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

NCT ID: NCT00860574

Last Updated: 2021-06-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 96 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-02-28

Brief Summary

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

Detailed 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.

Conditions

Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (allogeneic transplantation)

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.

Group Type: EXPERIMENTAL

treosulfan

Intervention Type: DRUG

Given IV

fludarabine phosphate

Intervention Type: DRUG

Given IV

total-body irradiation

Intervention Type: RADIATION

Low dose starting at 2Gy

peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

Given IV per institutional standard practice

tacrolimus

Intervention Type: DRUG

Given IV or PO

allogeneic bone marrow transplantation

Intervention Type: PROCEDURE

Given IV per institutional standard practice

allogeneic hematopoietic stem cell transplantation

Intervention Type: PROCEDURE

Given IV per institutional standard practice

methotrexate

Intervention Type: DRUG

Given IV

Interventions

treosulfan

Given IV

Intervention Type: DRUG

fludarabine phosphate

Given IV

Intervention Type: DRUG

total-body irradiation

Low dose starting at 2Gy

Intervention Type: RADIATION

peripheral blood stem cell transplantation

Given IV per institutional standard practice

Intervention Type: PROCEDURE

tacrolimus

Given IV or PO

Intervention Type: DRUG

allogeneic bone marrow transplantation

Given IV per institutional standard practice

Intervention Type: PROCEDURE

allogeneic hematopoietic stem cell transplantation

Given IV per institutional standard practice

Intervention Type: PROCEDURE

methotrexate

Given IV

Intervention Type: DRUG

Other Intervention Names

dihydroxybusulfan; Ovastat; tresulfon; 2-F-ara-AMP; Beneflur; Fludara; TBI; PBPC transplantation; PBSC transplantation; peripheral blood progenitor cell transplantation; transplantation, peripheral blood stem cell; FK 506; Prograf; bone marrow therapy, allogeneic; bone marrow therapy, allogenic; transplantation, allogeneic bone marrow; transplantation, allogenic bone marrow; amethopterin; Folex; methylaminopterin; Mexate; MTX

Eligibility Criteria

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

• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Joachim Deeg

Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Boglarka Gyurkocza

Role: PRINCIPAL_INVESTIGATOR

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Locations

University of Colorado

Denver, Colorado, United States

Oregon Health and Science University

Portland, Oregon, United States

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Seattle, Washington, United States

Countries

United States

Other Identifiers

NCI-2010-00315

Identifier Type: REGISTRY

Identifier Source: secondary_id

P01HL036444

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2272.00

Identifier Type: -

Identifier Source: org_study_id