Stem Cell Transplant for Bone Marrow Failure Syndromes

Phase 2

Completed

Conditions: Diamond-Blackfan Anemia
Kostmann's Neutropenia
Shwachman-Diamond Syndrome

Interventions: Procedure: Stem cell transplant
Drug: Fludarabine monophosphate
Procedure: Total lymphoid irradiation
Drug: Busulfan
Biological: anti-thymocyte globulin

Brief Summary: The researchers hypothesize that it will be possible to perform unrelated bone marrow or cord blood transplants in a safer manner by using less intensive therapy yet still achieve an acceptable level of donor cell engraftment for non-malignant congenital bone marrow failure disorders.

Detailed Description: Prior to transplantation, subjects will receive the drugs busulfan (orally or through the catheter), as well as fludarabine and anti-thymocyte globulin (ATG) via the catheter. Busulfan, fludarabine and ATG will be given with Total Lymphoid Irradiation (TLI) to help the new donor bone marrow take and grow after transplantation.

Those patients receiving donor marrow will have the T cells (a type of white blood cell in the donor marrow) removed to lower the risk that the new marrow will react to their body, a condition called Graft-Versus-Host-Disease (GVHD). After bone marrow transplantation, subjects will receive drugs to help prevent GVHD, including cyclosporin and mycophenolate mofetil (MMF).

Blood samples are taken at day 28, day 60, day 100, 1 year and as required by medical status yearly for five years after transplant to evaluate how well the new marrow is growing. A bone marrow biopsy is required at day 21, at day 100 and 1 year.

Recruitment & Eligibility

Inclusion Criteria

Patients eligible for transplantation under this protocol will be <35 years of age, and will be diagnosed with:
- a bone marrow failure syndrome unresponsive to available therapy, including but not limited to Diamond-Blackfan anemia, Shwachman Diamond syndrome or Kostmann's neutropenia but exclusive of aplastic anemia.
Diamond Blackfan Anemia:
- Patients must show evidence of steroid resistance requiring equivalent of >6 transfusions yearly despite steroid therapy.
- Evidence of developing aplasia or myelodysplasia will also be criteria for transplantation.
Kostmann's Neutropenia, Shwachman-Diamond syndrome:
- Patients must have been previously diagnosed as having a clinical picture characteristic of Shwachman-Diamond syndrome (exocrine pancreatic insufficiency, growth retardation, metaphyseal dysostosis, neutropenia), or must have a bone marrow aspirate consistent with Kostmann's neutropenia, with no evidence of acute leukemia.
- Patients must have failed therapy with granulocyte-colony stimulating factor (G-CSF), as determined by an inability to maintain an absolute neutrophil count (ANC) >750 cells/ml(3), or manifesting recurrent infections despite G-CSF administration resulting in life threatening infections or repeated hospitalizations (<4 /year).

Exclusion Criteria

Patients >35 years of age
Karnofsky score <70%
Hepatic dysfunction as determined by bilirubin >3.0, ALT >150, or active hepatitis
Pulmonary function tests with forced volume vital capacity (FVC) and forced expiratory volume (FEV) <70%; O2 saturation <94%
Renal dysfunction with glomerular filtration rate (GFR) <30% of predicted.
Cardiac compromise, with left ejection fraction <45%.
Severe, stable neurologic impairment.
Human immunodeficiency virus (HIV) positivity.
Pregnant or lactating females

Arm && Interventions

Group	Intervention	Description
Bone Marrow Failure Disorders	Stem cell transplant	Patients with Diamond-Blackfan Anemia, Kostmann's Neutropenia, Shwachman-Diamond Syndrome
Bone Marrow Failure Disorders	Fludarabine monophosphate	Patients with Diamond-Blackfan Anemia, Kostmann's Neutropenia, Shwachman-Diamond Syndrome
Bone Marrow Failure Disorders	Total lymphoid irradiation	Patients with Diamond-Blackfan Anemia, Kostmann's Neutropenia, Shwachman-Diamond Syndrome
Bone Marrow Failure Disorders	Busulfan	Patients with Diamond-Blackfan Anemia, Kostmann's Neutropenia, Shwachman-Diamond Syndrome
Bone Marrow Failure Disorders	anti-thymocyte globulin	Patients with Diamond-Blackfan Anemia, Kostmann's Neutropenia, Shwachman-Diamond Syndrome

Primary Outcome Measures

Name	Time	Method
Number of Patients Alive (Survival) at 2 Years	2 years	Calculated from day 1 of transplant to last contact.

Secondary Outcome Measures

Name	Time	Method
Number of Patients Alive at Three Years (Survival)	3 years	Number of subjects who survived 3 years post-transplant.
Number of Patients With Grade 2-4 Acute Graft Versus Host Disease	100 Days	Number of patients with Grade 2, 3 and 4 Acute (normally observed within the first 100 days) Graft Versus Host Disease. Acute GVHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of 1 to a high of 4. Patients with grade IV GVHD usually have a poor prognosis. Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening.
Number of Patients With Chronic Graft Versus Host Disease	2 years	Number of patients who exhibited chronic (normally occurs after 100 days) Graft Versus Host Disease at 2 years post transplant. Chronic graft-versus-host-disease, over its long-term course, can also cause damage to the connective tissue and exocrine glands.
Number of Patients With Disease Recurrence	2 years	Number of patients who exhibited disease recurrence at 2 years.
Number of Patients With Succcessful Engraftment After Transplantation	42 Days	Number of patients who received non-genotypic identical marrow or cord blood cells using a "non-myeloablative" preparative regimen and exhibited engraftment at Day 42.