Alpha/Beta TCD HCT in Patients With Inherited BMF Disorders
- Conditions
- Fanconi AnemiaSevere Aplastic AnemiaMyelodysplastic SyndromesT Cell Receptor Alpha/Beta DepletionTelomere Biology DisorderBone Marrow FailureDyskeratosis Congenita
- Interventions
- Drug: Total Body Irradiation (TBI) (Plan 1)Device: Donor mobilized PBSC infusion
- Registration Number
- NCT03579875
- Lead Sponsor
- Masonic Cancer Center, University of Minnesota
- Brief Summary
This is a phase II trial of T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell (PBSC) transplantation in patients with inherited bone marrow failure (BMF) disorders to eliminate the need for routine graft-versus-host disease (GVHD) immune suppression leading to earlier immune recovery and potentially a reduction in the risk of severe infections after transplantation.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 48
For FA patients:
-
Diagnosis of Fanconi anemia
- Age <65 years of age
-
Has one of the following risk factors:
- Severe aplastic anemia (SAA)
- Myelodysplastic syndrome (MDS)
- High risk genotype
- Immunodeficiency associated with history of recurrent infections
-
Karnofsky performance status ≥ 70% if ≥ 16 years of age or Lansky play score ≥ 50% for patients <16 years of age
- Adequate pulmonary, cardiac and liver function
- Voluntary written consent (minor assent if appropriate) prior to the performance of any study related procedures not part of standard medical care
For TBD patients:
• Diagnosis of TBD
-
Age <70 years of age
-
Has one of the following risk factors:
-
Severe aplastic anemia (SAA)
-
Myelodysplastic syndrome (MDS)
-
Karnofsky performance status ≥ 70% if ≥ 16 years of age or Lansky play score
≥ 50% for patients <16 years of age
-
Adequate pulmonary, cardiac and liver function
-
Voluntary written consent (minor assent if appropriate) prior to the performance of any study related procedures not part of standard medical care
- Pregnant or breastfeeding as the treatment used in this study are Pregnancy Category D. Females of childbearing potential must have a negative pregnancy test (serum or urine) within 14 days of study registration
- Active, uncontrolled infection within 1 week prior to starting study therapy
- Malignant solid tumor cancer within previous 2 years
Donor Selection (Inclusion Criteria): meets one of the following match criteria:
-
an HLA-A, B, DRB1 matched sibling donor (matched sibling)
-
an HLA-A, B, DRB1 matched related donor (other than sibling)
-
a related donor mismatched at 1 HLA-A, B, C and DRB1 antigen
-
7-8/8 HLA-A,B,C,DRB1 allele matched unrelated donor per current institutional guidelines Patients and donors are typed for HLA-A and B using serological or molecular techniques and for DRB1 using high resolution molecular typing. If a donor has been selected on the basis of HLA-A, B, C and DRB1 typing as above, preference will be made for donors matched at the HLA-C locus.
-
Body weight of at least 40 kilograms and at least 12 years of age
-
Willing and able to undergo mobilized peripheral blood apheresis
-
In general good health as determined by the medical provider
-
Adequate organ function defined as:
- Hematologic: hemoglobin, WBC, platelet within 10% of upper and lower limit of normal range of test (gender based for hemoglobin)
- Hepatic: ALT < 2 x upper limit of normal
- Renal: serum creatinine < 1.8 mg/dl
-
Performance of a donor infectious disease screen panel including CMV Antibody, Hepatitis B Surface Antigen, Hepatitis B Core Antibody, Hepatitis C Antibody, HIV 1/2 Antibody, HTLVA 1/2 Antibody, Treponema, and Trypanosoma Cruzi (T. Cruzi) plus HBV, HCV, WNV, HIV by nucleic acid testing (NAT); and screening for evidence of and risks factors for infection with Zika virus, or per current standard institutional donor screen - must be negative for HIV and active hepatitis B
-
Not pregnant - females of childbearing potential must have a negative pregnancy test within 7 days of mobilization start
-
Voluntary written consent (parent/guardian and minor assent, if < 18 years) prior to the performance of any research related procedure
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Treatment Plan 1: TBI 300 with Thymic Shielding, CY, FLU, MP in patients with Fanconi Anemia Total Body Irradiation (TBI) (Plan 1) Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type OR * Patients with an HLA- identical sibling donor recipient and MDS or acute leukemia Treatment Plan 1: TBI 300 with Thymic Shielding, CY, FLU, MP in patients with Fanconi Anemia Fludarabine (FLU) Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type OR * Patients with an HLA- identical sibling donor recipient and MDS or acute leukemia Treatment Plan 1: TBI 300 with Thymic Shielding, CY, FLU, MP in patients with Fanconi Anemia Donor mobilized PBSC infusion Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type OR * Patients with an HLA- identical sibling donor recipient and MDS or acute leukemia Treatment Plan 1: TBI 300 with Thymic Shielding, CY, FLU, MP in patients with Fanconi Anemia G-CSF Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type OR * Patients with an HLA- identical sibling donor recipient and MDS or acute leukemia Treatment Plan 1: TBI 300 with Thymic Shielding, CY, FLU, MP in patients with Fanconi Anemia Rituximab Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type OR * Patients with an HLA- identical sibling donor recipient and MDS or acute leukemia Treatment Plan 2: CY, FLU and MP in patients with Fanconi Anemia Fludarabine (FLU) Given to: • HLA-identical sibling donor recipients with aplastic anemia Treatment Plan 2: CY, FLU and MP in patients with Fanconi Anemia Methylprednisolone (MP) Given to: • HLA-identical sibling donor recipients with aplastic anemia Treatment Plan 2: CY, FLU and MP in patients with Fanconi Anemia Donor mobilized PBSC infusion Given to: • HLA-identical sibling donor recipients with aplastic anemia Treatment Plan 2: CY, FLU and MP in patients with Fanconi Anemia G-CSF Given to: • HLA-identical sibling donor recipients with aplastic anemia Treatment Plan 2: CY, FLU and MP in patients with Fanconi Anemia Cyclophosphamide (CY) (Plan 2) Given to: • HLA-identical sibling donor recipients with aplastic anemia Treatment Plan 2: CY, FLU and MP in patients with Fanconi Anemia Rituximab Given to: • HLA-identical sibling donor recipients with aplastic anemia Treatment Plan 3: BU, Cy, FLU, MP and Rituximab in patients with Fanconi Anemia Rituximab Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type who cannot tolerate TBI * Patients with an HLA- identical sibling donor recipient and MDS or acute leukemia who cannot tolerate TBI * Per treating physician preference Treatment Plan 1: TBI 300 with Thymic Shielding, CY, FLU, MP in patients with Fanconi Anemia Cyclophosphamide (CY) (Plan 1) Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type OR * Patients with an HLA- identical sibling donor recipient and MDS or acute leukemia Treatment Plan 3: BU, Cy, FLU, MP and Rituximab in patients with Fanconi Anemia Cyclophosphamide (CY) (Plan 1) Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type who cannot tolerate TBI * Patients with an HLA- identical sibling donor recipient and MDS or acute leukemia who cannot tolerate TBI * Per treating physician preference Treatment Plan 4: CY, FLU, and alemtuzumab Cyclophosphamide (CY) (Plan 1) given to TBD patients with: * Bone marrow failure AND * Any donor type including haploidentical (4/8) to 8/8-HLA matched related donor, or 7-8/8 HLA-matched unrelated donor Based on historical numbers, it is expected approximately 3 patients would be treated per year. Statistical outcomes will be descriptive. Treatment Plan 5: CY, FLU, melphalan (MEL), and alemtuzumab. Cyclophosphamide (CY) (Plan 1) given to TBD patients with: * Early MDS features (with or without cytogenetic abnormalities) AND * Any donor type including haploidentical (4/8) to 8/8-HLA matched related donor, or 7-8/8 HLA-matched unrelated donor Based on historical numbers, it is expected approximately 2 patients would be treated per year. Statistical outcomes will be descriptive. Treatment Plan 3: BU, Cy, FLU, MP and Rituximab in patients with Fanconi Anemia Fludarabine (FLU) Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type who cannot tolerate TBI * Patients with an HLA- identical sibling donor recipient and MDS or acute leukemia who cannot tolerate TBI * Per treating physician preference Treatment Plan 4: CY, FLU, and alemtuzumab Fludarabine (FLU) given to TBD patients with: * Bone marrow failure AND * Any donor type including haploidentical (4/8) to 8/8-HLA matched related donor, or 7-8/8 HLA-matched unrelated donor Based on historical numbers, it is expected approximately 3 patients would be treated per year. Statistical outcomes will be descriptive. Treatment Plan 5: CY, FLU, melphalan (MEL), and alemtuzumab. Fludarabine (FLU) given to TBD patients with: * Early MDS features (with or without cytogenetic abnormalities) AND * Any donor type including haploidentical (4/8) to 8/8-HLA matched related donor, or 7-8/8 HLA-matched unrelated donor Based on historical numbers, it is expected approximately 2 patients would be treated per year. Statistical outcomes will be descriptive. Treatment Plan 1: TBI 300 with Thymic Shielding, CY, FLU, MP in patients with Fanconi Anemia Methylprednisolone (MP) Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type OR * Patients with an HLA- identical sibling donor recipient and MDS or acute leukemia Treatment Plan 3: BU, Cy, FLU, MP and Rituximab in patients with Fanconi Anemia Methylprednisolone (MP) Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type who cannot tolerate TBI * Patients with an HLA- identical sibling donor recipient and MDS or acute leukemia who cannot tolerate TBI * Per treating physician preference Treatment Plan 3: BU, Cy, FLU, MP and Rituximab in patients with Fanconi Anemia Busulfan Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type who cannot tolerate TBI * Patients with an HLA- identical sibling donor recipient and MDS or acute leukemia who cannot tolerate TBI * Per treating physician preference Treatment Plan 4: CY, FLU, and alemtuzumab Alemtuzumab given to TBD patients with: * Bone marrow failure AND * Any donor type including haploidentical (4/8) to 8/8-HLA matched related donor, or 7-8/8 HLA-matched unrelated donor Based on historical numbers, it is expected approximately 3 patients would be treated per year. Statistical outcomes will be descriptive. Treatment Plan 5: CY, FLU, melphalan (MEL), and alemtuzumab. Alemtuzumab given to TBD patients with: * Early MDS features (with or without cytogenetic abnormalities) AND * Any donor type including haploidentical (4/8) to 8/8-HLA matched related donor, or 7-8/8 HLA-matched unrelated donor Based on historical numbers, it is expected approximately 2 patients would be treated per year. Statistical outcomes will be descriptive. Treatment Plan 5: CY, FLU, melphalan (MEL), and alemtuzumab. Melphalan given to TBD patients with: * Early MDS features (with or without cytogenetic abnormalities) AND * Any donor type including haploidentical (4/8) to 8/8-HLA matched related donor, or 7-8/8 HLA-matched unrelated donor Based on historical numbers, it is expected approximately 2 patients would be treated per year. Statistical outcomes will be descriptive.
- Primary Outcome Measures
Name Time Method Grade II-IV acute graft versus host disease (GVHD) Day 100 incidence of grade II-IV acute graft versus host disease (GVHD)
- Secondary Outcome Measures
Name Time Method Neutrophil engraftment Day 42 Rate of neutrophil engraftment (defined as the first of three consecutive days after HCT that the patient's absolute neutrophil counts is ≥ 0.5x109 per liter)
Platelet engraftment Day 42 Time to platelet engraftment (First of three consecutive days after HCT that the patient's platelet count ≥ 20x10\^9 per liter)
Acute graft versus host disease (aGVHD) Day 100 Incidence of grade III-IV acute graft versus host disease
Chronic graft versus host disease (cGVHD) 1 Year after transplant Incidence of chronic graft versus host disease after transplant
Bacterial, viral and fungal infections 1 Year after transplant Incidence of bacterial, viral and fungal infections
Opportunistic infections 100 Days after transplant Incidence of opportunistic infections
Overall survival (OS) 1 Year after transplant Incidence of overall survival
Regimen related toxicity 30 Days after transplant Incidence of regimen related toxicity based on CTCAE v5
Trial Locations
- Locations (1)
Masonic Cancer Center at University of Minnesota
🇺🇸Minneapolis, Minnesota, United States