Fludarabine-Based Conditioning for Matched Related Donor Bone Marrow Transplantation in Patients With Bone Marrow Failure Syndromes
Overview
- Phase
- Early Phase 1
- Intervention
- Not specified
- Conditions
- Bone Marrow Failure Syndromes
- Sponsor
- Children's Hospital of Philadelphia
- Enrollment
- 25
- Locations
- 1
- Primary Endpoint
- Rate of graft failure
- Status
- Recruiting
- Last Updated
- 11 months ago
Overview
Brief Summary
This is a pilot study to determine whether fludarabine-based reduced intensity conditioning (RIC) regimens facilitate successful donor engraftment of patients with acquired aplastic anemia (AA) and Inherited bone marrow failure (iBMF) syndromes undergoing Matched related donor bone marrow transplant (MRD-BMT).
Detailed Description
Acquired AA patients will receive the experimental regimen of fludarabine with dose-reduced cyclophosphamide, with results in this prospective single arm experimental group evaluated in the context of our institutional historical experience using HD Cy regimens as well as published outcomes using both fludarabine and high-dose cyclophosphamide-based regimens for MRD-BMT in aplastic anemia. iBMF syndrome patients will receive one of two fludarabine-containing regimens based on disease characteristics, and our outcomes will be compared to previously published data using a variety of regimens. Graft versus host disease (GvHD) prophylaxis will consist of cyclosporine/tacrolimus alone for patients with acquired AA or cyclosporine/tacrolimus plus mycophenolate for patients with iBMF syndromes. For both acquired AA and iBMF syndrome patients, donor chimerism will be assessed at scheduled intervals following BMT and will be used to define patients with full donor or mixed chimerism for comparisons of survival, graft failure, cytogenetic, GvHD, and immune reconstitution outcomes.
Investigators
Timothy Olson
Assistant Professor
Children's Hospital of Philadelphia
Eligibility Criteria
Inclusion Criteria
- •Ages 0-22 years at time of enrollment
- •Patients with severe or very severe acquired AA, defined by:
- •Bone marrow biopsy demonstrating cellularity of \<25% (at least 2 weeks from last dose of G-CSF), in addition to 2 of the following: absolute neutrophil count (ANC) \<500/µL, platelets \< 20,000/µL and absolute reticulocytes \<40,000/µL
- •Negative evaluation for inherited bone marrow failure conditions and negative evaluation for dysplasia or cytogenetic abnormalities associated with myelodysplastic syndromes
- •Patients with concurrent paroxysmal nocturnal hemoglobinuria (PNH) clones are eligible, as long as they meet criteria for severe or very severe aplastic anemia as defined above
- •Patients with clinically diagnosed and/or genetically proven iBMF syndromes, resulting in chronic red blood cell or platelet-transfusion dependence and/or an absolute neutrophil count \<500/µL. These disorders include, but are not limited to:
- •Fanconi Anemia
- •Dyskeratosis Congenita
- •Severe Congenital Neutropenia
- •Diamond-Blackfan Anemia
Exclusion Criteria
- •Uncontrolled bacterial, viral or fungal infections
- •HLA matched related donor unable to donate bone marrow.
- •No eligible fully HLA-matched related donor
- •Pregnant females
- •Patients with a clinical diagnosis of Myelodysplastic syndrome (MDS) defined by combination of bone marrow dysplasia and classic cytogenetic lesion (Monosomy 7, Trisomy 8 eg.), with or without excess blasts.
- •Patients with PNH without underlying bone marrow aplasia
Outcomes
Primary Outcomes
Rate of graft failure
Time Frame: Up to 1 year post transplant
Combined rate of primary and secondary graft failure. Primary graft failure is defined as no evidence of neutrophil engraftment by day +28 after stem cell infusion. Secondary graft failure is defined as an ANC\<100 for \>7-10 days after initial engraftment occurs and is confirmed by hypocellular bone marrow biopsy and donor engraftment \<20%.
Time to neutrophil engraftment
Time Frame: Up to 1 year post transplant
The time from the day of transplant until neutrophil engraftment, which is defined as the first day of ANC \>500/ul for the first of 3 consecutive days.
Transplant-related mortality
Time Frame: Up to 100 days post transplant
Secondary Outcomes
- Rate of disease free survival(Up to 1 year post transplant)
- Rate of overall survival(Up to 1 year post transplant)