Fludarabine Based RIC for Bone Marrow Failure Syndromes

Sponsor

Children's Hospital of Philadelphia (Other)

Overall Status

Recruiting

CT.gov ID

NCT02928991

Collaborator

(none)

Enrollment

Location

Arms

104

Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Bone Marrow Failure Syndromes	Other: MRD-BMT with Fludarabine-based RIC for Acquired AA Other: MRD-BMT with Fludarabine-based RIC for iBMF with trilineage aplasia Other: MRD-BMT with Fludarabine-based RIC for iBMF without trilineage aplasia	Early Phase 1

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

25 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Fludarabine-Based Conditioning for Matched Related Donor Bone Marrow Transplantation in Patients With Bone Marrow Failure Syndromes

Study Start Date :

Apr 1, 2015

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Acquired Aplastic Anemia (AA) Patients with severe or very severe acquired aplastic anemia (AA). Patients will receive a matched related donor bone marrow transplant following reduced intensity conditioning (RIC) including thymoglobulin (ATG), fludarabine and dose-reduced cyclophosphamide.	Other: MRD-BMT with Fludarabine-based RIC for Acquired AA Fludarabine: Dose: 30mg/m2/day (<10kg will receive 1mg/kg/day) Days: -7, -6, -5, -4, -3 Cyclophosphamide: Dose: 60mg/kg/day Days: -5, -4 Thymoglobulin: Dose: 3mg/kg/day Days: -4, -3, -2 Bone marrow infusion: Day 0
Experimental: Inherited Bone Marrow Failure Syndrome + Trilineage Aplasia Patients with inherited bone marrow failure (iBMF) syndromes with trilineage aplasia includes those with diagnoses of Fanconi Anemia, Dyskeratosis Congenita, and related conditions. Patients will receive a matched related donor bone marrow transplant following conditioning with fludarabine, cyclophosphamide, thymoglobulin.	Other: MRD-BMT with Fludarabine-based RIC for iBMF with trilineage aplasia Fludarabine: Dose: 30mg/m2/day (<10kg will receive 1mg/kg/day) Days: -7, -6, -5, -4, -3 Cyclophosphamide: Dose: 10 mg/kg/day Days: -6, -5, -4, -3 Thymoglobulin: Dose: 3mg/kg/day Days: -4, -3, -2 Bone marrow infusion: Day 0
Experimental: Inherited Bone Marrow Failure Syndrome no Trilineage Aplasia Patients with inherited bone marrow failure (iBMF) syndromes without trilineage aplasia includes those with diagnoses of Severe Congenital Neutropenia, Diamond-Blackfan Anemia, and related conditions. Patients will receive a matched related donor bone marrow transplant following conditioning with thymoglobulin, busulfan and fludarabine.	Other: MRD-BMT with Fludarabine-based RIC for iBMF without trilineage aplasia Fludarabine: Dose: 30mg/m2/day (<10kg will receive 1mg/kg/day) Days: -6, -5, -4, -3, -2 Busulfan: Dose: every 6 hours for a total of 12 doses with dosing adjustments to achieve a steady state concentration of 900-1200ng/mL OR daily for a total of 3 doses targeting AUC 3600-6000 (micromole/liter)*minute Days: -7, -6, -5, -4 Thymoglobulin: Dose: 3mg/kg/day Days: -10, -9, -8 Bone marrow infusion: Day 0

Arm

Intervention/Treatment

Experimental: Acquired Aplastic Anemia (AA)

Patients with severe or very severe acquired aplastic anemia (AA). Patients will receive a matched related donor bone marrow transplant following reduced intensity conditioning (RIC) including thymoglobulin (ATG), fludarabine and dose-reduced cyclophosphamide.

Other: MRD-BMT with Fludarabine-based RIC for Acquired AA

Fludarabine: Dose: 30mg/m2/day (<10kg will receive 1mg/kg/day) Days: -7, -6, -5, -4, -3 Cyclophosphamide: Dose: 60mg/kg/day Days: -5, -4 Thymoglobulin: Dose: 3mg/kg/day Days: -4, -3, -2 Bone marrow infusion: Day 0

Experimental: Inherited Bone Marrow Failure Syndrome + Trilineage Aplasia

Patients with inherited bone marrow failure (iBMF) syndromes with trilineage aplasia includes those with diagnoses of Fanconi Anemia, Dyskeratosis Congenita, and related conditions. Patients will receive a matched related donor bone marrow transplant following conditioning with fludarabine, cyclophosphamide, thymoglobulin.

Other: MRD-BMT with Fludarabine-based RIC for iBMF with trilineage aplasia

Fludarabine: Dose: 30mg/m2/day (<10kg will receive 1mg/kg/day) Days: -7, -6, -5, -4, -3 Cyclophosphamide: Dose: 10 mg/kg/day Days: -6, -5, -4, -3 Thymoglobulin: Dose: 3mg/kg/day Days: -4, -3, -2 Bone marrow infusion: Day 0

Experimental: Inherited Bone Marrow Failure Syndrome no Trilineage Aplasia

Patients with inherited bone marrow failure (iBMF) syndromes without trilineage aplasia includes those with diagnoses of Severe Congenital Neutropenia, Diamond-Blackfan Anemia, and related conditions. Patients will receive a matched related donor bone marrow transplant following conditioning with thymoglobulin, busulfan and fludarabine.

Other: MRD-BMT with Fludarabine-based RIC for iBMF without trilineage aplasia

Fludarabine: Dose: 30mg/m2/day (<10kg will receive 1mg/kg/day) Days: -6, -5, -4, -3, -2 Busulfan: Dose: every 6 hours for a total of 12 doses with dosing adjustments to achieve a steady state concentration of 900-1200ng/mL OR daily for a total of 3 doses targeting AUC 3600-6000 (micromole/liter)*minute Days: -7, -6, -5, -4 Thymoglobulin: Dose: 3mg/kg/day Days: -10, -9, -8 Bone marrow infusion: Day 0

Outcome Measures

Primary Outcome Measures

Rate of graft failure [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 [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 [Up to 100 days post transplant]

Secondary Outcome Measures

Rate of overall survival [Up to 1 year post transplant]
Rate of disease free survival [Up to 1 year post transplant]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 22 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Patients 0-22 years with acquired aplastic anemia or a diagnosed inherited bone marrow failure syndrome, and a fully Human leukocyte antigen (HLA)-matched (10/10) related donor.

Inclusion Criteria:

Patient:

Ages 0-22 years at time of enrollment
Diseases:

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
Congenital Dyserythropoietic/Sideroblastic Anemias
Congenital Amegakaryocytic Thrombocytopenia
Shwachman-Diamond Syndrome

Lansky or Karnofsky performance >60
HLA matched related donor available.
No active untreated infection
Females of childbearing potential must have negative pregnancy test.

Organ Function:

Serum creatinine <1.5xupper limit of normal for age Hepatic: Transaminases <5x normal
Cardiac shortening fraction >27%
Bilirubin <2.5x normal (unless elevation due to Gilberts disease).

Donor Selection Criteria:

Donor selection will comply with U.S. Food and Drug Administration's Code of Federal Regulations
Fully HLA-matched related donor.
Donor must be at least 6 months of age
Donor suitable for bone marrow collection and meets eligibility for donation, including fulfilling infectious disease criteria as per SOP, including HIV, Hepatitis B, Hepatitis C Polymerase chain reaction (PCR) negative.
If subject has confirmed iBMF syndrome, donor must be evaluated for this disorder and testing must be negative
Children's Hospital of Philadelphia (CHOP) bone marrow transplant (BMT) procedures apply for determining donor eligibility, including donor screening and testing for relevant communicable disease agents and diseases.
Donor evaluation and collection procedure as per CHOP Standard Operating Procedures (SOP)

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