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

• ClinicalTrials.gov Identifier: NCT00445744
• Recruitment Status: Completed
• First Posted: March 9, 2007
• Results First Posted: January 2, 2018
• Last Update Posted: January 2, 2018
• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Cancer Institute (NCI)
• Information provided by (Responsible Party): Joachim Deeg, Fred Hutchinson Cancer Center

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
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	Not Applicable

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 52 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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.
• Study Start Date: December 2006
• Actual Primary Completion Date: June 2011
• Actual Study Completion Date: June 2013

Arms and Interventions

Arm

Intervention/treatment

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

Outcome Measures

Primary Outcome Measures :

1. Effectiveness of Cyclophosphamide/Busulfan Regimen in Reducing Regimen-related Liver Toxicity [ Time Frame: Up to day +20 ]
   Number of patients with regimen-related liver toxicity. Diagnoses will be made according to the established criteria initially proposed in 1984 by McDonald et al.
2. Non-relapse Mortality (NRM) (Patients With AML/MDS) [ Time Frame: Up to day 200 ]
   Cumulative incidence rate with death as a competing risk, assessed at day 100.

Eligibility Criteria

• Ages Eligible for Study: up to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

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 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: Joachim Deeg, Investigator, Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT00445744
• Other Study ID Numbers: 2130.00; NCI-2010-00270 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); P01HL036444 ( U.S. NIH Grant/Contract )
• First Posted: March 9, 2007
• Results First Posted: January 2, 2018
• Last Update Posted: January 2, 2018
• Last Verified: December 2017

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Neoplasm Metastasis; Polycythemia Vera; Myelodysplastic Syndromes; Primary Myelofibrosis; Polycythemia; Thrombocytosis; Thrombocythemia, Essential; Syndrome; Disease; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Neoplastic Processes; Myeloproliferative Disorders; Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Blood Platelet Disorders; Blood Coagulation Disorders; Hemorrhagic Disorders; Cyclophosphamide; Busulfan; Methotrexate