Summary

This phase II trial tests whether treosulfan, fludarabine, and rabbit antithymocyte globulin (rATG) work when given before a blood or bone marrow transplant (conditioning regimen) to cause fewer complications for patients with bone marrow failure diseases. Chemotherapy drugs, such as treosulfan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Fludarabine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. rATG is used to decrease the body's immune response and may improve bone marrow function and increase blood cell counts. Adding treosulfan to a conditioning regimen with fludarabine and rATG may result in patients having less severe complications after a blood or bone marrow transplant.

Objectives

PRIMARY OBJECTIVE:
I. To assess the 1-year graft-versus-host disease (GVHD)-free, event-free survival (EFS) in patients with bone marrow failure diseases (BMFD) undergoing hematopoietic cell transplantation (HCT) using treosulfan-based conditioning.

SECONDARY OBJECTIVES:
I. Overall survival at day 100, 6 months, and 1-year post-HCT.
II. EFS at 1-year post-HCT.
III. Neutrophil recovery at day 42 and platelet recovery at day 100 post-HCT.
IV. Donor chimerism (CD3 and myeloid) at day 28, 100, and 1-year post-HCT.
V. Primary graft failure/rejection at day 42 and secondary graft failure/rejection post-HCT.
VI. Incidence of grade II-IV and grade III-IV GVHD at day 100 and chronic GVHD requiring systemic immune suppression at 1-year post-HCT.
VII. Acute GVHD will be defined as grade II-IV and grade III-IV.
VIII. Chronic GVHD will be defined as chronic GVHD (using National Institutes of Health [NIH] consensus criteria) requiring systemic immune suppression.
IX. Incidence of grade 3-5 toxicities at day 30 and day 100 post-HCT.
X. Incidence of grade 2-3 systemic infections by day 180 post-HCT.
XI. Incidence of Epstein-Barr virus (EBV)-reactivation requiring therapy and the incidence of EBV-associated lymphoproliferative disorder by day 180 post-HCT.
XII. Incidence of cytomegalovirus (CMV) reactivation requiring therapy by day 180 post-HCT.

EXPLORATORY OBJECTIVES:
I. Treosulfan Pharmacokinetic Studies: Treosulfan pharmacokinetic (PK) characteristics to determine the optimal dose of treosulfan and evaluate whether the exposure to treosulfan determined by area under the curve (AUC) for patients with BMFD impacts engraftment, transplant-related mortality, and overall and event-free survival.
II. Biological Studies: Collect blood and marrow samples (cells, deoxyribonucleic acid [DNA], serum) and establish fibroblast cell cultures as a source of germline DNA to investigate: 1) somatic mutations, 2) T cell phenotypes, and 3) cytokine levels.
III. Mutational Testing: Collect peripheral blood on patients who lack a known genetic mutation responsible for their bone marrow failure phenotype in order to perform whole exome or whole genome sequencing with the goal of identifying new mutations for patients with BMFD.
IV. Health-related quality of life using Patient Reported Outcomes Measurement Information System (PROMIS) at baseline, day +180 and day +365 post-HCT.

OUTLINE:
CONDITIONING REGIMEN: Patients receive treosulfan intravenously (IV) over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and lapine T-lymphocyte immune globulin (rATG) IV over 4-6 hours on days -4 to -2.

TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus orally (PO). Patients also receive methotrexate IV on days 1, 3, 6, and 11.

Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients may optionally undergo blood sample collection throughout the trial.

After completion of study treatment, patients are followed up at 1 year from transplant.

Eligibility

1. Patient must be >= 1.0 year of age and less than 50.0 years of age at the time of enrollment (i.e. patient must have celebrated their 1st birthday when enrolled and must NOT have celebrated their 50th birthday when enrolled; 49.99 years)
2. Underlying BMFD treatable by allogenic HCT
3. Shwachman-Diamond syndrome * Criteria for Diagnosis: ** A pathogenic mutation(s) for Shwachman-Diamond syndrome ** For those patients tested but lacking a genetic mutation they must meet both *** criteria below: *** Exocrine pancreatic dysfunction as defined by at least one of the following: **** Pancreatic isoamylase below normal (age >= 3 years old), OR **** Fecal elastase < 200, AND *** Bone marrow failure as evidence by at least one of the following: **** Intermittent or persistent neutropenia (absolute neutrophil count < 1,500/uL), OR **** Hypo-productive anemia with a hemoglobin concentration below the age-related adjusted norms, OR **** Unexplained macrocytosis, OR **** Platelet count < 150,000/uL without alternative etiology, OR **** Hypocellular bone marrow * Indications for HCT: ** Severe neutropenia (absolute neutrophil count [ANC] < 500/uL), OR ** Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia, OR ** Severe thrombocytopenia (platelet count < 20,000/uL) or transfusion-dependent thrombocytopenia, OR ** Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 eligibility review committee (ERC). In addition, patients with severe or recurrent infections will be reviewed by the ERC if they do not meet the indications for transplant listed above
4. Diamond Blackfan Anemia * Criteria for Diagnosis: ** A pathogenic mutation for Diamond Blackfan anemia ** For those patients tested but lacking a genetic mutation the patient must meet the first *** criteria and at least one of the subsequent *** criteria listed below: *** History of deficiency of erythroid precursors in an otherwise cellular bone marrow AND, *** Reticulocytopenia, OR *** Elevated adenosine deaminase activity, OR *** Elevated hemoglobin F, OR *** Macrocytosis, OR *** Congenital anomalies * Indications for HCT: ** Red blood cell (RBC) transfusion dependent anemia despite an adequate trial of steroids; OR ** Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC
5. Congenital Sideroblastic anemia * Criteria for Diagnosis: ** A pathogenic mutation(s) for sideroblastic anemia ** For those patients tested but lacking a genetic mutation: *** Presence of ringed sideroblasts in the bone marrow excluding acquired causes of ringed sideroblasts such as lead poisoning & zinc toxicity * Indications for HCT: ** Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia OR ** Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC
6. GATA2 mutation with associated marrow failure * Criteria for Diagnosis: ** A pathogenic mutation(s) for GATA2 * Indications for HCT: ** Severe neutropenia (ANC < 500/uL), OR ** Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia, OR ** Severe thrombocytopenia (platelet count < 20,000/uL) or transfusion-dependent thrombocytopenia, OR ** Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC. In addition, patients with severe or recurrent infections will be reviewed by the ERC if they do not meet indications for transplant listed above
7. SAMD9 or SAMD9L disorders * Criteria for Diagnosis: ** A pathogenic mutation(s) for SAMD9 or SAMD9L * Indications for HCT: ** Severe neutropenia (ANC < 500/uL), OR ** Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia, OR ** Severe thrombocytopenia (platelet count < 20,000/uL) or transfusion-dependent thrombocytopenia, OR ** Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC
8. Congenital amegakaryocytic thrombocytopenia * Criteria for Diagnosis: ** A pathogenic mutation(s) for congenital amegakaryocytic thrombocytopenia. ** For those patients tested but lacking a genetic mutation the patient must meet criteria below: *** Thrombocytopenia early in life, AND *** History of bone marrow demonstrating megakaryocyte hypoplasia * Indications for HCT: ** Severe thrombocytopenia (platelet count < 20,000/uL) or transfusion-dependent thrombocytopenia, OR ** Neutropenia defined as an ANC < 500/uL, OR ** Severe anemia (hemoglobin < 8 g/dL) or transfusion-dependent anemia, OR ** Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC
9. Paroxysmal nocturnal hemoglobinuria * Criteria for Diagnosis: ** Paroxysmal nocturnal hemoglobinuria (PNH) clone size in granulocytes >= 10%, AND ** Complement mediated intravascular hemolysis with an elevated LDH (above institutional upper limits of normal) * Indications for HCT: ** PNH with thrombosis despite adequate medical management, OR ** PNH with intravascular hemolysis requiring transfusion support despite adequate medical management, OR ** Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC. In addition, patients with PNH and cytopenias may be considered for the protocol eligibility following review by protocol 1904 ERC
10. An undefined BMFD: a patient with a BMFD for whom a genetic mutation responsible for their bone marrow failure phenotype has not been identified (excluding PNH) will be eligible for this clinical trial following approval by Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1904 ERC * A BMFD with a known genetic mutation but not listed above will be eligible for this clinical trial following approval by BMT CTN 1904 ERC
11. Patient and/or legal guardian must sign informed consent prior to initiation of conditioning for BMT CTN 1904
12. Note: The following patients MUST be reviewed by the BMT CTN 1904 ERC in order to determine if they are eligible for this trial: * All patients with Shwachman-Diamond syndrome, Diamond Blackfan anemia, congenital sideroblastic anemia, and congenital amegakaryocytic thrombocytopenia who have had genetic testing and a genetic mutation responsible for their disease was not identified * All patients with an undefined BMFD: a patient with a BMFD for whom a genetic mutation responsible for their bone marrow failure phenotype has not been identified, excluding PNH * All patients with a BMFD and a known genetic mutation that is not listed above * All patients with GATA2 mutation and associated marrow failure * All patients with SAMD9 or SAMD9L disorders * There may be circumstances where a treating physician will consider a transplant for a patient with a BMFD who does not meet all the criteria listed under “indications for HCT”. In these situations, treating physicians may submit their patient to the BMT CTN 1904 ERC for review in order to determine if the patient is eligible for this clinical trial based on additional clinical or laboratory information * Many patients with BMFD can have bone marrow evaluations that raise concern for possible myelodysplastic syndrome (MDS) including but not limited to dysplastic bone marrow evaluations or cytogenetic abnormalities. However, in patients BMFD these findings are not necessarily diagnostic or consistent with MDS. Therefore, given the complexities of diagnosing MDS in patients with BMFD, all patients with bone marrow evaluations concerning for possible MDS should be submitted to the ERC for review to confirm or exclude MDS. This is particularly important as we do not want to exclude potentially eligible patients due to an incorrect diagnosis of MDS
13. HLA-MATCHED RELATED DONOR: HLA-matched sibling: Must be a minimum HLA-6/6 matched to the recipient at HLA-A, -B (serologic typing) and DRB1 (high-resolution typing)
14. HLA-MATCHED RELATED DONOR: HLA-matched related (phenotypic match): Fully matched for HLA-A, -B, -C, -DRB1, and DQB1 by high-resolution typing.
15. HLA-MATCHED RELATED DONOR: If a genetic mutation is known for the patient, the HLA-matched related donor [either HLA-matched sibling or HLA-matched related (phenotypic match)] must be screened for the same genetic mutation if clinically appropriate and should be confirmed to not have the same genetic disease (this does not include patients with PNH). Consult the protocol team with questions
16. HLA-MATCHED RELATED DONOR: If a patient has an undefined BMFD (a patient with a BMFD for whom a genetic mutation responsible for their bone marrow failure phenotype has not been identified), the HLA-matched related donor [either HLA-matched sibling or HLA-matched related (phenotypic match)] must have an evaluation as directed by the treating physician to confirm that the donor does not have the same underlying disease. This will include a complete blood count (CBC) with differential and potentially a bone marrow evaluation or other studies as directed by the treating physician
17. UNRELATED DONOR: Fully matched for HLA-A, -B, -C, -DRB1, and DQB1 by high-resolution typing OR
18. UNRELATED DONOR: Mismatched for a single HLA-class 1 allele (HLA-A, -B, or -C) by high-resolution typing; OR
19. UNRELATED DONOR: Mismatched for a single HLA DQB1 allele or antigen by high-resolution typing * Note: donor patient (DP) matching per institutional practice
20. DONOR SELECTION RECCOMENDATIONS: in the case where there are multiple donor options, donors should be selected based on the following priority numbered below: * Unaffected fully HLA-matched sibling * Unaffected fully phenotypically HLA-matched related donor * Fully HLA-matched unrelated donor * Unrelated donor with single allele or antigen level mismatch at DQB1 * Unrelated donor with single allele level mismatch at class 1 (HLA-A, -B, or -C)