Hematologic, Immune, or Bone Marrow Disorders, Hemoglobinopathies, Metabolic Disorders, Non-malignant Disorders
Conditions
Keywords
Bone marrow, Transplant, Transplantation, Hematopoietic, Umbilical cord, Related, Unrelated, Reduced, Non-myeloablative, Nonmyeloablative, Non-malignant, Nonmalignant
Brief summary
The hypothesis for this study is that a preparative regimen that maximizes host immunosuppression without myeloablation will be well tolerated and sufficient for engraftment of donor hematopoietic cells. It is also to determine major toxicities from these conditioning regimens, within the first 100 days after transplantation.
Detailed description
The study uses reduced intensity conditioning that is immune suppressive to achieve donor cell engraftment without exposure to radiation or high dose chemotherapy in children with non-malignant disorders. The intent is to minimize early and late regimen related toxicities in the context of a reduced intensity regimen. In addition to maximizing opportunity for donor cell engraftment, the trial seeks to minimize toxicities associated with transplant such as graft versus host disease and employs GVHD prophylaxis that seeks to decrease rates of acute and chronic GVHD in the setting of matched and mismatched donor stem cell transplants from marrow and cord blood sources.
Interventions
DRUGTreatment Plan 1: Stratum 1
Day -50 to -21: Hydroxyurea 30mg/kg PO q day Day -22: Campath-1H 3 mg IV or SQ... Day -21: Campath-1H 10 mg IV or SQ... Day -20: Campath-1H 15 mg IV or SQ... Day -19: Campath-1H 20 mg IV or SQ... Day -8: Fludarabine 30mg/m2 IV... Day -7: Fludarabine 30mg/m2 IV... Day -6: Fludarabine 30mg/m2 IV... Day -5: Fludarabine 30mg/m2 IV... Day -4: Fludarabine 30mg/m2 IV... Day -3: Melphalan 140 mg/m2 IV... (dose modifications for patients \<10 kgs) Procedure/Surgery: Hematopoietic stem cell infusion on Day 0...
DRUGTreatment Plan 2: Strata 2, 3, or 4
Day -50 to -21: Hydroxyurea 30mg/kg PO q day… Day -22: Campath-1H 3 mg IV or SQ... Day -21: Campath-1H 10 mg IV or SQ... Day -20: Campath-1H 15 mg IV or SQ... Day -19: Campath-1H 20 mg IV or SQ... Day -8: Fludarabine 30mg/m2 IV... Day -7: Fludarabine 30mg/m2 IV... Day -6: Fludarabine 30mg/m2 IV... Day -5: Fludarabine 30mg/m2 IV... Day -4: Fludarabine 30mg/m2 IV... Day -4: Thiotepa 8mg/kg IV… Day -3: Melphalan 140 mg/m2 IV... (dose modifications for patients \<10 kgs) Procedure/Surgery: Hematopoietic stem cell infusion on day 0...
DRUGGVHD Regimen A: UCB Recipients
Day -3: Begin Tacrolimus or cyclosporine Begin MMF Day -1: Abatacept 10mg/kg IV Day +5: Abatacept 10mg/kg IV Day +14: Abatacept 10mg/kg IV Day +28: Abatacept 10mg/kg IV Day +60: Abatacept 10mg/kg IV Day +100: Abatacept 10mg/kg IV
DRUGGVHD Regimen B: BM Recipients
Day -3: Begin Tacrolimus or cyclosporine Begin MMF Day -1: Abatacept 10mg/kg IV Day +1: Methotrexate 7.5mg/m2 IV Day +3: Methotrexate 7.5mg/m2 IV Day +5: Abatacept 10mg/kg IV Day +6: Methotrexate 7.5mg/m2 IV Day +14: Abatacept 10mg/kg IV Day +28: Abatacept 10mg/kg IV Day +60: Abatacept 10mg/kg IV Day +100: Abatacept 10mg/kg IV Day +180: Abatacept 10mg/kg IV Day +270: Abatacept 10mg/kg IV Day +365: Abatacept 10mg/kg IV
Sponsors
Washington University School of Medicine
St. Louis Children's Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 20 Years
Healthy volunteers
No
Inclusion criteria
Stratum 1: Patient must have non-malignant disorder, excluding thalassemia. Must be receiving a 8/8 HLA-matched bone marrow, related or unrelated Stratum 2: Patient must have thalassemia receiving 8/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB. Related or unrelated. Stratum 3: Patient must have a hemoglobinopathy receiving 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB. Related or unrelated. Stratum 4: Patient must have a non-malignant disorder (excluding hemoglobinopathy) receiving 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB. Related or unrelated. All strata: * Recipient age \< 21 years * Lansky/Karnofsky \>/= 40 * Adequate pulmonary, renal, liver, and other organ function as defined in protocol * Negative pregnancy test * Adequate total nucleated cell or CD34+ dose of product as defined in protocol * If sickle cell, Hemoglobin S \<30%
Exclusion criteria
* HIV positive * Invasive infection * Pregnancy/lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Donor engraftment as measured by chimerism | 100 days post-transplant | Engraftment is measured in myeloid and lymphoid lineage cells |
| Major toxicities as graded by the CTC v4 | 100 days post-transplant | Toxicity monitoring includes unanticipated side effects (new) and all severe irreversible toxicities Grade 3 and above unexpected Grade 4 and above - all toxicities that are possibly, probably or definitely related to protocol therapy All deaths irrespective of attribution |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to neutrophil and platelet engraftment as measured by complete blood counts | Post transplant | Defined as an ANC \>500/microliter and platelets \>20,000 or 50,000/microliter depending on disorder |
| Incidence of acute graft-versus-host disease as measured by protocol grading scale | 100 days post-transplant | aGVHD - involving the skin, gut and liver. Classified according to grading described by Thomas et al. NEJM 1975; 292:895-902 |
| Incidence of chronic graft-versus-host disease as measured by protocol grading scale | 2 years post-transplant | cGVHD classified per Schulman et al. Am J Med 69: 204-17, 1980. |
| Long-term donor engraftment by donor chimerism | 2 years post-transplant | Donor chimerism is determined by PCR analysis after cell separation into lymphoid and myeloid lineage cells using antibodies. Can also be detected by FISH analysis in the event of donor and recipient sex discrepancy. |
| Immune reconstitution by laboratory evaluations | 1 year post-transplant | Immune reconstitution detected by absolute numbers of T cell phenotypes, B cells and NK cells. T cell function determined by proliferative response to mitogens. B cell function determined by evaluating anti-tetanus antibody titers. |
| Overall and disease free survival | 2 years post-transplant | Overall survival is defined as survival with or without disease Event free survival is defined as disease free, severe GVHD free survival, monitoring quality of life and relevant parameters. |
Countries
Canada, United States
Contacts
CONTACTLissy Keller, CCRP
CONTACTIan Snyder, CCRP
PRINCIPAL_INVESTIGATORShalini Shenoy, MD
Washington University School of Medicine (in St. Louis)
Outcome results
None listed