Stem Cell Transplant for Bone Marrow Failure Syndromes

• Sponsor: Masonic Cancer Center, University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT00176878
• Collaborator: (none)
• Enrollment: 10
• Location: 1
• Arm: 1
• Duration (Months): 105
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diamond-Blackfan Anemia; Kostmann's Neutropenia; Shwachman-Diamond Syndrome	Procedure: Stem cell transplant; Drug: Fludarabine monophosphate; Procedure: Total lymphoid irradiation; Drug: Busulfan; Biological: anti-thymocyte globulin	Phase 2/Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Bone Marrow Transplantation for Non-Malignant Congenital Bone Marrow Failure Disorders
• Study Start Date: Jun 1, 2000
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: Mar 1, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Bone Marrow Failure Disorders Patients with Diamond-Blackfan Anemia, Kostmann's Neutropenia, Shwachman-Diamond Syndrome

Procedure: Stem cell transplant; Stem cell transplant on Day 0 - healthy marrow from an unrelated individual. A minimum of 1.0 x 10^9/kg nucleated cells/kg ideal body weight will be collected with a goal of 2.0 x 10^9/kg.; Other Names: BMT ; Drug: Fludarabine monophosphate; fludarabine 175 mg/m^2 (total) on Days -6 through -3.; Other Names: Fludara ; Procedure: Total lymphoid irradiation; Dose 500 cGy radiation therapy to specific areas of the body; Other Names: TLI ; Drug: Busulfan; Busulfan 8 mg/kg (total) on Days - 8 and -7 (orally or through the catheter),; Other Names: Busulfex ; Biological: anti-thymocyte globulin; anti-thymocyte globulin (ATG) 15 mg/kg on days -2 and -1 via catheter; Other Names: ATG

Outcome Measures

Primary Outcome Measures

1. Number of Patients Alive (Survival) at 2 Years [2 years]

   Calculated from day 1 of transplant to last contact.

Secondary Outcome Measures

1. Number of Patients Alive at Three Years (Survival) [3 years]

   Number of subjects who survived 3 years post-transplant.

2. 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.

3. 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.

4. 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.

5. Number of Patients With Disease Recurrence [2 years]

   Number of patients who exhibited disease recurrence at 2 years.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 35 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Minnesota Medical Center	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• Masonic Cancer Center, University of Minnesota

Investigators

• Principal Investigator: Paul Orchard, MD, University of Minnesota Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT00176878
• Other Study ID Numbers: MT2000-18; 9504M09637; NCT00005895
• First Posted: Sep 15, 2005
• Last Update Posted: Dec 28, 2017
• Last Verified: Dec 1, 2017

• Keywords provided by Masonic Cancer Center, University of Minnesota: Stem cell transplant; T-cell depletion; TLI; bone marrow failure disorders
• Additional relevant MeSH terms: Shwachman-Diamond Syndrome; Neutropenia; Bone Marrow Failure Disorders; Pancytopenia; Anemia, Diamond-Blackfan; Syndrome; Fludarabine; Fludarabine phosphate; Busulfan; Antilymphocyte Serum

Study Results

Participant Flow

Arm/Group Title	Bone Marrow Failure Patients
Arm/Group Description	All patients with non-malignant, congenital bone marrow failure disorders and treated with stem cell transplant, chemotherapy (Busulfan, ATG, Fludarabine) and irradiation.
Period Title: Overall Study
STARTED	10
COMPLETED	10
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Bone Marrow Failure Patients
Arm/Group Description	All patients with non-malignant, congenital bone marrow failure disorders and treated with stem cell transplant, chemotherapy (Busulfan, ATG, Fludarabine) and irradiation.
Overall Participants	10
Age (Count of Participants)
<=18 years	10 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.8 (7.6)
Sex: Female, Male (Count of Participants)
Female	3 30%
Male	7 70%
Region of Enrollment (participants) [Number]
United States	10 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bone Marrow Failure Patients
Arm/Group Description	All patients with non-malignant, congenital bone marrow failure disorders and treated with stem cell transplant, chemotherapy (Busulfan, ATG, Fludarabine) and irradiation.
Measure Participants	10
Number [Participants]	6 60%

2. Secondary Outcome

Title	Number of Patients Alive at Three Years (Survival)
Description	Number of subjects who survived 3 years post-transplant.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bone Marrow Failure Patients
Arm/Group Description	All patients with non-malignant, congenital bone marrow failure disorders and treated with stem cell transplant, chemotherapy (Busulfan, ATG, Fludarabine) and irradiation.
Measure Participants	10
Number [Participants]	6 60%

3. Secondary Outcome

Title	Number of Patients With Succcessful Engraftment After Transplantation
Description	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.
Time Frame	42 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bone Marrow Failure Patients
Arm/Group Description	All patients with non-malignant, congenital bone marrow failure disorders and treated with stem cell transplant, chemotherapy (Busulfan, ATG, Fludarabine) and irradiation.
Measure Participants	10
Number [Participants]	10 100%

4. Secondary Outcome

Title	Number of Patients With Grade 2-4 Acute Graft Versus Host Disease
Description	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.
Time Frame	100 Days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bone Marrow Failure Patients
Arm/Group Description	All patients with non-malignant, congenital bone marrow failure disorders and treated with stem cell transplant, chemotherapy (Busulfan, ATG, Fludarabine) and irradiation.
Measure Participants	10
Number [Participants]	5 50%

5. Secondary Outcome

Title	Number of Patients With Chronic Graft Versus Host Disease
Description	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.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bone Marrow Failure Patients
Arm/Group Description	All patients with non-malignant, congenital bone marrow failure disorders and treated with stem cell transplant, chemotherapy (Busulfan, ATG, Fludarabine) and irradiation.
Measure Participants	10
Number [Participants]	3 30%

6. Secondary Outcome

Title	Number of Patients With Disease Recurrence
Description	Number of patients who exhibited disease recurrence at 2 years.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bone Marrow Failure Patients
Arm/Group Description	All patients with non-malignant, congenital bone marrow failure disorders and treated with stem cell transplant, chemotherapy (Busulfan, ATG, Fludarabine) and irradiation.
Measure Participants	10
Number [Participants]	0 0%

Adverse Events

Time Frame	Day 1 of study up through 1 year
Adverse Event Reporting Description	Only serious adverse events are reported. Other adverse events were not collected.
Arm/Group Title	Bone Marrow Failure Patients
Arm/Group Description	All patients with non-malignant, congenital bone marrow failure disorders and treated with stem cell transplant, chemotherapy (Busulfan, ATG, Fludarabine) and irradiation.
All Cause Mortality
	Bone Marrow Failure Patients
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bone Marrow Failure Patients
	Affected / at Risk (%)	# Events
Total	5/10 (50%)
Blood and lymphatic system disorders
Bone marrow graft failure	3/10 (30%)	3
Graft-versus-host disease (acute)	1/10 (10%)	1
General disorders
Death	3/10 (30%)	3
Other (Not Including Serious) Adverse Events
	Bone Marrow Failure Patients
	Affected / at Risk (%)	# Events
Total	0/10 (0%)

Limitations/Caveats

Pharmacokinetic parameters in patients receiving 2 mg/kg/dose of busulfan twice daily was not performed. No data is available.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.