HSCT for Patients With Fanconi Anemia Using Risk-Adjusted Chemotherapy (RAFA)

A Phase II Trial of HSCT for the Treatment of Patients With Fanconi Anemia Lacking a Genotypically Identical Donor, Using a Risk-Adjusted Chemotherapy Only Cytoreduction With Busulfan, Cyclophosphamide and Fludarabine

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.

Study Overview

• Status: Recruiting
• Conditions: Fanconi Anemia; Myelodysplastic Syndrome (MDS); Acute Myelogenous Leukemia (AML); Severe Marrow Failure
• Intervention / Treatment: Drug: Busulfan; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: G-CSF; Drug: rabbit ATG; Biological: Peripheral blood stem cell

Detailed Description

The trial proposed is a three arm phase II treatment protocol designed to investigate the safety and efficacy of risk-adjusted chemotherapy-based cytoreductive regimen plus a CD34+ selected T-cell depleted peripheral blood stem cell (PBSC) stem cell transplant for the treatment of patients with Fanconi anemia and severe hematologic disease. Candidates for this trial will include patients with Fanconi anemia presenting with severe marrow failure (transfusion dependent) or myelodysplastic syndrome, or acute myelogenous leukemia for whom an allogeneic stem cell transplant is indicated.

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jamie Wilhelm; Phone Number: (513)803-1102; Email: Jamie.Wilhelm@cchmc.org
• Study Contact Backup: Name: Sara Loveless, RN; Phone Number: (513)803-7656; Email: Sara.Loveless@cchmc.org

Study Locations

• United States
  • New York
    • New York, New York, United States, 10174
      • Completed
      • Memorial Sloan Kettering Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Principal Investigator: Parinda Mehta, MD
  • Washington
    • Seattle, Washington, United States, 98109
      • Recruiting
      • Fred Hutchinson Cancer Research Center
      • Contact: Sheri Ballard; Phone Number: 206-667-4222; Email: sballard@fredhutch.org
      • Principal Investigator: K. Scott Baker, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have a diagnosis of Fanconi anemia

• Patients must have one of the following hematologic diagnoses:

  1. Severe Aplastic Anemia (SAA), with bone marrow cellularity of <25% OR Severe Isolated Single Lineage Cytopenia and at least one of the following features:

     1. Platelet count <20 x 109/L or platelet transfusion dependence*
     2. ANC <1000 x 109/L
     3. Hgb <8 gm/dl or red cell transfusion dependence*
  2. Myelodysplastic Syndrome (MDS) (based on WHO or IPSS Classification
  3. 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:

  1. 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%
  2. Hepatic: < 5 x upper limit of normal (ULN) alanine transaminase (ALT) and < 2.0 mg/dl total serum bilirubin.
  3. Renal: serum creatinine <1.5 mg/dl or if serum creatinine is outside the normal range, then CrCl > 50 ml/min/1.73 m2
  4. Pulmonary: asymptomatic or if symptomatic, DLCO > 50% of predicted
• Each patient must be willing to participate as a research subject and must sign an informed consent form.
• Female patients and donors must not be pregnant or breastfeeding at the time of signing consent. Women must be willing to undergo a pregnancy test prior to transplant and avoid becoming pregnant while on study.

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Good Risk Patients; 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; 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.; Other Names: Myleran; Busulfex IV; Drug: Fludarabine; 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.; Other Names: Fludara; Drug: Cyclophosphamide; 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.; Other Names: Cytoxan; Drug: G-CSF; All patients will also receive G-CSF post-transplant to foster engraftment.; Other Names: filgrastim; neupogen; Granulocyte colony-stimulating factor; Drug: rabbit ATG; Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment.; Other Names: thymoglobulin; Biological: Peripheral blood stem cell; 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).
Experimental: Arm B: Intermediate Risk Patients; 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; 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.; Other Names: Myleran; Busulfex IV; Drug: Fludarabine; 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.; Other Names: Fludara; Drug: Cyclophosphamide; 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.; Other Names: Cytoxan; Drug: G-CSF; All patients will also receive G-CSF post-transplant to foster engraftment.; Other Names: filgrastim; neupogen; Granulocyte colony-stimulating factor; Drug: rabbit ATG; Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment.; Other Names: thymoglobulin; Biological: Peripheral blood stem cell; 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).
Experimental: Arm C: High Risk Patients; 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; 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.; Other Names: Myleran; Busulfex IV; Drug: Fludarabine; 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.; Other Names: Fludara; Drug: Cyclophosphamide; 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.; Other Names: Cytoxan; Drug: G-CSF; All patients will also receive G-CSF post-transplant to foster engraftment.; Other Names: filgrastim; neupogen; Granulocyte colony-stimulating factor; Drug: rabbit ATG; Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment.; Other Names: thymoglobulin; Biological: Peripheral blood stem cell; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-transplant severe morbidity and mortality	The occurrence of severe post-transplant regimen-related severe morbidity (grade IV toxicity) and/or mortality will be the second endpoint of this study. In the context of the agents or agent-combination used for cytoreduction used, particular attention will be given to toxicity involving (1) the liver, (2) the lungs, (3) the oral mucosa and gastrointestinal tract, and (4) the central nervous system.	2 years post-transplant

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Graft Versus Host Disease	Patients will be observed for acute and/or chronic graft versus host disease (GvHD). Standard clinical criteria for the grading of acute and chronic GvHD will be done according to IBMTR guidelines.	One year
Leukemic Relapse	For patients with MDS or AML, relapse will be analyzed as to type and genetic origin of the MDS/leukemic cells.	5 years
Secondary malignancies	Patients will be followed for 5 years through annual contact with their treatment center in order to track the risk of developing a secondary malignancy.	5 years

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: Memorial Sloan Kettering Cancer Center; Fred Hutchinson Cancer Center
• Investigators: Principal Investigator: Parinda Mehta, MD, CCHMC

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: April 28, 2014
• First Submitted That Met QC Criteria: May 16, 2014
• First Posted (Estimated): May 21, 2014

Study Record Updates

• Last Update Posted (Estimated): November 12, 2025
• Last Update Submitted That Met QC Criteria: November 10, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: AML; myelodysplasia; bone marrow transplant; cytopenia; marrow aplasia; cytoreductive regimen; T-cell reduction
• Additional Relevant MeSH Terms: Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Neoplasms; Genetic Diseases, Inborn; Metabolic Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Anemia; Leukemia; Anemia, Refractory; DNA Repair-Deficiency Disorders; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Hemic and Lymphatic Diseases; Cytopenia; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Anemia, Refractory, with Excess of Blasts; Fanconi Anemia; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Sulfur Compounds; Organic Chemicals; Therapeutics; Surgical Procedures, Operative; Hydrocarbons, Acyclic; Hydrocarbons; Biological Factors; Carbohydrates; Transplantation; Alkanes; Alcohols; Butylene Glycols; Glycols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Sulfonic Acids; Sulfur Acids; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Intercellular Signaling Peptides and Proteins; Glycoproteins; Glycoconjugates; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Busulfan; fludarabine; fludarabine phosphate; Granulocyte Colony-Stimulating Factor; Filgrastim; thymoglobulin; Peripheral Blood Stem Cell Transplantation
• Other Study ID Numbers: 2013-7501