Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)

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)

Underlying BMFD treatable by allogenic HCT

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

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

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

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

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

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

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

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

Patient and/or legal guardian must sign informed consent prior to initiation of conditioning for BMT CTN 1904

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

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)

HLA-MATCHED RELATED DONOR: HLA-matched related (phenotypic match): Fully matched for HLA-A, -B, -C, -DRB1, and DQB1 by high-resolution typing.

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

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

UNRELATED DONOR: Fully matched for HLA-A, -B, -C, -DRB1, and DQB1 by high-resolution typing OR

UNRELATED DONOR: Mismatched for a single HLA-class 1 allele (HLA-A, -B, or -C) by high-resolution typing; OR

UNRELATED DONOR: Mismatched for a single HLA DQB1 allele or antigen by high-resolution typing

\* Note: donor patient (DP) matching per institutional practice

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)

What this study is about