Busulfan, Fludarabine Phosphate, and Anti-Thymocyte Globulin Followed By Donor Stem Cell Transplant and Azacitidine in Treating Patients With High-Risk Myelodysplastic Syndrome and Older Patients With Acute Myeloid Leukemia

Phase II Study of the Addition of Azacitidine (NSC#102816) to Reduced-Intensity Conditioning Allogeneic Transplantation for Myelodysplasia (MDS) and Older Patients With AML

This phase II clinical trial is studying how well giving busulfan, fludarabine phosphate, and anti-thymocyte globulin followed by donor stem cell transplant and azacitidine works in treating patients with high-risk myelodysplastic syndrome and older patients with acute myeloid leukemia. Giving low doses of chemotherapy, such as busulfan and fludarabine phosphate, before a donor stem cell transplant helps stop the growth of cancer cells. It also stops 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-vs-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving anti-thymocyte globulin before transplant and giving azacitidine, tacrolimus, and methotrexate after the transplant may stop this from happening.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts; Secondary Myelodysplastic Syndrome; de Novo Myelodysplastic Syndrome; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-MLL; Adult Erythroleukemia; Adult Pure Erythroid Leukemia
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Azacitidine; Drug: Methotrexate; Biological: Anti-Thymocyte Globulin; Drug: Fludarabine Phosphate; Drug: Busulfan; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Tacrolimus

Detailed Description

PRIMARY OBJECTIVE:

I. To determine if this treatment can improve 2-year progression-free survival (PFS) in patients with high risk myelodysplastic syndrome (MDS) and in patients with acute myeloid leukemia (AML) >= 60 yrs age

SECONDARY OBJECTIVES:

I. To determine the safety and feasibility of using post-transplantation azacitidine.

II. To determine the ability to use pharmacokinetic-directed busulfan to achieve area under the curve (AUC) within 20% of target AUC in > 80% of patients.

III. To determine the rate of grade II-IV and III-IV acute graft-vs-host disease (GVHD).

IV. To determine the incidence of extensive chronic GVHD. V. To determine treatment-related mortality at 100 days and at 1 year. VI. To determine 5-year overall survival.

OUTLINE:

REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]).

TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1.

GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus orally (PO) or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD).

CONSOLIDATION: Beginning on day 42, patients receive azacitidine subcutaneously (SC) or IV on days 1-5.

Treatment repeats every 4 weeks for 6 courses. Blood and bone marrow samples may be collected periodically for correlative and pharmacokinetic studies.

After completion of study treatment, patients are followed up every 6 months for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Beebe Medical Center
    • Newark, Delaware, United States, 19718
      • Christiana Care Health System-Christiana Hospital
  • Florida
    • Orlando, Florida, United States, 32803
      • AdventHealth Orlando
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa/Holden Comprehensive Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland/Greenebaum Cancer Center
    • Elkton, Maryland, United States, 21921
      • Christiana Care - Union Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper Hospital University Medical Center
  • New York
    • Lake Success, New York, United States, 11042
      • Northwell Health NCORP
    • Lake Success, New York, United States, 11042
      • Northwell Health/Center for Advanced Medicine
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
    • New York, New York, United States, 10065
      • NYP/Weill Cornell Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Meets one of the following sets of criteria:

  • Myelodysplastic syndromes (MDS):

    • Disease with high-risk features (found either at diagnosis or before initiation of cytotoxic therapy), defined as one of the following:

      • International prognostic scoring system (IPSS) risk >= intermediate-2
      • Refractory anemia with excess blasts by French-American-British (FAB) classification
      • High-risk cytogenetics (either complex or -7)
    • Less than 10% bone marrow blasts as determined by bone marrow biopsy within the past 4 weeks (reduction in marrow blast percentage may be achieved with chemotherapy or other therapy)
    • Less than 75 years old

  • Acute myeloid leukemia (AML):

    • No FAB M3
    • No acute leukemia following blast transformation of prior chronic myelogenous leukemia or other myeloproliferative disease
    • Patients with preceding MDS or treatment-related AML are eligible
    • Prior central nervous system (CNS) involvement is allowed provided the disease is in remission at transplantation

    • Morphologic complete remission (leukemia-free state) is defined as meeting all of the following criteria:

      • Bone marrow blasts < 5% (as determined by bone marrow within the past 4 weeks), but without requirement for normal peripheral blood counts
      • No extramedullary leukemia
      • No blasts in peripheral blood

    • Achieved complete remission (CR) after no more than 2 courses of induction chemotherapy

      • Patients treated with azacitidine or decitabine who achieve a leukemia-free state are eligible (may have required up to 4 courses of therapy to reach this status)
    • Age 60 to 74 years

• Donors must meet the following criteria:

  • One of the following:

    • HLA-identical sibling (6/6) by serologic typing for class (A, B) and low-resolution molecular typing for class II (DRB1)
    • Matched unrelated donor (8/8) by high-resolution molecular typing at HLA-A, -B, -C, and DRB1
  • No syngeneic donors
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Calculated creatinine clearance ≥ 40 mL/min
• Bilirubin < 2 mg/dL OR bilirubin 2-3 mg/dL provided direct bilirubin is normal
• Aspartate aminotransferase (AST) < 3 times upper limit of normal
• Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% with no symptomatic pulmonary disease
• Left ventricle ejection fraction (LVEF) >= 30% by echocardiogram (ECHO) or multigated acquisition (MUGA)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No uncontrolled diabetes mellitus or active serious infections
• No known hypersensitivity to E. coli-derived products, azacitidine, or mannitol
• No human immunodeficiency virus (HIV) infection or active hepatitis B or C

• Prior azacitidine or decitabine allowed

  • No patients who progressed from MDS to AML during treatment with azacitidine or decitabine
• At least 4 weeks since prior deoxyribonucleic acid (DNA)-hypomethylating chemotherapy, radiotherapy, and/or surgery

• No more than 2 courses of consolidation therapy before transplantation (for patients with AML)

  • Any consolidation regimen that does not require transplantation can be used
  • No more than 6 months from documentation of morphologic CR to transplantation

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 (chemotherapy and transplant); REDUCED-INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3, busulfan IV over 45 minutes on days -6 to -3, and anti-thymocyte globulin IV over 4-10 hours on days -6 to -5 (matched sibling donor [MSD]) or -6 to -4 (matched unrelated donor [MUD]). TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0 or on days 0-1. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus PO or IV on days -2 to 90 with taper on days 150-180. Patients also receive methotrexate IV on days 1, 3, 6 (MSD), and 11 (MUD). CONSOLIDATION: Beginning on day 42, patients receive azacitidine SC or IV on days 1.

Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Azacitidine; Given SC or IV; Other Names: 5 AZC; 5-AC; 5-Azacytidine; 5-AZC; Azacytidine; Azacytidine, 5-; Ladakamycin; Mylosar; U-18496; Vidaza; Onureg; Drug: Methotrexate; Given IV; Other Names: Abitrexate; Folex; Mexate; MTX; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate-AQ; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; Biological: Anti-Thymocyte Globulin; Given IV; Other Names: ATG; Antithymocyte Globulin; Antithymocyte Serum; ATS; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Drug: Busulfan; Given IV; Other Names: Busulfex; Misulfan; Mitosan; Myeloleukon; Myelosan; 1, 4-Bis[methanesulfonoxy]butane; BUS; Bussulfam; Busulfanum; Busulphan; CB 2041; CB-2041; Glyzophrol; GT 41; GT-41; Joacamine; Methanesulfonic Acid Tetramethylene Ester; Methanesulfonic acid, tetramethylene ester; Mielucin; Misulban; Myeleukon; Mylecytan; Myleran; Sulfabutin; Tetramethylene Bis(methanesulfonate); Tetramethylene bis[methanesulfonate]; WR-19508; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic hematopoietic stem cell transplantation; Other Names: Allogeneic; Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT; Stem Cell Transplantation, Allogeneic; Drug: Tacrolimus; Given PO or IV; Other Names: Prograf; Hecoria; FK 506; Fujimycin; Protopic

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	Progression-free survival rate (percentage) at 2 and 5 years is defined as the percentage of patients who are alive and progression free at 2 and 5 years from date of transplantation respectively. AML progression is defined as: Reappearance of leukemia blast cells in peripheral blood and > 5% blasts in marrow; If no circulating blasts, but the marrow contains 5-20% blasts, a repeat bone marrow >= 1 week later with > 5% blasts; Development of extramedullary leukemia MDS progression is defined as; For patients with <5% bone marrow blasts: ≥50% increase in blasts to >5% blasts; For patients with 5-10% bone marrow blasts: ≥50% increase to >10% blasts; Any of the following: Reappearance of prior documented characteristic cytogenetic abnormality or refractory cytopenias with unequivocal evidence of dysplasia on bone marrow biopsy/aspirate	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Overall survival rate (percentage) at 2 and 5 years is defined as the percentage of patients who are still alive 2 and 5 years after date of transplantation respectively. Estimated using the Kaplan-Meier product limit estimator.	Up to 5 years
100-day Mortality	The number of death reported within the first 100 days after transplant.	Up to 100 days post-treatment

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Ravi Vij, Alliance for Clinical Trials in Oncology

Publications and helpful links

General Publications

• Vij R, Le-Rademacher J, Laumann K, Hars V, Owzar K, Shore T, Vasu S, Cashen A, Isola L, Shea T, DeMagalhaes-Silverman M, Hurd D, Meehan K, Beardell F, Devine S. A Phase II Multicenter Study of the Addition of Azacitidine to Reduced-Intensity Conditioning Allogeneic Transplant for High-Risk Myelodysplasia (and Older Patients with Acute Myeloid Leukemia): Results of CALGB 100801 (Alliance). Biol Blood Marrow Transplant. 2019 Oct;25(10):1984-1992. doi: 10.1016/j.bbmt.2019.06.007. Epub 2019 Jun 15.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 15, 2010
• Primary Completion (ACTUAL): November 14, 2015
• Study Completion (ACTUAL): February 1, 2020

Study Registration Dates

• First Submitted: July 22, 2010
• First Submitted That Met QC Criteria: July 22, 2010
• First Posted (ESTIMATE): July 23, 2010

Study Record Updates

• Last Update Posted (ACTUAL): August 4, 2022
• Last Update Submitted That Met QC Criteria: August 3, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Anemia; Precancerous Conditions; Anemia, Refractory; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Monocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Anemia, Refractory, with Excess of Blasts; 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; Azacitidine; Fludarabine; Fludarabine phosphate; Methotrexate; Tacrolimus; Busulfan; Antilymphocyte Serum
• Other Study ID Numbers: NCI-2011-02053 (REGISTRY: CTRP (Clinical Trial Reporting Program)); U10CA180821 (U.S. NIH Grant/Contract); U10CA031946 (U.S. NIH Grant/Contract); CDR0000681025; CALGB-100801 (OTHER: CTEP); CALGB 100801 (OTHER: Alliance for Clinical Trials in Oncology)