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A Trial Comparing Unrelated Donor BMT With IST for Pediatric and Young Adult Patients With Severe Aplastic Anemia (TransIT, BMT CTN 2202)

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Boston Children's Hospital

Status and phase

Enrolling
Phase 3

Conditions

Severe Aplastic Anemia

Treatments

Drug: rabbit anti-thymocyte globulin (ATG)
Procedure: Matched Unrelated Donor Hematopoetic Stem Cell Transplant
Drug: Cyclophosphamide
Drug: cyclosporine
Drug: Fludarabine
Procedure: Immunosuppressive Therapy (IST)
Drug: Methotrexate
Radiation: low-dose total body irradiation (TBI)
Drug: horse anti-thymocyte globulin (ATG)

Study type

Interventional

Funder types

Other
NETWORK
NIH

Identifiers

NCT05600426
1UG3HL157564-01A1 (U.S. NIH Grant/Contract)
IRB-2020-0438
1U24HL157560-01A1 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

Severe Aplastic Anemia (SAA) is a rare condition in which the body stops producing enough new blood cells. SAA can be cured with immune suppressive therapy or a bone marrow transplant. Regular treatment for patients with aplastic anemia who have a matched sibling (brother or sister), or family donor is a bone marrow transplant. Patients without a matched family donor normally are treated with immune suppressive therapy (IST). Match unrelated donor (URD) bone marrow transplant (BMT) is used as a secondary treatment in patients who did not get better with IST, had their disease come back, or a new worse disease replaced it (like leukemia).

This trial will compare time from randomization to failure of treatment or death from any cause of IST versus URD BMT when used as initial therapy to treat SAA.

The trial will also assess whether health-related quality of life and early markers of fertility differ between those randomized to URD BMT or IST, as well as assess the presence of marrow failure-related genes and presence of gene mutations associated with MDS or leukemia and the change in gene signatures after treatment in both study arms.

This study treatment does not include any investigational drugs. The medicines and procedures in this study are standard for treatment of SAA.

Full description

This study is a multi-center randomized phase III trial to compare the failure free survival between those randomized to IST vs 9-10/10 HLA matched URD BMT. The study will also address patient-reported outcomes and gonadal function in each arm and explore critical biological correlates including assessing germline genetic mutations associated with pediatric SAA that may lead to a predisposition to the disease and the risk of development of clonal hematopoiesis following IST vs BMT in pediatric and young adult SAA.

This clinical trial will randomize 234 children/AYA over 3.3-4.7 years at a 1:1 ratio between initial treatment with immune suppression therapy (IST) with horse ATG (hATG)/cyclosporine (CsA) versus well- matched (9-10/10 allele) unrelated donor (URD) bone marrow transplantation (BMT) using a regimen of rabbit ATG (rATG)/fludarabine/cyclophosphamide and 200 cGy TBI. Duration of subject participation for all study procedures in this study will be up to 2 years after treatment; a single later timepoint between 3 and 5 years will be collected to follow patients for specific protocol defined late effects and survival.

Enrollment

234 estimated patients

Sex

All

Ages

Under 25 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

To be eligible to participate in the randomized trial, an individual must meet all the following criteria:

  1. Provision of signed and dated informed consent form for the randomized trial by patient and/or legal guardian.

  2. Age ≤25 years old at time of randomized trial consent.

  3. Confirmed diagnosis of idiopathic SAA, defined as:

    1. Bone marrow cellularity <25%, or <30% hematopoietic cells.
    2. Two of three of the following (in peripheral blood): neutrophils <0.5 x 10^9/L, platelets <20 x 10^9/L, absolute reticulocyte count <60 x 10^9/L or hemoglobin <8 g/dL.
  4. No suitable fully matched related donor available (minimum 6/6 match for HLA-A and B at intermediate or high resolution and DRB1 at high resolution using DNA based typing).

  5. At least 2 unrelated donors noted on NMDP search who are well matched (9/10 or 10/10 for HLA-A, B, C, DRB1, and DQB1 using high resolution).

  6. In the treating physician's opinion, no obvious contraindications precluding them from BMT or IST.

Exclusion criteria

  1. Presence of Inherited bone marrow failure syndromes (IBMFS). The diagnosis of Fanconi anemia must be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or marrow. Telomere length testing should be sent on all patients to exclude Dyskeratosis Congenita (DC), but if results are delayed or unavailable and there are no clinical manifestations of DC, patients may enroll. If patients have clinical characteristics suspicious for Shwachman-Diamond syndrome, this disorder should be excluded by pancreatic isoamylase testing or gene mutation analysis (note: pancreatic isoamylase testing is not useful in children <3). Other testing per center may be performed to exclude IBMFS.
  2. Clonal cytogenetic abnormalities or Fluorescence In-Situ Hybridization (FISH) pattern consistent with pre- myelodysplastic syndrome (pre-MDS) or MDS on marrow examination.
  3. Known severe allergy to ATG.
  4. Prior allogeneic or autologous stem cell transplant.
  5. Prior solid organ transplant.
  6. Infection with human immunodeficiency virus (HIV).
  7. Active Hepatitis B or C. This only needs to be excluded in patients where there is clinical suspicion of hepatitis (e.g., elevated LFTs).
  8. Female patients who are pregnant or breast-feeding.
  9. Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ.
  10. Disease modifying treatment prior to study enrollment, including but not limited to use of androgens, eltrombopag, romiplostim, or immune suppression. Note: Supportive care measures such as G-CSF, blood transfusion support and antibiotics are allowable

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

234 participants in 2 patient groups

Immunosuppressive Therapy
Active Comparator group
Description:
Patient will receive standard immunosuppressive therapy combination of drugs: horse anti-thymocyte globulin (ATG) and cyclosporine.
Treatment:
Drug: horse anti-thymocyte globulin (ATG)
Procedure: Immunosuppressive Therapy (IST)
Drug: cyclosporine
Matched Unrelated Stem Cell Transplant
Active Comparator group
Description:
Patient will under go matched unrelated donor transplant of hematopoietic stem cells as their therapy using fludarabine, cyclophosphamide, rabbit anti-thymocyte globulin (ATG), and low-dose total body irradiation (TBI) as preparative regimen and cyclosporine and methotrexate for graft versus host disease (GVHD) prevention.
Treatment:
Radiation: low-dose total body irradiation (TBI)
Drug: Methotrexate
Drug: Fludarabine
Drug: cyclosporine
Drug: Cyclophosphamide
Procedure: Matched Unrelated Donor Hematopoetic Stem Cell Transplant
Drug: rabbit anti-thymocyte globulin (ATG)

Trial contacts and locations

47

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Central trial contact

Kristi Wilmes, MS; Leah Cheng, MA

Data sourced from clinicaltrials.gov

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