HCT Using Treosulfan for Bone Marrow Failure Diseases (BMT CTN 1904)

• Status: Not yet recruiting
• Trial end date: 2026-12-01
• Target enrollment: 0
• Participant gender: All

Summary

This is a prospective, multicenter phase II study designed to evaluate the outcomes of patients with bone marrow failure diseases (BMFD) undergoing HLA-matched related, HLA-matched unrelated, or single HLA-class 1 allele or HLA-DQB1 antigen or allele mismatched unrelated hematopoietic cell transplantation (HCT) using treosulfan-based conditioning.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Fred Hutchinson Cancer Research Center
• Collaborators: Blood and Marrow Transplant Clinical Trials Network; National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); National Marrow Donor Program
• Treatments: Antilymphocyte Serum; Busulfan; Fludarabine; Fludarabine phosphate; Methotrexate; Tacrolimus; Thymoglobulin; Treosulfan; Vidarabine

Criteria

Inclusion Criteria:

• 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 bone marrow failure disorders treatable by allogenic HCT.

a. Shwachman-Diamond syndrome i. Criteria for Diagnosis:

1. A pathogenic mutation(s) for Shwachman-Diamond syndrome

2. For those patients tested but lacking a genetic mutation they must meet both criteria a and b below:

1. Exocrine pancreatic dysfunction as defined by at least one of the following:

i. Pancreatic isoamylase below normal (age >3 years old), OR ii. Fecal elastase <200, AND b. Bone marrow failure as evidenced by at least one of the following: i. Intermittent or persistent neutropenia (absolute neutrophil count < 1,500/μL), OR ii. Hypo-productive anemia with a hemoglobin concentration below the age-related adjusted norms, OR iii. Unexplained macrocytosis, OR iv. Platelet count <150,000/μL without alternative etiology, OR v. Hypocellular bone marrow

ii. Indications for HCT:

1. Severe neutropenia (ANC <500/μL), OR 2. Severe anemia (hemoglobin <8 g/dL) or transfusion-dependent anemia, OR 3. Severe thrombocytopenia (platelet count <20,000/μL) or transfusion-dependent thrombocytopenia, OR 4. 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 indications for transplant listed above.

b. Diamond Blackfan anemia i. Criteria for Diagnosis:

1. A pathogenic mutation for Diamond Blackfan anemia

2. For those patients tested but lacking a genetic mutation the patient must meet criteria a and at least one of the criteria listed in b-f:

a. History of deficiency of erythroid precursors in an otherwise cellular bone marrow AND, b. Reticulocytopenia, OR c. Elevated adenosine deaminase activity, OR d. Elevated hemoglobin F, OR e. Macrocytosis, OR f. Congenital anomalies ii. Indications for HCT:

1. RBC transfusion dependent anemia despite an adequate trial of steroids; OR 2. Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC.

c. Congenital Sideroblastic anemia i. Criteria for Diagnosis:

1. A pathogenic mutation(s) for sideroblastic anemia

2. For those patients tested but lacking a genetic mutation:

a. Presence of ringed sideroblasts in the bone marrow excluding acquired causes of ringed sideroblasts such as lead poisoning & zinc toxicity.

ii. Indications for HCT:

1. Severe anemia (hemoglobin <8 g/dL) or transfusion-dependent anemia OR

2. Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC.

d. GATA2 mutation with associated marrow failure i. Criteria for Diagnosis:

1. A pathogenic mutation(s) for GATA2

ii. Indications for HCT:

1. Severe neutropenia (ANC <500/μL), OR

2. Severe anemia (hemoglobin <8 g/dL) or transfusion-dependent anemia, OR

3. Severe thrombocytopenia (platelet count <20,000/μL) or transfusion-dependent thrombocytopenia, OR

4. 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 the indications for transplant listed above.

e. SAMD9 or SAMD9L disorders i. Criteria for Diagnosis:

1. A pathogenic mutation(s) for SAMD9 or SAMD9L

ii. Indications for HCT:

1. Severe neutropenia (ANC <500/μL), OR 2. Severe anemia (hemoglobin <8 g/dL) or transfusion-dependent anemia, OR 3. Severe thrombocytopenia (platelet count <20,000/μL) or transfusion-dependent thrombocytopenia, OR 4. Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC.

f. Congenital amegakaryocytic thrombocytopenia i. Criteria for Diagnosis:

1. A pathogenic mutation(s) for congenital amegakaryocytic thrombocytopenia. 2. For those patients tested but lacking a genetic mutation the patient must meet criteria a and b below:

1. Thrombocytopenia early in life, AND

2. History of bone marrow demonstrating megakaryocyte hypoplasia.

ii. Indications for HCT:

1. Severe thrombocytopenia (platelet count <20,000/μL) or transfusion-dependent thrombocytopenia, OR

2. Neutropenia defined as an ANC <500/μL, OR

3. Severe anemia (hemoglobin <8 g/dL) or transfusion-dependent anemia, OR

4. Additional clinical or laboratory data may be considered for protocol eligibility following review by protocol 1904 ERC.

g. Paroxysmal nocturnal hemoglobinuria (PNH) i. Criteria for Diagnosis:

1. PNH clone size in granulocytes > 10%, AND

2. Complement mediated intravascular hemolysis with an elevated LDH (above institutional upper limits of normal)

ii. Indications for HCT:

1. PNH with thrombosis despite adequate medical management, OR

2. PNH with intravascular hemolysis requiring transfusion support despite adequate medical management, OR

3. 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.

h. 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 BMT CTN 1904 ERC.

i. 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.

Note: The following patients MUST be reviewed by the BMT CTN 1904 ERC in order to determine if they are eligible for this trial:

a. All patients with Shwachman-Diamond syndrome, Diamond Blackfan anemia, congenital sideroblastic anemia, and congenital amegakaryocytic thrombocytopenia who lack a genetic mutation.

b. 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.

c. All patients with a BMFD and a known genetic mutation that is not listed above d. All patients with GATA2 mutation with associated marrow failure e. All patients with SAMD9 or SAMD9L disorders f. 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.

g. 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 with 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 expert 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.

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

4. Females and males of childbearing potential must agree to practice 2 effective methods of contraception at the same time or agree to abstinence.

Exclusion Criteria:

• 1. Patients with idiopathic aplastic anemia, Fanconi anemia, dyskeratosis congenita, and congenital neutropenia.

2. Patients with MDS as defined by the World Health Organization (WHO) or leukemia.

3. Prior allogeneic transplant 4. Patient's weight ≤10.0 kg at time of study enrollment 5. Lansky (patients < 16 years of age) or Karnofsky (patients ≥16 years of age) performance <70% 6. Organ Dysfunction defined as follows:

a. Cardiac: i. Left ventricular ejection fraction <50% by echocardiogram or multi-gated acquisition (MUGA) scan.

ii. For patients unable to obtain a left ventricular ejection fraction, left ventricular shortening fraction <26%.

b. Pulmonary: i. DLCO (corrected/adjusted for hemoglobin), FEV1, and FVC <50% predicted. ii. For patients unable to perform pulmonary function tests (PFTs) due to age or developmental delay: Oxygen saturation <92% on room air.

iii. On supplemental oxygen. c. Renal: i. Estimated creatinine clearance <60 mL/minute/1.73m2 (estimated per institutional practice).

ii. Dialysis dependent d. Hepatic: i. Conjugated bilirubin > 2x upper limit of normal for age (ULN, unless attributable to Gilbert's syndrome), or ii. AST or ALT > 4x ULN for age, or iii. Fulminant liver failure or cirrhosis 7. Iron overload - This exclusion criterion only applies to patients who are considered at risk for hepatic or cardiac iron overload. Therefore, not all patients enrolled on this protocol will undergo formal hepatic or cardiac iron assessment.

1. For patients ≥ 18 years with a history of significant transfusions defined as ≥8 packed red blood cell transfusions per year for ≥1 year or have received ≥20 packed red blood cell transfusions (lifetime cumulative) will require formal hepatic and cardiac iron measurement. In addition, patients with a prior history of hepatic or cardiac iron overload will also require formal assessment for iron overload. Patients are excluded if:

i. Hepatic iron content ≥ 8 mg Fe/g dry weight by liver MRI using a validated methodology (such as T2* MRI or ferriscan) or liver biopsy per institutional practice.

ii. Cardiac iron content < 25 msec by cardiac T2* MRI. b. For patients < 18 years old with a history of significant transfusions defined as ≥8 packed red blood cell transfusions per year for ≥1 year or have received ≥20 packed red blood cell transfusions (lifetime cumulative) will require formal hepatic iron measurement. In addition, patients with a prior history of hepatic iron overload will also require formal assessment for iron overload. Patients are excluded if: i. Hepatic iron content ≥ 8 mg Fe/g dry weight by liver MRI using a validated methodology (such as T2* MRI or ferriscan) or liver biopsy per institutional practice.

8. Uncontrolled bacterial infection within 1 week of study enrollment. Uncontrolled is defined as currently taking medication with no clinical improvement or progression on adequate medical treatment.

9. Uncontrolled viral or fungal infection within 30 days of study enrollment. Uncontrolled is defined as currently taking medication with no clinical improvement or progression on adequate medical treatment.

10. Positive for HIV (human immunodeficiency virus). 11. Presence of clinically significant anti-donor HLA-antibodies per institutional practice.

12. Prior solid organ transplant. 13. Patients with prior malignancies except resected non-melanoma skin cancer or treated cervical carcinoma in situ.

14. Demonstrated lack of compliance with prior medical care as determined by referring physician.

15. Females who are pregnant or breast-feeding. 16. Known hypersensitivity to treosulfan or fludarabine. Known life-threatening reaction (i.e. anaphylaxis) to Thymoglobulin that would prohibit use for the patient as this study requires use of the Thymoglobulin preparation of anti-thymocyte globulin (ATG).