Fanconi Anemia, Severe Marrow Failure, Myelodysplastic Syndrome (MDS), Acute Myelogenous Leukemia (AML)
Conditions
Keywords
marrow aplasia, cytopenia, myelodysplasia, AML, bone marrow transplant, cytoreductive regimen, T-cell reduction
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.
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.
Interventions
DRUGBusulfan
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.
DRUGCyclophosphamide
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.
DRUGFludarabine
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.
DRUGrabbit ATG
Arms A, B and C - 4 doses will be given prior to transplant to promote engraftment.
DRUGG-CSF
All patients will also receive G-CSF post-transplant to foster engraftment.
BIOLOGICALPeripheral 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).
Sponsors
Memorial Sloan Kettering Cancer Center
Fred Hutchinson Cancer Center
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Graft Failure or Rejection | 5 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Post-transplant severe morbidity and mortality | 2 years post-transplant | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Graft Versus Host Disease | One year | 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. |
| Leukemic Relapse | 5 years | For patients with MDS or AML, relapse will be analyzed as to type and genetic origin of the MDS/leukemic cells. |
| Secondary malignancies | 5 years | 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. |
Countries
United States
Contacts
Primary ContactJamie Wilhelm
Backup ContactSara Loveless, RN
Outcome results
None listed