HSCT for Patients With Fanconi Anemia Using Risk-Adjusted Chemotherapy

NCT02143830 | Recruiting Phase 2 DMC

• 1 other identifier: 2013-7501
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 3

Brief Summary

The purpose of this study is to determine whether the use of lower doses of busulfan and the elimination of cyclosporine will further reduce transplant-related side effects for patients with Fanconi Anemia (FA). Patients will undergo a transplant utilizing mis-matched related or matched unrelated donors following a preparative regimen of busulfan, fludarabine, anti-thymocyte globulin and cyclophosphamide.

Conditions

Fanconi Anemia; Severe Marrow Failure; Myelodysplastic Syndrome (MDS); Acute Myelogenous Leukemia (AML)

Keywords

marrow aplasia; cytopenia; myelodysplasia; AML; bone marrow transplant; cytoreductive regimen; T-cell reduction

Outcome Measures

Primary Outcomes (1)

• Graft Failure or Rejection

  Primary non-engraftment is diagnosed when the patient fails to achieve an ANC \>=500/mm3 at any time in the first 28 days post-transplant. If (1) after achievement of an absolute neutrophil count (ANC) \>=500/mm3, the ANC declines to \<500/mm3 for more than 3 consecutive days in the absence of relapse, or, (2) there is absence of donor cells in the marrow and/or blood as demonstrated by chimerism assay in the absence of relapse, a diagnosis of secondary graft failure is made. The patient is not evaluable for graft failure or rejection if recurrence of host MDS is detected concurrently.

  5 years

Secondary Outcomes (1)

• Post-transplant severe morbidity and mortality

  2 years post-transplant

Other Outcomes (3)

• Graft Versus Host Disease

  One year

• Leukemic Relapse

  5 years

• Secondary malignancies

  5 years

Study Arms (3)

Arm A: Good Risk Patients

EXPERIMENTAL

Patients 18 years old or younger with marrow aplasia or single lineage cytopenias will be receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days), as used in our most current study that led to \> 90% survival rates . Busulfan pharmacokinetics will not be used. All patients will receive rabbit ATG (4 doses x 4 days) prior to and granulocyte-colony stimulating factor (G-CSF) after transplant to promote engraftment. Cyclosporine will not be used for GVHD prophylaxis. The source of the stem cells for all patients will be peripheral blood stem cells mobilized by treatment of the donor with G-CSF. T-cell depletion will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). Enrollment on this arm will include up to 50 patients.

Drug: Busulfan; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: rabbit ATG; Drug: G-CSF; Biological: Peripheral blood stem cell

Arm B: Intermediate Risk Patients

EXPERIMENTAL

Patients 18 years old or younger with MDS or AML will receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days). Busulfan pharmacokinetics will be used in this arm, as the dose of busulfan is higher. All patients will receive rabbit ATG (thymoglobulin) (4 doses x 4 days) prior to and G-CSF post transplant to promote engraftment. Cyclosporine will not be used for prophylaxis against GVHD. The source of the stem cells for all patients will be peripheral blood stem cells induced and mobilized by treatment of the donor. T-cell will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). The maximum number of patients enrolled in this arm will be 10.

Drug: Busulfan; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: rabbit ATG; Drug: G-CSF; Biological: Peripheral blood stem cell

Arm C: High Risk Patients

EXPERIMENTAL

Patients 19 years old or older with marrow aplasia or MDS or AML will receive intravenous busulfan (4 doses x 2 days), cyclophosphamide (4 doses x 4 days) and fludarabine (4 doses x 4 days). In this study, we will test whether outcomes can be improved, yet engraftment maintained, with a slightly reduced dose of busulfan. Patients will receive rabbit ATG (4 doses x 4 days) prior to and G-CSF post transplant to promote engraftment. Cyclosporine will not be used for GVHD prophylaxis. The source of the stem cells will be peripheral blood stem cells collected from donors treated with G-CSF. T-cell depletion will be performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). The maximum number of patients enrolled will be 10.

Drug: Busulfan; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: rabbit ATG; Drug: G-CSF; Biological: Peripheral blood stem cell

Interventions

Busulfan DRUG

A standard dose of busulfan, associated with excellent outcomes in our previous trial will be used for young patients with marrow aplasia (arm A). A higher dose of busulfan will be used in younger patients with MDS and AML (arm B) to maximize disease control. A lower dose of busulfan will be used in older patients (arm C) to minimize toxicity.

Also known as: Myleran, Busulfex IV

Arm A: Good Risk Patients; Arm B: Intermediate Risk Patients; Arm C: High Risk Patients

Cyclophosphamide DRUG

Arms A, B and C - Cytoxan will be given as a 1-2 hour infusion for 4 days. The dose will be adjusted according to patients ideal body weight for obese patients.

Also known as: Cytoxan

Arm A: Good Risk Patients; Arm B: Intermediate Risk Patients; Arm C: High Risk Patients

Fludarabine DRUG

Arms A, B and C - Fludarabine will be given IV over 30 minutes daily for 4 days. The dose will be adjusted according to renal function according to Institutional guidelines.

Also known as: Fludara

Arm A: Good Risk Patients; Arm B: Intermediate Risk Patients; Arm C: High Risk Patients

rabbit ATG DRUG

Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment.

Also known as: thymoglobulin

Arm A: Good Risk Patients; Arm B: Intermediate Risk Patients; Arm C: High Risk Patients

G-CSF DRUG

All patients will also receive G-CSF post-transplant to foster engraftment.

Also known as: Granulocyte colony-stimulating factor, filgrastim, neupogen

Arm A: Good Risk Patients; Arm B: Intermediate Risk Patients; Arm C: High Risk Patients

Peripheral blood stem cell BIOLOGICAL

The source of stem cells for all patients will be peripheral blood stem cells (PBSC) induced and mobilized by treatment of the donor with G-CSF for 4-6 days. T-cell depletion will be uniformly performed by positive CD34 selection with the use of the Miltenyi system (CliniMACS device).

Arm A: Good Risk Patients; Arm B: Intermediate Risk Patients; Arm C: High Risk Patients

Eligibility Criteria

• Age: 3 Months+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have a diagnosis of Fanconi anemia
• Patients must have one of the following hematologic diagnoses:
• Severe Aplastic Anemia (SAA), with bone marrow cellularity of \<25% OR Severe Isolated Single Lineage Cytopenia and at least one of the following features:
• Platelet count \<20 x 109/L or platelet transfusion dependence\*
• ANC \<1000 x 109/L
• Hgb \<8 gm/dl or red cell transfusion dependence\*
• Myelodysplastic Syndrome (MDS) (based on WHO or IPSS Classification
• Acute Myelogenous Leukemia (untreated, in remission or with refractory or relapsed disease)
• Donors will be either human leukocyte antigen (HLA) compatible unrelated or HLA-genotypically matched related donors (no fully matched sibling donor).
• Patients and donors may be of either gender or any ethnic background.
• Patients must have a Karnofsky adult, or Lansky pediatric performance scale status \> 70%.
• Patients must have adequate physical function measured by:
• Cardiac: asymptomatic or if symptomatic then 1) left ventricular ejection fraction (LVEF) at rest must be \> 50% and must improve with exercise or 2) Shortening Fraction \> 29%
• Hepatic: \< 5 x upper limit of normal (ULN) alanine transaminase (ALT) and \< 2.0 mg/dl total serum bilirubin.
• Renal: serum creatinine \<1.5 mg/dl or if serum creatinine is outside the normal range, then CrCl \> 50 ml/min/1.73 m2

You may not qualify if:

• Active CNS leukemia
• Female patients who are pregnant (positive serum or urine HCG) or breast-feeding.
• Active uncontrolled viral, bacterial or fungal infection
• Patient seropositive for HIV-I/II; HTLV -I/II

Sponsors & Collaborators

• Children's Hospital Medical Center, Cincinnati: lead
• Memorial Sloan Kettering Cancer Center: collaborator
• Fred Hutchinson Cancer Center: collaborator

Study Sites (3)

Memorial Sloan Kettering Cancer Center

New York, New York, 10174, United States

COMPLETED

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

RECRUITING

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

RECRUITING

MeSH Terms

Conditions

Fanconi Anemia; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Cytopenia; Anemia, Refractory, with Excess of Blasts

Interventions

Busulfan; Cyclophosphamide; fludarabine; fludarabine phosphate; thymoglobulin; Granulocyte Colony-Stimulating Factor; Filgrastim; Peripheral Blood Stem Cell Transplantation

Condition Hierarchy (Ancestors)

Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Bone Marrow Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Anemia, Refractory

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative

Study Officials

• Parinda Mehta, MD

  CCHMC

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jamie Wilhelm

CONTACT

(513)803-1102; Jamie.Wilhelm@cchmc.org

Sara Loveless, RN

CONTACT

(513)803-7656; Sara.Loveless@cchmc.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 28, 2014
• First Posted: May 21, 2014
• Study Start: April 1, 2014
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2028
• Last Updated: November 12, 2025

Record last verified: 2025-11

Locations

US (3)