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

Fred Hutchinson Cancer Center (FHCC)

Status

Completed

Conditions

Myelodysplastic Syndrome With Isolated Del(5q)

Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

Untreated Adult Acute Myeloid Leukemia

Polycythemia Vera

de Novo Myelodysplastic Syndromes

Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)

Childhood Acute Myeloid Leukemia in Remission

Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)

Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

Adult Acute Myeloid Leukemia in Remission

Previously Treated Myelodysplastic Syndromes

Childhood Myelodysplastic Syndromes

Secondary Myelodysplastic Syndromes

Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)

Recurrent Childhood Acute Myeloid Leukemia

Secondary Myelofibrosis

Primary Myelofibrosis

Secondary Acute Myeloid Leukemia

Recurrent Adult Acute Myeloid Leukemia

Essential Thrombocythemia

Adult Acute Myeloid Leukemia With Del(5q)

Treatments

Drug: busulfan

Other: pharmacogenomic studies

Procedure: allogeneic hematopoietic stem cell transplantation

Procedure: peripheral blood stem cell transplantation

Other: pharmacological study

Drug: cyclophosphamide

Drug: tacrolimus

Genetic: cytogenetic analysis

Other: flow cytometry

Drug: methotrexate

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00445744

P01HL036444 (U.S. NIH Grant/Contract)

2130.00

NCI-2010-00270 (Registry Identifier)

Details and patient eligibility

About

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

Full 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.

Enrollment

52 patients

Sex

All

Ages

Under 65 years old

Volunteers

No Healthy Volunteers

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)

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

52 participants in 1 patient group

Treatment (cyclophosphamide, busulfan, transplant)

Experimental group

Description:

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.

Treatment: