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

Cincinnati Children's Hospital Medical Center

Status and phase: Enrolling; Phase 2

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

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

Study type: Interventional

Funder types: Other

Identifiers

NCT02143830

2013-7501

Details and patient eligibility

About

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.

Full 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.

Enrollment: 70 estimated patients

Sex: All

Ages: 3+ months old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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70 participants in 3 patient groups

Arm A: Good Risk Patients

Experimental group

Description:

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.

Treatment:

Drug: G-CSF

Drug: Fludarabine

Biological: Peripheral blood stem cell

Drug: Cyclophosphamide

Drug: rabbit ATG

Drug: Busulfan

Arm B: Intermediate Risk Patients

Experimental group

Description:

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.

Treatment:

Drug: G-CSF

Drug: Fludarabine

Biological: Peripheral blood stem cell

Drug: Cyclophosphamide

Drug: rabbit ATG

Drug: Busulfan

Arm C: High Risk Patients

Experimental group

Description:

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.

Treatment:

Drug: G-CSF

Drug: Fludarabine

Biological: Peripheral blood stem cell

Drug: Cyclophosphamide

Drug: rabbit ATG

Drug: Busulfan