Fanconi Anemia, Severe Aplastic Anemia, Myelodysplastic Syndromes, T Cell Receptor Alpha/Beta Depletion, Telomere Biology Disorder, Bone Marrow Failure, Dyskeratosis Congenita, Telomere Biology Disorders
Conditions
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.
Interventions
DRUGTotal Body Irradiation (TBI) (Plan 1)
300 cGy with thymic shielding on day -6
DRUGCyclophosphamide (CY) (Plan 1)
10 mg/kg IV daily on days -5, -4, -3, and -2
35 mg/m2 IV daily on days -5, -4, -3, and -2
1 mg/kg IV q12h on days -5, -4, -3, -2, and -1
DEVICEDonor mobilized PBSC infusion
T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell (PBSC) transplantation on day 0
DRUGG-CSF
Initiate G-CSF 5mcg/kg per day IV on day +1 (continue until ANC \>2.5 x 10\^9/L for 3 consecutive days or single day ANC \>3000 Arm 1 and Arm 3)
DRUGCyclophosphamide (CY) (Plan 2)
5 mg/kg IV daily on days -5, -4, -3, and -2
DRUGRituximab
200 mg/m2 IV once on day -1
DRUGBusulfan
Busulfan 0.6 mg/kg if \> 4 years old and/or \>12 kg (0.8 mg/kg IV if ≤ 4 years old and/or ≤ 12 kg) is given IV over 2 hours every 12 hours for 2 days.
DRUGAlemtuzumab
Alemtuzumab 0.2 mg/kg is given IV over 2 hours daily for 5 days (total dose 1 mg/kg)
DRUGMelphalan
If available, MEL dosing will be model-based using Bayesian methodology. If Bayesian methodology is unavailable, MEL dosing will be weight-based: MEL 70 mg/m2 for patients ≥10 kg (2.35 mg/kg for patients \<10 kg\^) IV for one dose over 30 minutes.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 65 Years
Healthy volunteers
No
Inclusion criteria
Patient Selection: Inclusion Criteria: For FA patients: * Diagnosis of Fanconi anemia * Age \<65 years of age * Has one of the following risk factors: * Severe aplastic anemia (SAA) * Myelodysplastic features * 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 features * 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
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Grade II-IV acute graft versus host disease (GVHD) | Day 100 | incidence of grade II-IV acute graft versus host disease (GVHD) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Regimen related toxicity | 30 Days after transplant | Incidence of regimen related toxicity based on CTCAE v5 |
| 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 |
Countries
United States
Contacts
CONTACTMargaret MacMillan, MD, Msc, FRCPC
PRINCIPAL_INVESTIGATORMargaret MacMillan, MD, Msc, FRCPC
Masonic Cancer Center, University of Minnesota
Outcome results
None listed