Purine Analog-Based Conditioning in Patients With Severe Aplastic Anemia

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00427336
• Collaborator: (none)
• Enrollment: 9
• Location: 1
• Arm: 1
• Duration (Months): 104
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Primary Objectives:

1. To determine the feasibility and toxicity of employing purine-analog based conditioning for allogeneic donor stem cell transplantation in patients with severe aplastic anemia (AA).

2. To determine the engraftment kinetics and degree of chimerism that can be achieved with this strategy.

Condition or Disease	Intervention/Treatment	Phase
Aplastic Anemia	Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Antithymocyte Globulin	N/A

Detailed Description

Before treatment starts, patients will have their bone marrow checked and will have lung, heart, and kidney tests.

Patients in this study will receive the drugs fludarabine, cyclophosphamide, and antithymocyte globulin by vein through a previously inserted plastic catheter that extends into the large chest vein. Fludarabine will be given daily for four days, cyclophosphamide will given daily for four days, and antithymocyte globulin will be given daily for four days (three days for related donor transplants).

Two days after the last dose of cyclophosphamide, donor marrow or stem cells will be infused through a catheter (thin plastic tube). Drugs will be given to lower the chance of an allergic reaction to the stem cells. Patients will also get shots of filgrastim (a drug that helps white blood cell growth) and antibiotics by mouth. The blood cell counts will fall to low levels during the first 2 weeks when patients may need transfusions of red blood cells and platelets. The chemotherapy will be given in the hospital. After the infusion of stem cells, patients will be monitored in the hospital. They will later be closely followed as outpatients and will be required to remain in the Houston area for about three months after the transplant.

Drugs (cyclosporine and methotrexate) to lower the chance of graft-versus-host disease will be given. Cyclosporine will be given as a continuous infusion starting 2 days before transplantation. Methotrexate will be given through the catheter on Days 1, 3, 6 and 11 after transplantation. Cyclosporine will be given as pills when the patient is able to swallow. Cyclosporine will be continued for no less than 6 months after transplantation after which it will be gradually stopped. The drug tacrolimus may be used instead of cyclosporine.

Blood, urine, bone marrow, and x-ray exams will be done as needed to monitor the results of bone marrow transplantation. Patients may require blood and platelet transfusions. Blood tests will be done daily while hospitalized and several times a week until the blood counts recover. Bone marrow aspiration and biopsies will be performed before the transplant, when the donated cells show signs of engraftment, and at other times during the next 1 to 3 years. They will be done to evaluate the growth of the transplant marrow, possible recurrence of malignancy, and recovery of immunity. If this treatment proves unsuccessful in more than three of the first ten patients, the study will be stopped.

This is an investigational study. The FDA has approved all of the drugs in this study for other indications. Up to 30 patients will be treated on this study. All will be enrolled at M.D. Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Purine Analog-Based Conditioning for Allogeneic Stem Cell Transplantation in Patients With Severe Aplastic Anemia
• Study Start Date: Dec 1, 2000
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fludarabine + Cyclophosphamide + ATG Fludarabine 30 mg/m^2/day by vein (IV), Cyclophosphamide IV 300 mg/m^2/day, ATG (Antithymocyte Globulin) IV 3.75 mg/kg/day	Drug: Fludarabine; 30 mg/m^2 by vein daily over 30 minutes; Other Names: Fludarabine Phosphate Fludara ; Drug: Cyclophosphamide; 300 mg/m^2 by vein daily over 2 hours; Other Names: Cytoxan Neosar ; Drug: Antithymocyte Globulin; 3.75 mg/kg by vein daily over 4 hours; Other Names: ATG Thymoglobulin

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Engraftment Response [First 100 days post transplant.]

   Engraftment defined as (1) the first of three consecutive days of an Absolute neutrophil count (ANC) >500/mL (b) the first of seven consecutive days of an unsupported platelet count 20,000. Patient needs to survive at least 28 days to be evaluable for engraftment. Chimerism studies need to demonstrate donor-derived hematopoiesis (>90%)

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients up to 70 years of age with a diagnosis of severe AA (Camitta et al., 1979) and a matched unrelated donor who are unresponsive to IS or who have relapsed after an initial response to IS. Patients with a diagnosis of SAA and an human leukocyte antigen (HLA) - compatible sibling donor are eligible only if they are 40 years of age or older (up to age 70) and regardless whether they have received IS or not. Patients with primary or secondary graft failure following autologous or allogeneic stem cell transplant are eligible.

• Patients must have a serum bilirubin of 2 mg/dl or less, serum creatinine < 2.0 mg/dl, no symptomatic cardiac or pulmonary disease and a PS of no more than 2. Life expectancy not severely limited by concomitant illness (> 12 weeks). Left ventricular ejection fraction > 40%, no uncontrolled arrhythmia or symptomatic cardiac disease. Forced Expiratory Volume in 1 Second (FEV1), Forced Vital Capacity (FVC) and Carbon Monoxide Diffusing Capacity (DLCO) > 40%. No symptomatic pulmonary disease. Negative pregnancy test.

• Patients must have an HLA-compatible related or unrelated donor willing to donate marrow or rhG-CSF-mobilized peripheral blood stem cells. In the event of transplants from matched unrelated donors, a high-resolution allele match for HLA-A, -B, -C, -DRB1 and DQB1 ("10 of 10 match") is preferred. However, a one-antigen mismatch ("micromismatch") is also considered acceptable matching ("9 of 10 match").

• Patients must sign informed consent. In the event of a pediatric patient (i.e., a minor), consent will be provided by their guardian/parent.

• Lack of clonal cytogenetic abnormalities associated with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or other hematologic malignancies.

Exclusion Criteria:

• Life expectancy of less than 8 weeks. Inability to provide informed consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	U.T.M.D. Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center

Investigators

• Principal Investigator: Paolo Anderlini, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• The University of Texas M.D.Anderson Cancer Center

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00427336
• Other Study ID Numbers: IDP00-266
• First Posted: Jan 29, 2007
• Last Update Posted: Oct 27, 2011
• Last Verified: Sep 1, 2011

• Keywords provided by M.D. Anderson Cancer Center: Severe Aplastic Anemia; Bone Marrow Failure; Stem Cell Transplantation; Fludarabine; Cyclophosphamide; Antithymocyte Globulin; SAA; ATG; Cytoxan; Neosar; Fludarabine Phosphate; Thymoglobulin
• Additional relevant MeSH terms: Anemia; Anemia, Aplastic; Vidarabine; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Thymoglobulin; Antilymphocyte Serum

Study Results

Participant Flow

Recruitment Details	Recruitment Period: December 2000 to August 2009. All participants recruited at UT MD Anderson Cancer Center.

Arm/Group Title	Fludarabine + Cyclophosphamide + ATG
Arm/Group Description	Fludarabine 30 mg/m^2/day by vein (IV), Cyclophosphamide IV 300 mg/m^2/day, ATG (Antithymocyte Globulin) IV 3.75 mg/kg/day
Period Title: Overall Study
STARTED	9
COMPLETED	9
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Fludarabine + Cyclophosphamide + ATG
Arm/Group Description	Fludarabine 30 mg/m^2/day by vein (IV), Cyclophosphamide IV 300 mg/m^2/day, ATG (Antithymocyte Globulin) IV 3.75 mg/kg/day
Overall Participants	9
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	39
Sex: Female, Male (Count of Participants)
Female	6 66.7%
Male	3 33.3%
Region of Enrollment (participants) [Number]
United States	9 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Engraftment Response
Description	Engraftment defined as (1) the first of three consecutive days of an Absolute neutrophil count (ANC) >500/mL (b) the first of seven consecutive days of an unsupported platelet count 20,000. Patient needs to survive at least 28 days to be evaluable for engraftment. Chimerism studies need to demonstrate donor-derived hematopoiesis (>90%)
Time Frame	First 100 days post transplant.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fludarabine + Cyclophosphamide + ATG
Arm/Group Description	Fludarabine 30 mg/m^2/day by vein (IV), Cyclophosphamide IV 300 mg/m^2/day, ATG (Antithymocyte Globulin) IV 3.75 mg/kg/day
Measure Participants	9
Number [Participants]	9 100%

Adverse Events

Time Frame	7 years, 10 months
Arm/Group Title	Fludarabine + Cyclophosphamide + ATG
Arm/Group Description	Fludarabine 30 mg/m^2/day by vein (IV), Cyclophosphamide IV 300 mg/m^2/day, ATG (Antithymocyte Globulin) IV 3.75 mg/kg/day
All Cause Mortality
	Fludarabine + Cyclophosphamide + ATG
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Fludarabine + Cyclophosphamide + ATG
	Affected / at Risk (%)	# Events
Total	6/9 (66.7%)
Cardiac disorders
Hypotension	1/9 (11.1%)	1
General disorders
Headache	1/9 (11.1%)	1
Hepatobiliary disorders
Elevated Bilirubin	3/9 (33.3%)	3
Elevated Transaminases	1/9 (11.1%)	2
Infections and infestations
Infection	2/9 (22.2%)	2
Fever	1/9 (11.1%)	1
Renal and urinary disorders
Elevated Creatinine	1/9 (11.1%)	1
Respiratory, thoracic and mediastinal disorders
Shortness of Breath	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
Rash	1/9 (11.1%)	1
Other (Not Including Serious) Adverse Events
	Fludarabine + Cyclophosphamide + ATG
	Affected / at Risk (%)	# Events
Total	9/9 (100%)
Cardiac disorders
Hypotension	1/9 (11.1%)	1
Gastrointestinal disorders
Nausea	8/9 (88.9%)	8
Diarrhea	6/9 (66.7%)	6
Mucositis	2/9 (22.2%)	2
Hepatobiliary disorders
Elevated Bilirubin	1/9 (11.1%)	1
Infections and infestations
Fever	2/9 (22.2%)	2
Infection	1/9 (11.1%)	2
Musculoskeletal and connective tissue disorders
Bone Pain	1/9 (11.1%)	1
Renal and urinary disorders
Elevated Creatinine	1/9 (11.1%)	1
Respiratory, thoracic and mediastinal disorders
Embolism	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
Rash	2/9 (22.2%)	2

Limitations/Caveats

[Not Specified]

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.