Fludarabine and Busulfan Followed by Allogeneic Stem Cell Transplant in Treating Older Patients With Acute Myeloid Leukemia in First Complete Remission

A Phase II Study Of Allogeneic Transplant For Older Patients With AML In First Morphologic Complete Remission Using A Non-Myeloablative Preparative Regimen

This phase II trial studies how well fludarabine and busulfan followed by a donor (allogeneic) stem cell transplant work in treating older patients with acute myeloid leukemia that is in first complete remission. Giving low doses of chemotherapy, such as fludarabine and busulfan, before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stops 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. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving tacrolimus, methotrexate, and rabbit antithymocyte globulin before or after the transplant may stop this from happening.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia in Remission
• Intervention / Treatment: Drug: fludarabine phosphate; Drug: methotrexate; Biological: filgrastim; Biological: Anti-Thymocyte Globulin; Drug: busulfan; Drug: tacrolimus; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Detailed Description

PRIMARY OBJECTIVES:

I. Determine if allogeneic transplantation from a matched sibling or unrelated donor using a non-myeloablative preparative regimen results in a 2-year disease-free survival (DFS) that is better than historical results using standard chemotherapy.

SECONDARY OBJECTIVES:

I. Determine 2-year actuarial risks of transplant-related mortality, acute and chronic graft-versus-host (GVHD) disease and relapse among patients with acute myeloid leukemia (AML) in first complete remission (CR1) following a non-myeloablative preparative regimen.

II. To examine recovery of T and B cell number and function following non-myeloablative stem cell transplant.

III. To examine the time course of T, B and myeloid progenitor chimerism following this preparative regimen.

IV. To characterize the pharmacokinetics of intravenous busulfan used in a non-myeloablative preparation regimen in AML patients age >= 60 years.

OUTLINE:

PREPARATIVE REGIMEN: Patients receive fludarabine intravenously (IV) over 30 minutes on days -7 to -3 and busulfan IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive tacrolimus orally (PO) or IV twice daily (BID) on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin IV over 4-6 hours on days -4 through -2.

ALLOGENEIC PERIPHERAL BLOOD STEM CELL TRASNPLANTATION (PBSC): Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim subcutaneously (SC) daily beginning on day 12 and continuing until blood counts recover.

Patients are followed monthly for 1 year, every 3 months for 1 year, and then every 6 months for 3 years.

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Tunnell Cancer Center at Beebe Medical Center
    • Newark, Delaware, United States, 19713
      • CCOP - Christiana Care Health Services
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Greenebaum Cancer Center at University of Maryland Medical Center
    • Elkton, Maryland, United States, 21921
      • Union Hospital of Cecil County
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Brigham and Women's Cancer Center
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center at University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
  • New Jersey
    • Voorhees, New Jersey, United States, 08043
      • Cancer Institute of New Jersey at Cooper - Voorhees
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
    • Lake Success, New York, United States, 11042
      • Monter Cancer Center of the North Shore-LIJ Health System
    • Manhasset, New York, United States, 11030
      • CCOP - North Shore University Hospital
    • Manhasset, New York, United States, 11030
      • Don Monti Comprehensive Cancer Center at North Shore University Hospital
    • New Hyde Park, New York, United States, 11040
      • Long Island Jewish Medical Center
    • New York, New York, United States, 10021
      • New York Weill Cornell Cancer Center at Cornell University
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157-1096
      • Wake Forest University Comprehensive Cancer Center
  • Ohio
    • Columbus, Ohio, United States, 43210-1240
      • Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 74 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Eligibility Criteria:

• Patients with acute myeloid leukemia (AML) (excluding French-American-British [FAB] classification system M3) who have achieved a first morphologic complete remission and who meet the criteria below; patients with preceding myelodysplastic syndrome (MDS) or treatment-related AML are eligible; patients with prior central nervous system (CNS) involvement are eligible as long as disease is in remission at transplant; patients with acute leukemia following blast transformation of prior chronic myeloid leukemia (CML) or other myeloproliferative disease are excluded

• Complete remission (CR) will be defined according to the revised recommendations of the International Working Group (24) as all of the following:

  • Normal bone marrow morphology with < 5% blasts
  • Absolute neutrophil count (ANC) > 1,000/uL, referring to the count needed to confirm that the patient achieved a CR
  • Platelet count > 100,000/uL
  • No extramedullary leukemia
  • No blasts in peripheral blood
• CR was achieved after one or two (but no more than two) cycles of induction chemotherapy with standard cytotoxic chemotherapy (e.g., cytarabine and an anthracycline) or after no more than four cycles of a hypomethylating agent containing regimen including either 5-azacytidine or decitabine
• Patients may have received as many as but no more than two cycles of consolidation therapy prior to transplant; any consolidation regimen that does not require transplant can be used; no more than 6 months can elapse from documentation of morphologic CR to transplant; the platelet count does not need to be > 100,000/uL after consolidation, as long as the bone marrow assessment prior to transplant does not show relapse
• Identification of hematopoietic cell donor
• >= 4 weeks since prior chemotherapy, radiation therapy, and surgery
• Performance status 0-2
• Diffusion capacity of carbon monoxide (DLCO) > 40% with no symptomatic pulmonary disease
• Left ventricular ejection fraction (LVEF) by multi gated acquisition scan (MUGA) or echocardiogram (ECHO) >= 30%
• No uncontrolled diabetes mellitus or active serious infection requiring antibiotics
• No known hypersensitivity to E. coli-derived products
• No human immunodeficiency virus (HIV) infection
• Calculated creatinine clearance >= 40 cc/min

• Bilirubin < 2 mg/dL

  * If bilirubin is 2-3 mg/dL, but direct bilirubin is normal then patient will be considered eligible

• Aspartate aminotransferase (AST) < 3 x upper limit of normal
• DONOR: HLA-identical sibling (6/6); the donor must be determined to be an human leukocyte antigen (HLA)-identical sibling (6/6) by serologic typing for class (A, B) and low resolution molecular typing for class II (DRB1)
• DONOR: Matched unrelated donor (10/10); high resolution molecular typing at the following loci is required: HLA-A, -B, -C, -DRB1, and -DQB1
• DONOR: the donor must be healthy and must be an acceptable donor as per institutional standards for stem cell donation
• DONOR: the donor must have no significant cardiopulmonary, renal, endocrine, or hepatic disease
• DONOR: there is no donor age restriction if the donor is a matched sibling
• DONOR: syngeneic donors are not eligible

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Treatment (fludarabine, busulfan, allogeneic PBSC); PREPARATIVE REGIMEN: Patients receive fludarabine IV over 30 minutes on days -7 to -3 and busulfan IV over 2 hours 4 times per day (every 6 hours) on days -4 and -3. GVHD PROPHYLAXIS: Patients receive tacrolimus PO or IV BID on days -2 with taper between days 90-120, and stopping by days 150-180. Patients also receive methotrexate IV on days 1, 3, 6, and 11 and rabbit antithymocyte globulin IV over 4-6 hours on days -4 through -2. ALLOGENEIC PBSC: Patients undergo allogeneic PBSC transplant on day 0. Patients then receive filgrastim SC daily beginning on day 12 and continuing until blood counts recover.

Drug: fludarabine phosphate; Given IV; Drug: methotrexate; Given IV; Biological: filgrastim; Given SC; Biological: Anti-Thymocyte Globulin; Given IV; Drug: busulfan; Given IV; Drug: tacrolimus; Given PO or IV; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic PBSC transplantation; Other Names: HSC, HSCT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
2 Year Disease Free Survival In Unrelated Donor Recipient Group	Percentage of participants who were alive and relapse free at 2 years for patients who were matched with an unrelated donor for transplant. The 2 year disease free survival, with 95% confidence interval, was estimated using the Kaplan Meier method. A relapse is defined as any of the following: Reappearance of leukemia blasts cells in peripheral blood; >5% blasts in the marrow, not attributable to another cause (e.g., bone marrow regeneration); If there are no circulating blasts, but the marrow contains 5-20% blasts, a repeat bone marrow ≥ 1 week later with >5% blasts is necessary to meet the criteria for relapse; The development of extramedullary leukemia or leukemic cells in the cerebral spinal fluid	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
2 Year DFS for All Patients	Percentage of participants who were alive and relapse free at 2 years for all patients. The 2 year disease free survival, with 95% confidence interval, was estimated using the Kaplan Meier method.	Up to 2 years
Non-relapse Mortality (NRM)	Percentage of patients who died due to causes other than relapse	Up to 5 years

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Steven M. Devine, MD, Ohio State University Comprehensive Cancer Center

Publications and helpful links

General Publications

• Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP. Phase II Study of Allogeneic Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J Clin Oncol. 2015 Dec 10;33(35):4167-75. doi: 10.1200/JCO.2015.62.7273. Epub 2015 Nov 2.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 1, 2004
• Primary Completion (ACTUAL): December 1, 2013
• Study Completion (ACTUAL): June 15, 2016

Study Registration Dates

• First Submitted: October 3, 2003
• First Submitted That Met QC Criteria: October 6, 2003
• First Posted (ESTIMATE): October 7, 2003

Study Record Updates

• Last Update Posted (ACTUAL): June 12, 2018
• Last Update Submitted That Met QC Criteria: May 14, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: adult acute myeloid leukemia with 11q23 (MLL) abnormalities; 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); secondary acute myeloid leukemia; adult acute myeloid leukemia in remission; adult acute erythroid leukemia (M6); adult acute megakaryoblastic leukemia (M7); adult acute minimally differentiated myeloid leukemia (M0); adult acute monoblastic leukemia (M5a); adult acute monocytic leukemia (M5b); adult acute myeloblastic leukemia with maturation (M2); adult acute myeloblastic leukemia without maturation (M1); adult acute myelomonocytic leukemia (M4)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; 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; Fludarabine; Fludarabine phosphate; Methotrexate; Tacrolimus; Busulfan; Antilymphocyte Serum
• Other Study ID Numbers: CALGB-100103; U10CA180821 (U.S. NIH Grant/Contract); CDR0000330001 (REGISTRY: NCI Physician Data Query); NCI-2009-00438 (REGISTRY: NCI Clinical Trial Reporting Program)