * ANC (WBC x % neutrophils + bands) \< 500/ul * Significant effusions (eg. pleural or pericardial) or ascites * EBV-related PTLD * Persistent or increasing mixed chimerism requiring therapeutic DLI as defined on the LCH BMT 09-01 protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Immune Recovery Following Transplantation | 120 days after transplant | Immune recovery was measured by CD4+ cells \> 100/μL by Day 120 following transplantation |
| Incidence and Severity of GVHD | 180 days after transplant | Patients were evaluated for acute GVHD due to prophylactic DLI between the day of prophylactic DLI infusion and Day +180 after transplant. GVHD was graded using standard criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | 1 year | Subjects were actively monitored for adenovirus, cytomegalovirus (CMV), human herpes virus 6 (HHV6), and Epstein-Barr virus (EBV) as part of standard post-transplant care. All infections were collected from date of DLI until 1 year after transplant. |
Countries
United States
Participant flow
Recruitment details
Patients who received a CD34+ selected peripheral blood stem cell (PBSC) transplant on the companion study, LCH BMT 09-01, at Levine Children's Hospital between December 2009 and June 2016.
Pre-assignment details
Subjects were enrolled to two cohorts based on donor type, Mismatched Related Donor (MMRD) and Matched Unrelated Donor (MUD).
Participants by arm
| Arm | Count |
|---|---|
| Infusion of Donor Lymphocytes Patients will receive an infusion of donor lymphocyte after T-cell depleted transplant.
Infusion of donor lymphocytes: A donor lymphocyte infusion will be given to provide T cells. There will be a dose escalation: 3 x 10\^4, 4 x 10\^4, 5 x 10\^4, 6 X 10\^4, 8 x 10\^4, and 10 X10\^4 cells/kg body weight. At least three patients will be assessed at each dose to determine safety before dose is increased. | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Received subsequent therapy | 1 | 2 | 0 | 4 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Infusion of Donor Lymphocytes |
|---|---|
| Age, Customized 10-12 years | 4 participants |
| Age, Customized 12-14 years | 4 participants |
| Age, Customized 1-2 years | 3 participants |
| Age, Customized 14-16 years | 3 participants |
| Age, Customized 16-18 years | 6 participants |
| Age, Customized > 18 years | 4 participants |
| Age, Customized < 1 year | 2 participants |
| Age, Customized 2-4 years | 3 participants |
| Age, Customized 4-6 years | 3 participants |
| Age, Customized 6-8 years | 3 participants |
| Age, Customized 8-10 years | 3 participants |
| Race/Ethnicity, Customized African American | 19 Participants |
| Race/Ethnicity, Customized Caucasian | 8 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 10 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 12 / 38 |
| other Total, other adverse events | 27 / 38 |
| serious Total, serious adverse events | 32 / 38 |
Outcome results
Primary
Incidence and Severity of GVHD
Patients were evaluated for acute GVHD due to prophylactic DLI between the day of prophylactic DLI infusion and Day +180 after transplant. GVHD was graded using standard criteria.
Time frame: 180 days after transplant
Population: Patients that had not had grade II-IV acute GVHD following prophylactic DLI but received therapeutic DLI (eg. for treatment of viral infection or relapse), chemotherapy, or a PBSC infusion prior to Day +180 were considered not evaluable because these therapies may cause or prevent GVHD and affect the determination of this endpoint.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Incidence and Severity of GVHD | Grade II GVHD | 0 Participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Incidence and Severity of GVHD | No GVHD/ Grade I GVHD | 2 Participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Incidence and Severity of GVHD | Grade III/IV GVHD | 1 Participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +52 | Incidence and Severity of GVHD | Grade III/IV GVHD | 0 Participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +52 | Incidence and Severity of GVHD | Grade II GVHD | 1 Participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +52 | Incidence and Severity of GVHD | No GVHD/ Grade I GVHD | 1 Participants |
| MMRD: 4 x 10^4/kg DLI + MTX to Day +52 | Incidence and Severity of GVHD | No GVHD/ Grade I GVHD | 1 Participants |
| MMRD: 4 x 10^4/kg DLI + MTX to Day +52 | Incidence and Severity of GVHD | Grade II GVHD | 1 Participants |
| MMRD: 4 x 10^4/kg DLI + MTX to Day +52 | Incidence and Severity of GVHD | Grade III/IV GVHD | 0 Participants |
| MMRD: 4 x 10^4/kg DLI + MTX to Day +80 | Incidence and Severity of GVHD | Grade II GVHD | 1 Participants |
| MMRD: 4 x 10^4/kg DLI + MTX to Day +80 | Incidence and Severity of GVHD | No GVHD/ Grade I GVHD | 9 Participants |
| MMRD: 4 x 10^4/kg DLI + MTX to Day +80 | Incidence and Severity of GVHD | Grade III/IV GVHD | 0 Participants |
| MMRD: 5 x 10^4/kg DLI + MTX to Day +80 | Incidence and Severity of GVHD | Grade II GVHD | 1 Participants |
| MMRD: 5 x 10^4/kg DLI + MTX to Day +80 | Incidence and Severity of GVHD | No GVHD/ Grade I GVHD | 8 Participants |
| MMRD: 5 x 10^4/kg DLI + MTX to Day +80 | Incidence and Severity of GVHD | Grade III/IV GVHD | 0 Participants |
| MUD: 3 x 10^4/kg DLI + MTX to Day +24 | Incidence and Severity of GVHD | No GVHD/ Grade I GVHD | 1 Participants |
| MUD: 3 x 10^4/kg DLI + MTX to Day +24 | Incidence and Severity of GVHD | Grade III/IV GVHD | 0 Participants |
| MUD: 3 x 10^4/kg DLI + MTX to Day +24 | Incidence and Severity of GVHD | Grade II GVHD | 0 Participants |
| MUD: 3 x 10^4/kg DLI + MTX to Day +52 | Incidence and Severity of GVHD | Grade III/IV GVHD | 0 Participants |
| MUD: 3 x 10^4/kg DLI + MTX to Day +52 | Incidence and Severity of GVHD | Grade II GVHD | 0 Participants |
| MUD: 3 x 10^4/kg DLI + MTX to Day +52 | Incidence and Severity of GVHD | No GVHD/ Grade I GVHD | 1 Participants |
Comparison: This was a dose-escalation study to determine a target DLI dose at which the:~1. Probability of CD4+ cells \> 100/µL by Day +120 is at least 66% and~2. Probability of grade II and III GVHD is at most 33%, probability of grade III GVHD is at most 17%, and no grade IV GVHD occurs Patients were assigned in cohorts of 3.
Primary
Number of Participants With Immune Recovery Following Transplantation
Immune recovery was measured by CD4+ cells \> 100/μL by Day 120 following transplantation
Time frame: 120 days after transplant
Population: Patients who received subsequent therapy, such as therapeutic DLI (eg. for treatment of viral infection or relapse), chemotherapy, or a PBSC infusion were considered not evaluable as this could interfere with response assessments.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Immune Recovery Following Transplantation | 1 Participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +52 | Number of Participants With Immune Recovery Following Transplantation | 1 Participants |
| MMRD: 4 x 10^4/kg DLI + MTX to Day +52 | Number of Participants With Immune Recovery Following Transplantation | 1 Participants |
| MMRD: 4 x 10^4/kg DLI + MTX to Day +80 | Number of Participants With Immune Recovery Following Transplantation | 4 Participants |
| MMRD: 5 x 10^4/kg DLI + MTX to Day +80 | Number of Participants With Immune Recovery Following Transplantation | 6 Participants |
| MUD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Immune Recovery Following Transplantation | 1 Participants |
| MUD: 3 x 10^4/kg DLI + MTX to Day +52 | Number of Participants With Immune Recovery Following Transplantation | 1 Participants |
Comparison: This was a dose-escalation study to determine a target DLI dose at which the:~1. Probability of CD4+ cells \> 100/µL by Day +120 is at least 66% and~2. Probability of grade II and III GVHD is at most 33%, probability of grade III GVHD is at most 17%, and no grade IV GVHD occurs Patients were assigned in cohorts of 3.
Secondary
Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD)
Subjects were actively monitored for adenovirus, cytomegalovirus (CMV), human herpes virus 6 (HHV6), and Epstein-Barr virus (EBV) as part of standard post-transplant care. All infections were collected from date of DLI until 1 year after transplant.
Time frame: 1 year
Population: Patients who relapsed and received subsequent chemotherapy were no longer followed for infections as these therapies increase the risk of infections.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | HHV-6 reactivation, no disease | 18 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Viral upper respiratory infections | 17 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Adenovirus reactivation, no disease | 11 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Clostridium difficile colitis | 9 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Sinusitis | 8 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | CMV reactivation, no disease | 5 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Galactomannan positive | 5 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | BK virus, no disease | 5 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | BK virus, hemorrhagic cystitis | 4 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | EBV-related lymphoproliferative disease | 4 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Bacteremia, gram negative | 4 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Herpes simplex virus | 4 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Bacteremia, gram positive | 4 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Acute otitis media | 3 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Candidiasis (non-invasive) | 3 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Pneumonia | 3 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Infection with normal ANC - grade 3 | 3 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Adenovirus disease | 2 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | EBV reactivation, no disease | 2 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Varicella | 2 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Nocardia | 2 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Pneumonia- fungal | 1 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Methicillin-resistant staphylococcus aureus (MRSA) | 1 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Norovirus | 1 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Parvovirus B19 (low level) | 1 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Rotavirus | 1 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Sapovirus | 1 participants |
| MMRD: 3 x 10^4/kg DLI + MTX to Day +24 | Number of Participants With Infection and EBV-related Post-transplant Lymphoproliferative Disease (PTLD) | Possible respiratory fungal infection (rhizomucor) | 1 participants |