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Cyclophosphamide and Busulfan Followed by Donor Stem Cell Transplant in Treating Patients With Myelofibrosis, Acute Myeloid Leukemia, or Myelodysplastic Syndrome

This study has been completed.
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00445744
First received: March 7, 2007
Last updated: April 3, 2014
Last verified: April 2014
History of Changes
  Purpose
This trial is studying the side effects and how well giving cyclophosphamide and busulfan followed by donor stem cell transplant works in treating patients with myelofibrosis, acute myeloid leukemia, or myelodysplastic syndrome. Giving chemotherapy, such as cyclophosphamide and busulfan, before a donor stem cell transplant helps stops the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus and methotrexate after the transplant may stop this from happening

Condition Intervention
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Childhood Acute Myeloid Leukemia in Remission
Childhood Myelodysplastic Syndromes
de Novo Myelodysplastic Syndromes
Essential Thrombocythemia
Myelodysplastic Syndrome With Isolated Del(5q)
Polycythemia Vera
Previously Treated Myelodysplastic Syndromes
Primary Myelofibrosis
Recurrent Adult Acute Myeloid Leukemia
Recurrent Childhood Acute Myeloid Leukemia
Secondary Acute Myeloid Leukemia
Secondary Myelodysplastic Syndromes
Secondary Myelofibrosis
Untreated Adult Acute Myeloid Leukemia
Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies
 Drug: cyclophosphamide
Drug: busulfan
Drug: tacrolimus
Drug: methotrexate
Genetic: cytogenetic analysis
Other: flow cytometry
Other: pharmacological study
Other: pharmacogenomic studies
Procedure: peripheral blood stem cell transplantation
Procedure: allogeneic hematopoietic stem cell transplantation

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Cyclophosphamide Followed by Intravenous Busulfan as Conditioning for Hematopoietic Cell Transplantation in Patients With Myelofibrosis, Acute Myeloid Leukemia, or Myelodysplastic Syndrome.

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Effectiveness of cyclophosphamide/busulfan regimen in reducing regimen-related toxicity [ Time Frame: Up to day +20 ] [ Designated as safety issue: Yes ]
    Diagnoses will be made according to the established criteria initially proposed in 1984 by McDonald et al.

  • Non-relapse mortality (NRM) (patients with AML/MDS) [ Time Frame: At day +200 ] [ Designated as safety issue: No ]
Enrollment: 52
Study Start Date: December 2006
Study Completion Date: June 2013
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (cyclophosphamide, busulfan, transplant)

CONDITIONING REGIMEN: Patients receive cyclophosphamide IV on days -7 and -6 and busulfan IV over 3 hours on days -5 to -2.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplant on day 0.

POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV or PO twice daily on days -1 to 200 with taper on day 56 and methotrexate on days 1, 3, 6, and 11.

 Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Drug: busulfan
Given IV
Other Names:
  • BSF
  • BU
  • Misulfan
  • Mitosan
  • Myeloleukon
Drug: tacrolimus
Given IV or PO
Other Names:
  • FK 506
  • Prograf
Drug: methotrexate
Given IV
Other Names:
  • amethopterin
  • Folex
  • methylaminopterin
  • Mexate
  • MTX
Genetic: cytogenetic analysis
Correlative studies
Other: flow cytometry
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: pharmacogenomic studies
Correlative studies
Other Name: Pharmacogenomic Study
Procedure: peripheral blood stem cell transplantation
Undergo PBPC transplantation
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Procedure: allogeneic hematopoietic stem cell transplantation
Undergo allogeneic transplantation

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the incidence of hepatotoxicity with a conditioning regimen of CY (cyclophosphamide)/tBU (busulfan) in patients receiving hematopoietic cell transplant (HCT).

SECONDARY OBJECTIVES:

I. To determine overall and non-relapse mortality at day +200 after HCT.

II. To determine the peak bilirubin levels through day +20 after HCT.

III. To determine the incidence of pulmonary toxicity in the form of idiopathic pulmonary syndrome (IPS).

IV. To determine the rate of graft failure.

V. To determine the time to engraftment.

VI. To determine the rate of relapse.

VII. To determine the incidence and severity of graft-versus-host disease (GVHD).

VIII. To evaluate the pharmacokinetics/dynamics of BU and CY.

X. To evaluate the pharmacogenomics of response, toxicity and pharmacokinetics of CY/tBU.

OUTLINE:

CONDITIONING REGIMEN: Patients receive cyclophosphamide intravenously (IV) on days -7 and -6 and busulfan IV over 3 hours on days -5 to -2.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplant on day 0.

POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV or orally (PO) twice daily on days -1 to 200 with taper on day 56 and methotrexate on days 1, 3, 6, and 11.

After completion of study treatment, patients are followed periodically.

  Eligibility
Ages Eligible for Study:   up to 65 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Idiopathic myelofibrosis (CIMF)
  • Myelofibrosis developing with polycythemia vera or essential thrombocythemia
  • Acute myeloid leukemia with or without antecedent hematologic disorder, at any disease stage (complete remission, minimal residual disease, or relapsed leukemia)
  • Myelodysplastic syndrome of any World Health Organization (WHO) or French-American-British (FAB) category, at any disease stage
  • Less than 61 years of age if transplanted from an unrelated donor, or less than 66 years of age if transplanted from a related donor
  • Receiving unmanipulated peripheral blood stem cells from an human leukocyte antigen (HLA)-identical or 1-allele-mismatched related or unrelated donor, or receiving G-CSF-stimulated bone marrow if co-enrolled on Fred Hutchinson Cancer Research Center (FHCRC) protocol 2250
  • With a Karnofsky Performance score of > 70% at the time of pre-transplant evaluation
  • Able to give informed consent (if >= 18 years of age), or with a legal guardian capable of giving consent (if < 18 years of age)
  • DONOR: HLA-identical or 1-allele-mismatched related or unrelated donors (by high resolution typing)
  • DONOR: Undergoing peripheral blood stem cell harvest or G-CSF-stimulated bone marrow harvest (bone marrow permitted only as part of FHCRC protocol 2250)
  • DONOR: In good general health, with a Karnofsky performance score of > 80%
  • DONOR: Able to give informed consent (if >= 18 years of age), or with a legal guardian able to give informed consent (if < 18 years of age and donating for a related transplant)

Exclusion Criteria:

  • Without an HLA-identical or 1-allele-mismatched related or unrelated donor
  • With human immunodeficiency virus (HIV) positivity or active infectious hepatitis
  • Receiving a medication known to strongly inhibit enzymes in the CYP450 pathway, and which, in the judgment of the consenting provider, cannot be safely discontinued for the duration of conditioning
  • Whose life expectancy is severely limited by diseases other than the hematologic disorder for which they are undergoing HCT (HCT-comorbidity index [CI] > 3)
  • Women who are pregnant or lactating
  • With known hypersensitivity to BU or CY
  • With hepatic dysfunction as evidenced by total bilirubin or AST > 2x the upper limit of normal, or evidence of synthetic dysfunction or cirrhosis
  • With impaired renal function, as evidenced by creatinine clearance < 50% of expected, creatinine > 2x the upper limit of normal, or dialysis dependence
  • With impaired pulmonary function, as evidenced by pO2 < 70 mm Hg and diffusing capacity of carbon monoxide (DLCO) < 70% predicted or by pO2 < 80 mm Hg and DLCO < 60%, or receiving continuous supplementary oxygen
  • With impaired cardiac function, as evidenced by ejection fraction < 35% or active coronary artery disease
  • Unable to give informed consent
  • DONOR: Deemed unable to undergo stem cell collection, for any reason
  • DONOR: HIV-positive, or hepatitis B or C antigen-positive
  • DONOR: Women with a positive pregnancy test
  • DONOR: Unable to give informed consent (if >= 18 years of age), or without a legal guardian able to give informed consent (if <18 years of age)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00445744

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Investigators
Principal Investigator: Andrew Rezvani Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00445744     History of Changes
Other Study ID Numbers: 2130.00  NCI-2010-00270  P01HL036444 
Study First Received: March 7, 2007
Last Updated: April 3, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Syndrome
Myelodysplastic Syndromes
Preleukemia
Neoplasm Metastasis
Primary Myelofibrosis
Polycythemia
Polycythemia Vera
Thrombocytosis
Thrombocythemia, Essential
Neoplasms by Histologic Type
Neoplasms
Disease
 Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplastic Processes
Myeloproliferative Disorders
Blood Platelet Disorders
Blood Coagulation Disorders
Hemorrhagic Disorders
Cyclophosphamide
Methotrexate
Tacrolimus
Busulfan
Immunosuppressive Agents
Immunologic Factors

ClinicalTrials.gov processed this record on September 23, 2016