Aplastic Anemia, Dyskeratosis Congenita
Conditions
Keywords
severe aplastic anemia, Hematopoietic Stem Cell Transplant
Brief summary
Fludarabine-based preparative regimen followed by an allogeneic hematopoietic stem cell transplant using related or unrelated donor in persons 0-70 years of age diagnosed with dyskeratosis congenita or severe aplastic anemia who have bone marrow failure characterized by a requirement for red blood cell and platelet transfusions. Three different preparative regimens are included based on disease and donor type.
Interventions
DRUGAlemtuzumab
Alemtuzumab 0.2 mg/kg IV over 2 hours on days -10 to -6 from transplant.
DRUGFludarabine
Fludarabine 40 mg/m2 IV over 1 hour on days -6 to -2 from transplant.
DRUGCyclophosphamide
Cyclophosphamide 50 mg/kg IV over 2 hours on day -7 from transplant.
RADIATIONTotal Body Irradiation
TBI 200 cGy as a single fraction on day -1 from transplant.
BIOLOGICALStem Cell Transplant
Stem cell transplant on day 0.
DRUGAnti-thymocyte globulin
ATG (Thymoglobulin - Rabbit ) 3 mg/kg IV on days -5 to -3 from stem cell transplant.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Aged 0 - 70 years * Acceptable hematopoeitic stem cell donor * Dyskeratosis Congenita (DC) with evidence of BM failure defined as: * requirement for red blood cell and/or platelet transfusions or * requirement for G-CSF or GM-CSF or erythropoietin or * refractory cytopenias having one of the following three * platelets \<50,000/uL or transfusion dependent * absolute neutrophil count \<500/uL without hematopoietic growth factor support * hemoglobin \<9g/uL or transfusion dependent * Diagnosis of DC with a triad of mucocutaneous features: * oral leukoplakia * nail dystrophy * abnormal reticular skin hyperpigmentation, or * Diagnosis of DC with one of the following: * short telomeres (under a research study) * mutation in telomerase holoenzyme (DKC1, TERT, TERC, NOP10, NHP2, TCAB1) * mutation in shelterin complex (TINF2) * mutation in telomere-capping complex (CTC1) * Severe Aplastic Anemia (SAA) primary transplant with evidence of BM failure: * Refractory cytopenia defined by bone marrow cellularity \<50% (with \< 30% residual hematopoietic cells) * Diagnosis of SAA with refractory cytopenias having one of the following three: * platelets \<20,000/uL or transfusion dependent * absolute neutrophil count \<500/uL without hematopoietic growth factor support * absolute reticulocyte count \<20,000/uL * Severe Aplastic Anemia (SAA) requiring a 2nd transplant * Graft failure as defined by blood/marrow chimerism of \< 5% * Early myelodysplastic features * With or without clonal cytogenetic abnormalities * Adequate organ function defined as: * cardiac: left ventricular ejection fraction ≥ 35% with no evidence of decompensated heart failure * pulmonary: DLCO ≥30% predicted, no supplemental oxygen requirement * renal: Glomerular filtration rate (GFR) ≥30% predicted * Voluntary written consent
Exclusion criteria
* Acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on biopsy * Pregnant or lactating * Uncontrolled infection * Prior radiation therapy (applies to SAA patients only) * Diagnosis of Fanconi anemia based on DEB * Diagnosis of dyskeratosis congenita with advanced MDS or acute myeloid leukemia with \>30% blasts
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Neutrophil Engraftment | Day 42 | Incidence of neutrophil engraftment by day 42. |
| Incidence of Platelet Engraftment | 1 year | Incidence of platelet engraftment at 1 year |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Regimen Related Mortality | Day 100 | Incidence of regimen related mortality by day 100. |
| Incidence of Acute Graft-versus-host Disease | Day 100 | Incidence of acute graft-versus-host disease by day 100. |
| Incidence of Chronic Graft-versus-host Disease | 6 Months | Incidence of chronic graft-versus-host disease by 6 months |
| Incidence of Secondary Malignancies | 1 Year | Incidence of secondary malingancies |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Dyskeratosis Congenita, Non-Haploidentical Donor Arm A Dyskeratosis Congenita (DKC) (non-haploidentical donor) | 12 |
| Arm B: Severe Aplastic Anemia, Non-Matched Related, Non-Haploidentical Donor Arm B: Severe Aplastic Anemia (SAA ) (non-matched related, non-haploidentical donor) | 18 |
| Arm C: Severe Aplastic Anemia, Matched Related Donor Arm C: Severe Aplastic Anemia (matched related donor) | 23 |
| Arm D: Dyskeratosis Congenita, PTCy Platform Arm D: Dyskeratosis Congenita (DKC), PTCy platform | 0 |
| Arm E: Severe Aplastic Anemia, PTCy Platform Arm E: Severe Aplastic Anemia (SAA), PTCy platform | 8 |
| Total | 61 |
Baseline characteristics
| Characteristic | Arm A: Dyskeratosis Congenita, Non-Haploidentical Donor | Arm B: Severe Aplastic Anemia, Non-Matched Related, Non-Haploidentical Donor | Arm C: Severe Aplastic Anemia, Matched Related Donor | Arm D: Dyskeratosis Congenita, PTCy Platform | Arm E: Severe Aplastic Anemia, PTCy Platform | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 9 Participants | 15 Participants | 13 Participants | 0 Participants | 4 Participants | 41 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 9 Participants | 0 Participants | 4 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 17 Participants | 21 Participants | 0 Participants | 7 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) White | 8 Participants | 13 Participants | 14 Participants | 0 Participants | 1 Participants | 36 Participants |
| Region of Enrollment United States | 12 participants | 18 participants | 23 participants | — | 8 participants | 61 participants |
| Sex: Female, Male Female | 6 Participants | 11 Participants | 10 Participants | 0 Participants | 2 Participants | 29 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 13 Participants | 0 Participants | 6 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 12 | 3 / 18 | 1 / 23 | 0 / 0 | 0 / 8 |
| other Total, other adverse events | 0 / 12 | 0 / 18 | 0 / 23 | 0 / 0 | 0 / 8 |
| serious Total, serious adverse events | 0 / 12 | 0 / 18 | 0 / 23 | 0 / 0 | 0 / 8 |
Outcome results
Primary
Incidence of Neutrophil Engraftment
Incidence of neutrophil engraftment by day 42.
Time frame: Day 42
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Dyskeratosis Congenita, Non-Haploidentical Donor | Incidence of Neutrophil Engraftment | 100 Percentage of participants |
| Arm B: Severe Aplastic Anemia, Non-Matched Related, Non-Haploidentical Donor | Incidence of Neutrophil Engraftment | 100 Percentage of participants |
| Arm C: Severe Aplastic Anemia, Matched Related Donor | Incidence of Neutrophil Engraftment | 96 Percentage of participants |
| Arm E: Severe Aplastic Anemia, PTCy Platform | Incidence of Neutrophil Engraftment | 100 Percentage of participants |
Primary
Incidence of Platelet Engraftment
Incidence of platelet engraftment at 1 year
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Dyskeratosis Congenita, Non-Haploidentical Donor | Incidence of Platelet Engraftment | 100 Percentage of participants |
| Arm B: Severe Aplastic Anemia, Non-Matched Related, Non-Haploidentical Donor | Incidence of Platelet Engraftment | 100 Percentage of participants |
| Arm C: Severe Aplastic Anemia, Matched Related Donor | Incidence of Platelet Engraftment | 96 Percentage of participants |
| Arm E: Severe Aplastic Anemia, PTCy Platform | Incidence of Platelet Engraftment | 100 Percentage of participants |
Secondary
Incidence of Acute Graft-versus-host Disease
Incidence of acute graft-versus-host disease by day 100.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Dyskeratosis Congenita, Non-Haploidentical Donor | Incidence of Acute Graft-versus-host Disease | 0 Percentage of participants |
| Arm B: Severe Aplastic Anemia, Non-Matched Related, Non-Haploidentical Donor | Incidence of Acute Graft-versus-host Disease | 11 Percentage of participants |
| Arm C: Severe Aplastic Anemia, Matched Related Donor | Incidence of Acute Graft-versus-host Disease | 9 Percentage of participants |
| Arm E: Severe Aplastic Anemia, PTCy Platform | Incidence of Acute Graft-versus-host Disease | 0 Percentage of participants |
Secondary
Incidence of Chronic Graft-versus-host Disease
Incidence of chronic graft-versus-host disease by 6 months
Time frame: 6 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Dyskeratosis Congenita, Non-Haploidentical Donor | Incidence of Chronic Graft-versus-host Disease | 0 Percentage of participants |
| Arm B: Severe Aplastic Anemia, Non-Matched Related, Non-Haploidentical Donor | Incidence of Chronic Graft-versus-host Disease | 6 Percentage of participants |
| Arm C: Severe Aplastic Anemia, Matched Related Donor | Incidence of Chronic Graft-versus-host Disease | 0 Percentage of participants |
| Arm E: Severe Aplastic Anemia, PTCy Platform | Incidence of Chronic Graft-versus-host Disease | 0 Percentage of participants |
Secondary
Incidence of Chronic Graft-versus-host Disease
Incidence of chronic graft-versus-host disease by 1 year
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Dyskeratosis Congenita, Non-Haploidentical Donor | Incidence of Chronic Graft-versus-host Disease | 0 Percentage of participants |
| Arm B: Severe Aplastic Anemia, Non-Matched Related, Non-Haploidentical Donor | Incidence of Chronic Graft-versus-host Disease | 6 Percentage of participants |
| Arm C: Severe Aplastic Anemia, Matched Related Donor | Incidence of Chronic Graft-versus-host Disease | 0 Percentage of participants |
| Arm E: Severe Aplastic Anemia, PTCy Platform | Incidence of Chronic Graft-versus-host Disease | 0 Percentage of participants |
Secondary
Incidence of Regimen Related Mortality
Incidence of regimen related mortality by day 100.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Dyskeratosis Congenita, Non-Haploidentical Donor | Incidence of Regimen Related Mortality | 0 Percentage of participants |
| Arm B: Severe Aplastic Anemia, Non-Matched Related, Non-Haploidentical Donor | Incidence of Regimen Related Mortality | 6 Percentage of participants |
| Arm C: Severe Aplastic Anemia, Matched Related Donor | Incidence of Regimen Related Mortality | 6 Percentage of participants |
| Arm E: Severe Aplastic Anemia, PTCy Platform | Incidence of Regimen Related Mortality | 0 Percentage of participants |
Secondary
Incidence of Secondary Malignancies
Incidence of secondary malingancies
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Dyskeratosis Congenita, Non-Haploidentical Donor | Incidence of Secondary Malignancies | 0 Percentage of participants |
| Arm B: Severe Aplastic Anemia, Non-Matched Related, Non-Haploidentical Donor | Incidence of Secondary Malignancies | 0 Percentage of participants |
| Arm C: Severe Aplastic Anemia, Matched Related Donor | Incidence of Secondary Malignancies | 0 Percentage of participants |
| Arm E: Severe Aplastic Anemia, PTCy Platform | Incidence of Secondary Malignancies | 0 Percentage of participants |