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Fludarabine-based Conditioning for Severe Aplastic Anemia (BMT CTN 0301)

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ClinicalTrials.gov Identifier: NCT00326417
Recruitment Status : Completed
First Posted : May 16, 2006
Results First Posted : October 4, 2016
Last Update Posted : October 27, 2017
Information provided by (Responsible Party):

Study Description
Brief Summary:
The purpose of the current study is to continue to optimize conditioning regimens in high-risk patients with severe aplastic anemia transplanted with marrow from HLA-compatible unrelated donors. Specifically, the study will determine whether the addition of fludarabine to the conditioning regimen previously described by Deeg et al. will permit a reduction in the CY dose, to a point where sustained hematopoietic engraftment and survival are maintained (or improved), while the frequency of major regimen-related toxicity (RRT) and early deaths is reduced.

Condition or disease Intervention/treatment Phase
Anemia, Aplastic Drug: Fludarabine Drug: Cyclophosphamide 150mg Drug: Cyclophosphamide 100mg Drug: Cyclophosphamide 50mg Phase 1 Phase 2

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Detailed Description:


Aplastic anemia (AA) remains a life-threatening illness. Treatment options include supportive care (transfusions, growth factors, etc.), immunosuppression therapy and stem cell transplantation. Only the latter two have favorably impacted the natural history of the disease. The prognosis of AA patients, particularly severe aplastic anemia (SAA), as defined by Camitta et al., who fail to respond to immunosuppressive therapy (IS) or who relapse after an initial response to IS is poor. Although many of these patients can be supported in the short term with growth factors, transfusions and possibly rechallenged successfully with IS, the cumulative morbidity and mortality from infection, hemorrhage or transfusion-related complications is substantial.

While allogeneic bone marrow transplantation is potentially curative in AA, no more than 25% of patients have a human leukocyte antigen (HLA)-identical sibling donor. Cyclophosphamide (CY)-antithymocyte globulin (ATG) has been recommended as the preparative regimen of choice in sibling donor transplants. Results of bone marrow transplantation from alternative donors, such as matched unrelated donors and mismatched related donors in AA patients who have failed IS, have largely been unsatisfactory. The cyclophosphamide-ATG conditioning regimen has proved inadequate in ensuring engraftment in allogeneic transplants from matched, unrelated donors for AA. This was the major reason why total body radiation (TBI) has been added to the conditioning regimen.

Graft failure is a very serious and frequently life-threatening or fatal event following matched unrelated donor (MUD) allografts in aplastic anemia. It is an immunologically mediated event. Risk factors for graft failure include the use of HLA nonidentical or unrelated donors, a poor marrow nucleated cell dose as well as prolonged transfusional support prior to BMT (which increases the probability of patient sensitization to multiple antigens). While some patients may achieve autologous hematopoietic recovery, prolonged pancytopenia is common and infection-related morbidity and mortality are very substantial. Reconditioning for a second allograft from the same or a different donor is frequently not successful. While the addition of TBI and intensive pre-transplant conditioning has led to a sizable improvement in engraftment rates, this has come with a price, particularly in adult patients. Transplant-related toxicity has been a major and frequent problem. Radiation-induced pulmonary toxicity in particular has been common, usually in the form of diffuse alveolar damage or diffuse interstitial pneumonitis. In addition, Graft Versus Host Disease (GVHD)-related morbidity and mortality in these patients have also been substantial.


The study is a prospective Phase I/II dose optimization study. All patients are given a fixed dose of ATG (either thymoglobulin: 3 mg/kg IV daily x 3 or ATGAM 30 mg/kg IV daily x 3, on Days -4 to -2), Fludarabine (30 mg/m^2 IV daily x 4, on Days - 5 to -2), and TBI (200 cGy (centigray) from a linear accelerator at less than 20 cGy/min on Day -1). The starting CY dose will be 150 mg/kg (50 mg/kg intravenously daily, Days -4 to -2), and will be de-escalated depending on engraftment and toxicity. The Phase I portion of the trial (maximum of 24-27 patients) tests each of four dose levels of CY for adequate safety and graft retention. The Phase II portion of the trial refines the dose selection and allocates an additional 70 patients to the optimal dose, at which two-year post-transplant survival will be assessed. The combined enrollment in Phase I and II will total 94 patients.

The study is a prospective single-arm Phase I/II dose-selection and evaluation study. The study will seek the optimal dose level of CY based on assessments of graft failure, toxicity and early death during 100 days of follow-up post-transplant. A brief synopsis is given below.

Phase I - Test Each Dose for Adequate Safety and Graft Retention

  1. Proceed from the highest dose (150 mg/kg CY) to the lowest dose (0 mg/kg CY), treating a minimum of six patients at each dose.
  2. Evaluate the 100-Day outcomes for toxicity, death and graft failure on each patient enrolled at the current dose, or until stopping criteria are met.
  3. If there are three or more graft failures at the current dose, the current dose and all lower doses are closed to further enrollment.
  4. If there are five or more severe regimen-related toxicities and/or early deaths at the current dose, the current dose is closed to further enrollment, and the next lower dose is tested.
  5. Dose de-escalation ceases once all four doses are tested or closed to further enrollment.

Phase II - Refine Dose Selection and Allocate Patients to the Optimal Dose

  1. Treat each newly enrolled patient at the most desirable of the dose levels remaining open to enrollment. This can involve de-escalation, escalation, or no change in dose.
  2. As each patient completes the observation period, evaluate the 100-Day outcomes for graft failure, toxicity and/or early death for this patient, or until stopping criteria are met.
  3. If there are excess (according to the criteria in Table 5.8) graft failures, that patient's dose and all lower doses are closed to further enrollment.
  4. If there are excess (according to the criteria in Table 5.8) toxicities and/or early deaths, that patient's dose is closed to further enrollment.
  5. Re-evaluate the desirability of the current dose level based on the 100-Day outcomes for toxicity and/or early death and graft failure.
  6. Repeat steps 1-5 until 54 patients are enrolled in Phase II, or all dose levels are closed to further enrollment.

Dosage Levels for CY:

3 Days (Day -4, -3, -2): Dose of 50 mg/kg/day; total dose of 150 mg/kg; dose level 3

2 Days (Day -3, -2): Dose of 50 mg/kg/day; total dose of 100 mg/kg; dose level 2

1 Day (Day -2): Dose of 50 mg/kg/day; total dose of 50 mg/kg; dose level 1

0 Days (None): No dose; no total dose; dose level 0

There may be wait periods between enrollment of successive patients and/or cohorts for endpoint assessment. Under these circumstances, the final decision about waiting versus treating the patient off study will be made at the local transplant center.

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 97 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Fludarabine-based Conditioning for Allogeneic Marrow Transplantation From HLA-compatible Unrelated Donors in Severe Aplastic Anemia (BMT CTN #0301)
Study Start Date : January 2006
Primary Completion Date : September 2015
Study Completion Date : January 2016

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Cyclophosphamide 150mg
Fludarabine plus 150 mg/kg Cyclophosphamide (total dose)
Drug: Fludarabine
Doses of 30 mg/m^2 IV will be given for no less than 30 minutes daily for 4 days (Days -5 to -2)
Other Name: Fludara
Drug: Cyclophosphamide 150mg
A total dose of 150 mg/kg will be given as 50 mg/kg per day for 3 days (Days -4, -3, -2)
Other Name: Cytoxan®
Experimental: Cyclophosphamide 100mg
Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)
Drug: Fludarabine
Doses of 30 mg/m^2 IV will be given for no less than 30 minutes daily for 4 days (Days -5 to -2)
Other Name: Fludara
Drug: Cyclophosphamide 100mg
A total dose of 100 mg/kg will be given as 50 mg/kg per day for 2 days (Days -3, -2)
Other Name: Cytoxan®
Experimental: Cyclophosphamide 50mg
Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)
Drug: Fludarabine
Doses of 30 mg/m^2 IV will be given for no less than 30 minutes daily for 4 days (Days -5 to -2)
Other Name: Fludara
Drug: Cyclophosphamide 50mg
A total dose of 50 mg/kg will be given once at 50 mg/kg per day on Day -2
Other Name: Cytoxan®
Experimental: Fludarabine
Fludarabine only (no Cyclophosphamide administered)
Drug: Fludarabine
Doses of 30 mg/m^2 IV will be given for no less than 30 minutes daily for 4 days (Days -5 to -2)
Other Name: Fludara

Outcome Measures

Primary Outcome Measures :
  1. Disease-free Survival (DFS) [ Time Frame: Day 100 ]
    DFS includes graft failure, regimen-related toxicity (RRT), and early death. Graft Failure is defined by lack of neutrophil engraftment (ANC less than 0.5 x 10^9/L for 3 consecutive days on different days). Major RRT is defined as severity of grade 4 in any organ system or grade 3 for pulmonary, cardiac, renal, oral mucosal or hepatic. Early death is defined as death prior to Day 100 post-transplant.

Secondary Outcome Measures :
  1. Cumulative Incidence of Graft Failure [ Time Frame: Day 365 ]
    Primary and secondary graft failure are included, secondary graft failure is defined by initial neutrophil engraftment followed by subsequent decline in the ANC to less than 0.5 x 10^9/L for three consecutive measurements on different days, unresponsive to growth factor.

  2. Acute Graft vs Host Disease (GVHD) [ Time Frame: Day 100 ]
    All GVHD grades 2-4 will be graded according to the BMT CTN Manual of Procedures (MOP)

  3. Chronic GVHD [ Time Frame: Day 365 ]
    Chronic GVHD is scored according to the BMT CTN MOP. The first day of chronic GVHD onset will be used to calculate cumulative incidence curves.

  4. Overall Survival (OS) [ Time Frame: Day 365 ]
    OS is defined as alive at 1 year, the event is death from any cause. Patients alive at the time of last observation, for statistical purposes, will have a survival time which is censored.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 65 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients up to 65 years of age at time of registration with a diagnosis of SAA; SAA is defined as follows:

    1. Bone marrow cellularity less than 25% or marrow cellularity less than 50% but with less than 30% residual hematopoietic cells
    2. Two out of three of the following (in peripheral blood): neutrophils less than 0.5 x 10^9/L; platelets less than 20 x 10^9/L; reticulocytes less than 20 x 10^9/L
  • Patient must have an available unrelated donor with a 7/8 or 8/8 match for HLA-A, B, C, and DRB1 antigen; typing is by DNA techniques: intermediate resolution for A, B, and C, and high resolution for DRB1; HLA-DQ typing is recommended but will not count in the match
  • Patient and/or legal guardian able to provide signed informed consent
  • Matched unrelated donor must consent to provide a marrow allograft
  • Patients with adequate organ function as measured by:

    1. Cardiac: left ventricular ejection fraction at rest must be greater than 40% or shortening fraction greater than 20%
    2. Hepatic: serum bilirubin less than 2x upper limit of normal for age as per local laboratory) (with the exception of isolated hyperbilirubinemia due to Gilbert's syndrome), alanine transaminase (ALT) and aspartate transaminase (AST) less than 4x upper limit of normal for age (as per local laboratory)
    3. Renal: serum creatinine less than 2x upper limit of normal for age (as per local laboratory)
    4. Pulmonary: Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) (corrected for Hb) greater than 50% predicted; for patients in which pulse oxymetry is performed, O2 saturation greater than 92%
  • Diagnosis of Fanconi anemia must be excluded in patients younger than 18 years of age by diepoxybutane testing on peripheral blood or comparable testing on marrow.

Exclusion Criteria:

  • Clonal cytogenetic abnormalities associated with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) on marrow examination
  • Diagnosis of other "congenital" aplastic anemias such as: Diamond-Blackfan; Shwachman-Diamond; congenital amegakaryocytosis
  • Symptomatic or uncontrolled cardiac failure or coronary artery disease
  • Karnofsky performance status less than 60% or Lansky less than 40% for patients younger than 16 years old
  • Uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms)
  • Seropositive for the human immunodeficiency virus (HIV)
  • Pregnant (positive total HCG) or breastfeeding
  • Presence of large accumulation of ascites or pleural effusions, which would be a contraindication to the administration of methotrexate for GVHD prophylaxis
  • Known severe or life-threatening allergy or intolerance to ATG or cyclosporine/ tacrolimus
  • Planned administration of alemtuzumab (Campath-1H) or other investigational agents as alternative agent for GVHD prophylaxis
  • Concomitant enrollment in a Phase I study
  • Positive patient anti-donor lymphocyte crossmatch in HLA-A or B mismatched transplants; the definition of match is in Section 2.2.1; the crossmatch would only apply to mismatches at HLA-A or B, not DRB1 or HLA-C
  • Prior allogeneic marrow or stem cell transplantation
  • Patients with prior malignancies except resected basal cell carcinoma or treated carcinoma in-situ; cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Medical Monitor or Protocol Chair; cancer treated with curative intent more than 5 years previously will be allowed
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00326417

  Show 22 Study Locations
Sponsors and Collaborators
Medical College of Wisconsin
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Study Director: Mary Horowitz, MD Center for International Blood and Marrow Transplant Research
More Information

Additional Information:

Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT00326417     History of Changes
Obsolete Identifiers: NCT00335608
Other Study ID Numbers: BMTCTN0301
U01HL069294 ( U.S. NIH Grant/Contract )
5U01HL069294-05 ( U.S. NIH Grant/Contract )
5U24CA076518 ( U.S. NIH Grant/Contract )
First Posted: May 16, 2006    Key Record Dates
Results First Posted: October 4, 2016
Last Update Posted: October 27, 2017
Last Verified: August 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Findings will be published in a manuscript.
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Time Frame: Within 6 months of official study closure at participating sites.
Access Criteria: Available to the public.
URL: https://biolincc.nhlbi.nih.gov/home/

Keywords provided by Medical College of Wisconsin:
Severe Aplastic Anemia

Additional relevant MeSH terms:
Anemia, Aplastic
Hematologic Diseases
Bone Marrow Diseases
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antiviral Agents
Anti-Infective Agents