Chemotherapy, Antithymocyte Globulin, Total-Body Irradiation, and a Donor Umbilical Cord Blood Transplant and Donor Stem Cell Transplant in Treating Patients With Severe Aplastic Anemia or Myelodysplastic Syndromes - Full Text View

Sponsored by:	National Heart, Lung, and Blood Institute (NHLBI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00608413

Purpose

RATIONALE: Giving chemotherapy, antithymocyte globulin, and total-body irradiation before a donor umbilical cord blood transplant and a donor peripheral stem cell transplant helps stop the growth of abnormal cells. It also stops the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving tacrolimus, mycophenolate mofetil, and prednisone or methylprednisolone before and after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving cyclophosphamide together with fludarabine, antithymocyte globulin, and total-body irradiation followed by donor umbilical cord blood transplant and donor peripheral stem cell transplant works in treating patients with severe aplastic anemia or myelodysplastic syndromes associated with severe neutropenia that has not responded to immunosuppressive therapy.

Condition	Intervention	Phase
Leukemia Myelodysplastic Syndromes Precancerous/Nonmalignant Condition	Biological: anti-thymocyte globulin Drug: cyclophosphamide Drug: fludarabine phosphate Drug: methylprednisolone Drug: mycophenolate mofetil Drug: prednisone Drug: tacrolimus Procedure: in vitro-treated peripheral blood stem cell transplantation Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation Procedure: umbilical cord blood transplantation Radiation: total-body irradiation	Phase II

Study Type:	Interventional
Study Design:	Treatment, Open Label
Official Title:	Co-Infusion of Umbilical Cord Blood and Haploidentical CD34+ Cells Following Nonmyeloablative Conditioning as Treatment for Severe Aplastic Anemia and MDS Associated With Severe Neutropenia Refractory to Immunosuppressive Therapy

Resource links provided by NLM:

MedlinePlus related topics: Anemia Leukemia, Adult Acute Leukemia, Adult Chronic Leukemia, Childhood Radiation Therapy

Drug Information available for: Cyclophosphamide Prednisone Fludarabine Fludarabine monophosphate Methylprednisolone Tacrolimus anhydrous Tacrolimus Mycophenolate mofetil hydrochloride Mycophenolate Mofetil

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Umbilical cord blood (UCB) engraftment (defined as UCB-derived absolute neutrophil count [ANC] ≥ 500 cells/μL) on day 42 [ Designated as safety issue: No ]

Secondary Outcome Measures:

CD34+ cell dose and CD3+ cell dose [ Designated as safety issue: No ]
Degrees of UCB, haploidentical related donor CD34+ cell, and recipient chimerism in T-lymphocyte, NK cell, and myeloid lineages assessed by PCR of short tandem repeats (STRs) [ Designated as safety issue: No ]
ANC recovery rate (ANC ≥ 500 cells/µL) on day 22 [ Designated as safety issue: Yes ]
Days to an UCB-derived ANC of 500 cells/µL and 1,000 cells/µL [ Designated as safety issue: Yes ]
Platelet recovery (days to a platelet count of 20,000/mm³ and 50,000/mm³ and days to transfusion independence) [ Designated as safety issue: Yes ]
Red blood cell recovery (days to transfusion independence) [ Designated as safety issue: Yes ]
Incidence and severity of acute graft-vs-host disease (GVHD) [ Designated as safety issue: Yes ]
Incidence and severity of chronic GVHD [ Designated as safety issue: Yes ]
Graft failure (loss of the graft ) as measured by chimerism [ Designated as safety issue: No ]
Non-hematological effects attributable to the preparative regimen [ Designated as safety issue: No ]
Disease progression or relapse [ Designated as safety issue: No ]
Transplant-related mortality before and after day 100 and day 200 [ Designated as safety issue: Yes ]
Disease free-survival and overall survival [ Designated as safety issue: No ]

Estimated Enrollment:	40
Study Start Date:	January 2008
Estimated Primary Completion Date:	December 2013 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Primary

To evaluate the potential of > 80% of patients with severe aplastic anemia or myelodysplastic syndromes associated with severe neutropenia refractory to immunosuppressive therapy to achieve engraftment of the umbilical cord blood (UCB) unit (defined as UCB-derived absolute neutrophil count [ANC] ≥ 500 cells/μL) by day 42 when treated with a nonmyeloablative conditioning regimen comprising cyclophosphamide, fludarabine phosphate, anti-thymocyte globulin, and total-body irradiation followed by donor umbilical cord blood transplantation and haploidentical related donor CD34+ peripheral blood stem cell transplantation.

Secondary

To evaluate ANC recovery rate (ANC ≥ 500 cells/μL) on day 22.
To evaluate the safety of this novel transplant regimen (non-hematologic toxicities).
To evaluate treatment-related mortality on day 100 and day 200.
To determine the incidence and severity of acute and chronic graft-versus-host disease (GVHD) following treatment with this transplant regimen.

OUTLINE:

Nonmyeloablative preparative conditioning regimen: Patients receive cyclophosphamide IV over 60 minutes once daily on days -7 and -6, fludarabine phosphate IV over 30 minutes once daily on days -5 to -1, and anti-thymocyte globulin IV over 4 hours once daily on days -5 to -2. Patients also receive a single dose of total-body irradiation over 30 minutes on day -1.
Donor stem cell transplantation: Patients undergo donor umbilical cord blood transplantation and haploidentical related donor CD34+ peripheral blood stem cell transplantation on day 0.
Graft-versus-host-disease (GVHD) prophylaxis: Patients receive tacrolimus IV continuously over 24 hours or orally twice daily beginning on day -4 and continuing for at least 6 months and mycophenolate mofetil IV or orally twice daily beginning on day 0 and continuing for 100 days. Patients also receive oral prednisone or methylprednisolone IV beginning on day -5 (prior to the first dose of ATG) and continuing until day 19.

After completion of study treatment, patients are followed every 3 months for 3 years, every 6 months for 2 years, and then annually thereafter.

Eligibility

Ages Eligible for Study:	8 Years to 55 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Diagnosed of 1 of the following:
- Severe aplastic anemia characterized by all of the following:
  - Bone marrow cellularity < 30% (excluding lymphocytes)
  - Transfusion dependence for platelets and/or RBCs
  - Neutropenia (absolute neutrophil count [ANC] < 500 cells/μL)
  - Failed at least two forms of immunosuppressive therapy
- Myelodysplastic syndromes characterized by all of the following:
  - Refractory anemia (RA) OR RA with ringed sideroblasts (RARS)
  - Neutropenia (ANC < 500 cells/μL)
  - Refractory to one or more lines of therapy
  - History of 1 or more opportunistic infections related to neutropenia
At least one HLA-haploidentical (≥ 3/6 HLA matched) related donor (2-75 years old) available
- No HLA identical or 5/6 HLA-matched related stem cell donor available
- At least 2 x 10^6 CD34+ cells/kg required from haploidentical related donor
- No haploidentical related donor with sickling hemoglobinopathies, including HbSS, HbAS, or HbSC
At least one 4/6 HLA-matched (HLA-A, B, and DR loci) umbilical cord blood (UCB) unit from the National Marrow Donor Program available
- UCB unit must contain a minimum total nucleated cells (TNC) (prior to thawing) of ≥ 1.5 x 10^7 cells/kg of recipient body weight
  - UCB unit must contain ≥ 1.7 x 10^5 CD34+ cells/kg (prior to thawing) if the minimum criterion of TNC is not met
Not deemed to be a candidate for a 6/6 HLA-matched related or unrelated stem cell transplantation

PATIENT CHARACTERISTICS:

ECOG performance status 0-1
Transaminases ≤ 5 times upper limit of normal
Serum bilirubin ≤ 4 mg/dL
Creatinine clearance ≥ 50 mL/min
DLCO ≥ 40% predicted
Left ventricular ejection fraction ≥ 40% by ECHO OR ≥ 30% by MUGA
HIV-negative
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No major anticipated illness or organ failure incompatible with survival from transplant
No severe psychiatric illness or mental deficiency sufficiently severe as to make compliance with the transplant regimen unlikely and make informed consent impossible
No active infection not adequately responding to appropriate therapy
No history of a malignant disease that is liable to relapse or progress within 5 years

PRIOR CONCURRENT THERAPY:

At least 45 days since prior immunosuppressive therapy with horse anti-thymocyte globulin (ATG) or rat-ATG

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00608413

Locations

United States, Maryland
NIH - Warren Grant Magnuson Clinical Center	Recruiting
Bethesda, Maryland, United States, 20892-1182
Contact: Clinical Trials Office - NIH - Warren Grant Magnuson Clinical 800-411-1222

Sponsors and Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Study Chair:

Richard W. Childs, MD

National Heart, Lung, and Blood Institute (NHLBI)

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	National Heart, Lung, and Blood Institute ( Richard W. Childs )
Study ID Numbers:	CDR0000585757, NHLBI-08-H-0046
Study First Received:	February 5, 2008
Last Updated:	June 23, 2009
ClinicalTrials.gov Identifier:	NCT00608413 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

refractory anemia with ringed sideroblasts
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
refractory anemia

aplastic anemia
de novo myelodysplastic syndromes
childhood myelodysplastic syndromes

Study placed in the following topic categories:

Antimetabolites
Anti-Inflammatory Agents
Prednisone
Immunologic Factors
Precancerous Conditions
Aplastic Anemia
Methylprednisolone
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Antiemetics
Prednisolone acetate
Cyclophosphamide
Tacrolimus
Hormones
Neuroprotective Agents

Refractory Anemia
Leukemia
Preleukemia
Anemia, Refractory
Anemia, Aplastic
Neoplasm Metastasis
Mycophenolate mofetil
Alkylating Agents
Methylprednisolone Hemisuccinate
Antineoplastic Agents, Hormonal
Hematologic Diseases
Myelodysplastic Syndromes
Anemia
Methylprednisolone acetate
Fludarabine monophosphate

Additional relevant MeSH terms:

Anti-Inflammatory Agents
Prednisone
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Methylprednisolone
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Antiemetics
Tacrolimus
Hormones
Preleukemia
Pathologic Processes
Therapeutic Uses
Mycophenolate mofetil
Methylprednisolone Hemisuccinate

Antineoplastic Agents, Hormonal
Hematologic Diseases
Glucocorticoids
Neoplasms
Fludarabine
Antimetabolites
Precancerous Conditions
Immunologic Factors
Antineoplastic Agents
Prednisolone acetate
Cyclophosphamide
Neuroprotective Agents
Leukemia
Syndrome
Anemia, Aplastic

ClinicalTrials.gov processed this record on July 06, 2009