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

Conditioning for Hematopoietic Cell Transplantation With Fludarabine Plus Targeted IV Busulfan and GVHD Prophylaxis With Thymoglobulin, Tacrolimus and Methotrexate in Patients With Myeloid Malignancies

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Adult Acute Myeloid Leukemia; 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(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myeloid Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Hematopoietic/Lymphoid Cancer; Accelerated Phase Chronic Myelogenous Leukemia; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Phase Chronic Myelogenous Leukemia; Previously Treated Myelodysplastic Syndromes; Recurrent Childhood Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; de Novo Myelodysplastic Syndromes; Blastic Phase Chronic Myelogenous Leukemia
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: fludarabine phosphate; Drug: methotrexate; Drug: busulfan; Biological: anti-thymocyte globulin; Procedure: peripheral blood stem cell transplantation; Procedure: allogeneic hematopoietic stem cell transplantation; Drug: tacrolimus

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (chemotherapy, PBSC transplant); 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.

Other: laboratory biomarker analysis; Correlative studies; Drug: fludarabine phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; Drug: methotrexate; Given IV; Other Names: amethopterin; Folex; methylaminopterin; Mexate; MTX; Drug: busulfan; Given IV; Other Names: BSF; BU; Misulfan; Mitosan; Myeloleukon; Biological: anti-thymocyte globulin; Given IV; Other Names: ATGAM; ATG; Thymoglobulin; lymphocyte immune globulin; Procedure: peripheral blood stem cell transplantation; Undergo allogeneic PBSC transplant; Other Names: PBPC transplantation; PBSC transplantation; peripheral blood progenitor cell transplantation; transplantation, peripheral blood stem cell; Procedure: allogeneic hematopoietic stem cell transplantation; Undergo allogeneic PBSC transplant; Drug: tacrolimus; Given IV and orally; Other Names: Prograf; FK 506

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of acute GvHD	Maximum grade of acute GVHD and the number of therapies required to treat GVHD will be determined.	Day 100 post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of IV busulfan including interdose variability and evaluation of a limited sampling strategy		At 3.25, 4.5, 6, 8, 11, and 24-hours after the beginning of infusion on days -5, -4, and -3
Thymoglobulin pharmacokinetics		On day -3 prior to the first dose, on day -1 one hour after completion of infusion and on day 1 at 0900
Incidence of donor cell engraftment		By day 100
Incidence of system toxicities >= grade 3 as graded per CTCAE v.3		Up to day 100 after transplantation
Incidence of chronic GvHD		Day 100
Incidence of non-relapse mortality defined as death without history of post-transplant relapse		At day 100
Incidence of non-relapse mortality defined as death without history of post-transplant relapse		At 1 year
Incidence of relapse	Defined by either morphological or cytogenetic evidence of chronic myelogenous leukemia (CML), AML, MDS or other myeloproliferative disease in marrow, blood, or other sites, or laboratory evidence of residual disease.	At 1 year
Relapse-free survival		At 1 year
Incidence of EBV activation defined as an increase in plasma EBV DNA to >= 1000 copies/mL as determined by quantitative polymerase chain reaction (PCR)		Up to 1 year

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: H. Joachim Deeg, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start: September 1, 2004
• Primary Completion (Actual): August 1, 2005
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: January 22, 2010
• First Submitted That Met QC Criteria: January 22, 2010
• First Posted (Estimate): January 26, 2010

Study Record Updates

• Last Update Posted (Estimate): May 6, 2016
• Last Update Submitted That Met QC Criteria: May 4, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Disease; Bone Marrow Diseases; Hematologic Diseases; Neoplastic Processes; Precancerous Conditions; Cell Transformation, Neoplastic; Carcinogenesis; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Recurrence; Preleukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Blast Crisis; Leukemia, Myeloid, Accelerated Phase; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Immunoglobulins; Fludarabine; Fludarabine phosphate; Methotrexate; Tacrolimus; Busulfan; Thymoglobulin; Antilymphocyte Serum
• Other Study ID Numbers: 1913.00 (Other Identifier: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); P01HL036444 (U.S. NIH Grant/Contract); NCI-2009-01785 (Registry Identifier: CTRP (Clinical Trial Reporting Program))