Title
TransIT A Phase III Randomized Trial Comparing Unrelated Donor Bone Marrow Transplantation with Immune Suppressive Therapy for Newly Diagnosed Pediatric and Young Adult

Description
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.

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.

Objective
The primary endpoint is time from randomization to treatment failure or death from any cause. Failure of IST is defined as initiation of a second definitive therapy (BMT, second course of ATG) and failure of BMT is defined as initiation of a second definitive therapy (second BMT, course of ATG).
Secondary endpoints:
1) The proportion of subjects with failure of IST or BMT before or at 2 years.
2) The proportion of subjects with inadequate counts at 2 years among those who have not died or failed treatment.
3) The proportion of subjects on systemic immune suppression at 2 years among those who have not died or failed treatment.
4) Time from randomization to initiation of IST or BMT.
5) The proportion of subjects who fail to receive randomized therapy and the frequency of reasons for failure.
6) Proportion of subjects in the first 2 years from randomization with each of the following:
1. Documented Bacteremia
2. Document Viremia
3. Documented Invasive fungal infection (confirmed or suspected based upon imaging)
7) Absolute CD3, CD4, CD8, CD19, and CD56 (NK cell) numbers will be tracked at 100 days, 180 days, 1 year and 2 years post initiation of therapy in URD BMT arm. IgG levels free of IVIG replacement will be collected at the same timepoints. The median time to T-cell and B-cell immune reconstitution will be estimated in the URD BMT arm.
8) Proportion of subjects who have died at 1 year and 2 years after randomization.
9) The rates of neutrophil recovery, platelet recovery, and red blood cell recovery from time of randomization.
10) The rates of neutrophil recovery, platelet recovery, and red blood cell recovery from time of therapy initiation.
11) Proportion of subjects with engraftment, primary and secondary graft failure and grade II-IV and III-IV acute GVHD, and extensive chronic GVHD in patients who receive URD BMT.
12) Proportion of subjects with IST response. Proportion of subjects with IST failure at 6 months.
13) Collect secondary therapies given for failure of primary randomized therapy (BMT after IST, second course of IST, second BMT) and outcome.
14) Proportion of subjects with i) subsequent neoplasms, ii) presence of a PNH clone at time of randomization who go on to develop symptomatic PNH through the duration of the protocol.
15) QOL endpoints include the change in score between baseline and 2 years and the trajectory of change over all time points.
16) Proportion of subjects with gonadal function values below of the 25th percentile of normal range for that age.
Correlative Biology and Exploratory Endpoints
1) Proportion of subjects who do not have genetic BM failure.
2) Clonal hematopoiesis following IST vs BMT will be compared at baseline and 1 year, 2 years and at one late timepoint from randomization. The proportion of subjects with clonal hematopoiesis, proportion of subjects with missense mutations, the frequency of mutated genes, the number of mutations per subject and the variant allele frequency (VAF) will be compared.
3) To analyze the 2-year immune suppression free survival-adequate Counts (ISFS-AC) composite variable, we will use a 2-year win ratio calculated using the unmatched pairs method (Pocock, S.J., et al. The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities.

Treatment 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

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

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

Age
Confirmed diagnosis of idiopathic SAA, defined as:



Bone marrow cellularity <25%, or <30% hematopoietic cells.

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.



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).

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).

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

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.

Clonal cytogenetic abnormalities or Fluorescence In-Situ Hybridization (FISH) pattern consistent with pre- myelodysplastic syndrome (pre-MDS) or MDS on marrow examination.

Known severe allergy to ATG.

Prior allogeneic or autologous stem cell transplant.

Prior solid organ transplant.

Infection with human immunodeficiency virus (HIV).

Active Hepatitis B or C. This only needs to be excluded in patients where there is clinical suspicion of hepatitis (e.g., elevated LFTs).

Female patients who are pregnant or breast-feeding.

Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ.

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

Applicable Disease Sites
Hematologic cancers, other

Participating Institutions
UW Health University Hospital