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

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

68 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-07-15

Study Completion Date

2020-02-01

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Acute Myeloid Leukemia Adult Acute Megakaryoblastic Leukemia 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 With t(9;11)(p21.3;q23.3); MLLT3-MLL Adult Acute Myeloid Leukemia Without Maturation Adult Acute Myelomonocytic Leukemia Adult Erythroleukemia Adult Pure Erythroid Leukemia Alkylating Agent-Related Acute Myeloid Leukemia de Novo Myelodysplastic Syndrome Myelodysplastic Syndrome Myelodysplastic Syndrome With Excess Blasts Recurrent Adult Acute Myeloid Leukemia Secondary Myelodysplastic Syndrome

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Intervention Type DRUG

Given PO or IV

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

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Maximum Eligible Age

74 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Ravi Vij

Role: PRINCIPAL_INVESTIGATOR

Alliance for Clinical Trials in Oncology

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United States

References

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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.

Reference Type DERIVED

PMID: 31212080 (View on PubMed)