Treosulfan, Fludarabine Phosphate, and Total-Body Irradiation Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome, Acute Lymphoblastic Leukemia

Fred Hutchinson Cancer Center (FHCC)

Status and phase

Completed

Phase 2

Conditions

Untreated Childhood Acute Lymphoblastic Leukemia

Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)

Recurrent Childhood Acute Lymphoblastic Leukemia

Adult Acute Myeloid Leukemia in Remission

Previously Treated Myelodysplastic Syndromes

Childhood Myelodysplastic Syndromes

Recurrent Childhood Acute Myeloid Leukemia

Recurrent Adult Acute Lymphoblastic Leukemia

Blastic Phase Chronic Myelogenous Leukemia

Chronic Myelomonocytic Leukemia

Adult Acute Myeloid Leukemia With Del(5q)

Childhood Chronic Myelogenous Leukemia

Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

de Novo Myelodysplastic Syndromes

Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)

Untreated Adult Acute Lymphoblastic Leukemia

Childhood Acute Myeloid Leukemia in Remission

Adult Acute Lymphoblastic Leukemia in Remission

Secondary Myelodysplastic Syndromes

Childhood Acute Lymphoblastic Leukemia in Remission

Accelerated Phase Chronic Myelogenous Leukemia

Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)

Recurrent Adult Acute Myeloid Leukemia

Treatments

Procedure: peripheral blood stem cell transplantation

Radiation: total-body irradiation

Procedure: allogeneic bone marrow transplantation

Drug: fludarabine phosphate

Procedure: allogeneic hematopoietic stem cell transplantation

Drug: treosulfan

Drug: tacrolimus

Drug: methotrexate

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00860574

2272.00

P01HL036444 (U.S. NIH Grant/Contract)

NCI-2010-00315 (Registry Identifier)

Details and patient eligibility

About

This phase II trial is studying how well giving treosulfan together with fludarabine phosphate and total-body irradiation followed by donor stem cell transplant works in treating patients with high-risk acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia. Giving chemotherapy, such as treosulfan and fludarabine phosphate, and total-body irradiation before a donor bone marrow or peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop 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-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus and methotrexate before and after transplant may stop this from happening

Full description

PRIMARY OBJECTIVES:

I. Decrease the incidence of relapse to < 15% at 6 month post transplant in patients with high risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) transplanted from related or unrelated donors, without unacceptably increasing toxicity (10% non-relapse mortality [NRM] at 6 months).

SECONDARY OBJECTIVES:

I. Evaluate the incidence of NRM at 180 days and 1 year after hematopoietic cell transplantation (HCT).

II. Evaluate overall survival (OS) and relapse-free survival (RFS). III. Incidence of grades II-IV acute graft-versus-host disease (GVHD). IV. Incidence of chronic GVHD. V. Donor chimerism on days +28 and +100.

OUTLINE:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -6 to day -2 and treosulfan IV over 2 hours on days -6 to day -4. Patients also undergo total-body irradiation on day 0.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or orally (PO) twice daily (BID) on days -1 to 56, followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

After completion of study treatment, patients are followed up periodically.

Enrollment

96 patients

Sex

All

Ages

Under 60 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Acute myeloid leukemia (AML):
- All AML patients beyond 1st remission;
- Intermediate or high risk AML patients (based on South West Oncology Group [SWOG] cytogenetic criteria) in 1st complete remission
Myelodysplastic syndrome (MDS)
Other myeloid malignancies as chronic myelogenous leukemia (CML), CML accelerated phase, CML blast crisis, chronic myelomonocytic leukemia (CMML) (to be approved by patient care conference [PCC])
With Karnofsky Index or Lansky Play-Performance Scale > 70% on pre-transplant evaluation
Able to give informed consent (if > 18 years), or with a legal guardian capable of giving informed consent (if < 18 years)
Previous autologous or allogeneic HCT is allowed
Donors must be:
- Human leukocyte antigen (HLA)-identical related donors or
- Unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 defined by high resolution deoxyribonucleic acid (DNA) typing or mismatched for one HLA allele, except for HLA-C where no mismatch is allowed
- Able to undergo peripheral blood stem cell collection or bone marrow harvest
- In good general health, with a Karnofsky or Lansky Play Performance score > 90%
- Able to give informed consent (if > 18 years), or with a legal guardian capable of giving informed consent (if < 18 years)
Acute lymphoblastic leukemia (ALL): all ALL patients not eligible for other protocols

Exclusion criteria

Receiving umbilical cord blood
With impaired cardiac function as evidenced by ejection fraction < 35% or cardiac insufficiency requiring treatment or symptomatic coronary artery disease
With impaired pulmonary function as evidenced by partial pressure of oxygen (pO2) < 70 mm Hg and diffusing capacity of the lung for carbon monoxide (DLCO) < 70% of predicted or pO2 < 80 mm Hg and DLCO < 60% of predicted; or receiving supplementary continuous oxygen
With impaired renal function as evidenced by creatinine-clearance < 50% for age, weight, height or serum creatinine > 2x upper normal limit or dialysis-dependent
With hepatic dysfunction as evidenced by total bilirubin or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.0 x upper normal limit or evidence of synthetic dysfunction or severe cirrhosis
With active infectious disease requiring deferral of conditioning, as recommended by an Infectious Disease specialist
With human immunodeficiency virus (HIV)-positivity or active infectious hepatitis because of possible risk of lethal infection when treated with immunosuppressive therapy
With central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy and/or cranial radiation prior to initiating conditioning (day -6)
With life expectancy severely limited by diseases other than malignancy
Women who are pregnant or lactating because of possible risk to the fetus or infant
With known hypersensitivity to treosulfan and/or fludarabine
Receiving another experimental drug within 4 weeks before initiation of conditioning (day -6)
Unable to give informed consent (if > 18 years) or with a legal guardian (if < 18 years) unable to give informed consent
Ineligible donors will be those:
- Deemed unable to undergo marrow harvesting or PBSC mobilization and leukapheresis
- Who are HIV-positive
- With active infectious hepatitis
- Females with a positive pregnancy test
- Unable to give informed consent (if > 18 years) or with a legal guardian (if < 18 years) unable to give informed consent

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

96 participants in 1 patient group

Treatment (allogeneic transplantation)

Experimental group

Description:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -6 to day -2 and treosulfan IV over 2 hours on days -6 to day -4. Patients also undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO BID on days -1 to 56, followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

Treatment: