HSCT for Patients With Fanconi Anemia Using Risk-Adjusted Chemotherapy

Myelodysplastic Syndrome (MDS) Clinical Trial

— RAFA  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02143830
• Other study ID #: 2013-7501
• Status: Recruiting
• Phase: Phase 2
• Start date: April 2014
• Est. completion date: July 2026

Study information

• Verified date: January 2024
• Source: Children's Hospital Medical Center, Cincinnati
• Contact: Jamie Wilhelm
• Phone: (513)803-1102
• Email: Jamie.Wilhelm[@]cchmc.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 70
• Est. completion date: July 2026
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myelogenous Leukemia (AML)
• Anemia
• Fanconi Anemia
• Fanconi Syndrome
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome (MDS)
• Myelodysplastic Syndromes
• Preleukemia
• Severe Marrow Failure

Intervention

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.
• 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.
• 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.
• rabbit ATG
Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment.
• G-CSF
All patients will also receive G-CSF post-transplant to foster engraftment.

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).

Locations

Country	Name	City	State
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington

Sponsors (3)

Lead Sponsor	Collaborator
Children's Hospital Medical Center, Cincinnati	Fred Hutchinson Cancer Center, Memorial Sloan Kettering Cancer Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Primary	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	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