Hemophagocytic Lymphohistiocytosis, X-Linked Lymphoproliferative Disorders, Chediak-Higashi Syndrome, Griscelli Syndrome, Immunologic Deficiency Syndromes, Langerhans-Cell Histiocytosis
Conditions
Keywords
Stem cell transplant, immunodeficiency, donor lymphocyte infusion
Brief summary
This study tests the clinical outcomes of a preparative regimen of fludarabine (FLU), anti-thymocyte globulin (ATG)/or Campath, and melphalan; followed by hematopoietic stem cell transplant, and a post transplant regimen of Cyclosporin A (CsA) in patients with immunologic or histiocytic disorders. The researchers hypothesize that this regimen will have a positive effect on post transplant engraftment and the incidence of graft-versus-host-disease (GVHD). Patients will be randomized biologically into one of 3 arms based upon donor availability: (a) human leukocyte antigen (HLA) genotypic matched sibling donor, (b) HLA phenotypic matched unrelated peripheral blood stem cell (PBSC) donor, (c) two HLA 0-2 antigen mismatched unrelated cord blood donors (double cord).
Detailed description
Prior to transplantation, subjects will receive Melphalan, Fludarabine and Anti-Thymocyte Globulin (ATG) or Campath. These three drugs are being given to subjects to help the new stem cells take and grow. On the day of transplantation, subjects will receive stem cells transfused via intravenous (IV) catheter. After stem cell transplantation, subjects will be given Cyclosporin A (CsA) and mycophenolate mofetil (MMF) to reduce the risk of graft-versus-host disease, the complication that occurs when the donor's stem cells react against the patient.
Interventions
PROCEDUREStem Cell Transplant
IV on Day 0
DRUGFludarabine
30mg/m\^2 IV Day -7 through Day -3
DRUGMelphalan
140 mg/m\^2 IV Day -1
30 mg/kg IV Day -5 through Day -1
DRUGCampath 1H
0.2 mg/kg IV X 5 days (used as an alternative to Anti-thymocyte globulin (ATG) if unable to tolerate ATG) Day -10 through Day -6
DRUGCyclosporin A
2.5 mg/kg IV every 12 hours (adults) or every 8 hours (children \<40 kg) maintaining a level of \>200mg/L Day -3 until Day +180 when, if no GVHD, the dose will be tapered 10% per week beginning on day 181
DRUGMycophenolate mofetil
15 mg/kg IV or orally bid and discontinued on Day +45 unless GVHD is present
500 mg/kg IV weekly beginning on Day +7 until Day +100
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 35 Years
Healthy volunteers
No
Inclusion criteria
Patients with immunodeficiencies or histiocytic disorders 0-35 years of age with an acceptable stem cell donor and disease characteristic defined by the following: * Patients with histocytic disorders (hemophagocytic lymphohistiocytosis of any etiology and refractory Langerhans cell histiocytosis) who do not meet eligibility criteria for a myeloablative transplant procedure * Patients with immunodeficiency disorders in whom residual immune function may not require a fully myeloablative preparative regimen or patient is ineligible for standard myeloablative preparative regimen (any form of severe combined immunodeficiency \[SCID\], or other immunodeficiency with T cell defect) * Patients with immunodeficiency disorders that have had poor outcome with myeloablative stem cell transplants (including, but not limited to, common variable immunodeficiency \[CVID\], Wiskott Aldrich Syndrome \[WAS\] if \> 5 years of age, ataxia telangiectasia) * Patients with immunodeficiencies or histocytic disorders that require a second stem cell transplant (SCT) for any reason
Exclusion criteria
* Karnofsky or Lansky performance score \<70 * Glomerular filtration rate (GFR)\<30% predicted * Cardiac function \<50% normal by echocardiogram * Serum creatinine \> 2x normal for age/weight * Pregnant or lactating females * Active serious infection that has not had an adequate course of therapy pre-SCT. Any patient with acquired immune deficiency syndrome (AIDS) or AIDS-related complex (ARC) or human immunodeficiency virus (HIV) seropositivity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Mixed Chimerism | Day 100 | \>10% Donor Cells at Day 100 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Alive at One Year | Day 365 | — |
| Percentage of Donor Chimerism at 180 Days | Day 180 | The percent of recipient bone marrow and blood cells that are of donor origin. |
| Percentage of Donor Chimerism at 365 Days | Day 365 | The percent of recipient bone marrow and blood cells that are of donor origin. |
| Incidence of Grade 2-4 Acute Graft Versus Host Disease (aGVHD) | Day 100 | Acute graft versus host disease (aGVHD) is a reaction occurring within the first 100 days after transplant where the T- cells of the donor graft attacks the recipient's (host's) skin, GI tract, liver and other organs. The severity of aGVHD is graded on a scale of 1 - 4 with the highest number representing the most severe disease. |
| Percentage of Donor Chimerism at 100 Days | Day 100 | The percent of recipient bone marrow and blood cells that are of donor origin. |
| Incidence of Grade 3-4 Acute Graft Versus Host Disease (aGVHD) | Day 100 | Acute graft versus host disease (aGVHD) is a reaction occurring within the first 100 days after transplant where the T- cells of the donor graft attacks the recipient's (host's) skin, GI tract, liver and other organs. The severity of aGVHD is graded on a scale of 1 - 4 with the highest number representing the most severe disease. |
| Incidence of Chronic Graft Versus Host Disease (cGVHD) | 6 months and 1 year | Chronic graft versus host disease (cGVHD) is a reaction which typically develops 3 to 6 months after transplant where the T- cells of the donor graft attacks the recipient's (host's) skin, GI tract, liver and other organs. |
| Number of Subjects Alive at 100 Days | Day 100 | — |
| Compare Quality of Life (QOL) | Pretransplant, 1 year, 2 years and 5 years | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 - Matched Sibling Donor human leukocyte antigen (HLA) genotypic matched sibling donor
Stem Cell Transplant: Reduced intensity chemotherapy followed by infusion of hematopoietic stem cells
Fludarabine, melphalan, ATG or Campath: all drugs are given intravenously (IV). Fludarabine x 5 days and melphalan x 1 day | 3 |
| Arm 2 - Matched Unrelated Donor HLA phenotypic matched unrelated peripheral blood stem cell (PBSC) donor,
Stem Cell Transplant: Reduced intensity chemotherapy followed by infusion of hematopoietic stem cells
Fludarabine, melphalan, ATG or Campath: all drugs are given intravenously (IV). Fludarabine x 5 days and melphalan x 1 day | 10 |
| Arm 3 - Mismatched Double Cord Donors two HLA 0-2 antigen mismatched unrelated cord blood donors (double cord).
Stem Cell Transplant: Reduced intensity chemotherapy followed by infusion of hematopoietic stem cells
Fludarabine, melphalan, ATG or Campath: all drugs are given intravenously (IV). Fludarabine x 5 days and melphalan x 1 day | 6 |
| Total | 19 |
Baseline characteristics
| Characteristic | Arm 1 - Matched Sibling Donor | Arm 2 - Matched Unrelated Donor | Arm 3 - Mismatched Double Cord Donors | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 10 Participants | 6 Participants | 19 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 3 participants | 10 participants | 6 participants | 19 participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 2 Participants | 7 Participants | 3 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 3 | 10 / 10 | 6 / 6 |
| serious Total, serious adverse events | 0 / 3 | 1 / 10 | 0 / 6 |
Outcome results
Primary
Number of Subjects With Mixed Chimerism
\>10% Donor Cells at Day 100
Time frame: Day 100
Population: Arm 2: 2 of 10 patients not evaluable due to failure to return to clinic for the Day 100 evaluation.~Arm 3: 2 of 6 patients not evaluable due to early death.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - Matched Sibling Donor | Number of Subjects With Mixed Chimerism | 3 participants |
| Arm 2 - Matched Unrelated Donor | Number of Subjects With Mixed Chimerism | 8 participants |
| Arm 3 - Mismatched Double Cord Donors | Number of Subjects With Mixed Chimerism | 4 participants |
Secondary
Compare Quality of Life (QOL)
Time frame: Pretransplant, 1 year, 2 years and 5 years
Population: PI made decision after IRB approval, but before opening the study to accrual, to not collect QOL data .
Secondary
Incidence of Chronic Graft Versus Host Disease (cGVHD)
Chronic graft versus host disease (cGVHD) is a reaction which typically develops 3 to 6 months after transplant where the T- cells of the donor graft attacks the recipient's (host's) skin, GI tract, liver and other organs.
Time frame: 6 months and 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - Matched Sibling Donor | Incidence of Chronic Graft Versus Host Disease (cGVHD) | 1 participants |
| Arm 2 - Matched Unrelated Donor | Incidence of Chronic Graft Versus Host Disease (cGVHD) | 0 participants |
| Arm 3 - Mismatched Double Cord Donors | Incidence of Chronic Graft Versus Host Disease (cGVHD) | 0 participants |
Secondary
Incidence of Grade 2-4 Acute Graft Versus Host Disease (aGVHD)
Acute graft versus host disease (aGVHD) is a reaction occurring within the first 100 days after transplant where the T- cells of the donor graft attacks the recipient's (host's) skin, GI tract, liver and other organs. The severity of aGVHD is graded on a scale of 1 - 4 with the highest number representing the most severe disease.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - Matched Sibling Donor | Incidence of Grade 2-4 Acute Graft Versus Host Disease (aGVHD) | 1 participants |
| Arm 2 - Matched Unrelated Donor | Incidence of Grade 2-4 Acute Graft Versus Host Disease (aGVHD) | 3 participants |
| Arm 3 - Mismatched Double Cord Donors | Incidence of Grade 2-4 Acute Graft Versus Host Disease (aGVHD) | 0 participants |
Secondary
Incidence of Grade 3-4 Acute Graft Versus Host Disease (aGVHD)
Acute graft versus host disease (aGVHD) is a reaction occurring within the first 100 days after transplant where the T- cells of the donor graft attacks the recipient's (host's) skin, GI tract, liver and other organs. The severity of aGVHD is graded on a scale of 1 - 4 with the highest number representing the most severe disease.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - Matched Sibling Donor | Incidence of Grade 3-4 Acute Graft Versus Host Disease (aGVHD) | 1 participants |
| Arm 2 - Matched Unrelated Donor | Incidence of Grade 3-4 Acute Graft Versus Host Disease (aGVHD) | 1 participants |
| Arm 3 - Mismatched Double Cord Donors | Incidence of Grade 3-4 Acute Graft Versus Host Disease (aGVHD) | 0 participants |
Secondary
Number of Subjects Alive at 100 Days
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - Matched Sibling Donor | Number of Subjects Alive at 100 Days | 3 participants |
| Arm 2 - Matched Unrelated Donor | Number of Subjects Alive at 100 Days | 8 participants |
| Arm 3 - Mismatched Double Cord Donors | Number of Subjects Alive at 100 Days | 4 participants |
Secondary
Number of Subjects Alive at One Year
Time frame: Day 365
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - Matched Sibling Donor | Number of Subjects Alive at One Year | 3 participants |
| Arm 2 - Matched Unrelated Donor | Number of Subjects Alive at One Year | 7 participants |
| Arm 3 - Mismatched Double Cord Donors | Number of Subjects Alive at One Year | 3 participants |
Secondary
Percentage of Donor Chimerism at 100 Days
The percent of recipient bone marrow and blood cells that are of donor origin.
Time frame: Day 100
Population: Arm 2: 2 of 10 patients not evaluable due to failure to return to clinic for the Day 100 evaluation.~Arm 3: 2 of 6 patients not evaluable due to early death.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Matched Sibling Donor | Percentage of Donor Chimerism at 100 Days | 96.5 percentage of donor cells | Standard Deviation 6 |
| Arm 2 - Matched Unrelated Donor | Percentage of Donor Chimerism at 100 Days | 75.5 percentage of donor cells | Standard Deviation 37.3 |
| Arm 3 - Mismatched Double Cord Donors | Percentage of Donor Chimerism at 100 Days | 100 percentage of donor cells | Standard Deviation 0 |
Secondary
Percentage of Donor Chimerism at 180 Days
The percent of recipient bone marrow and blood cells that are of donor origin.
Time frame: Day 180
Population: Arm 2: 2 of 10 patients not evaluable due to failure to return to clinic for the Day 100 evaluation.~Arm 3: 2 of 6 patients not evaluable due to early death.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Matched Sibling Donor | Percentage of Donor Chimerism at 180 Days | 88.9 percentage of donor cells | Standard Deviation 19.2 |
| Arm 2 - Matched Unrelated Donor | Percentage of Donor Chimerism at 180 Days | 73.3 percentage of donor cells | Standard Deviation 41.7 |
| Arm 3 - Mismatched Double Cord Donors | Percentage of Donor Chimerism at 180 Days | 90.5 percentage of donor cells | Standard Deviation 16.4 |
Secondary
Percentage of Donor Chimerism at 365 Days
The percent of recipient bone marrow and blood cells that are of donor origin.
Time frame: Day 365
Population: Arm 2: 2 of 10 patients not evaluable due to failure to return to clinic for the Day 100 evaluation.~Arm 3: 2 of 6 patients not evaluable due to early death.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 - Matched Sibling Donor | Percentage of Donor Chimerism at 365 Days | 81.9 percentage of donor cells | Standard Deviation 31.4 |
| Arm 2 - Matched Unrelated Donor | Percentage of Donor Chimerism at 365 Days | 78.6 percentage of donor cells | Standard Deviation 38.2 |
| Arm 3 - Mismatched Double Cord Donors | Percentage of Donor Chimerism at 365 Days | 91.7 percentage of donor cells | Standard Deviation 13.5 |