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| Name | Class |
|---|---|
| St. Louis Children's Hospital | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Stratum 1 | Experimental | Recipients with non-malignant disorders, excluding thalassemia. Related or unrelated 8/8 HLA-matched bone marrow |
|
| Stratum 2 | Experimental | Recipient with transfusion dependent thalassemia. Related or unrelated. 8/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB |
|
| Stratum 3 | Experimental | Recipient with hemoglobinopathy Related or unrelated. 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB |
|
| Stratum 4 | Experimental | Recipient with non-malignant disorder, excluding hemoglobinopathy Related or unrelated. 7/8 HLA-matched bone marrow or 5-8/8 HLA-matched UCB |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Treatment Plan 1: Stratum 1 | Drug | 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... |
| Measure | Description | Time Frame |
|---|---|---|
| Donor engraftment as measured by chimerism | Engraftment is measured in myeloid and lymphoid lineage cells | 100 days post-transplant |
| Major toxicities as graded by the CTC v4 | 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 | 100 days post-transplant |
| Measure | Description | Time Frame |
|---|---|---|
| Time to neutrophil and platelet engraftment as measured by complete blood counts | Defined as an ANC >500/microliter and platelets >20,000 or 50,000/microliter depending on disorder | Post transplant |
| Incidence of acute graft-versus-host disease as measured by protocol grading scale |
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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:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Lissy Keller, CCRP | Contact | 3142861168 | kellerl@wustl.edu | |
| Ian Snyder, CCRP | Contact | 3142735953 | ian.s@wustl.edu |
| Name | Affiliation | Role |
|---|---|---|
| Shalini Shenoy, MD | Washington University School of Medicine (in St. Louis) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Phoenix Children's Hospital | Recruiting | Phoenix | Arizona | 85016 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 18500373 | Result | Bhatla D, Davies SM, Shenoy S, Harris RE, Crockett M, Shoultz L, Smolarek T, Bleesing J, Hansen M, Jodele S, Jordan M, Filipovich AH, Mehta PA. Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman-Diamond syndrome. Bone Marrow Transplant. 2008 Aug;42(3):159-65. doi: 10.1038/bmt.2008.151. Epub 2008 May 26. | |
| 18026148 |
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| Treatment Plan 2: Strata 2, 3, or 4 | Drug | 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... |
|
| GVHD Regimen A: UCB Recipients | Drug | 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 |
|
| GVHD Regimen B: BM Recipients | Drug | 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 |
|
aGVHD - involving the skin, gut and liver. Classified according to grading described by Thomas et al. NEJM 1975; 292:895-902 |
| 100 days post-transplant |
| Incidence of chronic graft-versus-host disease as measured by protocol grading scale | cGVHD classified per Schulman et al. Am J Med 69: 204-17, 1980. | 2 years post-transplant |
| Long-term donor engraftment by donor chimerism | 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. | 2 years post-transplant |
| Immune reconstitution by laboratory evaluations | 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. | 1 year post-transplant |
| Overall and disease free survival | 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. | 2 years post-transplant |
| Children's Hospital of Orange County | Recruiting | Orange | California | 92868 | United States |
|
| University of California | Recruiting | San Diego | California | 92123 | United States |
|
| Yale School of Medicine | Recruiting | New Haven | Connecticut | 06510 | United States |
|
| George Washington University School of Medicine | Recruiting | Washington D.C. | District of Columbia | 20010 | United States |
|
| Nemours Children's Health | Completed | Jacksonville | Florida | 32207 | United States |
| University of Miami | Recruiting | Miami | Florida | 33136 | United States |
|
| Miami Children's Hospital | Completed | Miami | Florida | 33155 | United States |
| All Children's Hospital | Completed | St. Petersburg | Florida | 33701 | United States |
| Children's Memorial Hospital | Completed | Chicago | Illinois | 60614 | United States |
| Indiana University School of Medicine | Recruiting | Indianapolis | Indiana | 46202 | United States |
|
| Children's Hospital of New Orleans | Completed | New Orleans | Louisiana | 70118 | United States |
| Children's Mercy | Completed | Kansas City | Missouri | 64108 | United States |
| St. Louis University | Recruiting | St Louis | Missouri | 63104 | United States |
|
| Washington University School of Medicine (in St. Louis) | Recruiting | St Louis | Missouri | 63110 | United States |
|
| Hackensack University Medical Center | Completed | Hackensack | New Jersey | 07601 | United States |
| Columbia University Medical Center | Recruiting | New York | New York | 10032 | United States |
|
| University of North Carolina | Recruiting | Chapel Hill | North Carolina | 27514 | United States |
|
| Carolinas Medical Center | Completed | Charlotte | North Carolina | 28232 | United States |
| Duke Children's Hospital | Completed | Durham | North Carolina | 27705 | United States |
| The University of Oklahoma | Completed | Oklahoma City | Oklahoma | 73104 | United States |
| University of Pittsburg | Completed | Pittsburgh | Pennsylvania | 15224 | United States |
| Cook Children's Hospital | Completed | Forth Worth | Texas | 76104 | United States |
| Texas Transplant Institute | Completed | San Antonio | Texas | 78229 | United States |
| University of Utah | Recruiting | Salt Lake City | Utah | 84132 | United States |
|
| BC Children's Hospital | Completed | Vancouver | British Columbia | V6H 3N1 | Canada |
| University of Manitoba | Completed | Winnipeg | Manitoba | MB R3E 0T4 | Canada |
| University of Calgary | Completed | Calgary | Canada |
| Hansen MD, Filipovich AH, Davies SM, Mehta P, Bleesing J, Jodele S, Hayashi R, Barnes Y, Shenoy S. Allogeneic hematopoietic cell transplantation (HCT) in Hurler's syndrome using a reduced intensity preparative regimen. Bone Marrow Transplant. 2008 Feb;41(4):349-53. doi: 10.1038/sj.bmt.1705926. Epub 2007 Nov 19. |
| 16990602 | Result | Rao A, Kamani N, Filipovich A, Lee SM, Davies SM, Dalal J, Shenoy S. Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood. 2007 Jan 1;109(1):383-5. doi: 10.1182/blood-2006-05-025072. Epub 2006 Sep 21. |
| 15592491 | Result | Shenoy S, Grossman WJ, DiPersio J, Yu LC, Wilson D, Barnes YJ, Mohanakumar T, Rao A, Hayashi RJ. A novel reduced-intensity stem cell transplant regimen for nonmalignant disorders. Bone Marrow Transplant. 2005 Feb;35(4):345-52. doi: 10.1038/sj.bmt.1704795. |
| 26348869 | Derived | King AA, Kamani N, Bunin N, Sahdev I, Brochstein J, Hayashi RJ, Grimley M, Abraham A, Dioguardi J, Chan KW, Douglas D, Adams R, Andreansky M, Anderson E, Gilman A, Chaudhury S, Yu L, Dalal J, Hale G, Cuvelier G, Jain A, Krajewski J, Gillio A, Kasow KA, Delgado D, Hanson E, Murray L, Shenoy S. Successful matched sibling donor marrow transplantation following reduced intensity conditioning in children with hemoglobinopathies. Am J Hematol. 2015 Dec;90(12):1093-8. doi: 10.1002/ajh.24183. Epub 2015 Oct 6. |
| ID | Term |
|---|---|
| D008659 | Metabolic Diseases |
| D006453 | Hemoglobinopathies |
| ID | Term |
|---|---|
| D009750 | Nutritional and Metabolic Diseases |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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