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

National Cancer Institute (NCI)

Status and phase

Completed

Phase 2

Conditions

Secondary Myelodysplastic Syndrome

de Novo Myelodysplastic Syndrome

Alkylating Agent-Related Acute Myeloid Leukemia

Adult Erythroleukemia

Adult Acute Megakaryoblastic Leukemia

Adult Acute Myelomonocytic Leukemia

Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11

Adult Acute Myeloid Leukemia With Minimal Differentiation

Adult Acute Myeloid Leukemia Without Maturation

Adult Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-MLL

Adult Acute Monocytic Leukemia

Adult Acute Myeloid Leukemia With t(8;21); (q22; q22.1); RUNX1-RUNX1T1

Myelodysplastic Syndrome With Excess Blasts

Recurrent Adult Acute Myeloid Leukemia

Adult Pure Erythroid Leukemia

Adult Acute Monoblastic Leukemia

Myelodysplastic Syndrome

Adult Acute Myeloid Leukemia With Maturation

Acute Myeloid Leukemia

Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11

Treatments

Other: Laboratory Biomarker Analysis

Other: Pharmacological Study

Biological: Anti-Thymocyte Globulin

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Drug: Methotrexate

Drug: Busulfan

Drug: Azacitidine

Drug: Tacrolimus

Drug: Fludarabine Phosphate

Study type

Interventional

Funder types

NIH

Identifiers

NCT01168219

CALGB 100801 (Other Identifier)

NCI-2011-02053 (Registry Identifier)

CDR0000681025

U10CA031946 (U.S. NIH Grant/Contract)

CALGB-100801

U10CA180821 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment

68 patients

Sex

All

Ages

18 to 74 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

68 participants in 1 patient group

Treatment (chemotherapy and transplant)

Experimental group

Description:

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.

Treatment: