Fludarabine Phosphate, Busulfan, and Anti-Thymocyte Globulin Followed By Donor Peripheral Blood Stem Cell Transplant, Tacrolimus, and Methotrexate in Treating Patients With Myeloid Malignancies

Fred Hutchinson Cancer Center (FHCC)

Status and phase

Completed

Phase 2

Conditions

Childhood Chronic Myelogenous Leukemia

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

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

de Novo Myelodysplastic Syndromes

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

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

Childhood Acute Myeloid Leukemia in Remission

Hematopoietic/Lymphoid Cancer

Adult Acute Myeloid Leukemia in Remission

Previously Treated Myelodysplastic Syndromes

Relapsing Chronic Myelogenous Leukemia

Childhood Myelodysplastic Syndromes

Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

Accelerated Phase Chronic Myelogenous Leukemia

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

Recurrent Childhood Acute Myeloid Leukemia

Blastic Phase Chronic Myelogenous Leukemia

Recurrent Adult Acute Myeloid Leukemia

Chronic Phase Chronic Myelogenous Leukemia

Adult Acute Myeloid Leukemia With Del(5q)

Treatments

Other: laboratory biomarker analysis

Drug: busulfan

Biological: anti-thymocyte globulin

Drug: methotrexate

Procedure: peripheral blood stem cell transplantation

Drug: tacrolimus

Procedure: allogeneic hematopoietic stem cell transplantation

Drug: fludarabine phosphate

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT01056614

P01HL036444 (U.S. NIH Grant/Contract)

NCI-2009-01785 (Registry Identifier)

1913.00 (Other Identifier)

P30CA015704 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

This phase II trial is studying the side effects and how well giving fludarabine phosphate, busulfan, anti-thymocyte globulin followed by donor peripheral blood stem cell transplant, tacrolimus, and methotrexate works in treating patients with myeloid malignancies. Giving chemotherapy, such as fludarabine phosphate and busulfan, before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop 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 anti-thymocyte globulin before transplant and tacrolimus and methotrexate after transplant may stop this from happening.

Full description

PRIMARY OBJECTIVE:

I. Determine the incidence and severity of acute graft-versus-host disease (GvHD).

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics of intravenous (IV) busulfan including interdose variability and evaluation of a limited sampling strategy.

II. Determine thymoglobulin (anti-thymocyte globulin) pharmacokinetics.

III. Determine the incidence of donor engraftment.

IV. Determine system toxicities >= grade 3 per Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 3.

V. Determine the incidence and severity of chronic GvHD.

VI. Determine the incidence of non-relapse mortality at day +100 and at 1 year (yr).

VII. Determine the incidence of relapse.

VIII. Determine relapse-free survival.

IX. Determine the incidence of Epstein-Barr virus (EBV) activation.

OUTLINE:

Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -9 to -6, busulfan IV over 3 hours on days -5 to -2, and anti-thymocyte globulin IV over 6 hours on days -3 and -2 and over 4 hours on day -1. Patients undergo allogeneic peripheral blood stem cell (PBSC) transplant on day 0. Patients then receive tacrolimus IV continuously or orally (PO) every 12 hours beginning on day -1 and taper to day 180 and methotrexate IV on days 1, 3, 6, and 11.

After completion of study treatment, patients are followed at 1 year.

Enrollment

23 patients

Sex

All

Ages

Under 60 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Chronic myelogenous leukemia in chronic phase, accelerated phase and treated blast phase (CP2)
Acute myeloid leukemia (AML) in remission or early relapse (< 10% marrow blasts)
Myelodysplastic syndromes (MDS) ( all risk groups)
Other myeloproliferative disorders
DONOR: related or unrelated donors matched for human leukocyte antigen (HLA)-A, B, C, DRB1, and DQB1 defined by high resolution deoxyribonucleic acid (DNA) typing or mismatched for a single HLA-A, B, C, DRB1 or DQB1 allele
DONOR: donor must consent to peripheral blood stem cell (PBSC) mobilization with granulocyte colony-stimulating factor (G-CSF) and leukapheresis; related donors will be collected at Fred Hutchinson Cancer Research Center (FHCRC), while unrelated donors will be collected through the National Marrow Donor Program (NMDP) or other donor centers
DONOR: Age 12-75 yrs

Exclusion criteria

Cardiac insufficiency requiring treatment or symptomatic coronary artery disease
Hepatic disease, with aspartate aminotransferase (AST) > 2 times normal
Severe hypoxemia, oxygen partial pressure (pO2) < 70 mm Hg, with decreased diffusion capacity of carbon monoxide (DLCO) < 70% of predicted; or mild hypoxemia, pO2 < 80 mm Hg with severely decreased DLCO < 60% of predicted
Impaired renal function (creatinine > 2 times normal or estimated creatinine clearance < 60 ml/min)
- MALE: ([140 -age in years] x ideal body weight [kg])/72 x serum creatinine (SCr) (mg/dL)
- FEMALE: .85 x ([140-age in years] x ideal body weight [kg])/72 x SCr (mg/dL)
Human immunodeficiency virus (HIV)-positive patients due to risk of reactivation or acceleration of HIV replication
Female patients who are pregnant or breast feeding
Life expectancy severely limited by diseases other than malignancy
DONOR: donors who for any reason are unable to tolerate the mobilization and leukapheresis procedure
DONOR: donors who are HIV-positive, or hepatitis B or C antigen-positive
DONOR: female donors who have a positive pregnancy test

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

23 participants in 1 patient group

Treatment (chemotherapy, PBSC transplant)

Experimental group

Description:

Patients receive fludarabine phosphate IV over 30 minutes on days -9 to -6, busulfan IV over 3 hours on days -5 to -2, and anti-thymocyte globulin IV over 6 hours on days -3 and -2 and over 4 hours on day -1. Patients undergo allogeneic PBSC transplant on day 0. Patients then receive tacrolimus IV continuously or PO every 12 hours beginning on day -1 and taper to day 180 and methotrexate IV on days 1, 3, 6, and 11.

Treatment: