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 2

Completed

Conditions: Adult Acute Monoblastic Leukemia
Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11
Myelodysplastic Syndrome
Recurrent Adult Acute Myeloid Leukemia
Adult Acute Megakaryoblastic Leukemia
Adult Acute Monocytic Leukemia
Adult Acute Myeloid Leukemia With Maturation
Adult Acute Myeloid Leukemia With t(9;11)(p21.3;q23.3); MLLT3-MLL
Secondary Myelodysplastic Syndrome
Adult Acute Myeloid Leukemia With Minimal Differentiation

Interventions: Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
Biological: Anti-Thymocyte Globulin
Drug: Azacitidine
Drug: Busulfan
Drug: Fludarabine Phosphate
Other: Laboratory Biomarker Analysis
Drug: Methotrexate
Other: Pharmacological Study
Drug: Tacrolimus

Registration Number: NCT01168219

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 68

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (chemotherapy and transplant)	Pharmacological Study	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 (chemotherapy and transplant)	Laboratory Biomarker Analysis	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 (chemotherapy and transplant)	Anti-Thymocyte Globulin	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 (chemotherapy and transplant)	Allogeneic Hematopoietic Stem Cell Transplantation	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 (chemotherapy and transplant)	Busulfan	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 (chemotherapy and transplant)	Azacitidine	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 (chemotherapy and transplant)	Fludarabine Phosphate	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 (chemotherapy and transplant)	Tacrolimus	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 (chemotherapy and transplant)	Methotrexate	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.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival	Up to 5 years	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

Secondary Outcome Measures

Name	Time	Method
100-day Mortality	Up to 100 days post-treatment	The number of death reported within the first 100 days after transplant.
Overall Survival (OS)	Up to 5 years	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.

Trial Locations

Locations (17): Northwell Health NCORP
🇺🇸
Lake Success, New York, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸
Iowa City, Iowa, United States
Mount Sinai Hospital
🇺🇸
New York, New York, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Northwell Health/Center for Advanced Medicine
🇺🇸
Lake Success, New York, United States
NYP/Weill Cornell Medical Center
🇺🇸
New York, New York, United States
Cooper Hospital University Medical Center
🇺🇸
Camden, New Jersey, United States
Beebe Medical Center
🇺🇸
Lewes, Delaware, United States
Dartmouth Hitchcock Medical Center
🇺🇸
Lebanon, New Hampshire, United States
Christiana Care Health System-Christiana Hospital
🇺🇸
Newark, Delaware, United States
Christiana Care - Union Hospital
🇺🇸
Elkton, Maryland, United States
North Shore University Hospital
🇺🇸
Manhasset, New York, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
AdventHealth Orlando
🇺🇸
Orlando, Florida, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
University of Maryland/Greenebaum Cancer Center
🇺🇸
Baltimore, Maryland, United States
Ohio State University Comprehensive Cancer Center
🇺🇸
Columbus, Ohio, United States